Input: Using tumor mouse models (B16F10 melanoma, LS174 lung, and MA148 ovarian), we found that DB21 inhibits tumor angiogenesis and tumor growth significantly better than 6DBF7, DB16, or anginex.


Input: DB21 is currently being developed further and holds promise for the management of human cancer in the clinic.


Input: An integrated assessment of sediment remediation in a midwestern U. S. stream using sediment chemistry, water quality, bioassessment, and fish biomarkers.


Input: A comprehensive biological, sediment, and water quality study of the lower Little Scioto River near Marion, Ohio, USA, was undertaken to evaluate the changes or improvements in biotic measurements following the removal of creosote-contaminated sediment.


Input: The study area covered 7. 5 river miles (RMs), including a remediated section between RMs 6. 0 and 6. 8.


Input: Fish and macroinvertebrate assemblages, fish biomarkers (i. e., polycyclic aromatic hydrocarbon [PAH] metabolite levels in white sucker [Castostomus commersoni] and common carp [Cyprinus carpio] bile and DNA damage), sediment chemistry, and water quality were assessed at five locations relative to the primary source of historical PAH contamination-upstream (RM 9. 2), adjacent (RM 6. 5), and downstream (RMs 5. 7, 4. 4, and 2. 7).

polycyclic aromatic hydrocarbon

PAH

PAH


Input: Overall, the biomarker results were consistent with the sediment PAH results, showing a pattern of low levels of PAH bile metabolites and DNA damage at the upstream (reference or background location), as well as the remediated section, high levels at the two immediate downstream sites, and somewhat lower levels at the furthest downstream site.

PAH

PAH


Input: Results show that remediation was effective in reducing sediment contaminant concentrations and exposure of fish to PAHs and in improving fish assemblages (60% increase in index of biotic integrity scores) in remediated river sections.

PAHs


Input: Additional remedial investigation and potentially further remediation is needed to improve the downstream benthic fish community, which is still heavily exposed to PAH contaminants.

PAH


Input: A maternal " junk-food " diet reduces sensitivity to the opioid antagonist naloxone in offspring postweaning.

naloxone


Input: Perinatal exposure to a maternal " junk-food " diet has been demonstrated to increase the preference for palatable diets in adult offspring.


Input: We aimed to determine whether this increased preference could be attributed to changes in mu-opioid receptor expression within the mesolimbic reward pathway.


Input: We report here that mRNA expression of the mu-opioid receptor in the ventral tegmental area (VTA) at weaning was 1. 4-fold (males) and 1. 9-fold (females) lower in offspring of junk-food (JF)-fed rat dams than in offspring of dams fed a standard rodent diet (control) (P < 0. 05).


Input: Administration of the opioid antagonist naloxone to offspring given a palatable diet postweaning significantly reduced fat intake in control offspring (males: 7. 7 +/- 0. 7 vs. 5. 4 +/- 0. 6 g/kg/d; females: 6. 9 +/- 0. 3 vs. 3. 9 +/- 0. 5 g/kg/d; P < 0. 05), but not in male JF offspring (8. 6 +/- 0. 6 vs. 7. 1 +/- 0. 5 g/kg/d) and was less effective at reducing fat intake in JF females (42. 2 +/- 6. 0 vs. 23. 1 +/- 4. 1% reduction, P < 0. 05).

naloxone


Input: Similar findings were observed for total energy intake.


Input: Naloxone treatment did not affect intake of standard rodent feed in control or JF offspring.

Naloxone


Input: These findings suggest that exposure to a maternal junk-food diet results in early desensitization of the opioid system which may explain the increased preference for junk food in these offspring.


Input: Short-peptide fusion inhibitors with high potency against wild-type and enfuvirtide-resistant HIV-1.


Input: Peptides derived from the C-terminal heptad repeat (C peptides) of HIV-1 gp41 are potent inhibitors against virus entry.

C


Input: However, development of a short C peptide possessing high anti-HIV potency is considered a daunting challenge.


Input: We recently discovered that the residues Met626 and Thr627 preceding the pocket-binding domain of the C peptide adopt a unique M-T hook structure that is crucial for the design of HIV-1 fusion inhibitors.


Input: In this study, we first presented a proof-of-concept prototype that the M-T hook residues can dramatically improve the antiviral activity and thermostability of a short C peptide.


Input: We then generated a 24-mer peptide termed MT-SC22EK by incorporating the M-T hook structure to the N terminus of the poorly active short C peptide SC22EK.

N


Input: Amazingly, MT-SC22EK inhibited HIV-1-mediated cell fusion and infection at a level comparable to C34, T1249, SC29EK, and sifuvirtide, and it was highly active against diverse HIV-1 subtypes and variants, including those T20 (enfuvirtide) and SC29EK-resistant viruses.


Input: The high-resolution crystal structure of MT-SC22EK reveals the N-terminal M-T hook conformation folded by incorporated Met626 and Thr627 and identifies the C-terminal boundary critical for the anti-HIV activity.

N

C


Input: Collectively, our studies provide new insights into the mechanisms of HIV-1 fusion and its inhibition.


Input: Design and assessment of a microfluidic network system for oxygen transport in engineered tissue.

oxygen


Input: Oxygen and nutrients cannot be delivered to cells residing in the interior of large-volume scaffolds via diffusion alone.

Oxygen


Input: Several efforts have been made to meet the metabolic needs of cells in a scaffold by constructing mass transport channels, particularly in the form of bifurcated networks.


Input: In contrast to progress in fabrication technologies, however, an approach to designing an optimal network based on experimental evaluation has not been actively reported.


Input: The main objective of this study was to establish a procedure for designing an effective microfluidic network system for a cell-seeded scaffold and to develop an experimental model to evaluate the design.


Input: We proposed a process to design a microfluidic network by combining an oxygen transport simulation with biomimetic principles governing biological vascular trees.

oxygen


Input: The simulation was performed with the effective diffusion coefficient (D (e, s)), which was experimentally measured in our previous study.


Input: Porous scaffolds containing an embedded microfluidic network were fabricated using the lost mold shape-forming process and salt leaching method.


Input: The reliability of the procedure was demonstrated by experiments using the scaffolds.


Input: This approach established a practical basis for designing an effective microfluidic network in a cell-seeded scaffold.


Input: Mapping the ion current distribution in nanopore/electrode devices.


Input: Solid-state nanopores with integrated electrodes have interesting prospects in next-generation single-molecule biosensing and sequencing.


Input: These include " gated " nanopores with a single electrode integrated into the membrane, as well as two-electrode designs, such as a transversal tunneling junction.


Input: Here we report the first comprehensive analysis of current flow in a three-electrode device as a model for this class of sensors.


Input: As a new feature, we observe apparent rectification in the pore current that is rooted in the current distribution of the cell, rather than the geometry or electrostatics of the pore.


Input: We benchmark our results against a recently developed theoretical model and define operational parameters for nanopore/electrode structures.


Input: Our findings thus facilitate the rational design of such sensor devices.


Input: Novobiocin analogues with second-generation noviose surrogates.

Novobiocin

noviose


Input: Hsp90 is a promising therapeutic target for the treatment of cancer.


Input: Novobiocin is the first Hsp90 C-terminal inhibitor ever identified and recent structure-activity relationship studies on the noviose sugar identified several commercially available amines as suitable surrogates.

Novobiocin

noviose sugar

amines


Input: In an effort to further understand this region of the molecule, analogues containing various N'-amino substituents were prepared and evaluated against two breast cancer cell lines for determination of their efficacy.

N'-amino


Input: Compound 37j manifested the most potent anti-proliferative activity from these studies and induced Hsp90-dependent client protein degradation at mid nano-molar concentrations.


Input: Enhancement of electrical and thermomechanical properties of silver nanowire composites by the introduction of nonconductive nanoparticles: experiment and simulation.

silver


Input: Electrically conductive polymer nanocomposites have been applied extensively in many fields to develop the next generation of devices.


Input: Large amounts of conductive nanofillers in polymer matrices are, however, often required for a sufficiently high electrical conductivity, which in turn deteriorates the desired thermomechanical properties.


Input: We illustrate a novel but facile strategy to improve the electrical conductivity and the thermomechanical property of silver nanowire/polymer nanocomposites.

silver


Input: We find that one may increase the electrical conductivity of silver nanowire/polymer nanocomposites by up to about 8 orders of magnitude by introducing silica nanoparticles with nanocomposites.

silver

silica


Input: The electrical percolation threshold volume fraction of silver nanowires decreases from 0. 12 to 0. 02.

silver


Input: Thermomechanical properties also improve as silica nanoparticles are introduced.

silica


Input: We carry out extensive Monte Carlo simulations to elucidate the effects of silica nanoparticles at a molecular level and find that van der Waals attractive interaction between silica nanoparticles and silver nanowires dominates over the depletion-induced interaction between silver nanowires, thus improving the dispersion of silver nanowires.

silica

silica

silver

silver

silver


Input: Without silica nanoparticles, silver nanowires tend to aggregate, which is why additional silver nanowires are required for a desired electrical conductivity.

silica

silver

silver


Input: On the other hand, with silica nanoparticles mixed, the electrical percolating network is likely to form at a smaller volume fraction of silver nanowires.

silica

silver


Input: Impact of the redox-cycling herbicide diquat on transcript expression and antioxidant enzymatic activities of the freshwater snail Lymnaea stagnalis.

diquat


Input: The presence of pesticides in the environment results in potential unwanted effects on non-target species.


Input: Freshwater organisms inhabiting water bodies adjacent to agricultural areas, such as ditches, ponds and marshes, are good models to test such effects as various pesticides may reach these habitats through several ways, including aerial drift, run-off, and drainage.


Input: Diquat is a non-selective herbicide used for crop protection or for weed control in such water bodies.

Diquat


Input: In this study, we investigated the effects of diquat on a widely spread aquatic invertebrate, the holarctic freshwater snail Lymnaea stagnalis.

diquat


Input: Due to the known redox-cycling properties of diquat, we studied transcript expression and enzymatic activities relative to oxidative and general stress in the haemolymph and gonado-digestive complex (GDC).

diquat


Input: As diquat is not persistent, snails were exposed for short times (5, 24, and 48 h) to ecologically relevant concentrations (22. 2, 44. 4, and 222. 2 mu g l (-1)) of diquat dibromide.

diquat

diquat dibromide


Input: RT-qPCR was used to quantify the transcription of genes encoding catalase (cat), a cytosolic superoxide dismutase (Cu/Zn-sod), a selenium-dependent glutathione peroxidase (gpx), a glutathione reductase (gred), the retinoid X receptor (rxr), two heat shock proteins (hsp40 and hsp70), cortactin (cor) and the two ribosomal genes r18S and r28s.

superoxide

Cu

Zn

selenium

glutathione

glutathione

retinoid


Input: Enzymatic activities of SOD, Gpx, Gred and glutathione S-transferase (GST) were investigated in the GDC using spectrophoto/fluorometric methods.

glutathione S


Input: Opposite trends were obtained in the haemolymph depending on the herbicide concentration.


Input: At the lowest concentration, effects were mainly observed after 24 h of exposure, with over-transcription of cor, hsp40, rxr, and sod, whereas higher concentrations down-regulated the expression of most of the studied transcripts, especially after 48 h of exposure.


