Input: As they became available, the bioanalytical scientist has observed that implementing these technologies in the regulated environment has become increasingly challenging.


Input: For one, scientific developments and regulatory expectations may not go hand in hand.


Input: At the same time, the pharmaceutical industry has become increasingly risk averse in their response to these real or perceived higher expectations in regulated bioanalysis.


Input: As a downstream consequence, the potential result of overinterpretation of guidance or occasional widespread and premature implementation of responses to health authority inspections, industry may be contributing significantly to raising the bar on some processes related to day-to-day practices in the bioanalytical laboratory.


Input: Last but not least, with the community being satisfied with the performance of the current tools, potential complacency can be observed in the regulated bioanalytical community because existing technologies, such as LC-MS/MS and ligand-binding assays, have served and still are serving them extremely well.


Input: Hence, the question' what' s next after LC-MS/MS or ELISA?' is not resonating with many scientists as pertinently compared with' What' s next after RIA, GC or LC-UV?', which was the key question in the 1990s, certainly in the context of an increasing effort needed to validate these new tools.


Input: With this article, the European Bioanalysis Forum aims to stimulate an open dialogue between all stakeholders in regulated bioanalysis to positively influence how we balance science, process and regulations in day-to-day work.


Input: This discussion should facilitate the evaluation and the subsequent implementation of innovative techniques for the benefit of the patient, while stimulating our community to raise the bar on added-value science, but at the same time removing the bar on processes with limited or no added value.


Input: Semi-Synthetic Mithramycin SA Derivatives with Improved AntiCancer Activity.

Mithramycin SA


Input: Mithramycin (MTM) is a potent anti-cancer agent that has recently garnered renewed attention.

Mithramycin

MTM


Input: This manuscript describes the design and development of mithramycin derivatives through a combinational approach of biosynthetic analogue generation followed by synthetic manipulation for further derivatization.

mithramycin


Input: Mithramycin SA is a previously discovered analogue produced by the M7W1 mutant strain alongside the improved mithramycin analogues mithramycin SK and mithramycin SDK.

Mithramycin SA

mithramycin

mithramycin SK

mithramycin SDK


Input: Mithramycin SA shows decreased anti-cancer activity compared to mithramycin and has a shorter, two carbon aglycon side chain that is terminated in a carboxylic acid.

Mithramycin SA

mithramycin

carbon

carboxylic acid


Input: The aglycon side chain is responsible for an interaction with the DNA-phosphate backbone as mithramycin interacts with its target DNA.

phosphate

mithramycin


Input: It was therefore decided to further functionalize this side chain through reactions with the terminal carboxylic acid in an effort to enhance the interaction with the DNA phosphate backbone and improve the anti-cancer activity.

carboxylic acid

phosphate


Input: This side chain was modified with a variety of molecules increasing the anti-cancer activity to a comparable level to mithramycin SK.

mithramycin SK


Input: This work shows the ability to transform the previously useless mithramycin SA into a valuable molecule and opens the door to further functionalization and semi-synthetic modification for the development of molecules with increased specificity and/or drug formulation.

mithramycin SA


Input: Oxytocin in the central amygdaloid nucleus modulates the neuroendocrine responses induced by hypertonic volume expansion in the rat.

Oxytocin


Input: The present study investigated the involvement of the oxytocinergic neurones that project into the central amygdala (CeA) in the control of electrolyte excretion and hormone secretion in unanaesthetised rats subjected to acute hypertonic blood volume expansion (BVE; 0. 3 M NaCl, 2 ml/100 g of body weight over 1 min).

NaCl


Input: Oxytocin and vasopressin mRNA expression in the paraventricular (Pa) and supraoptic nucleus (SON) of the hypothalamus were also determined using the real time-polymerase chain reaction and in situ hybridisation.

Oxytocin


Input: Male Wistar rats with unilaterally implanted stainless steel cannulas in the CeA were used.


Input: Oxytocin (1 mu g/0. 2 mu l), vasotocin, an oxytocin antagonist (1 mu g/0. 2 mu l) or vehicle was injected into the CeA 20 min before the BVE.

Oxytocin

vasotocin

oxytocin


Input: In rats treated with vehicle in the CeA, hypertonic BVE increased urinary volume, sodium excretion, plasma oxytocin (OT), vasopressin (AVP) and atrial natriuretic peptide (ANP) levels and also increased the expression of OT and AVP mRNA in the Pa and SON.

oxytocin


Input: In rats pre-treated with OT in the CeA, previously to the hypertonic BVE, there were further significant increases in plasma AVP, OT and ANP levels, urinary sodium and urine output, as well as in gene expression (AVP and OT mRNA) in the Pa and SON compared to BVE alone.

sodium


Input: Vasotocin reduced sodium, urine output and ANP levels, although no changes were observed in plasma AVP and OT levels or in the expression of the AVP and OT genes in both hypothalamic nuclei.

Vasotocin

sodium


Input: The results of the present study suggest that oxytocin in the CeA exerts a facilitatory role in the maintenance of hydroelectrolyte balance in response to changes in extracellular volume and osmolality.


Input: Testosterone deficiency induces markedly decreased serum triglycerides, increased small dense LDL, and hepatic steatosis mediated by dysregulation of lipid assembly and secretion in mice fed a high-fat diet.

Testosterone

triglycerides


Input: OBJECTIVE: Although low serum testosterone (T) is associated with metabolic disorders, the mechanism of this association is unclear.

testosterone


Input: The objective of the present study was to investigate the combined effects of T deficiency and a high-fat diet (HFD) on hepatic lipid homeostasis in mice.


Input: MATERIALS/METHODS: Orchiectomized (ORX) mice and sham-operated (SHAM) mice were randomly divided into five groups: SHAM mice fed a standard diet (SD), SHAM mice fed HFD, ORX mice fed SD, ORX mice fed HFD, and ORX mice fed HFD with T supplementation.


Input: After 4weeks of treatment, we investigated the synthesis and secretion of lipids in the liver and detailed serum lipoprotein profiles in each group.


Input: RESULTS: ORX mice fed HFD showed increased hepatic steatosis, markedly decreased serum triglyceride (TG) and TG-VLDL content, and increased serum very small-LDL content.

triglyceride


Input: Gene expression analysis revealed that ORX mice fed HFD showed significantly decreased expression of microsomal triglyceride transfer protein, lipin-1, peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma coactivator 1-alpha, and significantly increased sterol regulatory element-binding protein-1, diacylglycerol acyltransferase-2 and fatty acid synthase.

triglyceride

sterol

diacylglycerol

fatty acid


Input: Reduction of hepatic AMPK phosphorylation was observed in ORX mice fed HFD.


Input: These perturbations in ORX mice fed HFD were normalized to the levels of SHAM mice fed HFD by T supplementation.


Input: CONCLUSION: T deficiency is associated with failure of lipid homeostasis mediated by altered expression of genes involved in hepatic assembly and secretion of lipids.


Input: Novel anticoagulants in the therapy of peripheral arterial and coronary artery disease.


Input: Anticoagulant and antiplatelet drugs are used and studied in numerous trials for primary and secondary prevention of atherothrombosis since decades.


