Input: Here we show that hearing and vestibular function can be rescued in a mouse model of human hereditary deafness.


Input: An antisense oligonucleotide (ASO) was used to correct defective pre-mRNA splicing of transcripts from the USH1C gene with the c. 216G > A mutation, which causes human Usher syndrome, the leading genetic cause of combined deafness and blindness.


Input: Treatment of neonatal mice with a single systemic dose of ASO partially corrects Ush1c c. 216G > A splicing, increases protein expression, improves stereocilia organization in the cochlea, and rescues cochlear hair cells, vestibular function and low-frequency hearing in mice.


Input: These effects were sustained for several months, providing evidence that congenital deafness can be effectively overcome by treatment early in development to correct gene expression and demonstrating the therapeutic potential of ASOs in the treatment of deafness.


Input: Formation of polymersomes with double bilayers templated by quadruple emulsions.


Input: Polymersomes, vesicles composed of bilayer membranes of amphiphilic block-copolymers, are promising delivery vehicles for long-term storage and controlled release of bioactives; enhanced stability of the membrane makes polymersomes potentially useful in a wide range of biological delivery applications by comparison with liposomes.


Input: However, unilamellar structure is intrinsically fragile when subjected to external stress.


Input: Here, we report a microfluidic approach to produce polymersomes with double bilayers, providing higher stability and lower permeability than unilamellar polymersomes.


Input: To achieve this, we developed a new design of a capillary microfluidic device to produce quadruple-emulsion drops which serve as a template for the polymersomes-in-polymersomes.


Input: When two bilayers are attracted by depletion in polymersomes-in-polymersomes, the inner polymersomes protrude and bud, forming double bilayers.


Input: We confirm these structures are indeed double bilayers using microaspiration and selective doping of the leaflets with nanoparticles.


Input: The resultant polymersomes have great potential as highly stable and biocompatible microcarriers for robust encapsulation and storage of bioactives such as drugs, cosmetics and nutrients.


Input: Kocurin, the true structure of PM181104, an anti-methicillin-resistant Staphylococcus aureus (MRSA) thiazolyl peptide from the marine-derived bacterium Kocuria palustris.

Kocurin

methicillin

thiazolyl


Input: A new thiazolyl peptide, kocurin (1), was isolated from culture broths of a marine-derived Kocuria palustris.

thiazolyl

kocurin


Input: Its structural elucidation was accomplished using a combination of spectroscopic and chemical methods, including HRMS, extensive 1D and 2D NMR analysis, MS/MS fragmentation, and chemical degradation and Marfey' s analysis of the resulting amino acid residues.

amino acid


Input: The structure herein reported corrects that previously assigned to PM181104 (3).


Input: Kocurin displayed activity against methicillin-resistant Staphylococcus aureus (MRSA), with MIC values in the submicromolar range.

Kocurin

methicillin


Input: Anisole hydrolysis in high temperature water.

Anisole


Input: We investigated the hydrolysis of anisole to phenol in high-temperature water with and without water-tolerant Lewis acid catalysis.

anisole

phenol

Lewis acid


Input: With no catalyst present, anisole hydrolyzes to phenol in 97% yield after 24 hours at 365 degrees C, our experimentally determined optimal temperature and time.

anisole

phenol


Input: Experiments with varied water density and analysis of comparable literature data suggest that anisole hydrolysis is almost third order in water, when the S (N) 2 mechanism dominates.

anisole


Input: Of the water-tolerant Lewis acid catalysts studied, In (OTf) (3) offered the best phenol yield.

Lewis acid

In (OTf) (3)

phenol


Input: Anisole hydrolysis was first order in catalyst and first order in substrate.

Anisole


Input: Introducing In (OTf) (3) catalysis lowered the activation energy for anisole hydrolysis to 31 +/- 1 kcal mol (-1).

In (OTf) (3)

anisole


Input: Anisole hydrolysis in high-temperature water with In (OTf) (3) catalysis is competitive with other techniques in the literature based on rate and yield.

Anisole

In (OTf) (3)


Input: In the presence of 5 mol% In (OTf) (3) catalyst, anisole hydrolyzes to phenol in 97% yield after 90 minutes at 300 degrees C.

In (OTf) (3)

anisole

phenol


Input: Application of MCD spectroscopy and TD-DFT to endohedral metallofullerenes for characterization of their electronic transitions.

metallofullerenes


Input: We describe, for the first time, the application of magnetic circular dichroism (MCD) spectroscopy and time-dependent density functional theory (TD-DFT) calculations using B3LYP and M06-2X functionals to characterize the electronic transitions of endohedral metallofullerenes (EMFs).


Input: Results revealed that the electronic transitions of La @C (2v)-C (82), La (2) @I (h)-C (80), and Sc (3) N @I (h)-C (80) can be assigned using these techniques.

La

C (82)

La (2)

C (80)

Sc (3) N

C (80)


Input: Particularly, a difference in the electronic transitions between La (2) @I (h)-C (80) and Sc (3) N @I (h)-C (80), which is invisible in absorption spectra, was observed clearly in MCD spectra.

La (2)

C (80)

Sc (3) N

C (80)


Input: The observed MCD bands agree well with the oscillator strengths calculated using the B3LYP functional.


Input: In addition, the MCD bands of La (2) @I (h)-C (80) were altered upon [5, 6]-addition, demonstrating that the MCD spectroscopy is sensitive to chemical functionalization of EMFs, and that it is therefore powerful to distinguish [5, 6]-adducts from pristine La (2) @I (h)-C (80), although no marked difference exists in their absorption spectra.

La (2)

C (80)

La (2)

C (80)


Input: Properties and mechanisms of action of naturally occurring antifungal peptides.


Input: Antimicrobial peptides are a vital component of the innate immune system of all eukaryotic organisms and many of these peptides have potent antifungal activity.


Input: They have potential application in the control of fungal pathogens that are a serious threat to both human health and food security.


Input: Development of antifungal peptides as therapeutics requires an understanding of their mechanism of action on fungal cells.


Input: To date, most research on antimicrobial peptides has focused on their activity against bacteria.


Input: Several antimicrobial peptides specifically target fungal cells and are not active against bacteria.


Input: Others with broader specificity often have different mechanisms of action against bacteria and fungi.


Input: This review focuses on the mechanism of action of naturally occurring antifungal peptides from a diverse range of sources including plants, mammals, amphibians, insects, crabs, spiders, and fungi.


Input: While antimicrobial peptides were originally proposed to act via membrane permeabilization, the mechanism of antifungal activity for these peptides is generally more complex and often involves entry of the peptide into the cell.


Input: Bayesian methods for pharmacokinetic/pharmacodynamic modeling of pazopanib-induced increases in blood pressure and transaminases.

pazopanib


Input: Relationships between plasma pazopanib concentrations and the probability of elevations in blood pressure, a marker of vascular endothelial growth factor receptor inhibition, and alanine aminotransferase (ALT) were investigated with logistic regression models.

pazopanib

alanine


Input: Data from a Phase I dose-escalation study in cancer patients (n = 57) were examined to determine the relationship between steady-state trough plasma pazopanib concentrations (C tau) and a clinically significant blood pressure increase, using a Bayesian logistic regression model.

pazopanib


Input: Data from 5 monotherapy studies in cancer patients (n = 344) were pooled to investigate the relationship between C tau and maximum ALT >= 3 x the upper limit of normal (ULN), using a Bayesian logistic regression model incorporating an asymptote.


Input: Both models were fit using WinBUGS.


Input: The median (95% credible interval, CrI) C tau at which the probability of a clinically significant increase in blood pressure was 50% (EC50) was 12. 3 mu g/mL (6. 12, 18. 4).


Input: The median (95% CrI) EC50 for the maximum probability of ALT >= 3 x ULN was 15. 4 mu g/mL (3. 8, 41. 2) and the median (95% CrI) maximum probability of ALT >= 3 x ULN was 21% (14. 5, 43. 1).


Input: Results suggest that dose adjustments could be useful in managing the potential for hepatotoxicity.


Input: Clopidogrel, CYP2C19, and a Black Box.

Clopidogrel


Input: It has been presumed that CYP2C19 has a major role in the metabolism of clopidogrel.

clopidogrel


Input: This presumption has been based on in vitro drug metabolism studies using microsomes from baculovirus infected insect cells (BD-Supersomes (TM)).


Input: If clopidogrel were primarily a CYP2C19 substrate, a drug/drug interaction with CYP2C19 inhibitors, such as proton pump inhibitors (PPIs), for example, omeprazole and lansoprazole would be anticipated.

clopidogrel

omeprazole

lansoprazole


Input: Several ex vivo studies, using ADP stimulated platelet aggregation, suggested that there was such an interaction.

ADP


Input: The data from these studies served as a basis for FDA to provide a " Black Box " warning for the clopidogrel label in March of 2010.

clopidogrel


Input: However, a prospective clinical study, COGENT, and several large meta-analyses have failed to demonstrate a negative effect on major adverse cardiovascular events (MACE), with concomitant administration of clopidogrel and PPIs.

clopidogrel


Input: The in vitro work using " Supersomes " was revisited.


Input: In vitro metabolism using hepatosomes, which resemble the native cytochrome P-450 enzyme expression, has confirmed the earlier work that clopidogrel is primarily a CYP3A substrate.

clopidogrel


Input: This result correlates better with clinical findings.


Input: The absence of an increase in MACE by concomitant administration of PPIs, which are CYP2C19 inhibitors, to a regimen including clopidogrel, is therefore not surprising.

clopidogrel


Input: A hypothesis is offered to explain why subjects, who carry two reduced function alleles of CYP2C19, may have more reactive platelets.


Input: A decision-analysis tool for benefit-risk assessment of nonprescription drugs.


Input: A decision analysis tool is proposed for regulatory assessment of nonprescription drugs.


Input: The tool is based on evaluation of each of the drug' s potential benefit and risk attributes identified using a value-tree framework.


Input: The decision tool is designed as two-factor, two-stage instrument.


Input: Each attribute is independently assessed based on both the frequency of occurrence and clinical impact of the attribute.


Input: Frequency and clinical impact are scored on a 0-3 scale where a 0 score means no occurrence or no clinical impact, and a 3 means high frequency of occurrence or high clinical impact.


Input: The tool is initially used early in drug development to facilitate communication amongst stakeholders and to identify important data gaps.


Input: After new data are generated during the development program the tool is used again across the same attributes to yield a final benefit-risk assessment.


Input: In both the early assessment and subsequent evaluation use of the Group-Delphi technique and a benefit-risk trade-off heuristic may yield more consistent and coherent outputs.


Input: The tool allows regulators to maintain flexibility with respect to how final decisions are made, yet allows specificity and transparency during the evaluation.


Input: Further modifications can be incorporated to address drug-specific requirements or regulatory preferences.


Input: Ultralow reflection from a-Si nanograss/Si nanofrustum double layers.