Input: In the GDC, earlier responses were observed and the fold-change magnitude was generally much higher: transcription of all target genes increased significantly (or non-significantly for cat) after 5 h of exposure, and went back to control levels afterwards, suggesting the onset of an early response to oxidative stress associated to the unbalance of reactive oxygen species (ROS) in hepatocytes.

oxygen


Input: Although increases obtained for Gred and SOD activities were globally consistent with their respective transcript expressions, up-regulation of transcription was not always correlated with increase of enzymatic activity, indicating that diquat might affect steps downstream of transcription.

diquat


Input: However, constitutive levels of enzymatic activities were at least maintained.


Input: In conclusion, diquat was shown to affect expression of the whole set of studied transcripts, reflecting their suitability as markers of early response to oxidative stress in L. stagnalis.

diquat


Input: Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D2 partial agonists.

aminothiazole

benzazepines

dopamine


Input: Dopamine (D (2)) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics.

Dopamine


Input: Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D (2) partial agonists.

aminothiazole

benzazepines


Input: These compounds have good selectivity, CNS drug-like properties and tunable D (2) partial agonism.


Input: One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model.

amphetamine


Input: Synthesis and antimycobacterial evaluation of pyrazinamide derivatives with benzylamino substitution.

pyrazinamide

benzylamino


Input: A series of 19 new compounds related to pyrazinamide were synthesized, characterized with analytical data and screened for in vitro whole cell antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium kansasii and two types of Mycobacterium avium.

pyrazinamide


Input: The series consisted of 3-(benzylamino)-5-cyanopyrazine-2-carboxamides and 3-(benzylamino) pyrazine-2, 5-dicarbonitriles with various substituents on the phenyl ring.

3-(benzylamino)-5-cyanopyrazine-2-carboxamides

3-(benzylamino) pyrazine-2, 5-dicarbonitriles

phenyl


Input: RP-HPLC method was used to determine the lipophilicity of the prepared compounds.


Input: Nine compounds exerted similar or better activity against Mycobacterium tuberculosis compared to pyrazinamide (MIC = 6. 25-12. 5 mu g/mL).

pyrazinamide


Input: 3-(Benzylamino) pyrazine-2, 5-dicarbonitrile inhibited all of the tested mycobacterial strains with MIC within the range 12. 5-25 mu g/mL.

3-(Benzylamino) pyrazine-2, 5-dicarbonitrile


Input: Although not the most active, 4-NH (2) substituted compounds possessed the lowest in vitro cytotoxicity (hepatotoxicity), leading to selectivity index SI = 5. 5 and SI > 21.

4-NH (2)


Input: 2'-Fluoro-6'-methylene-carbocyclic adenosine phosphoramidate (FMCAP) prodrug: in vitro anti-HBV activity against the lamivudine-entecavir resistant triple mutant and its mechanism of action.

2'-Fluoro-6'-methylene-carbocyclic adenosine phosphoramidate

FMCAP

lamivudine

entecavir


Input: Novel 2'-fluoro-6'-methylene-carbocyclic adenosine (FMCA) monophosphate prodrug (FMCAP) was synthesized and evaluated for its in vitro anti-HBV potency against a lamivudine-entecavir resistant clone (L180M + M204V + S202G).

2'-fluoro-6'-methylene-carbocyclic adenosine

FMCA

monophosphate

FMCAP

lamivudine

entecavir


Input: FMCA demonstrated significant antiviral activity against wild-type as well as lamivudine-entecavir resistant triple mutant (L180M + M204V + S202G).

FMCA

lamivudine

entecavir


Input: The monophosphate prodrug (FMCAP) demonstrated greater than 12-fold (12 x) increase in anti-HBV activity without increased cellular toxicity.

monophosphate

FMCAP


Input: Mitochondrial and cellular toxicity studies of FMCA indicated that there is no significant toxicity up to 100 mu M.

FMCA


Input: Mode of action studies by molecular modeling indicate that the 2'-fluoro moiety by hydrogen bond as well as the Van der Waals interaction of the carbocyclic ring with the phenylalanine moiety of the polymerase promote the positive binding, even in the drug-resistant mutants.

hydrogen

carbocyclic

phenylalanine


Input: Osteocyte apoptosis.


Input: Apoptotic death of osteocytes was recognized over 15years ago, but its significance for bone homeostasis has remained elusive.


Input: A new paradigm has emerged that invokes osteocyte apoptosis as a critical event in the recruitment of osteoclasts to a specific site in response to skeletal unloading, fatigue damage, estrogen deficiency and perhaps in other states where bone must be removed.

estrogen


Input: This is accomplished by yet to be defined signals emanating from dying osteocytes, which stimulate neighboring viable osteocytes to produce osteoclastogenic cytokines.


Input: The osteocyte apoptosis caused by chronic glucocorticoid administration does not increase osteoclasts; however, it does negatively impact maintenance of bone hydration, vascularity, and strength.


Input: This article is part of a Special Issue entitled " The Osteocyte ".


Input: Bisphenol A interferes with thyroid specific gene expression.

Bisphenol A


Input: Bisphenol A (BPA) is an endocrine-disrupting chemical that leads to low-dose human exposure due to its ability to leach from chemically derived products, as polycarbonate plastics and epoxy resin.

Bisphenol A

BPA

polycarbonate

epoxy


Input: In addition to its known xeno-endocrine action, BPA exerts a wide range of metabolic effects.

BPA


Input: Despite the documented BPA exposure outcomes on synthesis of thyroid hormones, there are not any data available on its actions on the thyroid follicular cells, site of synthesis of the thyroid hormones.

BPA

thyroid hormones

thyroid hormones


Input: Recently, it has been shown that several environmental pollutants, as BPA, can exert a thyroid disrupting activity.

BPA


Input: In this study, we employed in vitro and in vivo (zebrafish) models to examine the effects of BPA in regulating the expression of genes involved in the thyroid hormone synthesis and of their transcriptional regulators at BPA doses as low as 10 (-9) M, a dose that is environmentally pertinent and far below the one detected in infants plasma.

BPA

thyroid hormone

BPA


Input: In both systems we could detect an altered expression of the genes involved in thyroid hormones synthesis and of thyroid specific transcriptional factors in BPA dose and time dependent manner.

thyroid hormones

BPA


Input: Our results suggest that BPA exerts a direct effect on thyroid follicular cell.

BPA


Input: We show that these cells can " sense " very low amount of BPA.

BPA


Input: Thus they, potentially, represent an ideal in vitro system to develop assays to detect BPA and other pollutants with thyroid disrupting activity at level far below the ones considered to be environmental relevant.

BPA


Input: Moreover, this report may provide new insight into the mode of BPA-induced deregulation of physiological processes as well as on the extensively debated molecular pathways underlying its biological activities.

BPA


Input: A re-evaluation of fifteen years of European risk assessment using effect models.


Input: Ecological risk assessments of chemicals can be informed by a suite of effect models, including population and food web models.


Input: In the risk assessments conducted under EU regulation 793/93/EC, however, applications of such effect models are extremely scarce and toxicity-extrapolation approaches are often used instead.


Input: The objective of the present study was to re-evaluate these risk assessments using two types of effect models: species sensitivity distributions (SSDs, non-mechanistic), and food web models (mechanistic).


Input: Species sensitivity distributions significantly fitted the available toxicity data for up to 35% of the chemicals, depending on the trophic levels included and the amount of data available.


Input: Median hazardous concentrations for 5% of the species (HC5-50) estimated by the SSDs were less accurate predictors of measured community-level no observed effect concentration than food web model-derived HC5-50s, albeit data were available for seven chemicals only.


Input: For datasets with more than 10 data points, the 90% confidence interval of the estimated HC5s was narrower for the food web modeling approach than for the SSD approach.


Input: The HC5-50s predicted by the two approaches were two to five times (metals) and 10 to 100 times (organic chemicals) higher than the predicted no effect concentrations (PNECs) for the aquatic environment listed in the risk assessment reports.


Input: This suggests that the derived PNECs are protective for aquatic ecosystems.


Input: Threshold collision-induced dissociation of hydrated magnesium: experimental and theoretical investigation of the binding energies for Mg (2 +) (H2O) x complexes (x = 2-10).

hydrated magnesium

Mg (2 +) (H2O) x


Input: The sequential bond energies of Mg (2 +) (H2O) x complexes, in which x = 2-10, are measured by threshold collision-induced dissociation in a guided ion beam tandem mass spectrometer.

Mg (2 +) (H2O) x


Input: From an electrospray ionization source that produces an initial distribution of Mg (2 +) (H2O) x complexes in which x = 7-10, complexes down to x = 3 are formed by using an in-source fragmentation technique.

Mg (2 +) (H2O) x


Input: Complexes smaller than Mg (2 +) (H2O) 3 cannot be formed in this source because charge separation into MgOH (+) (H2O) and H3O (+) is a lower-energy pathway than simple water loss from Mg (2 +) (H2O) 3.

Mg (2 +) (H2O) 3

MgOH (+) (H2O)

H3O (+)

Mg (2 +) (H2O) 3


Input: The kinetic energy dependent cross sections for dissociation of Mg (2 +) (H2O) x complexes, in which x = 3-10, are examined over a wide energy range to monitor all dissociation products and are modeled to obtain 0 and 298 K binding energies.

Mg (2 +) (H2O) x


Input: Analysis of both primary and secondary water molecule losses from each sized complex provides thermochemistry for the sequential hydration energies of Mg (2 +) for x = 2-10 and the first experimental values for x = 2-4.

Mg (2 +)


Input: Additionally, the thermodynamic onsets leading to the charge-separation products from Mg (2 +) (H2O) 3 and Mg (2 +) (H2O) 4 are determined for the first time.

Mg (2 +) (H2O) 3

Mg (2 +) (H2O) 4


Input: Our experimental results for x = 3-7 agree well with quantum chemical calculations performed here and previously calculated binding enthalpies, as well as previous measurements for x = 6.


Input: The present values for x = 7-10 are slightly lower than previous experimental results and theory, but within experimental uncertainties.


Input: Boron-based inhibitors of acyl protein thioesterases 1 and 2.

Boron

acyl


Input: Ras proteins are of importance in cell proliferation, and hence their mutated forms play causative roles in many kinds of cancer in different tissues.


Input: Inhibition of the Ras-depalmitoylating enzyme acyl protein thioesterases APT1 and-2 is a new approach to modulating the Ras cycle.

acyl


Input: Here we present boronic and borinic acid derivatives as a new class of potent and nontoxic APT inhibitors.

boronic

borinic acid


Input: These compounds were detected by extensive library screening using chemical arrays and turned out to inhibit human APT1 and-2 in a competitive mode.


Input: Furthermore, one of the molecules was demonstrated to inhibit Erk1/2 phosphorylation significantly.


Input: Three-Dimensional CdS-Titanate Composite Nanomaterials for Enhanced Visible-Light-Driven Hydrogen Evolution.

CdS

Titanate

Hydrogen


Input: 3D Hierarchical echinus-like titanate spheres (HETSs), serving as the supporting material for CdS nanoparticles, are synthesized via a fast one-step hydrothermal method.

titanate

CdS


Input: The obtained 3D CdS-HETS composite materials show enhanced H2 generation under visible light irradiation.

CdS


Input: Enzyme-catalyzed crosslinking in a partly frozen state: a new way to produce supermacroporous protein structures.


Input: In this study a new way to produce supermacroporous protein structures was investigated.