Input: The annual rate for cardiovascular morbidity and mortality is high in patients following an acute coronary syndrome and in patients with peripheral arterial disease (PAD) due to concomitant cardiac and cerebrovascular diseases.


Input: Plaque rupture and subsequent thrombosis involves activation of both platelets and coagulation factors.


Input: Therefore the combination of aspirin and warfarin to improve prevention of atherothrombosis compared to antiplatelet therapy alone was studied but could not be established due to significantly increased risk of major bleeding compared to a nonsignificant reduction in ischemic events.

aspirin

warfarin


Input: During the past two decades, clinical trials focused on combined antiplatelet therapies for the prevention of secondary events following acute coronary syndromes and very recently on the new oral anticoagulants in combination with antiplatelet therapy.


Input: This review discusses the role of the new oral anticoagulants such as Factor IIa (thrombin) and Factor Xa inhibitors in atherothrombosis, their pharmacological properties and recently published clinical data in secondary prevention of atherothrombotic events and potential implications for patients with PAD.


Input: Mineralocorticoid receptor antagonists for therapy of coronary artery disease and related complications.


Input: The perception of aldosterone action to be restricted to regulation of fluid balance via sodium reabsorption and potassium excretion is incomplete; plenty of experimental and clinical studies have shown that aldosterone plays a pivotal role in a variety of (patho-) physiologic conditions within the cardiovascular continuum.

aldosterone

sodium

potassium

aldosterone


Input: Deleterious effects include cardiovascular inflammation, endothelial dysfunction, structural and electrical remodelling.


Input: Mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone, prevent some of these maladaptive effects on the cardiovascular system and have proven to be a highly efficacious pharmacological therapy.

spironolactone

eplerenone


Input: In this article we review the current clinical impact of MRAs in the treatment of coronary artery disease (CAD) and its related complications, for example, acute myocardial infarction (MI) and chronic heart failure.


Input: Design and synthesis of D 1 agonist/D 2 antagonist for treatment of schizophrenia.


Input: A series of tetrahydroisoquinolines were designed, synthesized and evaluated as the first non-natural product type of compounds with dual D (1) receptor (D (1) R) agonism and D (2) receptor (D (2) R) antagonism properties for treatment of schizophrenia.

tetrahydroisoquinolines


Input: The initial SAR of the series was explored.


Input: The lead in the series, 3g, exhibited high affinity and good potency.


Input: Compound 3g displayed 95% of D (1) R occupancy (10 mg/kg, sc) and 75% of D (2) R occupancy (10 mg/kg, sc) in the striatum of male CD-1 mice.


Input: The series exhibited unique pharmacology and merit as tool compounds for target validation and future optimizations.


Input: RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection.


Input: The appropriate execution of DNA double-strand break (DSB) repair is critical for genome stability and tumor avoidance.


Input: 53BP1 and BRCA1 directly influence DSB repair pathway choice by regulating 5' end resection, but how this is achieved remains uncertain.


Input: Here we report that Rif1 (-/-) mice are severely compromised for 53BP1-dependent class switch recombination (CSR) and fusion of dysfunctional telomeres.


Input: The inappropriate accumulation of RIF1 at DSBs in S phase is antagonized by BRCA1, and deletion of Rif1 suppresses toxic nonhomologous end joining (NHEJ) induced by PARP inhibition in Brca1-deficient cells.


Input: Mechanistically, RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1.

N

phospho


Input: Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination.


Input: Mitochondrial electron transport is inhibited by disappearance of metallothionein in human bronchial epithelial cells following exposure to silver nitrate.

silver nitrate


Input: Silver (Ag) possesses antibacterial activity and has been used in wound dressings and deodorant powders worldwide.

Silver

Ag


Input: However, the metabolic behavior and biological roles of Ag in mammals have not been well characterized.

Ag


Input: In the present study, we exposed human bronchial epithelial cells (BEAS-2B) to AgNO3 and investigated uptake and intracellular distribution of Ag, expression of metallothionein (MT), generation of reactive oxygen species (ROS), and changes in mitochondrial respiration.

Ag

oxygen


Input: The culture medium concentration of Ag decreased with time and stabilized at 12h.

Ag


Input: The concentration of both Ag and MT in the soluble cellular fraction increased up to 3h and then decreased, indicating that cytosolic Ag relocated to the insoluble fraction of the cells.

Ag

Ag


Input: The levels of mRNAs for the major human MT isoforms MT-I and MT-II paralleled with the protein levels of Ag-MT.

Ag


Input: The intensity of fluorescence derived from ROS was elevated in the mitochondrial region at 24h.


Input: Ag decreased mitochondrial oxygen consumption in a dose-dependent manner and the activity of mitochondrial complex I-IV enzymes was significantly inhibited following exposure to Ag.

Ag

oxygen

Ag


Input: In a separate experiment, we found that hydrogen peroxide (H2O2) at concentrations as low as 0. 001% (equivalent to the concentration of H2O2 in Ag-exposed cells) removed Ag from MT.

hydrogen peroxide

Ag

Ag


Input: These results suggest MT was decomposed by cytosolic H2O2, and then Ag released from MT relocated to insoluble cellular fractions and inhibited electron chain transfer of mitochondrial complexes, which eventually led to cell damage.

Ag


Input: Nitric oxide generated by the compound RuBPY promotes the vascular smooth cell membrane hyperpolarization.

Nitric oxide

RuBPY


Input: The cis-[Ru (bpy) (2) (py) NO (2)] (PF (6)) specie (RuBPY) has been used as nitric oxide (NO) delivery agent.

cis-[Ru (bpy) (2) (py) NO (2)] (PF (6))

RuBPY

nitric oxide

NO


Input: It is an NO reservoir and it is thermodynamically stable in aqueous solution.

NO


Input: This study aimed to evaluate the NO specie generated by RuBPY as compared to NO released from sodium nitroprusside (SNP) and to study the cellular mechanisms specially focusing the activation of soluble guanylyl-cyclase (sGC), K (+) channels and the cell membrane hyperpolarization, which are the main targets for NO-inducing vascular relaxation.

NO

RuBPY

NO

sodium nitroprusside

SNP

guanylyl

K (+)

NO


Input: NO generated by RuBPY and the vascular smooth muscle cell (VSMC) membrane potential were measured by confocal microscopy.

NO

RuBPY


Input: The cellular mechanisms of aorta relaxation were investigated using K (+) channel blockers and sGC inhibitor.

K (+)


Input: NO released from RuBPY was higher than NO released from SNP.

NO

RuBPY

NO

SNP


Input: RuBPY released only radicalar NO (0) and SNP released both NO (-) and NO (0).

RuBPY

radicalar NO

SNP

NO (-)

NO


Input: The concentration-effect curves for RuBPY-induced relaxation was shifted to the right by inhibition of sGC with ODQ and by the non-selective blockade of K (+) channels with TEA.

RuBPY

ODQ

K (+)

TEA


Input: The simultaneous combination of ODQ and TEA abolished the vasorelaxation induced by RuBPY.