Si

Si


Input: A double-layer nanostructure comprising amorphous Si nanograss on top of Si nanofrustums (NFs) with a total height of 680 nm exhibits ultralow reflection.

Si

Si


Input: Almost near-unity absorption and near-zero reflectance result in this layered nanostructure, over a broad range of wavelengths and a wide range of angles of incidence, due to the low packing density of a-Si and the smooth transition of the refractive index from the air to the Si substrate across both the nanograss and NF layers.

Si

Si


Input: A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex.


Input: Although many functions and targets have been attributed to the histone and protein deacetylase SIRT1, a comprehensive analysis of SIRT1 binding proteins yielding a high-confidence interaction map has not been established.


Input: Using a comparative statistical analysis of binding partners, we have assembled a high-confidence SIRT1 interactome.


Input: Employing this method, we identified the deubiquitinating enzyme ubiquitin-specific protease 22 (USP22), a component of the deubiquitinating module (DUBm) of the SAGA transcriptional coactivating complex, as a SIRT1-interacting partner.


Input: We found that this interaction is highly specific, requires the ZnF-UBP domain of USP22, and is disrupted by the inactivating H363Y mutation within SIRT1.

ZnF


Input: Moreover, we show that USP22 is acetylated on multiple lysine residues and that alteration of a single lysine (K129) within the ZnF-UBP domain is sufficient to alter interaction of the DUBm with the core SAGA complex.

lysine

lysine

ZnF


Input: Furthermore, USP22-mediated recruitment of SIRT1 activity promotes the deacetylation of individual SAGA complex components.


Input: Our results indicate an important role of SIRT1-mediated deacetylation in regulating the formation of DUBm subcomplexes within the larger SAGA complex.


Input: Mammalian myosin-18A, a highly divergent myosin.


Input: The Mus musculus myosin-18A gene is expressed as two alternatively spliced isoforms, alpha and beta, with reported roles in Golgi localization, in maintenance of cytoskeleton, and as receptors for immunological surfactant proteins.


Input: Both myosin-18A isoforms feature a myosin motor domain, a single predicted IQ motif, and a long coiled-coil reminiscent of myosin-2.


Input: The myosin-18A alpha isoform, additionally, has an N-terminal PDZ domain.

N


Input: Recombinant heavy meromyosin-and subfragment-1 (S1)-like constructs for both myosin-18A alpha and-18 beta species were purified from the baculovirus/Sf9 cell expression system.


Input: These constructs bound both essential and regulatory light chains, indicating an additional noncanonical light chain binding site in the neck.


Input: Myosin-18A alpha-S1 and-18A beta-S1 molecules bound actin weakly with Kd values of 4. 9 and 54 mu m, respectively.


Input: The actin binding data could be modeled by assuming an equilibrium between two myosin conformations, a competent and an incompetent form to bind actin.


Input: Actin binding was unchanged by presence of nucleotide.

nucleotide


Input: Both myosin-18A isoforms bound N-methylanthraniloyl-nucleotides, but the rate of ATP hydrolysis was very slow (< 0. 002 s (-1)) and not significantly enhanced by actin.

N-methylanthraniloyl-nucleotides

ATP


Input: Phosphorylation of the regulatory light chain had no effect on ATP hydrolysis, and neither did the addition of tropomyosin or of GOLPH3, a myosin-18A binding partner.

ATP


Input: Electron microscopy of myosin-18A-S1 showed that the lever is strongly angled with respect to the long axis of the motor domain, suggesting a pre-power stroke conformation regardless of the presence of ATP.

ATP


Input: These data lead us to conclude that myosin-18A does not operate as a traditional molecular motor in cells.


Input: Supervillin-mediated suppression of p53 protein enhances cell survival.


Input: Integrin-based adhesions promote cell survival as well as cell motility and invasion.


Input: We show here that the adhesion regulatory protein supervillin increases cell survival by decreasing levels of the tumor suppressor protein p53 and downstream target genes.


Input: RNAi-mediated knockdown of a new splice form of supervillin (isoform 4) or both isoforms 1 and 4 increases the amount of p53 and cell death, whereas p53 levels decrease after overexpression of either supervillin isoform.


Input: Cellular responses to DNA damage induced by etoposide or doxorubicin include down-regulation of endogenous supervillin coincident with increases in p53.

etoposide

doxorubicin


Input: In DNA-damaged supervillin knockdown cells, p53 knockdown or inhibition partially rescues the loss of cell metabolic activity, a measure of cell proliferation.


Input: Knockdown of the p53 deubiquitinating enzyme USP7/HAUSP also reverses the supervillin phenotype, blocking the increase in p53 levels seen after supervillin knockdown and accentuating the decrease in p53 levels triggered by supervillin overexpression.


Input: Conversely, supervillin overexpression decreases the association of USP7 and p53 and attenuates USP7-mediated p53 deubiquitination.


Input: USP7 binds directly to the supervillin N terminus and can deubiquitinate and stabilize supervillin.

N


Input: Supervillin also is stabilized by derivatization with the ubiquitin-like protein SUMO1.


Input: These results show that supervillin regulates cell survival through control of p53 levels and suggest that supervillin and its interaction partners at sites of cell-substrate adhesion constitute a locus for cross-talk between survival signaling and cell motility pathways.


Input: Menopause, estrogens and frailty.

estrogens


Input: Abstract The controversy surrounding the results from the Women' s Health Initiative (WHI) trials published a decade ago caused a significant decline in the use of menopausal hormone replacement therapy.


Input: However, these results have been vehemently contested and several lines of evidence suggest that in perimenopausal and non-obese women, estrogen therapy may indeed be of benefit.

estrogen


Input: There is ample proof that menopause causes a loss of musculoskeletal tissue mass and quality, thereby causing a loss of health and quality of life.


Input: There is also solid evidence that hormone replacement therapy in itself prevents most of these effects in connective tissue in it self.


Input: Besides the independent, direct effects on the musculoskeletal tissues, estrogen deficiency also reduces the ability to adequately respond and adapt to external mechanical and metabolic stressors, e. g. exercise, which are otherwise the main stimuli that should maintain musculoskeletal integrity and metabolic function.

estrogen


Input: Thus, normophysiological estrogen levels appear to exert a permissive effect on musculoskeletal adaptations to loading, thereby likely improving the outcome of rehabilitation following critical illness, musculoskeletal trauma or orthopedic surgical therapy.

estrogen


Input: These effects add to the evidence supporting the use of estrogen therapy, particularly accelerated gain of functional capacity and independence following musculoskeletal disuse.

estrogen


Input: Isolation of a mixed valence diiron hydride: evidence for a spectator hydride in hydrogen evolution catalysis.

diiron hydride

hydride

hydrogen


Input: The mixed-valence diiron hydrido complex (mu-H) Fe2 (pdt) (CO) 2 (dppv) 2 ([H1] (0), where pdt = 1, 3-propanedithiolate and dppv = cis-1, 2-C2H2 (PPh2) 2), was generated by reduction of the differous hydride [H1] (+) using decamethylcobaltocene.

diiron hydrido

(mu-H) Fe2 (pdt) (CO) 2 (dppv) 2

pdt

1, 3-propanedithiolate

dppv

cis-1, 2-C2H2 (PPh2) 2

hydride [H1] (+)

decamethylcobaltocene


Input: Crystallographic analysis shows that [H1] (0) retains the stereochemistry of its precursor, where one dppv ligand spans two basal sites and the other spans apical and basal positions.

dppv


Input: The Fe---Fe bond elongates to 2. 80 from 2. 66 A, but the Fe-P bonds only change subtly.

Fe---Fe

Fe-P


Input: Although the Fe-H distances are indistinguishable in the precursor, they differ by 0. 2 A in [H1] (0).

Fe-H


Input: The X-band electron paramagnetic resonance (EPR) spectrum reveals the presence of two stereoisomers, the one characterized crystallographically and a contribution of about 10% from a second symmetrical (sym) isomer wherein both dppv ligands occupy apical-basal sites.

dppv


Input: The unsymmetrical (unsym) arrangement of the dppv ligands is reflected in the values of A ((31) P), which range from 31 MHz for the basal phosphines to 284 MHz for the apical phosphine.

dppv

(31) P

phosphines

phosphine


Input: Density functional theory calculations were employed to rationalize the electronic structure of [H1] (0) and to facilitate spectral simulation and assignment of EPR parameters including (1) H and (31) P hyperfine couplings.

(1) H

(31) P


Input: The EPR spectra of [H1] (0) and [D1] (0) demonstrate that the singly occupied molecular orbital is primarily localized on the Fe center with the longer bond to H, that is, Fe (II)-H... Fe (I).

Fe

H

Fe (II)-H

Fe (I)


Input: The coupling to the hydride is A ((1) H) = 55 and 74 MHz for unsym-amd sym-[H1] (0), respectively.

hydride

(1) H


Input: Treatment of [H1] (0) with H (+) gives 0. 5 equiv of H2 and [H1] (+).

H (+)

[H1] (+)


Input: Reduction of D (+) affords D2, leaving the hydride ligand intact.

D (+)

hydride


Input: These experiments demonstrate that the bridging hydride ligand in this complex is a spectator in the hydrogen evolution reaction.

hydride

hydrogen


Input: Femtosecond Dynamics of Excitons and Hole-Polarons in Composite P3HT/PCBM Nanoparticles.

PCBM


Input: The dynamics of charge separation in aqueous suspensions of regioregular P3HT nanoparticles containing PCBM were investigated for the first time using femtosecond transient absorption spectroscopy.

PCBM


Input: This investigation is supported by the recently reported use of regioregular P3HT/PCBM nanoparticles as charge trapping and storage devices.

PCBM


Input: In this study, the presence of excited-state and charge-separated species, including singlet excitons, polymer polarons and free charges, generated in rr-P3HT/PCBM nanoparticles was identified through visible pump and visible/near-infrared probe femtosecond transient absorption spectroscopy at a range of electron acceptor concentrations.

PCBM


Input: The decrease of the singlet exciton lifetime by charge transfer to PCBM is well described by a one-dimensional diffusion model with a P3HT domain size of approximately 5 nm for 5-50 wt% PCBM.

PCBM

PCBM


Input: This model also indicates that bimolecular recombination is the dominant charge recombination mechanism at 20 wt% PCBM and above.

PCBM


Input: Surface behavior of malonic acid adsorption at the air/water interface.

malonic acid


Input: The presence of organic materials adsorbed to the surfaces of aerosol particles has been demonstrated to be a determining factor in relevant atmospheric processes.


Input: Malonic acid is a small, water-soluble organic acid that is common in aerosols and is surface-active.

Malonic acid


Input: A comprehensive investigation of the adsorption of malonic acid to the air/water interface was accomplished using vibrational sum frequency spectroscopy (VSFS) and surface tension measurements as functions of concentration and pH.

malonic acid


Input: Malonic acid was found to be weakly solvated at the air/water interface, and its orientation as a function of concentration was explored through different VSFS polarization schemes.