Input: Enzyme-mediated crosslinking of gelatin or casein was performed in a partly frozen state, which yielded stable, protein-based cryogels.


Input: The reaction kinetics for the formation of cryogels were found to be fairly slow, most likely due to the low temperature (-12 degrees C) used or due to an increased viscosity owing to the cryo-concentration taking place.


Input: The produced cryogels were characterized with regards to their physical properties and in vitro degradation.


Input: Furthermore, cryogels produced from gelatin and casein were evaluated as potential scaffolds by fibroblast cultivation to confirm their in vitro biocompatibility.


Input: Gelatin-and casein-based scaffolds both supported cell proliferation and migration through the scaffold.


Input: Molecular insights into vesicle tethering at the Golgi by the conserved oligomeric Golgi (COG) complex and the golgin TATA element modulatory factor (TMF).


Input: Protein sorting between eukaryotic compartments requires vesicular transport, wherein tethering provides the first contact between vesicle and target membranes.


Input: Here we map and start to functionally analyze the interaction network of the conserved oligomeric Golgi (COG) complex that mediates retrograde tethering at the Golgi.


Input: The interactions of COG subunits with members of transport factor families assign the individual subunits as specific interaction hubs.


Input: Functional analysis of selected interactions suggests a mechanistic tethering model.


Input: We find that the COG complex interacts with two different Rabs in addition to each end of the golgin " TATA element modulatory factor " (TMF).


Input: This allows COG to potentially bridge the distance between the distal end of the golgin and the target membrane thereby promoting tighter docking.


Input: Concurrently we show that the central portion of TMF can bind to Golgi membranes that are liberated of their COPI cover.


Input: This latter interaction could serve to bring vesicle and target membranes into close apposition prior to fusion.


Input: A target selection mechanism, in which a hetero-oligomeric tethering factor organizes Rabs and coiled transport factors to enable protein sorting specificity, could be applicable to vesicle targeting throughout eukaryotic cells.


Input: FINDSITE (comb): a threading/structure-based, proteomic-scale virtual ligand screening approach.


Input: Virtual ligand screening is an integral part of the modern drug discovery process.


Input: Traditional ligand-based, virtual screening approaches are fast but require a set of structurally diverse ligands known to bind to the target.


Input: Traditional structure-based approaches require high-resolution target protein structures and are computationally demanding.


Input: In contrast, the recently developed threading/structure-based FINDSITE-based approaches have the advantage that they are as fast as traditional ligand-based approaches and yet overcome the limitations of traditional ligand-or structure-based approaches.


Input: These new methods can use predicted low-resolution structures and infer the likelihood of a ligand binding to a target by utilizing ligand information excised from the target' s remote or close homologous proteins and/or libraries of ligand binding databases.


Input: Here, we develop an improved version of FINDSITE, FINDSITE (filt), that filters out false positive ligands in threading identified templates by a better binding site detection procedure that includes information about the binding site amino acid similarity.

amino acid


Input: We then combine FINDSITE (filt) with FINDSITE (X) that uses publicly available binding databases ChEMBL and DrugBank for virtual ligand screening.


Input: The combined approach, FINDSITE (comb), is compared to two traditional docking methods, AUTODOCK Vina and DOCK 6, on the DUD benchmark set.


Input: It is shown to be significantly better in terms of enrichment factor, dependence on target structure quality, and speed.


Input: FINDSITE (comb) is then tested for virtual ligand screening on a large set of 3576 generic targets from the DrugBank database as well as a set of 168 Human GPCRs.


Input: Excluding close homologues, FINDSITE (comb) gives an average enrichment factor of 52. 1 for generic targets and 22. 3 for GPCRs within the top 1% of the screened compound library.


Input: Around 65% of the targets have better than random enrichment factors.


Input: The performance is insensitive to target structure quality, as long as it has a TM-score >= 0. 4 to native.


Input: Thus, FINDSITE (comb) makes the screening of millions of compounds across entire proteomes feasible.


Input: The FINDSITE (comb) web service is freely available for academic users at http://cssb. biology. gatech. edu/skolnick/webservice/FINDSITE-COMB/index. html.


Input: Optimization of brush-like cationic copolymers for nonviral gene delivery.


Input: Polyethylenimine (PEI) is one of the most broadly used polycations for gene delivery due to its high transfection efficiency and commercial availability but materials are cytotoxic and often polydisperse.

Polyethylenimine

PEI


Input: The goal of current work is to develop an alternative family of polycations based on controlled living radical polymerization (CLRP) and to optimize the polymer structure for efficient gene delivery.


Input: In this study, well-defined poly (glycidyl methacrylate) (P (GMA)) homopolymers were synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization followed by decoration using three different types of oligoamines, i. e., tetraethylenepentamine (TEPA), pentaethylenehexamine (PEHA), and tris (2-aminoethyl) amine (TREN), respectively, to generate various P (GMA-oligoamine) homopolycations.

poly (glycidyl methacrylate)

P (GMA)

oligoamines

tetraethylenepentamine

TEPA

pentaethylenehexamine

PEHA

tris (2-aminoethyl) amine

TREN

P (GMA-oligoamine)


Input: The effect of P (GMA) backbone length and structure of oligoamine on gene transfer efficiency was then determined.

P (GMA)

oligoamine


Input: The optimal polymer, P (GMA-TEPA) (50), provided comparable transfection efficiency but lower cytotoxicity than PEI.

P (GMA-TEPA) (50)

PEI


Input: P (GMA-TEPA) (50) was then used as the cationic block in diblock copolymers containing hydrophilic N-(2-hydroxypropyl) methacrylamide (HPMA) and oligo (ethylene glycol) monomethyl ether methacrylate (OEGMA).

P (GMA-TEPA) (50)

N-(2-hydroxypropyl) methacrylamide

HPMA

oligo (ethylene glycol) monomethyl ether methacrylate

OEGMA


Input: Polyplexes of block copolymers were stable against aggregation in physiological salt condition and in Opti-MEM due to the shielding effect of P (HPMA) and P (OEGMA).

P (HPMA)

P (OEGMA)


Input: However, the presence of the HPMA/OEGMA block significantly decreased the transfection efficacy of P (GMA-TEPA) (50) homopolycation.

HPMA

OEGMA

P (GMA-TEPA) (50)


Input: To compensate for reduced cell uptake caused by the hydrophilic shell of polyplex, the integrin-binding peptide, RGD, was conjugated to the hydrophilic chain end of P (OEGMA) (15)-b-P (GMA-TEPA) (50) copolymer by Michael-type addition reaction.

P (OEGMA) (15)-b-P (GMA-TEPA) (50)


Input: At low polymer to DNA ratios, the RGD-functionalized polymer showed increased gene delivery efficiency to HeLa cells compared to analogous polymers lacking RGD.


Input: Optomechanical Shutter Modulated Broad-Band Cavity-Enhanced Absorption Spectroscopy of Molecular Transients of Astrophysical Interest.


Input: We describe a sensitive spectroscopic instrument capable of measuring broad-band absorption spectra through supersonically expanding planar plasma pulses.


Input: The instrument utilizes incoherent broad-band cavity-enhanced absorption spectroscopy (IBBCEAS) and incorporates an optomechanical shutter to modulate light from a continuous incoherent light source, enabling measurements of durations as low as ~ 400 mu s.


Input: The plasma expansion is used to mimic conditions in translucent interstellar clouds.


Input: The new setup is particularly applicable to test proposed carriers of the diffuse interstellar bands, as it permits swift measurements over a broad spectral range with a resolution comparable to astronomical observations.


Input: The sensitivity is estimated to be better than 10 ppm/pass, measured with an effective exposure time of only 1 s.


Input: Acid-degradable cationic poly (ketal amidoamine) for enhanced RNA interference in vitro and in vivo.

poly (ketal amidoamine)


Input: Efficient delivery of small interfering RNA (siRNA) is one of major challenges in the successful applications of siRNA in clinic.


Input: In the present study, we report a new acid-degradable poly (ketal amidoamine) (PKAA) as a siRNA carrier, which has high delivery efficiency and low cytotoxicity.

poly (ketal amidoamine)

PKAA


Input: PKAA was designed to have acid-cleavable ketal linkages in the backbone of cationic biodegradable poly (amidoamine).

PKAA

poly (amidoamine)


Input: PKAA efficiently self-assembled with siRNA to form nanocomplexes with a diameter of ~ 200 nm and slightly positive charges, which are stable under physiological conditions, but rapidly release siRNA at acidic pH.

PKAA


Input: PKAA exhibited sufficient buffering capability and endosomolytic activity due mainly to the presence of secondary amine groups in its backbone and rapid degradation in acidic endosomes, leading to the enhanced release of siRNA to cytoplasm.

PKAA

secondary amine


Input: Cell culture studies demonstrated that PKAA is capable of delivering anti-TNF (tumor necrosis factor)-alpha siRNA to lipopolysaccharide (LPS)-stimulated macrophages and significantly inhibits the expression of TNF-alpha.

PKAA


Input: A mouse model of acetaminophen (APAP)-induced acute liver failure was used to evaluate in vivo siRNA delivery efficacy of PKAA.

acetaminophen

APAP

PKAA


Input: PKAA/anti-TNF-alpha siRNA nanocomplexes significantly reduced the ALT (alanine transaminase) and the hepatic cellular damages in APAP-intoxicated mice.

PKAA

alanine

APAP


Input: We anticipate that acid-degradable PKAA has great potential as siRNA carriers based on its excellent biocompatibility, pH sensitivity, potential endosomolytic activity, and high delivery efficiency.

PKAA


Input: Lysozyme hydration in concentrated aqueous solutions.


Input: Effect of an equilibrium cluster phase.


Input: Water close to proteins plays a key role in determining their structural and functional properties.


Input: Despite being a subject of considerable interest, the characterization of hydration water, as far as its total amount is concerned, is still controversial and its influence on protein structure and folding is not yet fully understood.


Input: In this work, we have investigated the dielectric properties of lysozyme aqueous solutions over the frequency range where the orientational polarization relaxation of the aqueous phase occurs (from 500 MHz to 50 GHz).


Input: Measurements extend over a wide concentration range, up to 300 mg/mL, corresponding to a volume fraction of the order of 0. 4.


Input: The analysis of the dielectric spectra, based on the decrease of the dielectric increment of the gamma-dispersion as a function of protein concentration, allows us to estimate the total amount of hydration water (both bound water and loosely bound water) present in the system investigated.


Input: We observe a decrease of the hydration number as a function of the protein concentration.


Input: This behavior is well accounted for by considering the formation of small equilibrium clusters with aggregation number of some units, as recently reported by Stradner et al.


Input: (1) on the basis of small-angle X-ray and neutron scattering measurements.


Input: 5-Benzylglycinyl-amiloride kills proliferating and nonproliferating malignant glioma cells through caspase-independent necroptosis mediated by apoptosis-inducing factor.


Input: 5'-Beta enzylglycinyl-amiloride (UCD38B) and glycinyl-amiloride (UCD74A) are cell-permeant and cell-impermeant derivatives of amiloride, respectively, and used here to identify the cellular mechanisms of action underlying their antiglioma effects.

5'-Beta enzylglycinyl-amiloride

glycinyl-amiloride

amiloride


Input: UCD38B comparably kills proliferating and nonproliferating gliomas cells when cell cycle progression is arrested either by cyclin D1 siRNA or by acidification.