ODQ

TEA

RuBPY


Input: The membrane potential measured by the sensitive dye 4-Di-ANNEPS demonstrated that RuBPY induces cell membrane hyperpolarization.

RuBPY


Input: Taken together, our results indicate that the large amount of NO (0) specie generated by RuBPY induces vasorelaxation due to activation of sGC, K (+) channels sensitive to TEA, and cell membrane hyperpolarization.

NO

RuBPY

K (+)

TEA


Input: These results indicate that NO (0) generated from RuBPY can also directly activate the K (+) channels in an independent way of sGC.

NO

RuBPY

K (+)


Input: The inhibition of HIF-2 alpha on the ATM/Chk-2 pathway is involved in the promotion effect of arsenite on benzo (a) pyrene-induced cell transformation.

arsenite

benzo (a) pyrene


Input: Both arsenite and benzo (a) pyrene (BaP) are known human carcinogens.

arsenite

benzo (a) pyrene

BaP


Input: Studies on the mode-of-action of arsenite indicate that it can also act as co-carcinogen or as a cancer promoter, and that it can facilitate progression of cancers.

arsenite


Input: Some studies on development of lung cancers have suggested a synergism between arsenite exposure and cigarette smoking.

arsenite


Input: The mechanism of action for such an effect, however, remains obscure.


Input: In the present study, we investigated the effects of HIF-2 alpha on arsenite-and BaP-induced cell malignant transformation as well as on signal transduction pathways in human bronchial epithelial (HBE) cells.

arsenite

BaP


Input: The results show that arsenite accelerates the neoplastic transformation and migration of cells and enhances chromosomal aberrations induced by BaP.

arsenite

BaP


Input: HIF-2 alpha is involved in blocking the effects of arsenite in activating the ATM/Chk-2 pathway and in repair of DNA damage induced by BaP.

arsenite

BaP


Input: Moreover, blocking of HIF-2 alpha prevents the effects of arsenite on the neoplastic transformation, cell migration, and chromosomal aberrations caused by BaP.

arsenite

BaP


Input: These results indicate that the repressive effect of HIF-2 alpha on the ATM/Chk-2 pathway leads to genomic instability, which is involved in arsenite-accelerated, BaP-induced malignant transformation of HBE cells.

arsenite

BaP


Input: Cryptotanshinone and dihydrotanshinone I exhibit strong inhibition towards human liver microsome (HLM)-catalyzed propofol glucuronidation.

Cryptotanshinone

dihydrotanshinone I

propofol


Input: Danshen is one of the most famous herbs in the world, and more and more danshen-prescribed drugs interactions have been reported in recent years.


Input: Evaluation of inhibition potential of danshen' s major ingredients towards UDP-glucuronosyltransferases (UGTs) will be helpful for understanding detailed mechanisms for danshen-drugs interaction.

UDP


Input: Therefore, the aim of the present study is to investigate the inhibitory situation of cryptotanshinone and dihydrotanshinone I towards UGT enzyme-catalyzed propofol glucuronidation.

cryptotanshinone

dihydrotanshinone I

propofol


Input: In vitro the human liver microsome (HLM) incubation system was used, and the results showed that cryptotanshinone and dihydrotanshinone I exhibited dose-dependent inhibition towards HLM-catalyzed propofol glucuronidation.

cryptotanshinone

dihydrotanshinone I

propofol


Input: Dixon plot and Lineweaver-Burk plot showed that the inhibition type was best fit to competitive inhibition type for both cryptotanshinone and dihydrotanshinone I.

cryptotanshinone

dihydrotanshinone I


Input: The second plot using the slopes from the Lineweaver-Burk plot versus the concentrations of cryptotanshinone or dihydrotanshinone I was employed to calculate the inhibition parameters (Ki) to be 0. 4 and 1. 7 mu M, respectively.

cryptotanshinone

dihydrotanshinone I


Input: Using the reported maximum plasma concentration (Cmax), the altered in vivo exposure of propofol increased by 10% and 8. 2% for the co-administration of dihydrotanshinone I and cryptotanshinone, respectively.

propofol

dihydrotanshinone I

cryptotanshinone


Input: All these results indicated the possible danshen-propofol interaction due to the inhibition of dihydrotanshinone I and cryptotanshinone towards the glucuronidation reaction of propofol.

propofol

dihydrotanshinone I

cryptotanshinone

propofol


Input: A new method of segmentation of compact-appearing, transitional and trabecular compartments and quantification of cortical porosity from high resolution peripheral quantitative computed tomographic images.


Input: A transitional or cortico-trabecular junctional zone exists at any location composed of both cortical and trabecular bones such as the metaphyses of tubular bones and short bones like the femoral neck.


Input: The transitional zone comprises the inner cortex adjacent to the medullary canal and trabeculae abutting against the cortex contiguous with the endocortical surface.


Input: This is a site of vigorous remodeling.


Input: Intracortical remodeling cavitates the inner cortex expanding this transitional zone at the price of compact-appearing cortex so that it contains porosity, cortical fragments that resemble trabeculae, and trabeculae abutting the eroding cortex.


Input: The porosity of the transitional zone is an important source of bone loss.


Input: It reduces bone strength exponentially and is a quantifiable `fingerprint' of structural deterioration.


Input: A new automated method of segmentation of bone from background and bone into its compact-appearing cortex, transitional zone, and trabecular compartment is described, with a new approach to quantification of cortical porosity.


Input: Segmentation is achieved by automatically selecting attenuation profile curves perpendicular to the periosteal surface.


Input: Local bone edges are identified as the beginning and the end of the rising and falling S-shaped portions of the curve enabling the delineation of the compartments.


Input: Analyzing ~ 3600 consecutive overlapping profiles around the perimeter of each cross-sectional slice segments the compartments.


Input: Porosity is quantified as the average void volume fraction of all voxels within each compartment.


Input: To assess accuracy at the distal radius and tibia, mu CT images of cadaveric specimens imaged at 19 mu m voxel size served as the gold standard.


Input: To assess accuracy at the proximal femur, scanning electron microscopy (SEM) images of specimens collected at 2. 5 mu m resolution served as the gold standard.


Input: Agreement between HRpQCT and the gold standards for segmentation and quantification of porosity at the distal radius and tibia ranged from R (2) = 0. 87 to 0. 99, and for the proximal femur ranged from 0. 93 to 0. 99.


Input: The precision error in vivo for segmentation and quantification of porosity in HRpQCT images at the distal radius, given by the root mean square error of the coefficient of variation, ranged from 0. 54% for porosity of the transitional zone to 3. 98% for area of the compact-appearing cortex.


Input: Segmentation of the transitional zone minimizes errors in apportioning cortical fragments and cortical porosity to the medullary compartment and so is likely to allow accurate assessment of fracture risk and the morphological effects of growth, aging, diseases and therapies.