Malonic acid


Input: pH-dependent experiments revealed that the surface-active species is the fully protonated species.


Input: Computational analyses were used to obtain depth-specific geometries of malonic acid at the air/water interface that confirm and enrich the experimental results.

malonic acid


Input: Development of quantitative structure-metabolism (QSMR) relationships for substituted anilines based on computational chemistry.

anilines


Input: Abstract 1.


Input: A novel stepwise classification approach for predicting the metabolic fate of substituted anilines, based on calculated physicochemical parameters of the parent anilines, was developed.

anilines

anilines


Input: Based on multivariate pattern recognition methods (PLS-DA or soft independent modelling of class analogy [SIMCA]), these models allowed prediction of N-acetylation and subsequent N-oxanilic acid formation.

N

N-oxanilic acid


Input: These classification methods provided an improved classification success when compared with existing quantitative structure-metabolism relationship models for substituted anilines.

anilines


Input: Modelling the physicochemical properties of the N-acetylated compounds was considered as an addition to the stepwise model.

N


Input: Inclusion of parameters describing the N-acetyl moiety had little effect on the predictive ability of a stepwise parent to N-acetyl to N-oxanilic acid PLS-DA model, and had a negative impact on that of SIMCA models.

N-acetyl

N-acetyl

N-oxanilic acid


Input: This was attributed to the relatively small contribution to the total parameter variance caused by differences arising as a result of N-acetylation compared to the contribution made by the substituent effects.

N


Input: Calculation of physicochemical properties incorporating the effect of solvation using ab initio methods improved the classification model in terms of both the visual separation in multivariate projections and prediction accuracy.


Input: Frequency-multiplication high-output triboelectric nanogenerator for sustainably powering biomedical microsystems.


Input: An attractive method to response the current energy crisis and produce sustainable nonpolluting power source is harvesting energy from our living environment.


Input: However, the energy in our living environment always exists in low-frequency form, which is very difficult to be utilized directly.


Input: Here, we demonstrated a novel sandwich-shape triboelectric nanogenerator to convert low-frequency mechanical energy to electric energy with double frequency.


Input: An aluminum film was placed between two polydimethylsiloxane (PDMS) membranes to realize frequency multiplication by twice contact electrifications within one cycle of external force.

aluminum

polydimethylsiloxane

PDMS


Input: The working mechanism was studied by finite element simulation.


Input: Additionally, the well-designed micro/nano dual-scale structures (i. e., pyramids and V-shape grooves) fabricated atop PDMS surface was employed to enhance the device performance.

PDMS


Input: The output peak voltage, current density, and energy volume density achieved 465 V, 13. 4 mu A/cm (2), and 53. 4 mW/cm (3), respectively.


Input: This novel nanogenerator was systematically investigated and also demonstrated as a reliable power source, which can be directly used to not only lighten five commercial light-emitting diodes (LEDs) but also drive an implantable 3-D microelectrode array for neural prosthesis without any energy storage unit or rectification circuit.


Input: This is the first demonstration of the nanogenerator for directly driving biomedical microsystems, which extends the application fields of the nanogenerator and drives it closer to practical applications.


Input: The salicylate 1, 2-dioxygenase as a model for a conventional gentisate 1, 2-dioxygenase: crystal structures of the G106A mutant and its adducts with gentisate and salicylate.

salicylate

gentisate

gentisate

salicylate


Input: The salicylate 1, 2-dioxygenase (SDO) from the bacterium Pseudaminobacter salicylatoxidans BN12 is a versatile gentisate 1, 2-dioxygenase (GDO) that converts both gentisate (2, 5-dihydroxybenzoate) and various monohydroxylated substrates.

salicylate

gentisate

gentisate

2, 5-dihydroxybenzoate


Input: Several variants of this enzyme were rationally designed based on the previously determined enzyme structure and sequence differences between the SDO and the' conventional' GDO from Corynebacterium glutamicum.


Input: This was undertaken in order to define the structural elements that give the SDO its unique ability to dioxygenolytically cleave (substituted) salicylates.

salicylates


Input: SDO variants M103L, G106A, G111A, R113G, S147R and F159Y were constructed and it was found that G106A oxidized only gentisate; 1-hydroxy-2-naphthoate and salicylate were not converted.

gentisate

salicylate


Input: This indicated that this enzyme variant behaves like previously known' conventional' GDOs.


Input: Crystals of the G106A SDO variant and its complexes with salicylate and gentisate were obtained under anaerobic conditions, and the structures were solved and analyzed.

salicylate

gentisate


Input: The amino acid residue Gly106 is located inside the SDO active site cavity but does not directly interact with the substrates.

amino acid


Input: Crystal structures of G106A SDO complexes with gentisate and salicylate showed a different binding mode for salicylate when compared with the wild-type enzyme.

gentisate

salicylate

salicylate


Input: Thus, salicylate coordinated in the G106A variant with the catalytically active Fe (II) ion in an unusual and unproductive manner because of the inability of salicylate to displace a hydrogen bond that was formed between Trp104 and Asp174 in the G106A variant.

salicylate

Fe (II)

salicylate

hydrogen


Input: It is proposed that this type of unproductive substrate binding might generally limit the substrate spectrum of' conventional' GDOs.


Input: DATABASE: Structural data are available in the Protein Data Bank databases under the accession numbers 3NST, 3NWA, 3NVC.


Input: Three-dimensional high-resolution rotational tracking with superlocalization reveals conformations of surface-bound anisotropic nanoparticles.


Input: The ability to directly follow three-dimensional rotational movement of anisotropic nanoparticles will greatly enhance our understanding of the way nanoparticles interact with surfaces.


Input: Herein, we demonstrate dual-color total internal reflection scattering microscopy as a tool to probe the interactions of plasmonic gold nanorods with functional surfaces.


Input: By taking advantage of both the short and long axis surface plasmon resonance scattering enhancement, we are able to decipher both in-plane and out-of-plane gold nanorod motion relative to the sample surface with equally high resolution.


Input: In combination with superlocalization through point spread function fitting, we overcome the four-quadrant angular degeneracy of gold nanorods in the focal plane of the objective and resolve conformations of surface-bound anisotropic nanoparticles in unprecedented detail.


Input: The transferrin receptor-1 membrane stub undergoes intramembrane proteolysis by signal peptide peptidase-like 2b.


Input: The successive events of shedding and regulated intramembrane proteolysis are known to comprise a fundamental biological process of type I and II membrane proteins (e. g. amyloid precursor protein, Notch receptor and pro-tumor necrosis factor-alpha).


Input: Some of the resulting fragments were shown to be involved in important intra-and extracellular signalling events.


Input: Although shedding of the human transferrin receptor-1 (TfR1) has been known for > 30 years and soluble TfR1 is an accepted diagnostic marker, the fate of the remaining N-terminal fragment (NTF) remains unknown.

N


Input: In the present study, we demonstrate for the first time that TfR1-NTF is subject to regulated intramembrane proteolysis and, using MALDI-TOF-TOF-MS, we have identified the cleavage site as being located C-terminal from Gly-84.

C

Gly


Input: We showed that the resulting C-terminal peptide is extracellularly released after regulated intramembrane proteolysis and it was detected as a monomer with an internal disulfide bridge.

C

disulfide


Input: We further identified signal peptide peptidase-like 2a and mainly signal peptide peptidase-like 2b as being responsible for the intramembrane proteolysis of TfR1-NTF.


Input: Northern contaminant mixtures induced morphological and functional changes in human coronary artery endothelial cells under culture conditions typifying high fat/sugar diet and ethanol exposure.

sugar

ethanol


Input: It has been reported that Northern populations are exposed to mixtures of various environmental contaminants unique to the Arctic (Northern contaminant mixtures-NCM) at a large range of concentrations, depending on their geological location, age, lifestyle and dietary habits.


Input: To determine if these contaminants may contribute to a cardiovascular health risk, especially when combined with a high fat and sugar diet and ethanol exposure, we treated human coronary artery endothelial cells (HCAEC) with two mixtures of 4 organic (NCM1) or 22 organic and inorganic (NCM2) chemicals detected in Northerners' blood during 2004-2005 in the presence or absence of low-density lipoprotein (1. 5mg/ml), very-low-density lipoprotein (1. 0mg/ml) and glucose (10mmol/L) (LVG), and in the absence or presence of 0. 1% ethanol.

sugar

ethanol

glucose

ethanol


Input: After 24h of exposure, cell morphology and markers of cytotoxicity and endothelial function were examined.


Input: NCM1 treatment did not affect cell viability, but increased cell size, disrupted cell membrane integrity, and decreased cell density, uptake of small peptides, release of endothelin-1 (ET-1) and plasminogen activator inhibitor (PAI), while causing no changes in endothelial nitric oxide synthase (eNOS) protein expression and nitric oxide (NO) release.

nitric oxide

nitric oxide

NO


Input: In contrast, NCM2 decreased cell viability, total protein yield, uptake of small peptides, eNOS protein expression, and NO release and caused membrane damage, but caused no changes in the secretion of ET-1, prostacyclin and PAI.

prostacyclin


Input: The presence of LVG and/or alcohol did or did not influence the effects of NCM1 or NCM2 depending on the endpoint and the mixture examined.

alcohol


Input: These results suggested that the effects of one or one group of contaminants may be altered by the presence of other contaminants, and that with or without the interaction of high fat and sugar diet and/or ethanol exposure, NCMs at the concentrations used caused endothelial dysfunction in vitro.

sugar

ethanol


Input: It remains to be investigated if these effects of NCMs also occur in vivo.


Input: Epigenetic modifications in rheumatoid arthritis, a review.


Input: Rheumatoid arthritis is an autoimmune disease characterized by chronic joint inflammation and progressive destruction of cartilage and bone which leads to ultimately loss of function and pain.


Input: Activated synovial fibroblasts are key effector cells in the pathogenesis of rheumatoid arthritis.


Input: In the recent years, epigenetic changes including DNA methylation, histone acetylation and other histone modifications were identified that are associated with an intrinsic activation and the aggressive phenotype of these cells.


Input: So far, no therapies targeting rheumatoid arthritis synovial fibroblasts exist.


Input: This review comprises recent research efforts that propose epigenetic mechanisms behind the activation of rheumatoid arthritis synovial fibroblasts and other cell types.


Input: Antitumor drug delivery in multicellular spheroids by electropermeabilization.


Input: Electrochemotherapy (ECT) is a physical technique that allows cytotoxic molecules to be efficiently released in tumor cells by inducing transient cell plasma membrane permeabilization.


Input: The main antitumoral drugs used in ECT are nonpermeant bleomycin and low permeant cisplatin.

bleomycin

cisplatin


Input: The method is nowadays applied in clinics as a palliative treatment.


Input: In order to improve it, we took advantage of a human 3D multicellular tumor spheroid as a model of tumor to visually and molecularly assess the effect of ECT.