Input: Cell impermeant UCD74A inhibits plasmalemmal urokinase plasminogen activator (uPA) and the type 1 sodium-proton exchanger with potencies analogous to UCD38B, but is cytostatic.

sodium


Input: In contrast, UCD38B targets intracellular uPA causing mistrafficking of uPA into perinuclear mitochondria, reducing the mitochondrial membrane potential, and followed by the release of apoptotic inducible factor (AIF).


Input: AIF nuclear translocation is followed by a caspase-independent necroptotic cell death.


Input: Reduction in AIF expression by siRNA reduces the antiglioma cytotoxic effects of UCD38B, while not activating the caspase pathway.


Input: Ultrastructural changes shortly following treatment with UCD38B demonstrate dilation of endoplasmic reticulum (ER) and mitochondrial swelling followed by nuclear condensation within hours consistent with a necroptotic cell death differing from apoptosis and from autophagy.


Input: These drug mechanism of action studies demonstrate that UCD38B induces a cell cycle-independent, caspase-independent necroptotic glioma cell death that is mediated by AIF and independent of poly (ADP-ribose) polymerase and H2AX activation.

poly (ADP-ribose)


Input: Polyazamacrocycles as potential antitumor agents for human prostate cancer cells.

Polyazamacrocycles


Input: Polyazamacrocycles are currently being studied and used in a variety of applications beyond their traditional place in supramolecular and co-ordination chemistry.

Polyazamacrocycles


Input: This study suggests additional applications of these compounds with particular emphasis on their use as antiproliferative agents that could be potentially used to treat cancer.


Input: Four polyazamacrocycles were tested in human prostate cancer LNCaP and prostate epithelial PNTA1 cells to analyze changes in cell proliferation and cell death capabilities.

polyazamacrocycles


Input: Their intracellular localization was also evaluated by confocal microscopy.


Input: The results show a decrease in proliferation rate and cell viability of LNCaP and PNTA1, after treatment with these compounds.


Input: The decrease in the number of viable cells is similar for the majority of the compounds studied, and at higher concentration, the proliferation efficiency decreased significantly in the cell lines studied.


Input: Also, our results suggest that L and L2 induce early apoptosis in PNTA1 cells and late apoptosis/necrosis in LNCaP cells.


Input: The compounds did not induce a significant increase in necrosis of both cell types.


Input: Although the compounds did not localize in a unique organelle, all of them have as main target the Golgi apparatus and other localization profiles differed depending on the cell line.


Input: PreCisIon: PREdiction of CIS-regulatory elements improved by gene' s positION.


Input: Conventional approaches to predict transcriptional regulatory interactions usually rely on the definition of a shared motif sequence on the target genes of a transcription factor (TF).


Input: These efforts have been frustrated by the limited availability and accuracy of TF binding site motifs, usually represented as position-specific scoring matrices, which may match large numbers of sites and produce an unreliable list of target genes.


Input: To improve the prediction of binding sites, we propose to additionally use the unrelated knowledge of the genome layout.


Input: Indeed, it has been shown that co-regulated genes tend to be either neighbors or periodically spaced along the whole chromosome.


Input: This study demonstrates that respective gene positioning carries significant information.


Input: This novel type of information is combined with traditional sequence information by a machine learning algorithm called PreCisIon.


Input: To optimize this combination, PreCisIon builds a strong gene target classifier by adaptively combining weak classifiers based on either local binding sequence or global gene position.


Input: This strategy generically paves the way to the optimized incorporation of any future advances in gene target prediction based on local sequence, genome layout or on novel criteria.


Input: With the current state of the art, PreCisIon consistently improves methods based on sequence information only.


Input: This is shown by implementing a cross-validation analysis of the 20 major TFs from two phylogenetically remote model organisms.


Input: For Bacillus subtilis and Escherichia coli, respectively, PreCisIon achieves on average an area under the receiver operating characteristic curve of 70 and 60%, a sensitivity of 80 and 70% and a specificity of 60 and 56%.


Input: The newly predicted gene targets are demonstrated to be functionally consistent with previously known targets, as assessed by analysis of Gene Ontology enrichment or of the relevant literature and databases.


Input: Primary hepatocyte cultures for pharmaco-toxicological studies: at the busy crossroad of various anti-dedifferentiation strategies.


Input: Continuously increasing understanding of the molecular triggers responsible for the onset of diseases, paralleled by an equally dynamic evolution of chemical synthesis and screening methods, offers an abundance of pharmacological agents with a potential to become new successful drugs.


Input: However, before patients can benefit of newly developed pharmaceuticals, stringent safety filters need to be applied to weed out unfavourable drug candidates.


Input: Cost effectiveness and the need to identify compound liabilities, without exposing humans to unnecessary risks, has stimulated the shift of the safety studies to the earliest stages of drug discovery and development.


Input: In this regard, in vivo relevant organotypic in vitro models have high potential to revolutionize the preclinical safety testing.


Input: They can enable automation of the process, to match the requirements of high-throughput screening approaches, while satisfying ethical considerations.


Input: Cultures of primary hepatocytes became already an inherent part of the preclinical pharmaco-toxicological testing battery, yet their routine use, particularly for long-term assays, is limited by the progressive deterioration of liver-specific features.


Input: The availability of suitable hepatic and other organ-specific in vitro models is, however, of paramount importance in the light of changing European legal regulations in the field of chemical compounds of different origin, which gradually restrict the use of animal studies for safety assessment, as currently witnessed in cosmetic industry.


Input: Fortunately, research groups worldwide spare no effort to establish hepatic in vitro systems.


Input: In the present review, both classical and innovative methodologies to stabilize the in vivo-like hepatocyte phenotype in culture of primary hepatocytes are presented and discussed.


Input: Profiling genome-wide chromatin methylation with engineered posttranslation apparatus within living cells.


Input: Protein methyltransferases (PMTs) have emerged as important epigenetic regulators in myriad biological processes in both normal physiology and disease conditions.


Input: However, elucidating PMT-regulated epigenetic processes has been hampered by ambiguous knowledge about in vivo activities of individual PMTs particularly because of their overlapping but nonredundant functions.


Input: To address limitations of conventional approaches in mapping chromatin modification of specific PMTs, we have engineered the chromatin-modifying apparatus and formulated a novel technology, termed clickable chromatin enrichment with parallel DNA sequencing (CliEn-seq), to probe genome-wide chromatin modification within living cells.


Input: The three-step approach of CliEn-seq involves in vivo synthesis of S-adenosyl-L-methionine (SAM) analogues from cell-permeable methionine analogues by engineered SAM synthetase (methionine adenosyltransferase or MAT), in situ chromatin modification by engineered PMTs, subsequent enrichment and sequencing of the uniquely modified chromatins.

S-adenosyl-L-methionine

SAM

methionine

SAM

methionine


Input: Given critical roles of the chromatin-modifying enzymes in epigenetics and structural similarity among many PMTs, we envision that the CliEn-seq technology is generally applicable in deciphering chromatin methylation events of individual PMTs in diverse biological settings.


Input: Self-assembly of segmented anisotropic particles: tuning compositional anisotropy to form vertical or horizontal arrays.


Input: Columnar arrays of anisotropic nano-and microparticles, in which the long axes of the particles are oriented perpendicular to the substrate, are of interest for photovoltaics and other applications.


Input: Array assembly typically requires applied electric or magnetic fields and/or controlled drying, which are challenging over large areas.


Input: Here, we describe a scalable approach to self-assemble multicomponent nanowires into columnar arrays.


Input: Self-assembly of partially etched nanowires (PENs) occurred spontaneously during sedimentation from suspension, without drying or applied fields.


Input: PENs, which have segments that are either gold or " empty " (solvent-filled) surrounded by a silica shell, were produced from striped metal nanowires by first coating with silica and then removing sacrificial segments by acid etching.

silica

silica


Input: Electrostatic repulsion between the particles was necessary for array assembly; however, details of PEN surface chemistry were relatively unimportant.


Input: The aspect ratio and relative center of mass (COM) of the PENs were important for determining whether the PEN long axes were vertically or horizontally aligned with respect to the underlying substrate.


Input: Arrays with predominantly vertically aligned particles were achieved for PENs with a large offset in COM relative to the geometric center, while other types of PENs formed horizontal arrays.


Input: Assemblies were formed over > 10 cm (2) areas, with over 60% of particles standing.


Input: We assessed array uniformity and reproducibility by imaging many positions within each sample and performing multiple assemblies of differently segmented PENs.


Input: This work demonstrates the versatility of gravity-driven PEN array assembly and provides a framework for designing other anisotropic particle systems that self-assemble into columnar arrays.


Input: Xyloglucan-derivatized films for the culture of adherent cells and their thermocontrolled detachment: a promising alternative to cells sensitive to protease treatment.


Input: By taking advantage of a natural and abundant polymer as well as a straightforward film formation technique, this paper focuses on the conception and use of a new alternative tool for thermo-controlled cell detachment.


Input: Thermoresponsive xyloglucan was produced after partial galactose removal by a 24 h reaction with beta-galactosidase.

galactose


Input: The obtained polymer (T24) was then activated by reaction with 4-nitrophenyl chloroformate (NPC) in order to graft a cyclic peptide presenting an arginine-glycine-aspartic acid (RGD) motif.

4-nitrophenyl chloroformate

NPC

arginine

glycine

aspartic acid


Input: The effect of RGD grafting on the sol-gel transition temperature of T24 is evaluated by rheological measurements.


Input: Solvent-casted films of T24-RGD successfully promoted cell adhesion, proliferation, and thermo-controlled detachment.


Input: The presented approach is a new alternative for cells sensitive to the proteolytic treatment routinely used for cell detachment.


Input: Because the RGD sequence used herein is widely recognized by different cell types, this protocol may be extended to other cells.


Input: Besides, the presented chemical route can be applied to different peptide sequences.


Input: Anion-pi interactions: generality, binding strength, and structure.


Input: Anion-pi interactions have been systematically studied using tetraoxacalix [2] arene [2] triazine 1, an electron-deficient and cavity self-tunable macrocyclic host, as an electron-neutral molecular probe.

tetraoxacalix [2] arene [2] triazine


Input: As revealed by electrospray ionization mass spectrometry (ESI-MS), fluorescence titration and X-ray crystallography, tetraoxacalix [2] arene [2] triazine has been found to form 1: 1 complexes with four typical polyatomic anions of different geometries and shapes in the gaseous phase, in solution, and in the solid state.

tetraoxacalix [2] arene [2] triazine


Input: The association constants for the formation of anion-pi complexes in acetonitrile are in the range of 239 to 16950 M (-1), following the order of 1. NO (3) (-) > 1. BF (4) (-) > 1. PF (6) (-) > 1. SCN (-).

acetonitrile

NO (3) (-)

BF (4) (-)

PF (6) (-)

SCN (-)


Input: X-ray molecular structures of the complexes showed that two opposing triazine rings of tetraoxacalix [2] arene [2] triazine act as a pair of tweezers to interact with the included anions through cooperative anion-pi and lone-pair electron-pi interactions.

triazine

tetraoxacalix [2] arene [2] triazine


Input: The generality of anion-pi interactions and diverse anion-pi interaction motifs can provide a new dimension in the study of molecular recognition and self-assembly.