Input: Investigations of dipeptide structures containing pyrrolysine as N-terminal residues: a DFT study in gas and aqueous phase.

dipeptide

pyrrolysine

N


Input: A set of six dipeptides containing pyrrolysine invariably at their N-terminal positions is studied in gas and aqueous phase using a polarizable continuum model (PCM).

dipeptides

pyrrolysine

N


Input: The molecular geometries of the dipeptides are fully optimized at B3LYP/6-31 + + G (d, p) level of theory and a second derivative (frequency) analysis confirms that all the optimized geometries are true minima.

dipeptides


Input: The effects of solvation and identity of the varying C-terminal residue on the energetics, structural features of the peptide planes, values of the psi and phi dihedrals, geometry around the alpha-carbon atoms and theoretically predicted vibrational spectra of the dipeptides are thoroughly analyzed.

C

alpha-carbon

dipeptides


Input: Solvation effects are found to modify the gas phase conformation of the dipeptides around psi dihedrals while the identity of the varying C-terminal residue affect the values of phi, planarity of the peptide planes and geometry around the alpha-carbon atoms.

dipeptides

C

alpha-carbon


Input: The presence or absence of three types of intramolecular H-bonds, namely O... H-N, N... H-N and O... H-C that leave noticeable signatures in the IR spectra, play crucial roles in influencing the geometry of the peptide planes and in determining the energetics of the dipeptides.

H

O

H-N

N

H-N

O

H-C

dipeptides


Input: NMR investigation on the DNA binding and B-Z transition pathway of the Z alpha domain of human ADAR1.


Input: Human ADAR1, which has two left-handed Z-DNA binding domains, preferentially binds Z-DNA rather than B-DNA with a high binding affinity.


Input: Z-DNA can be induced in long genomic DNA by Z-DNA binding proteins through the formation of two B-Z junctions with the extrusion of one base pair from each junction.


Input: We performed NMR experiments on complexes of Z alpha (ADAR1) with three DNA duplexes at a variety of protein-to-DNA molar ratios.


Input: This study confirmed that the Z alpha (ADAR1) first binds to an 8-bp CG-rich DNA segment via a unique conformation during B-Z transition and the neighboring AT-rich region becomes destabilized.


Input: We also found that, when DNA duplexes have only 6-bp CG-rich segment, the interaction with Z alpha (ADAR1) did not affect the thermal stabilities of the 6-bp CG-rich segment as well as the neighboring two A. T base pairs.


Input: These results indicate that four Z alpha (ADAR1) proteins interact with the 8-bp DNA sequence containing a 6-bp CG-repeat segment as well as a dinucleotide step, even though the dinucleotid step contains A. T base pairs.


Input: Thus this study suggests that the length of the CG-rich region is more important than the specific DNA sequence for determining which base-pair is extruded from the B-Z junction structure.


Input: This study also found that the Z alpha (ADAR1) in complex with a 11-bp DNA duplex exhibits a Z-DNA-bound conformation distinct from that of free Z alpha (ADAR1) and the initial contact conformations of Z alpha (ADAR1) complexed with 13-bp DNA duplexes.


Input: Electrochemical synthesis of CdTe/SWNT hybrid nanostructures and their tunable electrical and optoelectrical properties.

CdTe


Input: A facile electrodeposition technique was utilized to deposit single-walled carbon nanotubes (SWNTs) with cadmium telluride (CdTe) with well-controlled size, density, surface morphology, and composition.

carbon

cadmium telluride

CdTe


Input: By controlling the applied charge, the morphology of these hybrid nanostructures was altered from CdTe nanoparticles on SWNTs to SWNT/CdTe core/shell nanostructures and the composition of the CdTe nanoparticles was altered from Te-rich (29 at% Cd) to Cd-rich (79 at% Cd) CdTe by adjusting the deposition potential.

CdTe

CdTe

CdTe

Te

Cd

Cd

Cd

CdTe


Input: The electrical and optoelectrical properties of these hybrid nanostructures showed that photo-induced current can be tuned by tailoring the conductivity type (n-type or p-type), morphology, and size of the CdTe nanostructures, with a maximum photosensitivity (Delta I/I (0)) of about 30% for SWNT/Cd-rich CdTe (n-type) core/shell nanostructures.

CdTe

Cd

CdTe


Input: This work demonstrates a novel approach for synthesizing metal chalcogenide/SWNT hybrid nanostructures for various electrical and optoelectrical applications.


Input: Cloning and functional analysis of three genes encoding polygalacturonase-inhibiting proteins from Capsicum annuum and transgenic CaPGIP1 in tobacco in relation to increased resistance to two fungal pathogens.


Input: Polygalacturonase-inhibiting proteins (PGIPs) are plant cell wall glycoproteins that can inhibit fungal endopolygalacturonases (PGs).


Input: The PGIPs directly reduce the aggressive potential of PGs.


Input: Here, we isolated and functionally characterized three members of the pepper (Capsicum annuum) PGIP gene family.


Input: Each was up-regulated at a different time following stimulation of the pepper leaves by Phytophthora capcisi and abiotic stresses including salicylic acid, methyl jasmonate, abscisic acid, wounding and cold treatment.

salicylic acid

methyl jasmonate

abscisic acid


Input: Purified recombinant proteins individually inhibited activity of PGs produced by Alternaria alternata and Colletotrichum nicotianae, respectively, and virus-induced gene silencing in pepper conferred enhanced susceptibility to P. capsici.


Input: Because three PGIP genes acted similarily in conferring resistance to infection by P. capsici, and because individually purified proteins showed consistent inhibition against PG activity of both pathogens, CaPGIP1 was selected for manipulating transgenic tobacco.


Input: The crude proteins from transgenic tobacco exhibited distinct enhanced resistance to PG activity of both fungi.


Input: Moreover, the transgenic tobacco showed effective resistance to infection and a significant reduction in the number of infection sites, number of lesions and average size of lesions in the leaves.


Input: All results suggest that CaPGIPs may be involved in plant defense response and play an important role in a plant' s resistance to disease.


Input: Iron overload inhibits osteoblast biological activity through oxidative stress.

Iron


Input: Iron overload has recently been connected with bone mineral density in osteoporosis.

Iron


Input: However, to date, the effect of iron overload on osteoblasts remains poorly understood.

iron


Input: The purpose of this study is to examine osteoblast biological activity under iron overload.

iron


Input: The osteoblast cells (hFOB1. 19) were cultured in a medium supplemented with different concentrations (50, 100, and 200 mu M) of ferric ammonium citrate as a donor of ferric ion.

ferric ammonium citrate

ferric


Input: Intracellular iron was measured with a confocal laser scanning microscope.

iron


Input: Reactive oxygen species (ROS) were detected by 2, 7-dichlorofluorescin diacetate fluorophotometry.

oxygen

2, 7-dichlorofluorescin diacetate


Input: Osteoblast biological activities were evaluated by measuring the activity of alkaline phosphatase (ALP) and mineralization function.


Input: Results indicated that iron overload could consequently increase intracellular iron concentration and intracellular ROS levels in a concentration-dependent manner.

iron

iron


Input: Additionally, ALP activity was suppressed, and a decline in the number of mineralized nodules was observed in in vitro cultured osteoblast cells.


Input: According to these results, it seems that iron overload probably inhibits osteoblast function through higher oxidative stress following increased intracellular iron concentrations.

iron

iron


Input: A novel canine model for prostate cancer.