Input: We used bleomycin and cisplatin to confirm its relevance and doxorubicin to show its potential to screen new antitumor drug candidates for ECT.

bleomycin

cisplatin

doxorubicin


Input: Confocal microscopy was used to visualize the topological distribution of permeabilized cells in 3D spheroids subjected to electric pulses.


Input: Our results revealed that all cells were efficiently permeabilized, whatever their localization in the spheroid, even those in the core.


Input: The combination of antitumor drugs and electric pulses (ECT) led to changes in spheroid macroscopic morphology and cell cohesion, to tumor spheroid growth arrest and finally to its complete apoptosis-mediated dislocation, mimicking previously observed in vivo situations.


Input: Taken together, these results indicate that the spheroid model is relevant for the study and optimization of electromediated drug delivery protocols.


Input: Transdermal delivery of human epidermal growth factor facilitated by a peptide chaperon.


Input: Peptide chaperon TD1 was discovered to facilitate several proteins' transdermal delivery via topical co-administration.


Input: To design a practical, safe system for advanced transdermal peptide, a novel method was carried out.


Input: Human epidermal growth factor (hEGF) was selected as the model biological agent and a fusion protein: TD1-hEGF was designed.


Input: Study showed that TD1-hEGF not only had the similar bioactivity with native hEGF, but also possessed considerable higher transdermal ability than hEGF and a co-administration of TD1 and hEGF.


Input: These results provided convincing evidence for the advantages of TD1-hEGF in cosmetic and medical applications.


Input: Moreover, the fusion pattern between the cargoes and TD1 offered a new approach to facilitate other hydrophilic drugs' transdermal delivery for therapeutic application.


Input: New pyrazole derivatives containing 1, 2, 4-triazoles and benzoxazoles as potent antimicrobial and analgesic agents.

pyrazole

1, 2, 4-triazoles

benzoxazoles


Input: Azole class of compounds are well known for their excellent therapeutic properties.

Azole


Input: Present paper describes about the synthesis of three series of new 1, 2, 4-triazole and benzoxazole derivatives containing substituted pyrazole moiety (11a-d, 12a-d and 13a-d).

1, 2, 4-triazole

benzoxazole

pyrazole


Input: The newly synthesized compounds were characterized by spectral studies and also by C, H, N analyses.

C

H

N


Input: All the synthesized compounds were screened for their analgesic activity by the tail flick method.


Input: The antimicrobial activity of the new derivatives was also performed by Minimum Inhibitory Concentration (MIC) by the serial dilution method.


Input: The results revealed that the compound 11c having 2, 5-dichlorothiophene substituent on pyrazole moiety and a triazole ring showed significant analgesic and antimicrobial activity.

2, 5-dichlorothiophene

pyrazole

triazole


Input: Transcriptional Analysis of Hair Follicle-Derived Keratinocytes from Donors with Atopic Dermatitis Reveals Enhanced Induction of IL32 Gene by IFN-gamma.


Input: We cultured human hair follicle-derived keratinocytes (FDKs) from plucked hairs.


Input: To gain insight into gene expression signatures that can distinguish atopic dermatitis from non-atopic controls without skin biopsies, we undertook a comparative study of gene expression in FDKs from adult donors with atopic dermatitis and non-atopic donors.


Input: FDK primary cultures (atopic dermatitis, n = 11; non-atopic controls, n = 7) before and after interferon gamma (IFN-gamma) treatment were used for microarray analysis and quantitative RT-PCR.


Input: Comparison of FDKs from atopic and non-atopic donors indicated that the former showed activated pathways with innate immunity and decreased pathways of cell growth, as indicated by increased NLRP2 expression and decreased DKK1 expression, respectively.


Input: Treatment with IFN-gamma induced the enhanced expression of IL32, IL1B, IL8, and CXCL1 in the cells from atopic donors compared to that in cells from non-atopic donors at 24 h after treatment.


Input: IL1B expression in FDKs after IFN-gamma treatment correlated with IL32 expression.


Input: We hypothesized that overexpression of IL32 in hair follicle keratinocytes of patients with atopic dermatitis would lead to the excessive production of pro-IL1 beta and that the activation of IL1 beta from pro-IL1 beta by inflammasome complex, in which NLRP2 protein might be involved, would be augmented.


Input: This is the first report to show enhanced induction of cytokine/chemokine genes by IFN-gamma in atopic dermatitis using cultured FDKs.


Input: Selenite and tellurite form mixed seleno-and tellurotrisulfides with CstR from Staphylococcus aureus.

Selenite

tellurite

seleno-and tellurotrisulfides


Input: Staphylococcus aureus CstR (CsoR-like sulfur transferase repressor) is a member of the CsoR family of transition metal sensing metalloregulatory proteins.

sulfur

transition metal


Input: Unlike CsoR, CstR does not form a stable complex with transition metals but instead reacts with sulfite to form a mixture of di-and trisulfide species, CstR2 (RS-SR') and CstR2 (RS-S-SR') n) n = 1 or 2, respectively.

transition metals

sulfite

di-and trisulfide

RS-SR'

RS-S-SR'


Input: Here, we investigate if CstR performs similar chemistry with related chalcogen oxyanions selenite and tellurite.

chalcogen oxyanions selenite

tellurite


Input: In this work we show by high resolution tandem mass spectrometry that CstR is readily modified by selenite (SeO3 (2-)) or tellurite (TeO3 (2-)) to form a mixture of intersubunit disulfides and selenotrisulfides or tellurotrisulfides, respectively, between Cys31 and Cys60'.

selenite

SeO3 (2-)

tellurite

TeO3 (2-)

disulfides

selenotrisulfides

tellurotrisulfides


Input: Analogous studies with S. aureus CsoR reveals no reaction with selenite and minimal reaction with tellurite.

selenite

tellurite


Input: All cross-linked forms of CstR exhibit reduced DNA binding affinity.


Input: We show that Cys31 initiates the reaction with sulfite through the formation of S-sulfocysteine (RS-SO3 (2-)) and Cys60 is required to fully derivatize CstR to CstR2 (RS-SR') and CstR2 (RS-S-SR').

sulfite

S-sulfocysteine

RS-SO3 (2-)

RS-SR'

RS-S-SR'


Input: The modification of Cys31 also drives an allosteric switch that negatively regulates DNA binding while derivatization of Cys60 alone has no effect on DNA binding.


Input: These results highlight the differences between CstRs and CsoRs in chemical reactivity and metal ion selectivity and establish Cys31 as the functionally important cysteine residue in CstRs.

cysteine


Input: Study of Environmental and Antimicrobial Agents Impact on Features of Bacterial Growth.


Input: Continuous, real-time observation of bacterial growth has a great advantage for studying the mechanisms of interactions of various compounds with the bacterial cell membrane.


Input: With the use of physical methods, which are specific for assessment of continuous changes in turbidity over time, we have shown that bacterial growth was affected by not only on types of antibiotics and phages, but also by their concentration in media.


Input: Low concentration of antibiotics and bacteriophages in media has no effect on the bacterial growth process.


Input: Our research has shown that if bacterial cell membrane is not completely saturated with antibiotics membrane sensitive sites (MSS), or bacteriophages free unbounded receptors are remained, bacterial growth continues unimpeded.


Input: Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox.

Manganese

Trolox


Input: While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive Mn exposure may lead to neurotoxicity.

manganese

Mn

Mn


Input: Mn preferentially accumulates in the basal ganglia, and in adults it may cause Parkinson' s disease-like disorder.

Mn


Input: Compared to adults, younger individuals accumulate greater Mn levels in the CNS and are more vulnerable to its toxicity.

Mn


Input: Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood.

Mn


Input: The present study investigated the developmental neurotoxicity elicited by Mn exposure (5, 10 and 20 mg/kg; i. p.) from postnatal day 8 to PN27 in rats.

Mn


Input: Neurochemical analyses were carried out on PN29, with a particular focus on striatal alterations in intracellular signaling pathways (MAPKs, Akt and DARPP-32), oxidative stress generation and cell death.


Input: Motor alterations were evaluated later in life at 3, 4 or 5 weeks of age.


Input: Mn exposure (20 mg/kg) increased p38 (MAPK) and Akt phosphorylation, but decreased DARPP-32-Thr-34 phosphorylation.

Mn


Input: Mn (10 and 20 mg/kg) increased caspase activity and F (2)-isoprostane production (a biological marker of lipid peroxidation).

Mn

F (2)-isoprostane


Input: Paralleling the changes in striatal biochemical parameters, Mn (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, decreased distance traveled and motor speed in the open-field test.

Mn


Input: Notably, the antioxidant Trolox (TM) reversed the Mn (20 mg/kg)-dependent augmentation in p38 (MAPK) phosphorylation and reduced the Mn (20 mg/kg)-induced caspase activity and F (2)-isoprostane production.

Trolox

Mn

Mn

F (2)-isoprostane


Input: Trolox (TM) also reversed the Mn-induced motor coordination deficits.

Trolox

Mn


Input: These findings are the first to show that long-term exposure to Mn during a critical period of neurodevelopment causes motor coordination dysfunction with parallel increment in oxidative stress markers, p38 (MAPK) phosphorylation and caspase activity in the striatum.

Mn


Input: Moreover, we establish Trolox (TM) as a potential neuroprotective agent given its efficacy in reversing the Mn-induced neurodevelopmental effects.

Trolox

Mn


Input: Dose finding by concentration-response versus dose-response: a simulation-based comparison.


Input: AIM: The investigations reported here aimed to evaluate the incremental benefit for dose finding by concentration-response analysis versus dose-response analysis.


Input: METHODS: Trials were simulated using an Emax model for a range of scenarios of drug properties, trial design options and target response levels.


Input: The simulated data were analysed by concentration-response and dose-response modelling; a dose was then chosen to target a specific response level in a confirmatory trial.


Input: The two approaches were compared in terms of the quality of model parameter estimation and the success rate for the confirmatory trial.


Input: RESULTS: While the accuracy for ED50 estimation was comparably good with both approaches, the precision was up to 90% higher with concentration-response approach.


Input: The difference was most notable when clearance was highly variable between subjects and the top dose was relatively low.


Input: The higher precision by the concentration-response analysis lead to better dose selection and up to 20% higher success rate for the subsequent confirmatory trial.


Input: The relatively small difference in success rate translated into a remarkable difference in sample size requirement.


Input: CONCLUSION: By customising these parameters, the approach and the findings can be applied to assessing the value of pharmacokinetic sampling in particular trial situations.


Input: Refining the UGT1A haplotype associated with irinotecan-induced hematological toxicity in metastatic colorectal cancer patients treated with 5-fluorouracil/irinotecan-based regimens.

irinotecan

irinotecan


Input: Despite the importance of UDP-glucuronosyltransferase (UGT) 1A1 * 28 in irinotecan pharmacogenetics, our capability to predict drug-induced severe toxicity remains limited.