Input: Moreover, this study potentiates the effect of anion-pi interactions in chemical and biological systems, especially those involving anion and electron-deficient aromatic species.


Input: Effects and mechanism of organ protection by cardiotrophin-1.


Input: Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 family, is reported to exhibit a plethora of pleiotropic effects in the heart such as cytoprotective, pro-proliferative and pro-fibrotic ones.


Input: An extensive research has been devoted on proliferative and profibrotic effects of CT-1 on the heart.


Input: Thus the present review has been aimed to critically define the cytoprotective effects of CT-1 and the cellular and molecular mechanisms involved in them.


Input: Although many effects of CT-1 have been described on the heart, CT-1 has now also been reported to exhibit important protective effects in other organs such as liver, kidney or nervous system.


Input: CT-1 produces its effects through a unique receptor system comprising LIF receptor (LIFR beta) and a common signal transducer, the glycoprotein 130 (gp130).


Input: The signaling pathway downstream from gp130 is based on at least, three distinct pathways: 1) the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, 2) the p42/44 mitogen-activated protein kinase (p42/44 MAPK) pathway, also known as the extracellular receptor kinase-1/2 (ERK1/2) pathway, and 3) the phosphatidylinositol 3-OH kinase (PI3K)/Akt pathway.

phosphatidylinositol 3-OH


Input: Since CT-1 easily achieves its cytoprotective effects via a combination of the above three signaling pathways, it becomes quite necessary to determine which pathway (s) is involved in each particular effect of CT-1.


Input: In each of its target organs, CT-1 may also display differential mechanisms of cytoprotection, and thus it is relevant to understand how these mechanisms are locally regulated.


Input: Assessment of the antineoplastic potential of chalcones in animal models.

chalcones


Input: One part of chemical space that is endowed with interesting biological properties is the area of the chalcones.

chalcones


Input: With this review, we provide a comprehensive overview of the numerous in vivo animal studies on the antineoplastic potential of both natural and synthetic members of this flavonoid subclass (covering: up to mid-2011).

flavonoid


Input: The thus far identified modes of action of these compounds are also discussed.


Input: We hope that this overview may stimulate deeper investigations into the biochemical mechanisms by which chalcones exert their antineoplastic action.

chalcones


Input: As a result, in the foreseeable future, chalcones may prove suitable lead molecules or early drug candidates for the prevention or treatment of various neoplastic diseases.

chalcones


Input: Band gap engineering via controlling donor-acceptor compositions in conjugated copolymers.


Input: Varying composition of pi-donor/acceptor moieties has been considered as an effective strategy for fine-tuning of the electronic properties of D-A conjugated copolymers.


Input: In this study, the change of optoelectronic properties with the change of donor/acceptor ratios is investigated on the basis of first-principles density functional calculations.


Input: Copolymers containing moieties of similar pi-electron donating and/or accepting capabilities, e. g., thiophene (T)-methoxythiophene (OT), exhibit a linear dependence of electronic properties (especially, HOMO/LUMO, band gap, and bandwidth) on the D/A content.

thiophene

methoxythiophene


Input: In contrast, for strong D/A contrast systems, e. g., thiophene (T)-thienopyrazine (TP), the electronic properties vary nonlinearly with D/A compositions.

thiophene

thienopyrazine


Input: However, when the block size of one parent monomer in a strong D/A contrast system is fixed, the variation of electronic properties shows a remarkable linear correlation against D/A compositions.


Input: We found that the deviation of electronic properties from a linear composition dependence is dominated by the strength of orbital interactions between D and A.


Input: Weak orbital interactions between D and A moieties tend to lead to a nonlinear composition dependence.


Input: Our results provide useful insights for band gap tuning through the adjustment of D/A compositions in D-A conjugated copolymers.


Input: Microarray analysis of isolated human islet transcriptome in type 2 diabetes and the role of the ubiquitin-proteasome system in pancreatic beta cell dysfunction.


Input: To shed light on islet cell molecular phenotype in human type 2 diabetes (T2D), we studied the transcriptome of non-diabetic (ND) and T2D islets to then focus on the ubiquitin-proteasome system (UPS), the major protein degradation pathway.


Input: We assessed gene expression, amount of ubiquitinated proteins, proteasome activity, and the effects of proteasome inhibition and prolonged exposure to palmitate.

palmitate


Input: Microarray analysis identified more than one thousand genes differently expressed in T2D islets, involved in many structures and functions, with consistent alterations of the UPS.


Input: Quantitative RT-PCR demonstrated downregulation of selected UPS genes in T2D islets and beta cell fractions, with greater ubiquitin accumulation and reduced proteasome activity.


Input: Chemically induced reduction of proteasome activity was associated with lower glucose-stimulated insulin secretion, which was partly reproduced by palmitate exposure.

glucose

palmitate


Input: These results show the presence of many changes in islet transcriptome in T2D islets and underline the importance of the association between UPS alterations and beta cell dysfunction in human T2D.


Input: Dual action spirobicycloimidazolidine-2, 4-diones: antidiabetic agents and inhibitors of aldose reductase-an enzyme involved in diabetic complications.

spirobicycloimidazolidine-2, 4-diones

aldose


Input: The desired 3-(arylsulfonyl) spiroimidazolidine-2, 4-diones were synthesized by reacting spiroiminoimidazolidine-2, 4-dione with arylsulfonyl chlorides.

3-(arylsulfonyl) spiroimidazolidine-2, 4-diones

spiroiminoimidazolidine-2, 4-dione

arylsulfonyl chlorides


Input: Spiroimidazolidine-2, 4-dione was in turn synthesized from norcamphor.

Spiroimidazolidine-2, 4-dione

norcamphor


Input: Structures of the synthesized molecules were established by modern spectroscopic techniques.


Input: The synthesized compounds were screened for in vivo antidiabetic activity and aldose reductase inhibition.

aldose


Input: Compounds 2a, 2b and 2g exhibited excellent dual activity, compound 2a being most prominent.


Input: These results reveal that the synthesized compounds may serve as the molecule of choice to treat diabetes and diabetic complications using a single medication.


Input: A SWI/SNF chromatin-remodeling complex acts in noncoding RNA-mediated transcriptional silencing.


Input: RNA-mediated transcriptional silencing prevents deleterious effects of transposon activity and controls the expression of protein-coding genes.


Input: It involves long noncoding RNAs (lncRNAs).


Input: In Arabidopsis thaliana, some of those lncRNAs are produced by a specialized RNA Polymerase V (Pol V).


Input: The mechanism by which lncRNAs affect chromatin structure and mRNA production remains mostly unknown.


Input: Here we identify the SWI/SNF ATP-dependent nucleosome-remodeling complex as a component of the RNA-mediated transcriptional silencing pathway.

ATP


Input: We found that SWI3B, an essential subunit of the SWI/SNF complex, physically interacts with a lncRNA-binding protein, IDN2.


Input: SWI/SNF subunits contribute to lncRNA-mediated transcriptional silencing.


Input: Moreover, Pol V mediates stabilization of nucleosomes on silenced regions.


Input: We propose that Pol V-produced lncRNAs mediate transcriptional silencing by guiding the SWI/SNF complex and establishing positioned nucleosomes on specific genomic loci.


Input: We further propose that guiding ATP-dependent chromatin-remodeling complexes may be a more general function of lncRNAs.

ATP


Input: Dendritic cell activation by polysaccharide isolated from Angelica dahurica.


Input: Angelica dahurica is used in functional foods for the prevention and treatment of various diseases, such as inflammation and cancer.


Input: In the present study, we examined the effect of A. dahurica polysaccharide (ADP) on dendritic cell (DC) maturation.


Input: ADP increased the expressions of CD86 and MHC-II molecules, the production of IL-12, IL-1 beta, and TNF-alpha, and allogeneic T cell activation ability of DCs, and reduced DC endocytosis.


Input: As a mechanism of action, the knockdown of TLR4 with small interfering RNA decreased the ADP-induced production of nitric oxide and IL-12 by DCs, suggesting the membrane receptor candidate of ADP.

nitric oxide


Input: After binding to TLR4, ADP increased the phosphorylation of ERK, JNK, and p38 MAPKs, and the nuclear translocation of NF-kappa B p50/p65.


Input: These results indicate that ADP activates DCs through TLR4 and downstream signalings.


Input: Poly (ethylene glycol)-block-poly (epsilon-caprolactone) micelles for combination drug delivery: evaluation of paclitaxel, cyclopamine and gossypol in intraperitoneal xenograft models of ovarian cancer.

Poly (ethylene glycol)-block-poly (epsilon-caprolactone)

paclitaxel

cyclopamine

gossypol


Input: Ovarian cancer is the most lethal gynecological malignancy, characterized by a high rate of chemoresistance.


Input: Current treatment strategies for ovarian cancer focus on novel drug combinations of cytotoxic agents and molecular targeted agents or novel drug delivery strategies that often involve intraperitoneal (IP) injection.


Input: Poly (ethylene glycol)-block-poly (epsilon-caprolactone) (PEG-b-PCL) micelles were loaded with paclitaxel (cytotoxic agent), cyclopamine (hedgehog inhibitor), and gossypol (Bcl-2 inhibitor).

Poly (ethylene glycol)-block-poly (epsilon-caprolactone)

PEG-b-PCL

paclitaxel

cyclopamine

gossypol


Input: After physicochemical studies focusing on combination drug solubilization, 3-drug PEG-b-PCL micelles were evaluated in vitro in 2-D and 3-D cell culture and in vivo in xenograft models of ovarian cancer, tracking bioluminescence signals from ES-2 and SKOV3 human ovarian cancer cell lines after IP injection.

PEG-b-PCL


Input: 3-Drug PEG-b-PCL micelles were not significantly more potent in 2-D cell culture in comparison to paclitaxel; however, they disaggregated ES-2 tumor spheroids, whereas single drugs or 2-drug combinations only slowed growth of ES-2 tumor spheroids or had no noticeable effects.

PEG-b-PCL

paclitaxel


Input: In ES-2 and SKOV3 xenograft models, 3-drug PEG-b-PCL micelles had significantly less tumor burden than paclitaxel based on bioluminescence imaging, 3'-deoxy-3'-(18) F-fluorothymidine ((18) F-FLT) PET imaging, and overall survival.

PEG-b-PCL

paclitaxel

3'-deoxy-3'-(18) F-fluorothymidine

(18) F-FLT


Input: (18) F-FLT-PET images clearly showed that 3-drug PEG-b-PCL micelles dramatically reduce tumor volumes over paclitaxel and vehicle controls.

(18) F-FLT

PEG-b-PCL

paclitaxel


Input: In summary, PEG-b-PCL micelles enable the IP combination drug delivery of paclitaxel, cyclopamine and gossypol, resulting in tumor growth inhibition and prolonged survival over paclitaxel alone.

PEG-b-PCL

paclitaxel

cyclopamine

gossypol

paclitaxel


Input: These results validate a novel treatment strategy for ovarian cancer based on drug combinations of cytotoxic agents and molecular targeted agents, delivered concurrently by a nanoscale drug delivery system, e. g. PEG-b-PCL micelles.

PEG-b-PCL


Input: Torching the Haystack: modelling fast-fail strategies in drug development.


Input: By quickly clearing the development pipeline of failing or marginal products, fast-fail strategies release resources to focus on more promising molecules.