Input: BACKGROUND: No existing animal model fully recapitulates all features of human prostate cancer.


Input: The dog is the only large mammal, besides humans, that commonly develops spontaneous prostate cancer.


Input: Canine prostate cancer features many similarities with its human counterpart.


Input: We sought to develop a canine model of prostate cancer that would more fully represent the features of human prostate cancer than existing models.


Input: METHODS: The Ace-1 canine prostate cancer cell line was injected transabdominally under transrectal ultrasound (TRUS) guidance into the prostates of immunosuppressed, intact, adult male dogs.


Input: Tumor progression was monitored by TRUS imaging.


Input: Some dogs were subjected to positron emission tomography (PET) for tumor detection.


Input: Time of euthanasia was determined based on tumor size, impingement on urethra, and general well-being.


Input: Euthanasia was followed by necropsy and histopathology.


Input: RESULTS: Ace-1 tumor cells grew robustly in every dog injected.


Input: Tumors grew in subcapsular and parenchymal regions of the prostate.


Input: Tumor tissue could be identified using PET.


Input: Histological findings were similar to those observed in human prostate cancer.


Input: Metastases to lungs and lymph nodes were detected, predominantly in dogs with intraprostatic tumors.


Input: CONCLUSIONS: We have established a minimally invasive dog model of prostate cancer.


Input: This model may be valuable for studying prostate cancer progression and distant metastasis.


Input: Prostate (c) 2013 Wiley Periodicals, Inc.


Input: Chemopreventive effects of Ginkgo biloba extract in estrogen-negative human breast cancer cells.

estrogen


Input: Excessive level of estrogen is considered as a main cause of breast cancer, therefore, many studies have focused on estrogen receptor (ER)-positive breast cancer, even though ER-negative cancer has a poor prognosis than ER-positive breast cancer.

estrogen

estrogen


Input: We evaluated the anti-cancer effects of Ginkgo biloba extract (GBE) in estrogen-independent breast cancer.

estrogen


Input: GBE has been traditionally used as a platelet activating factor, a circulatory stimulant, a tonic, and anti-asthmatic drug, and anti-cancer agent. However, anti-cancer effects of GBE on ER-negative breast cancer have not been proved yet.


Input: In this study, we tested chemotherapeutic potential of GBE in the MDA-MB-231 (ER-negative) human breast cancer cell line. Our results showed that cytotoxicity effects of GBE in MDA-MB-231 lead to DNA fragmentation at high concentrations (500 and 1, 000 mu g/ml).


Input: Caspase-3 was significantly activated and mRNA levels of apoptosis-related genes (Bcl-2 and Bax) were altered.


Input: These results indicate that GBE induces apoptosis in MDA-MB-231 cells.


Input: It is presumed that GBE has chemopreventive effects in ER-independent breast cancer through anti-proliferation and apoptosis-inducing activities.


Input: Room-temperature ferromagnetism in ZnO-encapsulated 1. 9 nm FePt3 nanoparticle-composite thin films with giant interfacial anisotropy.

ZnO


Input: As synthesized 1. 9-nm FePt3 nanoparticles are superparamagnetic at room temperature.


Input: Coating those nanoparticles with ZnO renders them permanently ferromagnetic with coercivity field of 650 Oe at room temperature.

ZnO


Input: First-principles calculations indicate that giant interfacial anisotropy, induced by the strong spin-orbit interaction of enhanced orbit momentum of Fe, overcomes the superparamagnetic limit, leading to exceptional room-temperature permanent ferromagnetism.

Fe


Input: The findings are important for the understanding of the origin of permanent ferromagnetism at ultrasmall size and critical for ultrahigh density recording and information processing.


Input: Fast, reversible, and general photomechanical motion in single crystals of various azo compounds using visible light.

azo


Input: Pseudostilbene-type single crystals exhibit ubiquitous, fast, and reversible photomechanical motion under visible-light irradiation.


Input: Push-pull substituents impart extremely rapid switching using just one wavelength of light by shortening the lifetime of the cis-form.


Input: This results in a bending motion in the microsecond regime.


Input: The influence of crystal density, thickness, and molecular orientation on optimization of the photomechanical effect is investigated.


Input: Studies of enantiomeric degradation of the triazole fungicide hexaconazole in tomato, cucumber, and field soil by chiral liquid chromatography-tandem mass spectrometry.

triazole

hexaconazole


Input: Chiral pesticide enantiomers often show different bioactivity and toxicity; however, this property is usually ignored when evaluating their environmental and public health risks.


Input: Hexaconazole is a chiral fungicide used on a variety of crops for the control of many fungal diseases.

Hexaconazole


Input: This use provides opportunities for the pollution of food and soil.


Input: In this study, a sensitive and convenient chiral liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for measuring hexaconazole enantiomers in tomato, cucumber, and soil.

hexaconazole


Input: Separation was by a reversed-phase Chiralcel OD-RH column, under isocratic conditions using a mixture of acetonitrile-2 mM ammonium acetate in water (60/40, v/v) as the mobile phase at a flow rate of 0. 4 mL/min.

acetonitrile

ammonium acetate


Input: Parameters including the matrix effect, linearity, precision, accuracy and stability were undertaken.


Input: Then the proposed method was successfully applied to investigate the possible enantioselective degradation of rac-hexaconazole in plants (tomato and cucumber) and soil under field conditions.

rac-hexaconazole


Input: The degradation of the two enantiomers of hexaconazole proved to be enantioselective and dependent on the media: The (+)-enantiomer showed a faster degradation in plants, while the (-)-enantiomer dissipated faster than the (+)-form in field soil, resulting in relative enrichment of the opposite enantiomer.

hexaconazole


Input: The results of this work demonstrate that both the environmental media and environmental conditions influenced the direction and rate of enantioselective degradation of hexaconazole.

hexaconazole


Input: Electron transfer dissociation (ETD): the mass spectrometric breakthrough essential for O-GlcNAc protein site assignments-a study of the O-GlcNAcylated protein host cell factor C1.

O-GlcNAc

O


Input: The development of electron-based, unimolecular dissociation MS, i. e. electron capture and electron transfer dissociation (ECD and ETD, respectively), has greatly increased the speed and reliability of labile PTM site assignment.


Input: The field of intracellular O-GlcNAc (O-linked N-acetylglucosamine) signaling has especially advanced with the advent of ETD MS.

O-GlcNAc

O

N-acetylglucosamine


Input: Only within the last five years have proteomic-scale experiments utilizing ETD allowed the assignment of hundreds of O-GlcNAc sites within cells and subcellular structures.

O-GlcNAc


Input: Our ability to identify and unambiguously assign the site of O-GlcNAc modifications using ETD is rapidly increasing our understanding of this regulatory glycosylation and its potential interaction with other PTMs.

O-GlcNAc


Input: Here, we discuss the advantages of using ETD, complimented with collisional-activation MS, in a study of the extensively O-GlcNAcylated protein Host Cell Factor C1 (HCF-1).

O


Input: HCF-1 is a transcriptional coregulator that forms a stable complex with O-GlcNAc transferase and controls cell cycle progression.