UDP

irinotecan


Input: We aimed at identifying novel genetic markers that would improve prediction of irinotecan toxicity and response in advanced colorectal cancer patients treated with folic acid (leucovorin), fluorouracil (5-FU), and irinotecan (camptosar)-based regimens.

irinotecan

folic acid

leucovorin

fluorouracil

irinotecan

camptosar


Input: The relationships between UGT1A candidate markers across the gene (n = 21) and toxicity were prospectively evaluated in 167 patients.


Input: We included variants in the 3' untranscribed region (3' UTR) of the UGT1A locus, not studied in this context yet.


Input: These genetic markers were further investigated in 250 Italian FOLFIRI-treated patients.

FOLFIRI


Input: Several functional UGT1A variants, including UGT1A1 * 28, significantly influenced risk of severe hematologic toxicity.


Input: As previously reported in the Italian cohort, a 5-marker risk haplotype [haplotype II (HII); UGTs 1A9/1A7/1A1] was associated with severe neutropenia in our cohort [odds ratio (OR) = 2. 43; P = 0. 004].


Input: The inclusion of a 3' UTR single-nucleotide polymorphism (SNP) permitted refinement of the previously defined HI, in which HIa was associated with the absence of severe neutropenia in combined cohorts (OR = 0. 55; P = 0. 038).


Input: Among all tested UGT1A variations and upon multivariate analyses, no UGT1A1 SNPs remained significant, whereas three SNPs located in the central region of UGT1A were linked to neutropenia grade 3-4.


Input: Haplotype analyses of these markers with the 3' UTR SNP allowed the identification of a protective HI (OR = 0. 50; P = 0. 048) and two risk haplotypes, HII and HIII, characterized by 2 and 3 unfavorable alleles, respectively, revealing a dosage effect (ORs of 2. 15 and 5. 28; P <= 0. 030).


Input: Our results suggest that specific SNPs in UGT1A, other than UGT1A1 * 28, may influence irinotecan toxicity and should be considered to refine pharmacogenetic testing.

irinotecan


Input: Structural and Optoelectronic Characterization of RF Sputtered ZnSnN2.


Input: ZnSnN2, a new earth-abundant semiconductor, is synthesized and characterized for use as a photovoltaic absorber material.


Input: Results confirm the predicted orthorhombic Pna21 crystal structure in RF sputtered thin films.


Input: Additionally, optical measurements reveal a direct bandgap of about 2 eV, which is larger than our calculated bandgap of 1. 42 eV due to the Burstein-Moss effect.


Input: PHI: A powerful new program for the analysis of anisotropic monomeric and exchange-coupled polynuclear d-and f-block complexes.


Input: A new program, PHI, with the ability to calculate the magnetic properties of large spin systems and complex orbitally degenerate systems, such as clusters of d-block and f-block ions, is presented.

d-block

f-block


Input: The program can intuitively fit experimental data from multiple sources, such as magnetic and spectroscopic data, simultaneously.


Input: PHI is extensively parallelized and can operate under the symmetric multiprocessing, single process multiple data, or GPU paradigms using a threaded, MPI or GPU model, respectively.


Input: For a given problem PHI is been shown to be almost 12 times faster than the well-known program MAGPACK, limited only by available hardware.


Input: (c) 2013 Wiley Periodicals, Inc.


Input: Androgen Receptor mRNA Measured by Quantitative Real Time PCR is Decreased in the Urethral Mucosa of Patients with Middle Idiopathic Hypospadias.

Androgen


Input: Androgen action is exerted through the androgen receptor.

Androgen

androgen


Input: The normal 46, XY genital virilization depends on androgen receptor gene expression, which is tissue specific, and requires normal androgen receptor mRNA levels in androgen sensitive tissues.

androgen

androgen

androgen


Input: Hypospadias is a frequent male genital abnormality, potentially related to reduced androgen sensitivity in genital tissues.

androgen


Input: The aim of this study was to compare, by quantitative real time PCR, the amount of androgen receptor mRNA in cells obtained from the urethral mucosa of patients with middle idiopathic hypospadias with the androgen receptor mRNA levels observed in control phimosis subjects with eutopic urethral opening.

androgen

androgen


Input: Prepubertal individuals were studied, including 41 controls and 17 hypospadias patients with mean (SD) ages of 4. 7 (2. 1) years and 4. 0 (3. 0) years, respectively.


Input: We observed significantly less androgen receptor mRNA in the urethral mucosa of patients with hypospadias than in the controls (p = 0. 002).

androgen


Input: The correlation between the level of androgen receptor mRNA expression and the penile size was almost statistically significant only in hypospadias patients (r = 0. 47; p = 0. 053).

androgen


Input: We also established the number of CAG repeats in exon 1 of the androgen receptor gene by GeneScan analysis.

androgen


Input: No significant difference was observed in the number of CAG repeats when patients and controls were compared.


Input: A negative correlation between the CAG repeats and penile size was detected in patients with hypospadias, but not in controls.


Input: Our data suggest that a critical lower level of androgen receptor mRNA expression could be a determining factor in the development of middle hypospadias.

androgen


Input: Identification and characterization of bacterial diterpene cyclases that synthesize the cembrane skeleton.

diterpene


Input: Digging up skeletons: We report the identification and the functional characterization of two terpene cyclases (DtcycA and DtcycB) that were mined from the genome of Streptomyces sp.

terpene


Input: SANK 60404.


Input: DtcycA and DtcycB are novel bacterial diterpene cyclases for the synthesis of the cembrane skeleton.

diterpene


Input: A case-based approach to the practical application of dexmedetomidine in critically ill adults.

dexmedetomidine


Input: Dexmedetomidine is a selective alpha (2)-adrenoceptor agonist that offers unique sedation because patients are readily awakened while administration continues and the drug does not suppress the respiratory center.

Dexmedetomidine


Input: Limitations of use include higher acquisition cost, inability to produce deep sedation, and bradycardia and hypotension.


Input: Using a case-based approach, the purpose of this review was to qualitatively assess the role of dexmedetomidine in the care of the critically ill and in the management of alcohol withdrawal, and to formulate recommendations regarding its clinical application.

dexmedetomidine

alcohol


Input: Sixty-six studies were identified that investigated dexmedetomidine for the provision of sedation.

dexmedetomidine


Input: These studies were heterogeneous in design and patient populations; most investigated patients did not require heavy sedation, and few used propofol as the comparator.

propofol


Input: In general, though, the aggregate results of all studies demonstrate that dexmedetomidine provides comfort, possibly shortens the duration of mechanical ventilation to facilitate extubation, reduces the occurrence of acute brain dysfunction, and facilitates communication, but the drug is associated with hemodynamic instability and requires the supplemental use of traditional sedative and analgesic agents.

dexmedetomidine


Input: These outcomes need to be substantiated in additional studies that include assessments of cost-effectiveness.


Input: Dexmedetomidine should be considered when patients require mild to moderate levels of sedation of short to intermediate time frames, and they qualify for daily awakenings with traditional sedative therapies.

Dexmedetomidine


Input: The data for dexmedetomidine in relation to alcohol withdrawal are limited to 12 retrospective reports representing a total of 127 patients.

dexmedetomidine

alcohol


Input: Its role for this indication requires further study, but it may be considered as adjunctive therapy when clinicians are concerned about respiratory suppression associated with escalating doses of gamma-aminobutyric acid agonists.

gamma-aminobutyric acid


Input: Regardless of the indication for dexmedetomidine, the practitioner must closely monitor patient comfort and the occurrence of hemodynamic deviations with the realization that as-needed administration of traditional sedatives and analgesics will be required and some degree of bradycardia and hypotension expected but intervention rarely required.

dexmedetomidine


Input: The Sec7 Guanine Nucleotide Exchange Factor GBF1 Regulates Membrane Recruitment of BIG1 and BIG2 Guanine Nucleotide Exchange Factors to the Trans-Golgi Network (TGN).

Guanine Nucleotide

Guanine Nucleotide


Input: Three Sec7 guanine nucleotide exchange factors (GEFs) activate ADP-ribosylation factors (ARFs) to facilitate coating of transport vesicles within the secretory and endosomal pathways.

guanine nucleotide

ADP


Input: GBF1 recruits COPI to pre-Golgi and Golgi compartments, whereas BIG1 and BIG2 recruit AP1 and GGA clathrin adaptors to the trans-Golgi network (TGN) and endosomes.


Input: Here, we report a functional cascade between these GEFs by showing that GBF1-activated ARFs (ARF4 and ARF5, but not ARF3) facilitate BIG1 and BIG2 recruitment to the TGN.


Input: We localize GBF1 ultrastructurally to the pre-Golgi, the Golgi, and also the TGN.


Input: Our findings suggest a model in which GBF1 localized within pre-Golgi and Golgi compartments mediates ARF activation to facilitate recruitment of COPI to membranes, whereas GBF1 localized at the TGN mediates ARF activation that leads to the recruitment of BIG1 and BIG2 to the TGN.


Input: Membrane-associated BIG1/2 then activates ARFs that recruit clathrin adaptors.


Input: In this cascade, an early acting GEF (GBF1) activates ARFs that mediate recruitment of late acting GEFs (BIG1/2) to coordinate coating events within the pre-Golgi/Golgi/TGN continuum.


Input: Such coordination may optimize the efficiency and/or selectivity of cargo trafficking through the compartments of the secretory pathway.


Input: Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats.

apixaban


Input: The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition.

apixaban


Input: The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i. v. doses together with oral administration of activated charcoal (AC).

apixaban

charcoal


Input: Additionally, the role of P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats.

apixaban


Input: Approximately 20-50% of an apixaban i. v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC).

apixaban


Input: The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and P-gp inhibitor).

apixaban


Input: BCRP appeared to play a more important role for absorption and intestinal and renal elimination of apixaban than P-gp in transporter-KO rats after oral and i. v. dosing, which led to a higher level of active renal excretion in rat than other species.

apixaban


Input: These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters.

apixaban


Input: Intestinal reabsorption of apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect).

apixaban

charcoal


Input: This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban.

apixaban


Input: The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban.

apixaban


Input: IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition.

apixaban


Input: Removal of molecular adsorbates on gold nanoparticles using sodium borohydride in water.

sodium borohydride


Input: The mechanism of sodium borohydride removal of organothiols from gold nanoparticles (AuNPs) was studied using an experimental investigation and computational modeling.

sodium borohydride

organothiols


Input: Organothiols and other AuNP surface adsorbates such as thiophene, adenine, rhodamine, small anions (Br (-) and I (-)), and a polymer (PVP, poly (N-vinylpyrrolidone)) can all be rapidly and completely removed from the AuNP surfaces.