Input: The Quick-Kill model of drug development demonstrates that fast-fail strategies will: (1) reduce the expected time to market; (2) reduce expected R & D costs; and (3) increase R & D productivity.


Input: This paper outlines the model and demonstrates the impact of fast-fail strategies.


Input: The model is illustrated with costs and risks data from pharmaceutical and biopharmaceutical companies.


Input: Mechanisms underlying induction of LTP-associated changes in short-term dynamics of transmission at immature synapses.


Input: While the activity-dependent mechanisms guiding functional maturation of synaptic transmission postsynaptically are well characterized, less is known about the corresponding presynaptic mechanisms.


Input: Here we show that during the first postnatal week, a subset of CA3-CA1 synapses express postsynaptically induced LTP that is tightly associated with a robust decrease in synaptic facilitation, consistent with an increase in release probability (P (r)).


Input: The loss of facilitation is readily induced by physiologically relevant pairing protocols at immature synapses and is dependent on activation of NMDA-receptors but not L-type calcium channels.

NMDA

calcium


Input: The putative pre-and postsynaptic components of neonatal LTP were distinguished in their downstream signaling requirements, PKC activity being selectively needed for the decrease in facilitation but not for synaptic potentiation per se.


Input: These data suggest that maturation of glutamatergic synapses involves a critical period during which presynaptic function is highly susceptible to activity-dependent regulation via a PKC-dependent mechanism.


Input: In vitro neurotoxic effects of Pseudechis spp. venoms: A comparison of avian and murine skeletal muscle preparations.


Input: Two common in vitro skeletal muscle preparations used for the study of venom neurotoxicity are the indirectly stimulated chick isolated biventer cervicis nerve-muscle preparation and the rat isolated phrenic nerve-diaphragm preparation.


Input: The aim of the current study was to compare the in vitro neurotoxicity of six Pseudechis spp.


Input: (Black snakes) venoms in both avian (chicken) and mammalian (rat) skeletal muscle preparations to determine differences in sensitivity.


Input: All Pseudechis spp. venoms significantly inhibited indirect twitches, in both preparations, indicating the presence of post synaptic neurotoxins.


Input: The inhibitory effects of all venoms were more rapid in the avian preparation, except for Pseudechis colletti venom where no significant difference was seen between the murine and avian muscles.


Input: Time taken to produce 50% reduction in stimulated twitches (i. e. t (50)) was markedly shorter in the avian preparation.


Input: We have shown that the avian in vitro preparation is more sensitive to the neurotoxic activity of Pseudechis spp. than the murine preparation.


Input: This difference is likely to be due to species differences in the interaction between the neurotoxins and the nicotinic receptor binding sites as well as differences in the' safety factor' between the preparations.


Input: Development and evaluation of colloidal modified nanolipid carrier: Application to topical delivery of tacrolimus, Part II-In vivo assessment, drug targeting, efficacy, and safety in treatment for atopic dermatitis.

tacrolimus


Input: In atopic dermatitis (AD), topical anti-inflammatory therapy with skin barrier restoration to prevent repeated inflammatory episodes leads to long-term therapeutic success.


Input: Tacrolimus, although effective against AD, is a challenging molecule due to low solubility, low-penetration, poor-bioavailability, and toxicity.

Tacrolimus


Input: Part I of this paper, reported novel modified nanolipid carrier system for topical delivery of tacrolimus (T-MNLC), offering great opportunity to load low-solubility drug with improved entrapment efficiency, enhanced stability and improved skin deposition.

tacrolimus


Input: Present investigation focused on restoration of skin barrier, site-specific delivery, therapeutic effectiveness, and safety of novel T-MNLC.


Input: T-MNLC greatly enhanced occlusive properties, skin hydration potential and reduced transepidermal water loss.


Input: This might help to reduce the number of flares and better control the disease.


Input: Cutaneous uptake and drug deposition in albino rats by HPLC and confocal laser scanning microscopy revealed prominently elevated drug levels in all skin strata with T-MNLC as compared to reference.


Input: T-MNLC demonstrated efficient suppression of inflammatory responses in BALB/c mice model of AD.


Input: Safety assessment by acute and repeated-dose dermal toxicity demonstrated mild keratosis and collagenous mass infiltration at the treatment area with repeated application of reference.


Input: Interestingly, T-MNLC showed no evident toxicity exhibiting safe drug delivery.


Input: Thus, novel T-MNLC would be a safe, effective, and esthetically appealing alternative to conventional vehicles for treatment for AD.


Input: Size-dependent toxicity and cell interaction mechanisms of gold nanoparticles on mouse fibroblasts.


Input: Gold nanoparticles (AuNPs) are currently used in several fields including biomedical applications, although no conclusive information on their cytotoxicity is available.


Input: For this reason this work has investigated the effects of AuNPs in vitro on Balb/3T3 mouse fibroblasts.


Input: Results obtained exposing cells for 72 h to AuNPs 5 and 15 nm citrate stabilized, revealed cytotoxic effects only for AuNPs 5 nm at concentration >= 50 mu M if measured by colony forming efficiency (CFE).

citrate


Input: To understand the differences in cytotoxicity observed for the two AuNPs sizes, we investigated the uptake and the intracellular distribution of the nanoparticles.


Input: By TEM it was observed that 5 and 15 nm AuNPs are internalized by Balb/3T3 cells and located within intracellular endosomal compartments.


Input: Quantification of the uptake by ICP-MS showed that AuNPs internalization enhanced even up to 72 h.


Input: Disruption of the actin cytoskeleton was evident, with cell footprints narrow and contracted; effects more remarkable in cells exposed to 5 nm AuNP.


Input: The mechanism of NPs cell internalization was investigated using immunocytochemistry and western blot.


Input: No significant effect was observed in the expression level of caveolin, while reduction of the expression and degradation of the clathrin heavy chain was observed in cells exposed for 72 h to AuNPs.


Input: Failure to generate bone marrow adipocytes does not protect mice from ovariectomy-induced osteopenia.


Input: A reciprocal association between bone marrow fat and bone mass has been reported in ovariectomized rodents, suggesting that bone marrow adipogenesis has a negative effect on bone growth and turnover balance.


Input: Mice with loss of function mutations in kit receptor (kit (W/W-v)) have no bone marrow adipocytes in tibia or lumbar vertebra.


Input: We therefore tested the hypothesis that marrow fat contributes to the development of osteopenia by comparing the skeletal response to ovariectomy (ovx) in growing wild type (WT) and bone marrow adipocyte-deficient kit (W/W-v) mice.


Input: Mice were ovx at 4 weeks of age and sacrificed 4 or 10 weeks post-surgery.


Input: Body composition was measured at necropsy by dual-energy X-ray absorptiometry.


Input: Cortical (tibia) and cancellous (tibia and lumbar vertebra) bone architecture were evaluated by microcomputed tomography.


Input: Bone marrow adipocyte size and density, osteoblast-and osteoclast-lined bone perimeters, and bone formation were determined by histomorphometry.


Input: Ovx resulted in an increase in total body fat mass at 10 weeks post-ovx in both genotypes, but the response was attenuated in the in kit (W/W-v) mice.


Input: Adipocytes were present in bone marrow of tibia and lumbar vertebra in WT mice and bone marrow adiposity increased following ovx.


Input: In contrast, marrow adipocytes were not detected in either intact or ovx kit (W/W-v) mice.


Input: However, ovx in WT and kit (W/W-v) mice resulted in statistically indistinguishable changes in cortical and cancellous bone mass, cortical and cancellous bone formation rate, and cancellous osteoblast and osteoclast-lined bone perimeters.


Input: In conclusion, our findings do not support a causal role for increased bone marrow fat as a mediator of ovx-induced osteopenia in mice.


Input: Ameliorating effects of extracellular polymeric substances excreted by Thalassiosira pseudonana on algal toxicity of CdSe quantum dots.

CdSe


Input: Quantum dots (QDs) are engineered nanoparticles (ENs) that have found increasing applications and shown great potential in drug delivery, biological imaging and industrial products.


Input: Knowledge of their stability, fate and transport in the aquatic environment is still lacking, including details of how these nanomaterials interact with marine phytoplankton.


Input: Here, we examined the toxicity of functionalized CdSe/ZnS QDs (amine-and carboxyl-) by exposing them for five days to Thalassiosira pseudonana (marine diatom) grown under different nutrient-conditions (enriched versus nitrogen-limited media).

CdSe

ZnS

amine

carboxyl

nitrogen


Input: The released polysaccharides and proteins, the major components of extracellular polymeric substances (EPS), were measured to assess their potential effects on the interactions between QDs and T. pseudonana.


Input: The partitioning of QDs was analyzed by monitoring the concentration of Cd in different size fractions of the cultures (i. e., filtrate, < 0. 22 mu m and permeate, < 3 kDa).

Cd


Input: We found that the Cd release of QDs in the T. pseudonana culture was dependent on the nutrient conditions and nature of QDs' surface coating.

Cd


Input: Both amine-and carboxyl-functionalized QDs exhibited higher rates of Cd release in N-limited cultures than in nutrient enriched cultures.

amine

carboxyl

Cd


Input: The results also showed that amine-functionalized QDs aggregate with minimal Cd release, independent of nutrient conditions.

amine

Cd


Input: Laser scanning confocal microscopy images confirmed that aggregates are composed of QDs and the culture matrix (EPS).


Input: In addition, both types of QDs showed limited toxicity to T. pseudonana.


Input: The increasing production of proteins induced by QDs suggests that extracellular proteins might be involved in the detoxification of QDs to T. pseudonana via the Cd release of QDs.

Cd


Input: Our results here demonstrated that EPS can play an ameliorating role in QD toxicity, fate and transport in the aquatic environment.


Input: 17 beta estradiol regulation of connexin 43-based gap junction and mechanosensitivity through classical estrogen receptor pathway in osteocyte-like MLO-Y4 cells.

17 beta estradiol

estrogen


Input: Connexin 43 (Cx43) plays an essential role in osteocyte mechanotransduction.


Input: Although estrogen involves in the adaptive responses of bone cells to mechanical loadings, its effects on osteocytic Cx43-based gap junction intercellular communication (GJIC) remain obscure.

estrogen


Input: We found that 17 beta estradiol (E2) up-regulated Cx43, and enhanced GJIC in osteocyte-like MLO-Y4 cells in fluorescence recovery after photobleaching (FRAP) assay.

17 beta estradiol


Input: Combination of E2 pre-treatment and oscillating fluid flow (OFF) further enhanced Cx43 expression and mitogen-activated protein kinase (MAPK) phosphorylation, comparing to E2 or OFF treatment alone.


Input: Both blocking of classical estrogen receptors (ER alpha/beta) by fulvestrant and ER alpha knockdown by small interfering RNA inhibited E2-mediated Cx43 increase, while a GPR30-specific agonist G-1 failed to promote Cx43 expression.

estrogen


Input: Our results suggest that the presence of E2 enhanced Cx43-based GJIC mainly via ER alpha/beta pathway, and sensitized osteocytes to mechanical loading.


Input: Phase separation as a key to a thermoelectric high efficiency.


Input: This work elucidates the possible reasons for the outstanding, but never reproduced thermoelectric properties of the doped Ti (0. 5) Zr (0. 25) Hf (0. 25) NiSn Heusler compounds.