O-GlcNAc


Input: ETD, along with higher energy collisional dissociation (HCD) MS, was employed to assign the PTMs of the HCF-1 protein isolated from HEK293T cells.


Input: These include 19 sites of O-GlcNAcylation, two sites of phosphorylation, and two sites bearing dimethylarginine, and showcase the residue-specific, PTM complexity of this regulator of cell proliferation.

O

dimethylarginine


Input: ZnO is a CO (2)-selective steam reforming catalyst.

ZnO

CO (2)


Input: ZnO was tested as possible methanol and-since formaldehyde is one of the key intermediates in methanol conversion reactions-also as formaldehyde steam reforming catalyst.

ZnO

methanol

formaldehyde

methanol

formaldehyde


Input: Catalytic experiments in a batch as well as a flow reactor resulted in highly selective steam reforming, though at low specific activities, of formaldehyde and methanol over ZnO toward CO (2) (selectivity of 95-99. 6%).

formaldehyde

methanol

ZnO

CO (2)


Input: Comparison of the behavior of ZnPd near-surface intermetallic phases, unsupported intermetallic ZnPd and supported ZnPd/ZnO catalysts reveals that formaldehyde is formed from methanol in parallel with CO (2) on the former, while on unsupported intermetallic ZnPd and ZnO-supported ZnPd, it is efficiently reacted toward CO (2), thus, a beneficial role of ZnO in oxidizing formaldehyde-derived intermediates toward CO (2) is evident.

ZnPd

ZnPd

ZnPd

ZnO

formaldehyde

methanol

CO (2)

ZnPd

ZnO

ZnPd

CO (2)

ZnO

formaldehyde

CO (2)


Input: Novel anti-inflammatory phytoconstituents from Desmodium gangeticum.


Input: A new aliphatic enone, (17Z, 20Z)-hexacosa-17, 20-dien-9-one (3), and one new bisindole alkaloid, gangenoid (6), together with seven known compounds were isolated from the roots and aerial parts of Desmodium gangeticum (family: Leguminosae).

(17Z, 20Z)-hexacosa-17, 20-dien-9-one

bisindole alkaloid

gangenoid


Input: All the compounds except 2 and 7 were isolated from this plant for the first time, which may be of chemotaxonomic importance.


Input: Structures of compounds 3 and 6 were determined on the basis of their detailed spectroscopic analyses (NMR, IR and mass).


Input: In addition, compounds 3 and 6 were investigated for their effects on lipopolysaccharide-stimulated macrophages for the production of pro-inflammatory cytokines such as tumour necrosis factor-alpha and interleukin-6.


Input: Nanoscale mapping of lithium-ion diffusion in a cathode within an all-solid-state lithium-ion battery by advanced scanning probe microscopy techniques.

lithium

lithium


Input: High-resolution real-space mapping of Li-ion diffusion in the LiNi (1/3) Co (1/3) Mn (1/3) O 2 cathode within an all-solid-state thin film Li-ion battery has been conducted using advanced scanning probe microscopy techniques, namely, band excitation electrochemical strain microscopy (BE-ESM) and conductive atomic force microscopy.

Li

LiNi (1/3) Co (1/3) Mn (1/3) O 2

Li


Input: In addition, local variations of the electrochemical response in the LiNi (1/3) Co (1/3) Mn (1/3) O 2 thin film cathode at different cycling stages have been investigated.

LiNi (1/3) Co (1/3) Mn (1/3) O 2


Input: This work demonstrates the unique feature and applications of the BE-ESM technique on battery research.


Input: The results allow us to establish a direct relationship of the changes in ionic mobility as well as the electrochemical activity at the nanoscale with the numbers of charge/discharge cycles.


Input: Furthermore, various factors influencing the BE-ESM measurements, including sample mechanical properties (e. g., elastic and dissipative properties) as well as surface electrical properties, have also been studied to investigate the coupling effects on the electrochemical strain.


Input: The study on the relationships between the Li-ion redistribution and microstructure of the electrode materials within thin film Li-ion battery will provide further understanding of the electrochemical degradation mechanisms of Li-ion rechargeable batteries at the nanoscale.

Li

Li

Li


Input: Paradoxical Sost gene expression response to mechanical unloading in metaphyseal bone.


Input: The Sost gene encodes Sclerostin, an inhibitor of Wnt-signaling, generally considered a main response gene to mechanical loading in bone.


Input: Several papers describe that unloading leads to upregulation of Sost, which in turn may lead to loss of bone.


Input: These studies were based on whole bone homogenates or cortical bone.


Input: By serendipity, we noted an opposite response to unloading in the proximal rat tibia.


Input: Therefore, we hypothesized that Sost-expression in response to changes in mechanical load is bone site specific.


Input: One hind limb of male, 3 month old rats was unloaded by paralyzing the extensors with Botulinium toxin A (Botox) injections.


Input: A series of experiments compared the expression of Sost mRNA in the unloaded and contralateral, loaded limbs, after 3 or 10 days, in metaphyseal cancellous bone, metaphyseal cortical bone, and diaphyseal cortical bone.


Input: We also conducted mu CT to confirm changes in bone volume density related to unloading.


Input: Sost mRNA expression in the cancellous metaphyseal bone was downregulated almost 2-fold, both 3 days and 10 days after unloading (P < 0. 05).


Input: A similar tendency was seen in the metaphyseal cortical bone, in which Sost was 1. 5-fold downregulated (P < 0. 05) after 10days, but not significantly changed after 3days.


Input: In contrast, diaphyseal cortical Sost expression was instead upregulated 1. 4-fold (P < 0. 05) following 3-day unloading, while there was no significant change after 10days.


Input: Cancellous bone volume density was 58% lower (P < 0. 001, compared to cage controls) in the unloaded limb but not significantly affected in the loaded limb.


Input: The results suggest that Sost mRNA expression in metaphyseal bone responds to mechanical unloading in an opposite direction to that observed in diaphyseal cortical bone.


Input: This proposes a more complex expression pattern for Sost in response to unloading.


Input: Therapeutics that target Sclerostin during altered loading conditions may result in local bone mass changes that are difficult to predict.


Input: Polyphosphates inhibit extracellular matrix mineralization in MC3T3-E1 osteoblast cultures.

Polyphosphates


Input: Studies on various compounds of inorganic phosphate, as well as on organic phosphate added by post-translational phosphorylation of proteins, all demonstrate a central role for phosphate in biomineralization processes.

phosphate

phosphate

phosphate


Input: Inorganic polyphosphates are chains of orthophosphates linked by phosphoanhydride bonds that can be up to hundreds of orthophosphates in length.

polyphosphates

orthophosphates

phosphoanhydride

orthophosphates


Input: The role of polyphosphates in mammalian systems, where they are ubiquitous in cells, tissues and bodily fluids, and are at particularly high levels in osteoblasts, is not well understood.

polyphosphates


Input: In cell-free systems, polyphosphates inhibit hydroxyapatite nucleation, crystal formation and growth, and solubility.

polyphosphates


Input: In animal studies, polyphosphate injections inhibit induced ectopic calcification.


Input: While recent work has proposed an integrated view of polyphosphate function in bone, little experimental data for bone are available.