Organothiols

thiophene

adenine

rhodamine

Br (-)

I (-)

PVP

poly (N-vinylpyrrolidone)


Input: A computational study showed that hydride derived from sodium borohydride has a higher binding affinity to AuNPs than organothiols.

hydride

sodium borohydride

organothiols


Input: Thus, it can displace organothiols and all the other adsorbates tested from AuNPs.

organothiols


Input: Sodium borohydride may be used as a hazard-free, general-purpose detergent that should find utility in a variety of AuNP applications including catalysis, biosensing, surface enhanced Raman spectroscopy, and AuNP recycle and reuse.

Sodium borohydride


Input: Synthesis of MoS2 and MoSe2 films with vertically aligned layers.


Input: Layered materials consist of molecular layers stacked together by weak interlayer interactions.


Input: They often crystallize to form atomically smooth thin films, nanotubes, and platelet or fullerene-like nanoparticles due to the anisotropic bonding.

fullerene


Input: Structures that predominately expose edges of the layers exhibit high surface energy and are often considered unstable.


Input: In this communication, we present a synthesis process to grow MoS2 and MoSe2 thin films with vertically aligned layers, thereby maximally exposing the edges on the film surface.


Input: Such edge-terminated films are metastable structures of MoS2 and MoSe2, which may find applications in diverse catalytic reactions.


Input: We have confirmed their catalytic activity in a hydrogen evolution reaction (HER), in which the exchange current density correlates directly with the density of the exposed edge sites.

hydrogen


Input: Nevirapine bioactivation and covalent binding in the skin.

Nevirapine


Input: Nevirapine (NVP) treatment is associated with serious skin rashes that appear to be immune-mediated.

Nevirapine

NVP


Input: We previously developed a rat model of this skin rash that is immune-mediated and is very similar to the rash in humans.


Input: Treatment of rats with the major NVP metabolite, 12-OH-NVP, also caused the rash.

NVP


Input: Most idiosyncratic drug reactions are caused by reactive metabolites; 12-OH-NVP forms a benzylic sulfate, which was detected in the blood of animals treated with NVP or 12-OH-NVP.

benzylic sulfate

NVP


Input: This sulfate is presumably formed in the liver; however, the skin also has significant sulfotransferase activity.

sulfate


Input: In this study, we used a serum against NVP to detect covalent binding in the skin of rats.

NVP


Input: There was a large artifact band in immunoblots of whole skin homogenates that interfered with detection of covalent binding; however, when the skin was separated into dermal and epidermal fractions, covalent binding was clearly present in the epidermis, which is also the location of sulfotransferases.


Input: In contrast to rats, treatment of mice with NVP did not result in covalent binding in the skin or skin rash.

NVP


Input: Although the reaction of 12-OH-NVP sulfate with nucleophiles such as glutathione is slow, incubation of this sulfate with homogenized human and rat skin led to extensive covalent binding.

12-OH-NVP sulfate

glutathione

sulfate


Input: Incubations of 12-OH-NVP with the soluble fraction from a 9, 000g centrifugation (S9) of rat or human skin homogenate in the presence of 3'-phosphoadenosine-5'-phosphosulfate (PAPS) produced extensive covalent binding, but no covalent binding was detected with mouse skin S9, which suggests that the reason mice do not develop a rash is that they lack the required sulfotransferase.

PAPS


Input: This is the first study to report covalent binding of NVP to rat and human skin.

NVP


Input: These data provide strong evidence that covalent binding of NVP in the skin is due to 12-OH-NVP sulfate, which is likely responsible for NVP-induced skin rash.

NVP

12-OH-NVP sulfate

NVP


Input: Sulfation may represent a bioactivation pathway for other drugs that cause a skin rash.


Input: Development of Bacteriostatic DNA Aptamers for Salmonella.


Input: Salmonella is one of the most dangerous and common food-borne pathogens.


Input: The overuse of antibiotics for disease prevention has led to the development of multidrug resistant Salmonella.


Input: Now, more than ever, there is a need for new antimicrobial drugs to combat these resistant bacteria.


Input: Aptamers have grown in popularity since their discovery, and their properties make them attractive candidates for therapeutic use.


Input: In this work, we describe the selection of highly specific DNA aptamers to S. enteritidis and S. typhimurium.


Input: To evolve species-specific aptamers, twelve rounds of selection to live S. enteritidis and S. typhimurium were performed, alternating with a negative selection against a mixture of related pathogens.


Input: Studies have shown that synthetic pools combined from individual aptamers have the capacity to inhibit growth of S. enteritidis and S. typhimurium in bacterial cultures; this was the result of a decrease in their membrane potential.


Input: Minimal peptide motif for non-covalent peptide-heparin hydrogels.


Input: Reduction of complexity of the extracellular matrix (ECM) to a non-covalent structure with minimal chemically defined components represents an attractive avenue for understanding the biology of the ECM.


Input: The resulting system could lead to the design of tailor-made biomaterials that incorporate varying functionalities.


Input: Negatively charged glycosaminoglycans are the major components of the ECM.


Input: Their interaction with positively charged proteins is important for dynamic three-dimensional scaffold formation and function.


Input: We designed and screened minimal peptide motifs whose conjugates with polyethylene glycol interact with heparin to form non-covalent hydrogels.

polyethylene glycol


Input: Here we show the structure/function relationship of the (RA) (n) and (KA) (n) motifs and determined that both basic residues and the heparin-induced alpha-helix formation are important for the assembly process.


Input: Simple rules allowed us to tune various aspects of the matrix system such as the gelation rates, biodegradability, rheological properties, and biofunctionality.


Input: The hydrogels can encapsulate cells and support cell survival.


Input: Natural products as a source for treating neglected parasitic diseases.


Input: Infectious diseases caused by parasites are a major threat for the entire mankind, especially in the tropics.


Input: More than 1 billion people world-wide are directly exposed to tropical parasites such as the causative agents of trypanosomiasis, leishmaniasis, schistosomiasis, lymphatic filariasis and onchocerciasis, which represent a major health problem, particularly in impecunious areas.


Input: Unlike most antibiotics, there is no " general " antiparasitic drug available.


Input: Here, the selection of antiparasitic drugs varies between different organisms.


Input: Some of the currently available drugs are chemically de novo synthesized, however, the majority of drugs are derived from natural sources such as plants which have subsequently been chemically modified to warrant higher potency against these human pathogens.


Input: In this review article we will provide an overview of the current status of plant derived pharmaceuticals and their chemical modifications to target parasite-specific peculiarities in order to interfere with their proliferation in the human host.


Input: Oxidative Stress and DNA Damage in Human Gastric Carcinoma: 8-Oxo-7' 8-dihydro-2'-deoxyguanosine (8-oxo-dG) as a Possible Tumor Marker.

8-Oxo-7' 8-dihydro-2'-deoxyguanosine


Input: We characterized the oxidative stress (OS) status by the levels of reduced/oxidized glutathione (GSH/GSSG), malondialdehyde (MDA) and the mutagenic base 8-oxo-7' 8-dihydro-2'-deoxyguanosine (8-oxo-dG) in human gastric carcinoma (HGC) samples and compared the results with normal tissue from the same patients.

reduced/oxidized glutathione

GSH

GSSG

malondialdehyde

MDA

8-oxo-7' 8-dihydro-2'-deoxyguanosine


Input: We also analyzed 8-oxo-dG in peripheral mononuclear cells (PMNC) and urine from healthy control subjects and in affected patients in the basal state and one, three, six, nine and twelve months after tumor resection.


Input: The levels of DNA repair enzyme mRNA expression (hOGG1, RAD51, MUYTH and MTH1) were determined in tumor specimens and compared with normal mucosa.


Input: Tumor specimens exhibited increased levels of MDA and 8-oxo-dG compared with normal gastric tissue.

MDA


Input: GSH levels were also increased, while GSSG levels remained stable.

GSH

GSSG


Input: DNA repair enzyme mRNA expression was induced in the tumor tissues.


Input: Levels of 8-oxo-dG were significantly elevated in both urine and PMNC of gastric cancer patients compared with healthy controls.


Input: After gastrectomy, the levels of the damaged base in urine and PMNC decreased progressively to values close to those found in the healthy population.


Input: The high levels of 8-oxo-dG in urine may be related to the increased induction of DNA repair activity in tumor tissue, and the changes observed after tumor resection support its potential use as a tumor marker.


Input: Process engineering with planetary ball mills.


Input: Planetary ball mills are well known and used for particle size reduction on laboratory and pilot scales for decades while during the last few years the application of planetary ball mills has extended to mechanochemical approaches.


Input: Processes inside planetary ball mills are complex and strongly depend on the processed material and synthesis and, thus, the optimum milling conditions have to be assessed for each individual system.


Input: The present review focuses on the insight into several parameters like properties of grinding balls, the filling ratio or revolution speed.


Input: It gives examples of the aspects of grinding and illustrates some general guidelines to follow for modelling processes in planetary ball mills in terms of refinement, synthesis' yield and contamination from wear.


Input: The amount of energy transferred from the milling tools to the powder is significant and hardly measurable for processes in planetary ball mills.


Input: Thus numerical simulations based on a discrete-element-method are used to describe the energy transfer to give an adequate description of the process by correlation with experiments.


Input: The simulations illustrate the effect of the geometry of planetary ball mills on the energy entry.


Input: In addition the imaging of motion patterns inside a planetary ball mill from simulations and video recordings is shown.


Input: Cloning, characterization and heterologous expression of the indolocarbazole biosynthetic gene cluster from marine-derived Streptomyces sanyensis FMA.

indolocarbazole


Input: The indolocarbazole (ICZ) alkaloids have attracted much attention due to their unique structures and potential therapeutic applications.

indolocarbazole

ICZ


Input: A series of ICZs were recently isolated and identified from a marine-derived actinomycete strain, Streptomyces sanyensis FMA.

ICZs


Input: To elucidate the biosynthetic machinery associated with ICZs production in S. sanyensis FMA, PCR using degenerate primers was carried out to clone the FAD-dependent monooxygenase gene fragment for ICZ ring formation, which was used as a probe to isolate the 34. 6-kb DNA region containing the spc gene cluster.

ICZs

FAD

ICZ


Input: Sequence analysis revealed genes for ICZ ring formation (spcO, D, P, C), sugar unit formation (spcA, B, E, K, J, I), glycosylation (spcN, G), methylation (spcMA, MB), as well as regulation (spcR).

ICZ

sugar


Input: Their involvement in ICZ biosynthesis was confirmed by gene inactivation and heterologous expression in Streptomyces coelicolor M1152.

ICZ


Input: This work represents the first cloning and characterization of an ICZ gene cluster isolated from a marine-derived actinomycete strain and would be helpful for thoroughly understanding the biosynthetic mechanism of ICZ glycosides.

ICZ

ICZ glycosides


Input: Antimicrobial N-halamine polymers and coatings: a review of their synthesis, characterization, and applications.

N-halamine polymers


Input: Antimicrobial N-halamine polymers and coatings have been studied extensively over the past decade thanks to their numerous qualities such as effectiveness toward a broad spectrum of microorganisms, long-term stability, regenerability, safety to humans and environment and low cost.