Ti (0. 5) Zr (0. 25) Hf (0. 25) NiSn


Input: The structural investigations done via synchrotron X-ray diffraction measurements and scanning electron microscope measurements, which clearly show that the microstructure consists of three temperature stable C1 (b) phases with possible semi-coherent interfaces, are presented.


Input: The exceptional thermoelectric properties are due to this intrinsic phase separation.


Input: It is possible to reproduce the high Figure of Merit values with ZT = 1. 2 at 830 K.


Input: Furthermore, the influence of doping different elements on the Sn position in this Heusler material system is investigated.

Sn


Input: Halogen-bonding-triggered supramolecular gel formation.

Halogen


Input: Supramolecular gels are topical soft materials involving the reversible formation of fibrous aggregates using non-covalent interactions.


Input: There is significant interest in controlling the properties of such materials by the formation of multicomponent systems, which exhibit non-additive properties emerging from interaction of the components.


Input: The use of hydrogen bonding to assemble supramolecular gels in organic solvents is well established.

hydrogen


Input: In contrast, the use of halogen bonding to trigger supramolecular gel formation in a two-component gel (' co-gel') is essentially unexplored, and forms the basis for this study.

halogen


Input: Here, we show that halogen bonding between a pyridyl substituent in a bis (pyridyl urea) and 1, 4-diiodotetrafluorobenzene brings about gelation, even in polar media such as aqueous methanol and aqueous dimethylsulfoxide.

halogen

pyridyl

bis (pyridyl urea)

1, 4-diiodotetrafluorobenzene

methanol

dimethylsulfoxide


Input: This demonstrates that halogen bonding is sufficiently strong to interfere with competing gel-inhibitory interactions and create a' tipping point' in gel assembly.

halogen


Input: Using this concept, we have prepared a halogen bond donor bis (urea) gelator that forms co-gels with halogen bond acceptors.

halogen

bis (urea)

halogen


Input: Translational research: the changing landscape of drug discovery.


Input: Drug discovery represents the first step in the creation of new drugs, and takes place in academic institutions, biotech companies, and large pharmaceutical corporations.


Input: Until recently, these sectors have each operated independently with little collaboration between those at the forefront of discovery research and those with experience in developing drugs.


Input: With the rise of translational research these relationships are shifting and new hubs are emerging, as key players seek to pool the expertise necessary to generate new therapies by linking laboratory discoveries directly to unmet clinical needs.


Input: In this article I discuss how the increasing adoption of translational research is leading to novel integrated discovery nexuses that may change the landscape of drug discovery.


Input: Drug-drug interactions between rosuvastatin and oral antidiabetic drugs occurring at the level of OATP1B1.

rosuvastatin


Input: Organic anion-transporting polypeptide 1B1 (OATP1B1) is an important hepatic uptake transporter, of which the polymorphic variant OATP1B1 * 15 (Asn130Asp and Val174Ala) has been associated with decreased transport activity.


Input: Rosuvastatin is an OATP1B1 substrate and often concomitantly prescribed with oral antidiabetics in the clinic.

Rosuvastatin


Input: The aim of this study was to investigate possible drug-drug interactions between these drugs at the level of OATP1B1 and OATP1B1 * 15.


Input: We generated human embryonic kidney (HEK) 293 cells stably overexpressing OATP1B1 or OATP1B1 * 15 that showed similar protein expression levels of OATP1B1 and OATP1B1 * 15 at the cell membrane as measured by liquid chromatography-tandem mass spectrometry.


Input: In HEK-OATP1B1 * 15 cells, the V (max) for OATP1B1-mediated transport of E (2) 17 beta-G (estradiol 17 beta-d-glucuronide) was decreased > 60%, whereas K (m) values (Michaelis constant) were comparable.

estradiol 17 beta-d-glucuronide


Input: Uptake of rosuvastatin in HEK-OATP1B1 cells (K (m) 13. 1 +/- 0. 43 mu M) was nearly absent in HEK-OATP1B1 * 15 cells.

rosuvastatin


Input: Interestingly, several oral antidiabetics (glyburide, glimepiride, troglitazone, pioglitazone, glipizide, gliclazide, and tolbutamide), but not metformin, were identified as significant inhibitors of the OATP1B1-mediated transport of rosuvastatin.

glyburide

glimepiride

troglitazone

pioglitazone

glipizide

gliclazide

tolbutamide

metformin

rosuvastatin


Input: The IC (50) values for inhibition of E (2) 17 beta-G uptake were similar between OATP1B1 and OATP1B1 * 15.

E (2) 17 beta-G


Input: In conclusion, these studies indicate that several oral antidiabetic drugs affect the OATP1B1-mediated uptake of rosuvastatin in vitro.

rosuvastatin


Input: The next step will be to translate these data to the clinical situation, as it remains to be established whether the studied oral antidiabetics indeed affect the clinical pharmacokinetic profile of rosuvastatin in patients.

rosuvastatin


Input: Optical and electrical detection of single-molecule translocation through carbon nanotubes.

carbon


Input: Ion current through a single-walled carbon nanotube (SWCNT) was monitored at the same time as fluorescence was recorded from charged dye molecules translocating through the SWCNT.

carbon


Input: Fluorescence bursts generally follow ion current peaks with a delay time consistent with diffusion from the end of the SWCNT to the fluorescence collection point.


Input: The fluorescence amplitude distribution of the bursts is consistent with single-molecule signals.


Input: Thus each peak in the ion current flowing through the SWCNT is associated with the translocation of a single molecule.


Input: Ion current peaks (as opposed to blockades) were produced by both positively (Rhodamine 6G) and negatively (Alexa 546) charged molecules, showing that the charge filtering responsible for the current bursts is caused by the molecules themselves.

Rhodamine 6G

Alexa 546


Input: Reduced antinociception of opioids in rats and mice by vaccination with immunogens containing oxycodone and hydrocodone haptens.

oxycodone

hydrocodone


Input: Prescription opioids abuse and associated deaths are an emerging concern in the USA.


Input: Vaccination against prescription opioids may provide an alternative to pharmacotherapy.


Input: An oxycodone hapten containing a tetraglycine linker at the C6 position (6OXY (Gly) (4) OH) conjugated to keyhole limpet hemocyanin (KLH) has shown early proof-of-efficacy in rodents as a candidate immunogen (6OXY (Gly) (4)-KLH) for the treatment of oxycodone abuse.

oxycodone

tetraglycine

6OXY (Gly) (4) OH

6OXY (Gly) (4)

oxycodone


Input: In this study, oxycodone-based and hydrocodone-based haptens were conjugated to KLH to generate immunogens that would recognize both oxycodone and hydrocodone.

oxycodone

hydrocodone

oxycodone

hydrocodone


Input: Vaccination with 6OXY (Gly) (4)-KLH increased drug binding in serum, reduced drug distribution to brain, and blunted analgesia for both oxycodone and hydrocodone.

6OXY (Gly) (4)

oxycodone

hydrocodone


Input: An analogous C6-linked hydrocodone vaccine blocked hydrocodone effects but less so than 6OXY (Gly) (4)-KLH.

hydrocodone

hydrocodone

6OXY (Gly) (4)


Input: C8-Linked hydrocodone immunogens had only limited efficacy.

hydrocodone


Input: Amide conjugation showed higher haptenation ratios and greater efficacy than thioether conjugation to maleimide activated KLH (mKLH).

Amide

thioether

maleimide


Input: The 6OXY (Gly) (4)-KLH vaccine may be used for treatment of prescription opioid abuse.

6OXY (Gly) (4)


Input: Interactions of NO2 with Zr-based MOF: effects of the size of organic linkers on NO2 adsorption at ambient conditions.

Zr


Input: Zirconium-based metal organic framework (Zr-MOF), UiO-66 and UiO-67, were synthesized and used as adsorbents of NO (2) at ambient temperatures in either dry or moist conditions.

Zirconium

Zr

NO (2)


Input: The samples were characterized before and after exposure to NO (2) by X-ray diffraction, scanning electron microscopy, N (2)-adsorption at 77 K, thermal analysis, and infrared spectroscopy.

NO (2)

N (2)


Input: The results indicate the important effect of a ligand size on the adsorption of NO (2) on Zr-MOF materials.

NO (2)

Zr


Input: While the large size of the 4, 4-benzenebiphenyldicarboxylic acid (BDPC) ligand has a positive impact on the adsorption of NO (2) on UiO-67 in moist conditions, the opposite effect is found in dry conditions.

4, 4-benzenebiphenyldicarboxylic acid

BDPC

NO (2)


Input: The large pore volume of UiO-67 enhances the adsorption of moisture and formation of nitric and nitrous acids.

nitric and nitrous acids


Input: The small pore sizes of UiO-66 favor the NO (2) removal in dry conditions via dispersive forces.

NO (2)


Input: Upon interaction of NO (2) molecules with the Zr-MOF in dry conditions, the bond between the organic linker and metallic oxide center is broken, leading to the formation of nitrate and nitrite species.

NO (2)

Zr

oxide

nitrate

nitrite


Input: Moreover, organic ligands also contribute to the NO (2) reactive adsorption via nitration reaction.

NO (2)


Input: Potent microRNA suppression by RNA Pol II-transcribed' Tough Decoy' inhibitors.


Input: MicroRNAs (miRNAs) are key regulators of gene expression and modulators of diverse biological pathways.


Input: Analyses of miRNA function as well as therapeutic managing of miRNAs rely on cellular administration of miRNA inhibitors which may be achieved by the use of viral vehicles.


Input: This study explores the miRNA-suppressive capacity of inhibitors expressed intracellularly from lentivirus-derived gene vectors.


Input: Superior activity of two decoy-type inhibitors, a " Bulged Sponge " with eight miRNA recognition sites and a hairpin-shaped " Tough Decoy " containing two miRNA recognition sites, is demonstrated in a side-by-side comparison of seven types of miRNA inhibitors transcribed as short RNAs from an RNA Pol III promoter.


Input: We find that lentiviral vectors expressing Tough Decoy inhibitors are less vulnerable than Bulged Sponge-encoding vectors to targeting by the cognate miRNA and less prone, therefore, to reductions in transfer efficiency.


Input: Importantly, it is demonstrated that Tough Decoy inhibitors retain their miRNA suppression capacity in the context of longer RNA transcripts expressed from an RNA Pol II promoter.


Input: Such RNA Pol II-transcribed Tough Decoy inhibitors are new tools in managing of miRNAs and may have potential for temporal and spatial regulation of miRNA activity as well as for therapeutic targeting of miRNAs that are aberrantly expressed in human disease.


Input: Androgens promote prostate cancer cell growth through induction of autophagy.

Androgens


Input: Androgens regulate both the physiological development of the prostate and the pathology of prostatic diseases.

Androgens


Input: However, the mechanisms by which androgens exert their regulatory activities on these processes are poorly understood.

androgens


Input: In this study, we have determined that androgens regulate overall cell metabolism and cell growth, in part, by increasing autophagy in prostate cancer cells.

androgens


Input: Importantly, inhibition of autophagy using either pharmacological or molecular inhibitors significantly abrogated androgen-induced prostate cancer cell growth.

androgen


Input: Mechanistically, androgen-mediated autophagy appears to promote cell growth by augmenting intracellular lipid accumulation, an effect previously demonstrated to be necessary for prostate cancer cell growth.

androgen


Input: Further, autophagy and subsequent cell growth is potentiated, in part, by androgen-mediated increases in reactive oxygen species.

androgen

oxygen


Input: These findings demonstrate a role for increased fat metabolism and autophagy in prostatic neoplasias and highlight the potential of targeting underexplored metabolic pathways for the development of novel therapeutics.