Input: Here we demonstrate in osteoblast cultures producing an abundant collagenous matrix that normally show robust mineralization, that two polyphosphates (PolyP5 and PolyP65, polyphosphates of 5 and 65 phosphate residues in length) are potent mineralization inhibitors.

polyphosphates

polyphosphates

phosphate


Input: Twelve-day MC3T3-E1 osteoblast cultures with added ascorbic acid (for collagen matrix assembly) and beta-glycerophosphate (a source of phosphate for mineralization) were treated with either PolyP5 or PolyP65.

beta-glycerophosphate

phosphate


Input: Von Kossa staining and calcium quantification revealed that mineralization was inhibited in a dose-dependent manner by both polyphosphates, with complete mineralization inhibition at 10 mu M.

polyphosphates


Input: Cell proliferation and collagen assembly were unaffected by polyphosphate treatment, indicating that polyphosphate inhibition of mineralization results not from cell and matrix effects but from direct inhibition of mineralization.


Input: This was confirmed by showing that PolyP5 and PolyP65 bound to synthetic hydroxyapatite in a concentration-dependent manner.

hydroxyapatite


Input: Tissue-nonspecific alkaline phosphatase (TNAP, ALPL) efficiently hydrolyzed the two PolyPs as measured by Pi release.

PolyPs


Input: Importantly, at the concentrations of polyphosphates used in this study which inhibited bone cell culture mineralization, the polyphosphates competitively saturated TNAP, thus potentially interfering with its ability to hydrolyze mineralization-inhibiting pyrophosphate (PPi) and mineralizing-promoting beta-glycerophosphate (in cell culture).

polyphosphates

polyphosphates

pyrophosphate

PPi

beta-glycerophosphate


Input: In the biological setting, polyphosphates may regulate mineralization by shielding the essential inhibitory substrate pyrophosphate from TNAP degradation, and in the same process, delay the release of phosphate from this source.

polyphosphates

pyrophosphate

phosphate


Input: In conclusion, the inhibition of mineralization by polyphosphates is shown to occur via direct binding to apatitic mineral and by mixed inhibition of TNAP.

polyphosphates


Input: Sex differences in the antidepressant-like effects of ketamine.

ketamine


Input: Current medications for major depression suffer from numerous limitations.


Input: Once the right drug for treatment has been determined, it still takes several weeks for it to take effect and improve mood.


Input: This time lag is a serious concern for the healthcare community when dealing with patients with suicidal thoughts.


Input: However, recent clinical studies have shown that a single low-dose injection of ketamine, an N-methyl d-aspartate receptor (NMDAR) antagonist, has rapid antidepressant effects that are observed within hours and are long lasting.

ketamine

N-methyl d-aspartate


Input: Although major depression affects twice as many women as men, all studies examining the rapid antidepressant effects of ketamine have focused on male subjects.

ketamine


Input: Thus, we have investigated the behavioral and molecular effects of ketamine in both male and female rats and demonstrated greater sensitivity in female rats at a low dose of ketamine, a dose does not have antidepressant-like effects in male rats.

ketamine

ketamine


Input: The antidepressant-like effects of this low dose of ketamine were completely abolished when female rats were ovariectomized (OVX), and restored when physiological levels of estrogen and progesterone were supplemented, suggesting a critical role for gonadal hormones in enhancing the antidepressant-like effects of ketamine in female rats.

ketamine

estrogen

progesterone

ketamine


Input: In preclinical studies, the mammalian target of rapamycin (mTOR) in the medial prefrontal cortex and the eukaryotic elongation factor (eEF2) in the hippocampus have been proposed as critical mediators of ketamine' s rapid antidepressant actions.

rapamycin

ketamine


Input: In our hands, the increased sensitivity of female rats to a low dose of ketamine was not mediated through phosphorylation of mTOR or eEF2.

ketamine


Input: Differential contribution of mesoaccumbens and mesohabenular dopamine to intracranial self-stimulation.

dopamine


Input: The contribution of mesoaccumbens dopamine transmission to intracranial self-stimulation is well-established.

dopamine


Input: However, although the nucleus accumbens comprises two main subregions, the shell and the core, little is known of the contribution of each to this behaviour.


Input: Our first aim was to study the effects of d-amphetamine infusions into the shell and core in order to understand their relative importance to reward and operant responding.

d-amphetamine


Input: Our second aim was to examine the contribution of a lesser studied group of dopamine neurons, those within the mesohabenular pathway, to intracranial self-stimulation.

dopamine


Input: Male Sprague-Dawley rats were implanted with bilateral cannulae in the nucleus accumbens shell, core or in the lateral habenula and a monopolar stimulation electrode in the posterior mesencephalon, a brain site that is sensitive to changes in dopamine transmission.

dopamine


Input: Using curve-shift scaling, we measured the reward-and performance-enhancing effects of intra-accumbens (1-20 mu g) and intra-habenular (10-40 mu g) infusions of d-amphetamine or vehicle.

d-amphetamine


Input: Within the nucleus accumbens, the use of multiple doses and long test sessions allowed us to observe an interaction between drug effect and infusion site.


Input: We show, for the first time, differences in the minimal doses necessary to enhance rewarding effectiveness and operant responding, in the magnitude of these enhancements as well as in their duration.


Input: Conversely, regardless of dose, intra-habenular d-amphetamine did not alter rewarding effectiveness or operant rate, highlighting the differential contribution of mesoaccumbens and mesohabenular dopamine pathways to intracranial self-stimulation.

d-amphetamine

dopamine


Input: The hidden quality gap in discovery.


Input: Progress made through technological advances in drug discovery can be undermined by problems with measurement equipment, but it is often difficult to detect the issues without a specific investigation.


Input: This article describes the fundamentals of measurement systems analysis and focuses on the issue of precision.


Input: Three case studies are given where measurement systems were found to be flawed when subjected to a systematic analysis, and examples of the approaches needed for correction are described.


Input: Economic and technological drivers of generic sterile injectable drug shortages.


Input: Over the past few years, an increasing number of critically needed medicines have been in short supply.


Input: Using economic theory to frame the drug-shortage problem, this paper explores why and how manufacturing-quality problems could combine with other economic and technological factors to result in shortages of generic sterile injectable drugs.


Input: The fundamental problem we identify is the inability of the market to observe and reward quality.


Input: This lack of reward for quality can reinforce price competition and encourage manufacturers to keep costs down by minimizing quality investments.


Input: The US Food and Drug Administration' s (FDA' s) need to use its regulatory flexibility, on behalf of patients, to avoid shortages of medically necessary drugs may further strengthen the incentive to " push the envelope " on quality.


Input: These dynamics may have produced a market situation in which quality problems have become sufficiently common and severe to result in drug shortages.


Input: Reversal of diet-induced obesity increases insulin transport into cerebrospinal fluid and restores sensitivity to the anorexic action of central insulin in male rats.


Input: Diet-induced obesity (DIO) reduces the ability of centrally administered insulin to reduce feeding behavior and also reduces the transport of insulin from the periphery to the central nervous system (CNS).