N-halamine polymers


Input: In this review, recent developments are described by emphasizing the synthesis of polymers and/or coatings having N-halamine moieties.

N-halamine


Input: Actually, three main approaches of preparation are given in detail: polymerization, generation by electrochemical route with proteins as monomers and grafting with precursor monomers.


Input: Identification and characterization of the formation of the N-halamine bonds (> N-X with X = Cl or Br or I) by physical techniques such as Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), energy-dispersive X-ray spectroscopy (EDX), X-ray photoelectron spectroscopy (XPS), and by chemical reactions are described.

N-halamine

N

Cl

Br

I


Input: In order to check the antimicrobial activity of the N-halamine compounds, bacterial tests are also described.

N-halamine


Input: Finally, some examples of application of these N-halamines in the water treatment, paints, healthcare equipment, and textile industries are presented and discussed.

N-halamines


Input: Hollow block copolymer nanoparticles through a spontaneous one-step structural reorganization.


Input: The spontaneous one-step synthesis of hollow nanocages and nanotubes from spherical and cylindrical micelles based on poly (acrylic acid)-b-polylactide (P (AA)-b-P (LA)) block copolymers (BCPs) has been achieved.

poly (acrylic acid)-b-polylactide

P (AA)-b-P (LA)


Input: This structural reorganization, which occurs simply upon drying of the samples, was elucidated by transmission electron microscopy (TEM) and atomic force microscopy (AFM).


Input: We show that it was necessary to use stain-free imaging to examine these nanoscale assemblies, as the hollow nature of the particles was obscured by application of a heavy metal stain.


Input: Additionally, the internal topology of the P (AA)-b-P (LA) particles could be tuned by manipulating the drying conditions to give solid or compartmentalized structures.

P (AA)-b-P (LA)


Input: Upon resuspension, these reorganized nanoparticles retain their hollow structure and display significantly enhanced loading of a hydrophobic dye compared to the original solid cylinders.


Input: Photoelectrochemical properties of nanomultiple CaFe2O4/ZnFe2O4 pn junction photoelectrodes.


Input: Nanomultiple CaFe2O4/ZnFe2O4pn junctions are prepared by a pulsed laser deposition method to explore their photoelectrochemical properties as the photoelectrodes.


Input: It is demonstrated that the multiple-pn-junction structure is favorable to enhancing the photocurrent density and the onset potential of the photoelectrode.


Input: Furthermore, the 20-junction photoelectrode-based PEC cell yields a high open circuit photovoltage of up to 0. 97 V, which is much higher than that for a single pn junction photoelectrode PEC cell that yields an open circuit photovoltage of 0. 13 V.


Input: A multiple-junction band structure model is assumed to describe the behavior of the CaFe2O4/ZnFe2O4 multiple-junction photoelectrodes.


Input: It is suggested that the open circuit photovoltage is dominated by the number of pn junctions in a multiple-junction photoelectrode and the carrier transfer inside the photoelectrode is improved by narrowing the single-layer thickness.


Input: These findings provide a new approach to designing the multiple-junction structure to improve the PEC properties of the photoelectrodes.


Input: Preparation of novel porous starch microsphere foam for loading and release of poorly water soluble drug.


Input: Abstract Background: Organic porous material is a promising carrier for enhancing the dissolution of poorly water soluble drug.


Input: The aim of the present study was to enhance dissolution and oral bioavailability of lovastatin (LV) by preparing a porous starch microsphere foam (PSM) using a novel method, meanwhile, looking into the mechanism of improving dissolution of LV.

lovastatin


Input: Methods: PSM was prepared by the W/O emulsion-freeze thawing method.


Input: The porous structure of PSM was characterized by scanning electron microscopy (SEM) and nitrogen adsorption/desorption analysis.

nitrogen


Input: The adsorption role of nanopores on the drug dissolution and physical state of LV was systematically studied by instrumental analysis, and in vitro and in vivo drug dissolution studies.


Input: 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to evaluate carrier cytotoxicity.

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

MTT


Input: Results: The SEM images of PSM showed nanometer-sized pores.


Input: Physical state characterization indicated that porous structure effectively limited the degree of crystallinity of LV.


Input: The results of in vitro and in vivo tests testified that PSM accelerated the release of LV and enhanced its oral bioavailability in comparison with crude LV and commercial capsules.


Input: The loaded PSM powder indicated a good physical stability under storage for 12 months.


Input: MTT assay shows PSM has no toxicity for Caco-2 cell.

MTT


Input: Conclusion: The preparation was a promising method to produce small and uniform PSM with markedly enhanced dissolution rate and oral bioavailability due to the spatial confinement effect of porous structure.


Input: The present work demonstrates the significant potential for the use of PSM as a novel delivery system for poorly water soluble drugs.


Input: Different pharmacokinetics of the two structurally similar dammarane sapogenins, protopanaxatriol and protopanaxadiol, in rats.

dammarane sapogenins

protopanaxatriol

protopanaxadiol


Input: Dammarane Sapogenins (DS), with main ingredients of protopanaxatriol (PPT, 33%) and protopanaxadiol (PPD, 16%), is an alkaline hydrolyzed product of ginsenosides and had significant activities in improving learning and memory and decreasing chemotherapy-induced myelosuppression.

Dammarane Sapogenins

protopanaxatriol

PPT

protopanaxadiol

PPD

ginsenosides


Input: In the present study, the pharmacokinetics and oral bioavailabilities of PPT and PPD were investigated when a single dose of DS was administrated orally (75mg/kg) and intravenously (i. v., 30mg/kg) to rats.

PPT

PPD


Input: Their in vitro stabilities in the GI tract were also investigated.


Input: PPT and PPD concentrations were measured by LC-MS.

PPT

PPD


Input: The results showed that PPT was eliminated rapidly from the body with an average t1/2, lambda z value of 0. 80h and CL of 4. 27l/h/kg after i. v. administration, while PPD was eliminated relatively slowly with a t1/2, lambda z of 6. 25h and CL of 0. 98l/h/kg.

PPT

PPD


Input: After oral administration, both PPD and PPT could be absorbed into the body, but their systemic exposures were quite different.

PPD

PPT


Input: PPT was absorbed into the body quickly, with a Tmax of 0. 58h and a Cmax of 0. 13 mu g/ml, while PPD was absorbed relatively slowly with a Tmax of 1. 82h and a Cmax of 1. 04 mu g/ml.

PPT

PPD


Input: The absolute bioavailabilities of PPT and PPD were estimated as 3. 69% and 48. 12%, respectively.

PPT

PPD


Input: The stability test found that PPT was instable in the stomach with 40% degradation after 4h incubation at 37 degrees C, both in pH1. 2 buffer and in the stomach content solution.

PPT


Input: The instability in the stomach might be one of the reasons for PPT' s poor bioavailability.

PPT


Input: Image-guided percutaneous ablation therapies for local recurrences of thyroid tumors.


Input: The incidence of thyroid carcinoma has increased steadily over the last few decades.


Input: Most differentiated thyroid carcinomas (DTC) are cured thanks to the initial treatment with surgery and radioiodine therapy.

radioiodine


Input: Nevertheless, neck lymph node metastases are found in a few of these patients during their long-term clinical and ultrasound follow-up.


Input: In some of these cases radioiodine treatment may not be effective in eradicating nodal metastases due to scant 131-I uptake.

radioiodine


Input: Additionally, a few of these patients undergo repeated neck explorations and/or resections.


Input: Based on these considerations and on the frequently indolent course of DTC neck metastases, a non-surgical therapeutic approach should be considered to control small local foci of DTC.


Input: There is increasing interest in mini-invasive image-guided procedures that can be performed under local anesthesia which do not affect the performance status of the patient.


Input: Image-guided minimally invasive ablative therapies delivered by using needle-like applicators include both thermal and non-thermal source techniques.


Input: Over the past 25 years, these therapies have gained widespread attention and, in many cases, broad clinical acceptance as methods for treating focal malignancies.


Input: In an attempt to overcome the limitations of treating certain unresectable tumor types not amenable to a further surgical treatment, a few investigators have reported successfully combining percutaneous therapies with other oncologic treatment strategies (combined treatments).


Input: In this review, we reported mini-invasive techniques more commonly employed in selected cases to ameliorate local compressive symptoms, control hormonal production, and reduce the volume of neoplastic tissue prior to traditional palliative treatment.


Input: Impact of Baseline Insulin Regimen on Glycemic Response to a Group Medical Clinic Intervention.


Input: OBJECTIVEGroup medical clinics (GMC) combine medication management and self-management training, and may improve diabetes outcomes.


Input: It remains unclear which patients benefit most from GMC.


Input: This secondary analysis examined the impact of baseline insulin regimen on GMC response. RESEARCH DESIGN AND METHODSWe analyzed a trial of 239 veterans with type 2 diabetes randomized to GMC or usual care (UC).


Input: We categorized baseline insulin regimen as the following: no insulin; basal insulin only; or complex insulin (basal-prandial or mixed regimens).


Input: Using linear mixed models adjusted for clustering within GMC, we evaluated the differential impact of GMC relative to UC on hemoglobin A (1c) (HbA (1c)) and self-efficacy among patients on different baseline insulin regimens. RESULTSFrom linear mixed models, the effect of GMC on HbA (1c) differed by baseline insulin regimen versus UC (P = 0. 05); there was no differential effect on self-efficacy (P = 0. 29).


Input: Among those using complex insulin regimens at baseline, GMC reduced HbA (1c) by study end compared with UC (-1. 0%; 95% CI-1. 8 to-0. 2; P = 0. 01).


Input: We found no such HbA (1c) difference between GMC and UC patients using no insulin (P = 0. 65) or basal insulin only (P = 0. 71).


Input: There were no clinically significant differences in hypoglycemia by baseline insulin regimen and intervention group. CONCLUSIONSWe found that compared with UC, GMC lowered HbA (1c) specifically among patients using complex insulin regimens at study baseline, which may relate to this group' s demanding medication and self-management requirements.


Input: Implementing GMC among patients using complex insulin regimens may maximize this care delivery strategy' s potential.


Input: Polymer-coated echogenic lipid nanoparticles with dual release triggers.


Input: Although lipid nanoparticles are promising drug delivery vehicles, passive release of encapsulated contents at the target site is often slow.


Input: Herein, we report contents release from targeted, polymer-coated, echogenic lipid nanoparticles in the cell cytoplasm by redox trigger and simultaneously enhanced by diagnostic frequency ultrasound.


Input: The lipid nanoparticles were polymerized on the external leaflet using a disulfide cross-linker.

disulfide


Input: In the presence of cytosolic concentrations of glutathione, the lipid nanoparticles released 76% of encapsulated contents.

glutathione


Input: Plasma concentrations of glutathione failed to release the encapsulated contents.

glutathione


Input: Application of 3 MHz ultrasound for 2 min simultaneously with the reducing agent enhanced the release to 96%.