Input: Regulation of H2O2 stress-responsive genes through a novel transcription factor in the protozoan pathogen Entamoeba histolytica.


Input: Outcome of infection depends upon complex interactions between the invading pathogen and the host.


Input: As part of the host' s innate immune response, the release of reactive oxygen and nitrogen species by phagocytes represents a major obstacle to the establishment of infection.

oxygen

nitrogen


Input: The ability of the human parasite Entamoeba histolytica to survive reactive oxygen and nitrogen species is central to its pathogenic potential and contributes to disease outcome.

oxygen

nitrogen


Input: In order to define the transcriptional network associated with oxidative stress, we utilized the MEME and MAST programs to analyze the promoter regions of 57 amoebic genes that had increased expression specifically in response to H (2) O (2) exposure.

H (2) O (2)


Input: We functionally characterized an H (2) O (2)-regulatory motif (HRM) ((1) AAACCTCAATGAAGA (15)), which was enriched in these promoters and specifically bound amoebic nuclear protein (s).

H (2) O (2)


Input: Assays with promoter-luciferase fusions established the importance of key residues and that the HRM motif directly impacted the ability of H (2) O (2)-responsive promoters to drive gene expression.

H (2) O (2)


Input: DNA affinity chromatography and mass spectrometry identified EHI _ 108720 as an HRM DNA-binding protein.


Input: Overexpression and down-regulation of EHI _ 108720 demonstrated the specificity of EHI _ 108720 protein binding to the HRM, and overexpression increased basal expression from an H (2) O (2)-responsive wild-type promoter but not from its mutant counterpart.

H (2) O (2)


Input: Thus, EHI _ 108720, or HRM-binding protein, represents a new stress-responsive transcription factor in E. histolytica that controls a transcriptional regulatory network associated with oxidative stress.


Input: Overexpression of EHI _ 108720 increased parasite virulence.


Input: Insight into how E. histolytica responds to oxidative stress increases our understanding of how this important human pathogen establishes invasive disease.


Input: Palmitate and lipopolysaccharide trigger synergistic ceramide production in primary macrophages.

Palmitate

ceramide


Input: Macrophages play a key role in host defense and in tissue repair after injury.


Input: Emerging evidence suggests that macrophage dysfunction in states of lipid excess can contribute to the development of insulin resistance and may underlie inflammatory complications of diabetes.


Input: Ceramides are sphingolipids that modulate a variety of cellular responses including cell death, autophagy, insulin signaling, and inflammation.

Ceramides

sphingolipids


Input: In this study we investigated the intersection between TLR4-mediated inflammatory signaling and saturated fatty acids with regard to ceramide generation.

saturated fatty acids

ceramide


Input: Primary macrophages treated with lipopolysaccharide (LPS) did not produce C16 ceramide, whereas palmitate exposure led to a modest increase in this sphingolipid.

C16 ceramide

palmitate

sphingolipid


Input: Strikingly, the combination of LPS and palmitate led to a synergistic increase in C16 ceramide.

palmitate

C16 ceramide


Input: This response occurred via cross-talk at the level of de novo ceramide synthesis in the ER.

ceramide


Input: The synergistic response required TLR4 signaling via MyD88 and TIR-domain-containing adaptor-inducing interferon beta (TRIF), whereas palmitate-induced ceramide production occurred independent of these inflammatory molecules.

palmitate

ceramide


Input: This ceramide response augmented IL-1 beta and TNF alpha release, a process that may contribute to the enhanced inflammatory response in metabolic diseases characterized by dyslipidemia.

ceramide


Input: Substituent effect in 2-benzoylmethylenequinoline difluoroborates exhibiting through-space couplings.

2-benzoylmethylenequinoline difluoroborates


Input: Multinuclear magnetic resonance, X-ray diffraction, and computational study.


Input: The series of nine 2-benzoylmethylenequinoline difluoroborates have been synthesized and characterized by multinuclear magnetic resonance, X-ray diffraction (XRD), and computational methods.

2-benzoylmethylenequinoline difluoroborates


Input: The through-space spin-spin couplings between (19) F and (1) H/(13) C nuclei have been observed in solution.

(19) F

(1) H

(13) C


Input: The NMR chemical shifts have been correlated to the Hammett substituent constants.


Input: The crystal structures of six compounds have been solved by XRD.


Input: For two derivatives the X-ray wave function refinement was performed to evaluate the character of bonds in the NBF (2) O moiety by topological and integrated bond descriptors.

NBF (2) O


Input: Dynamic or nondynamic?


Input: Helical trajectory in hexabenzocoronene nanotubes biased by a detachable chiral auxiliary.

hexabenzocoronene


Input: When ether vapor was allowed to diffuse into a CH (2) Cl (2) solution of an enantiomer of a hexa-peri-hexabenzocoronene (HBC) derivative carrying a chiral (BINAP) Pt (II)-appended coordination metallacycle (HBC (Py) ([(R)-Pt]) or HBC (Py) ([(S)-Pt])), screw-sense-selective assembly took place to give optically active nanotubes (NT (Py) ([(R)-Pt]) or NT (Py) ([(S)-Pt])) with helical chirality, which were enriched in either left-handed (M)-NT (Py) ([(R)-Pt]) or right-handed (P)-NT (Py) ([(S)-Pt]), depending on the absolute configuration of the (BINAP) Pt (II) pendant.

ether

CH (2) Cl (2)

hexa-peri-hexabenzocoronene

HBC

(BINAP) Pt (II)

HBC (Py) ([(R)-Pt]

HBC (Py) ([(S)-Pt])

Py

[(R)-Pt]

Py

[(S)-Pt]

Py

[(R)-Pt]

Py

[(S)-Pt]

(BINAP) Pt (II)


Input: When MeOH was used instead of ether for the vapor-diffusion-induced assembly, nanocoils formed along with the nanotubes.

MeOH


Input: As determined by scanning electron microscopy, the diastereomeric excess of the nanocoils was 60% (80: 20 diastereomeric ratio).


Input: Removal of the (BINAP) Pt (II) pendants from NT (Py) ([(R)-Pt]) or NT (Py) ([(S)-Pt]) with ethylenediamine yielded metal-free nanotubes (NT (Py)) that remained optically active even upon heating without any change in the circular dichroism spectral profile.

(BINAP) Pt (II)

Py

[(R)-Pt]

Py

[(S)-Pt]

ethylenediamine

Py


Input: No helical inversion took place when NT (Py) derived from HBC (Py) ([(R)-Pt]) or HBC (Py) ([(S)-Pt]) was allowed to complex with (BINAP) Pt (II) with an absolute configuration opposite to the original one.

Py

HBC (Py) ([(R)-Pt])

HBC (Py) ([(S)-Pt])

(BINAP) Pt (II)


Input: Cooperative effects of drug-resistance mutations in the flap region of HIV-1 protease.


Input: Understanding the interdependence of multiple mutations in conferring drug resistance is crucial to the development of novel and robust inhibitors.


Input: As HIV-1 protease continues to adapt and evade inhibitors while still maintaining the ability to specifically recognize and efficiently cleave its substrates, the problem of drug resistance has become more complicated.


Input: Under the selective pressure of therapy, correlated mutations accumulate throughout the enzyme to compromise inhibitor binding, but characterizing their energetic interdependency is not straightforward.


Input: A particular drug resistant variant (L10I/G48V/I54V/V82A) displays extreme entropy-enthalpy compensation relative to wild-type enzyme but a similar variant (L10I/G48V/I54A/V82A) does not.


Input: Individual mutations of sites in the flaps (residues 48 and 54) of the enzyme reveal that the thermodynamic effects are not additive.


Input: Rather, the thermodynamic profile of the variants is interdependent on the cooperative effects exerted by a particular combination of mutations simultaneously present.


Input: Exploring the sequence-structure relationship for amyloid peptides.


Input: Amyloid fibril formation is associated with misfolding diseases, as well as fulfilling a functional role.


Input: The cross-beta molecular architecture has been reported in increasing numbers of amyloid-like fibrillar systems.


Input: The Waltz algorithm is able to predict ordered self-assembly of amyloidogenic peptides by taking into account the residue type and position.


Input: This algorithm has expanded the amyloid sequence space, and in the present study we characterize the structures of amyloid-like fibrils formed by three peptides identified by Waltz that form fibrils but not crystals.


Input: The structural challenge is met by combining electron microscopy, linear dichroism, CD and X-ray fibre diffraction.


Input: We propose structures that reveal a cross-beta conformation with' steric-zipper' features, giving insights into the role for side chains in peptide packing and stability within fibrils.


Input: The amenity of these peptides to structural characterization makes them compelling model systems to use for understanding the relationship between sequence, self-assembly, stability and structure of amyloid fibrils.


Input: Chemical Modification of Lysozyme, Glucose 6-Phosphate Dehydrogenase, and Bovine Eye Lens Proteins Induced by Peroxyl Radicals: Role of Oxidizable Amino Acid Residues.

Glucose 6-Phosphate

Peroxyl

Amino Acid


Input: Chemical and structural alterations to lysozyme (LYSO), glucose 6-phosphate dehydrogenase (G6PD), and bovine eye lens proteins (BLP) promoted by peroxyl radicals generated by the thermal decomposition of 2, 2'-azobis (2-amidinopropane) hydrochloride (AAPH) under aerobic conditions were investigated.

glucose 6-phosphate

peroxyl

2, 2'-azobis (2-amidinopropane) hydrochloride

AAPH


Input: SDS-PAGE analysis of the AAPH-treated proteins revealed the occurrence of protein aggregation, cross-linking, and fragmentation; BLP, which are naturally organized in globular assemblies, were the most affected proteins.

SDS

AAPH


Input: Transmission electron microscopy (TEM) analysis of BLP shows the formation of complex protein aggregates after treatment with AAPH.

AAPH


Input: These structural modifications were accompanied by the formation of protein carbonyl groups and protein hydroperoxides.

carbonyl

hydroperoxides


Input: The yield of carbonyls was lower than that for protein hydroperoxide generation and was unrelated to protein fragmentation.

carbonyls

hydroperoxide


Input: The oxidized proteins were also characterized by significant oxidation of Met, Trp, and Tyr (but not other) residues, and low levels of dityrosine.

Met

Trp

Tyr

dityrosine


Input: As the dityrosine yield is too low to account for the observed cross-linking, we propose that aggregation is associated with tryptophan oxidation and Trp-derived cross-links.

dityrosine

tryptophan

Trp


Input: It is also proposed that Trp oxidation products play a fundamental role in nonrandom fragmentation and carbonyl group formation particularly for LYSO and G6PD.

Trp

carbonyl


Input: These data point to a complex mechanism of peroxyl-radical mediated modification of proteins with monomeric (LYSO), dimeric (G6PD), and multimeric (BLP) structural organization, which not only results in oxidation of protein side chains but also gives rise to radical-mediated protein cross-links and fragmentation, with Trp species being critical intermediates.

peroxyl

Trp


Input: Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino) pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity.

4-(thiazol-5-yl)-2-(phenylamino) pyrimidine-5-carbonitrile