Input: Folic acid conjugated, doxorubicin-loaded nanoparticles showed enhanced uptake and higher cytotoxicity in cancer cells overexpressing the folate receptor (compared to the control).

Folic acid

doxorubicin

folate


Input: With further developments, these lipid nanoparticles have the potential to be used as multimodal nanocarriers for simultaneous targeted drug delivery and ultrasound imaging.


Input: Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl) cyclopropyl] pyrimidin-2-yl}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity.

4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl) cyclopropyl] pyrimidin-2-yl}-1H-indole


Input: ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo-or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways.


Input: We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition.

sulfonylmorpholinopyrimidines


Input: Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM.


Input: Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses.


Input: At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice.


Input: Compound 6 is a useful compound to explore ATR pharmacology in vivo.


Input: Surface structures of PDMS incorporated with quaternary ammonium salts designed for antibiofouling and fouling release applications.

PDMS

ammonium


Input: Poly (dimethylsiloxane) (PDMS) materials have been extensively shown to function as excellent fouling-release (FR) coatings in the marine environment.

Poly (dimethylsiloxane)

PDMS


Input: The incorporation of biocide moieties, such as quaternary ammonium salts (QAS), can impart additional antibiofouling properties to PDMS-based FR coating systems.

ammonium

PDMS


Input: In this study, the molecular surface structures of two different types of QAS-incorporated PDMS systems were investigated in different chemical environments using sum frequency generation vibrational spectroscopy (SFG).

PDMS


Input: Specifically, a series of PDMS coatings containing either a QAS with a single ammonium salt group per molecule or a quaternary ammonium-functionalized polyhedral oligomeric silsesquioxane (Q-POSS) were measured with SFG in air, water, and artificial seawater (ASW) to investigate the relationships between the interfacial surface structures of these materials and their antifouling properties.

PDMS

ammonium

ammonium

polyhedral oligomeric silsesquioxane

POSS


Input: Although previous studies have shown that the above-mentioned materials are promising contact-active antifouling coatings, slight variations of the QAS structure can lead to substantial differences in the antifouling performance.


Input: Indeed, the SFG results presented here indicated that the surface structures of these materials depend on several factors, such as the extent of quaternization, the molecular weight of the PDMS component, and the functional groups of the QAS used for incorporation into the PDMS matrix.

PDMS

PDMS


Input: It was concluded that in aqueous environments a lower extent of Q-POSS quaternization and the use of ethoxy (instead of methoxy) functional groups for QAS incorporation facilitated the extension of the alkyl chains away from the nitrogen atom of the QAS on the surface.

POSS

ethoxy

methoxy

nitrogen


Input: The SFG results correlated well with the antifouling activity studies that indicated that the coatings exhibiting a lower concentration of longer alkyl chains protruding out of the surface can neutralize microorganisms more effectively, ultimately leading to better antifouling performance.


Input: Furthermore, the results of this study provide additional evidence that incorporated QAS exert their antimicrobial activity through a two-step interaction.


Input: The first step is the adsorption of the bacteria on the surface as a result of the electrostatic attraction between the negatively charged microorganisms and the positively charged QAS nitrogen atoms on the surface.

nitrogen


Input: The second step is the disruption of the cell membranes by the penetration of the QAS long, extended alkyl chains.


Input: Glargine safety, diabetes and cancer.


Input: INTRODUCTION: In 2009, several epidemiological studies suggested a higher frequency of malignancy in insulin glargine-treated patients.


Input: A number of follow-up epidemiological population studies as well as two randomized, controlled clinical studies, one a 5000-patient retinopathy study and the other a 12, 000-patient cardiovascular outcomes trial (ORIGIN), found no higher frequency of malignancy in glargine-treated patients.


Input: AREAS COVERED: We reviewed the existing literature as well as U. S.


Input: FDA records to investigate the association of cancer, diabetes, and insulin.


Input: There is a 20-40% higher incidence of malignancy in type 2 diabetes patients.


Input: Certain cancers are more common, including hepatocellular and pancreatic carcinoma, colorectal cancer, renal cancer, and breast and endometrial cancer, and non-Hodgkin' s lymphoma.


Input: There are numerous inter-related factors which may promote both diabetes and malignancy, including dietary patterns, obesity, insulin resistance, and alcoholism.


Input: Patients who receive insulin treatment are typically older and " sicker " than those who receive oral agents.


Input: EXPERT OPINION: It is very difficult to prove causal associations between diabetes and cancer due to the host of confounding factors.


Input: The hypothesis that hyperinsulinemia and IGF-1 receptor activation promote cancer is strong, but confounded by the association of hyperinsulinemia with obesity, which separately promotes malignancy.


Input: Although statistical techniques to adjust for confounding variables can improve epidemiological comparisons, the lesson of the glargine cancer controversy is that controlled clinical trials are the only means to definitely prove hypotheses.


Input: Transforming drug discovery and development through innovation: past, present and future.


Input: This annual meeting began in 1998 and was the first industry-led event to focus on the specific needs of industry researchers.


Input: The goal of Clinical and Pharmaceutical Solutions Through Analysis (CPSA) is to provide an in-depth review of innovative technology and industry practices through open discussion of industry-related issues and needs.


Input: Education and specialized training are the foundation of all CPSA events.


Input: As the industry has evolved so has CPSA.


Input: Thus, the year the name was changed from Chemical and Pharmaceutical Structural Analysis to CPSA was to reflect the growing focus on clinical applications and the emergence of personalized medicine.


Input: Most importantly, the CPSA annual meeting has retained the same high-quality scientific content, open interaction from industry opinion leaders and a collegial environment.


Input: Personalized medicine for targeted and platinum-based chemotherapy of lung and bladder cancer.

platinum


Input: The personalized medicine revolution is occurring for cancer chemotherapy.


Input: Biomarkers are increasingly capable of distinguishing genotypic or phenotypic traits of individual tumors, and are being linked to the selection of treatment protocols.


Input: This review covers the molecular basis for biomarkers of response to targeted and cytotoxic lung and bladder cancer treatment with an emphasis on platinum-based chemotherapy.

platinum


Input: Platinum derivatives are a class of drugs commonly employed against solid tumors that kill cells by covalent attachment to DNA.

Platinum


Input: Platinum-DNA adduct levels in patient tissues have been correlated to response and survival.

Platinum


Input: The sensitivity and precision of adduct detection has increased to the point of enabling subtherapeutic dosing for diagnostics applications, termed diagnostic microdosing, prior to the initiation of full-dose therapy.


Input: The clinical status of this unique phenotypic marker for lung and bladder cancer applications is detailed along with discussion of future applications.


Input: Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation.

CpG


Input: Polycomb repressive complex 1 (PRC1) catalyzes lysine 119 monoubiquitylation on H2A (H2AK119ub1) and regulates pluripotency in embryonic stem cells (ESCs).

lysine


Input: However, the mechanisms controlling the binding of PRC1 to genomic sites and its catalytic activity are poorly understood.


Input: Here, we show that Fbxl10 interacts with Ring1B and Nspc1, forming a noncanonical PRC1 that is required for H2AK119ub1 in mouse ESCs.


Input: Genome-wide analyses reveal that Fbxl10 preferentially binds to CpG islands and colocalizes with Ring1B on Polycomb target genes.

CpG


Input: Notably, Fbxl10 depletion causes a decrease in Ring1B binding to target genes and a major loss of H2AK119ub1.


Input: Furthermore, genetic analyses demonstrate that Fbxl10 DNA binding capability and integration into PRC1 are required for H2AK119 ubiquitylation.


Input: ESCs lacking Fbxl10, like previously characterized Polycomb mutants, cannot differentiate properly.


Input: These results demonstrate that Fbxl10 has a key role in regulating Ring1B recruitment to its target genes and H2AK119 ubiquitylation in ESCs.


Input: Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease.

NO


Input: Nitric oxide (NO) produced by the endothelial NO synthase (eNOS) is an antihypertensive, antithrombotic and anti-atherosclerotic molecule.

Nitric oxide

NO

NO


Input: Hypercholesterolemia leads to a reduction in vascular NO bioavailability.

NO


Input: This is attributed to a dysfunction of the eNOS enzyme and a reduced eNOS activity.


Input: NADPH oxidase-mediated oxidative stress leads to oxidation of tetrahydrobiopterin (BH4), the essential cofactor of eNOS.

NADPH

tetrahydrobiopterin


Input: In BH4 deficiency, oxygen reduction uncouples from NO synthesis, thereby converting eNOS to a superoxide-producing enzyme.

oxygen

NO

superoxide


Input: As a consequence of eNOS uncoupling, NO production is reduced and the pre-existing oxidative stress is enhanced, which contribute significantly to atherogenesis.


Input: Therefore, pharmacological approaches that prevent eNOS uncoupling and enhance eNOS activity are of therapeutic interest.


Input: Angiotensin-converting enzyme inhibitors, AT1 receptor blockers, statins, nebivolol and resveratrol have been shown to reverse eNOS uncoupling and to stimulate eNOS activity concurrently.

nebivolol

resveratrol


Input: Molecular mechanisms of the aforementioned drugs/compounds on eNOS functionality is summarized and discussed in this review.


Input: How sugar tunes your clock.

sugar


Input: While cellular circadian clocks are set by the light/dark cycle, these clocks can be reset by what we eat.


Input: Two papers in this issue of Cell Metabolism reveal that O-GlcNAcylation of clock proteins, which is dependent on nutrients, adjusts our circadian clock (Kaasik et al., 2013; Li et al., 2013).

O


Input: Synthesis and characterization of novel quick-release propofol prodrug via lactonization.

propofol


Input: The water-soluble derivatives of propofol have gained attention as a method to increase solubility of propofol.

propofol

propofol


Input: According to the principle of lactonization, the lead compound HX0969 was synthesized first and then the pharmacological features of HX0969 were evaluated in a comparison with those of propofol in the SD rats.

propofol


Input: Then, HX0969 disodium phosphate monoester (HX0969W) and glycine ester trifluoroacetic acid salt (HX101230) were synthesized, and their pharmacological features were compared with those of Lusedra (R), which has been recognized and marketed as a water-soluble prodrug of propofol since 2008.

HX0969 disodium phosphate monoester

glycine ester trifluoroacetic acid salt

Lusedra

propofol


Input: The results showed that HX0969 could produce an anesthetic effect within a few seconds (3. 6 +/- 3. 0s) and its therapeutic index was 4. 66 in the SD rat.


Input: The pharmacodynamic characteristics of HX0969W were similar to those of the Lusedra (R).

Lusedra


Input: HX101230 could still produce an anesthetic effect within 60s in the rats though its therapeutic index was not so high (TI = 2. 96).


Input: Therefore, our study has indicated that HX0969 is a potentially useful lead compound of propofol derivative.

propofol


Input: Its rapid anesthetic effect is probably associated with lactonization.