Input: The current study was designed to determine whether reversal of high-fat DIO restores the anorexic efficacy of central insulin and whether this is accompanied by restoration of the compromised insulin transport.


Input: Adult male Long-Evans rats were initially maintained on either a low-fat chow diet (LFD) or a high-fat diet (HFD).


Input: After 22 weeks, half of the animals on the HFD were changed to the LFD, whereas the other half continued on the HFD for an additional 8 weeks, such that there were 3 groups: 1) a LFD control group (Con; n = 18), 2) a HFD-fed, DIO group (n = 17), and 3) a HFD to LFD, DIO-reversal group (DIO-rev; n = 18).


Input: The DIO reversal resulted in a significant reduction of body weight and epididymal fat weight relative to the DIO group.


Input: Acute central insulin administration (8 mU) reduced food intake and caused weight loss in Con and DIO-rev but not DIO rats.


Input: Fasting cerebrospinal fluid insulin was higher in DIO than Con animals.


Input: However, after a peripheral bolus injection of insulin, cerebrospinal fluid insulin increased in Con and DIO-rev rats but not in the DIO group.


Input: These data provide support for previous reports that DIO inhibits both the central effects of insulin and insulin' s transport to the CNS.


Input: Importantly, DIO-rev restored sensitivity to the effects of central insulin on food intake and insulin transport into the CNS.


Input: Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway.

arsenic trioxide


Input: Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects.

Arsenic trioxide

ATO

arsenic


Input: We recently found that, in primary osteoblasts, ATO produces oxidative stress and causes DNA tailing, but does not induce apoptosis.

ATO


Input: We further examined the signaling pathway by which osteoblasts survive ATO treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h.

ATO


Input: After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21 (waf1/cip1), which interacts with Cdc2.


Input: Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased.


Input: Moreover, phosphorylation/activation of the checkpoint kinases Chk1, Chk2 and p53 levels were increased, as were levels of activated ATM and gamma-H2AX.


Input: The cell viability was decreased as an ATM inhibitor was added.


Input: Additionally, these effects of ATO on gamma-H2AX, Chk1, Chk2, p53, and p21 (waf1/cip1) were reduced by an ATM inhibitor.

ATO


Input: These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM-dependent pathway by which osteoblasts survive.


Input: Anti-obesity effects of 3-hydroxychromone derivative, a novel small-molecule inhibitor of glycogen synthase kinase-3.


Input: Glycogen synthase kinase 3 (GSK-3) plays a central role in cellular energy metabolism, and dysregulation of GSK-3 activity is implicated in a variety of metabolic disorders, including obesity, type 2 diabetes, and cancer.


Input: Hence, GSK-3 has emerged as an attractive target molecule for the treatment of metabolic disorders.


Input: Therefore, this research focused on identification and characterization of a novel small-molecule GSK-3 inhibitor.


Input: Compound 1a, a structure based on 3-hydroxychromone bearing isothiazolidine-1, 1-dione, was identified from chemical library as a highly potent GSK-3 inhibitor.

isothiazolidine-1, 1-dione


Input: An in vitro kinase assay utilizing a panel of kinases demonstrated that compound 1a strongly inhibits GSK-3 beta.


Input: The potential effects of compound 1a on the inactivation of GSK-3 were confirmed in human liver HepG2 and human embryonic kidney HEK293 cells.


Input: Stabilization of glycogen synthase and beta-catenin, which are direct targets of GSK-3, by compound 1a was assessed in comparison with two other GSK-3 inhibitors: LiCl and SB-415286.

LiCl


Input: In mouse 3T3-L1 preadipocytes, compound 1a markedly blocked adipocyte differentiation.


Input: Consistently, intraperitoneal administration of compound 1a to diet-induced obese mice significantly ameliorated their key symptoms such as body weight gain, increased adiposity, dyslipidemia, and hepatic steatosis due to the marked reduction of whole-body lipid level.


Input: In vitro and in vivo effects were accompanied by upregulation of beta-catenin stability and downregulation of the expression of several critical genes related to lipid metabolism.


Input: From these results, it can be concluded that compound 1a, a novel small-molecule inhibitor of GSK-3, has potential as a new class of therapeutic agent for obesity treatment.


Input: Understanding drugs and diseases by systems biology?


Input: Systems biology aims to provide a holistic and in many cases dynamic picture of biological function and malfunction, in case of disease.


Input: Technology developments in the generation of genome-wide datasets and massive improvements in computer power now allow to obtain new insights into complex biological networks and to copy nature by computing these interactions and their kinetics and by generating in silico models of cells, tissues and organs.


Input: The expectations are high that systems biology will pave the way to the identification of novel disease genes, to the selection of successful drug candidates--that do not fail in clinical studies due to toxicity or lack of human efficacy--and finally to a more successful discovery of novel therapeutics.


Input: However, further research is necessary to fully unleash the potential of systems biology.


Input: Within this review we aim to highlight the most important and promising top-down and bottom-up systems biology applications in drug discovery.


Input: Polyoxometalate-biomolecule conjugates: a new approach to create hybrid drugs for cancer therapeutics.

Polyoxometalate


Input: Some polyoxometalate (POM) clusters have demonstrated attractive anticancer properties.

polyoxometalate

POM


Input: Unfortunately, their cytotoxicity upon normal cell is one of fateful side effects obstructing their further clinic application as inorganic drugs.


Input: In this communication, we report a new approach to create hybrid drugs potentially for cancer therapeutics.


Input: At first, the POM cluster bioconjugates were created by attaching the bioactive ligands on an amine grafted POM via simple amidation reaction.

POM

amine


Input: The cytotoxicity study with breast cancer cells (MCF-7 and MDA-MB-231) and non-cancerous breast epithelial cell (MCF-10A) showed that rationally selected ligands with cancer-cell targeting ability on POM-biomolecule conjugates can impart enhanced anti-tumor activity and selectivity, thus representing a new concept to develop novel POM-biomolecule hybrid drugs with the potential synergistic effect: increased bioactivity and lower side effect.

POM

POM


Input: Novel naphthoquinone derivatives: synthesis and activity against human African trypanosomiasis.

naphthoquinone


Input: A series of naphthoquinone derivatives has been synthesized and tested for its biological activity against human African trypanosomiasis.

naphthoquinone


Input: The use of reverse micellar medium not only enhanced the conversion rate, but also showed selectivity towards mono-coupled product in aryl chloride-aniline coupling reactions.

aryl chloride

aniline


Input: Two derivatives of naphthoquinone (9b and 9c) exhibited potent activity against Trypanosoma brucei in vitro with low cytotoxicity.

naphthoquinone


Input: 3H-1, 2, 4-Dithiazol-3-one compounds as novel potential affordable antitubercular agents.

3H-1, 2, 4-Dithiazol-3-one


Input: Small molecules with oxathiazol-2-one moiety were recently reported as potent inhibitors of Mycobacterium bovis var. bacilli Calmette-Gu e rin (BCG), among which HT1171 was the most potent and selective proteasome inhibitor.


Input: Herein we synthesized a series of novel compounds by bioisosteric replacement of the oxathiazol-2-one ring with 3H-1, 2, 4-dithiazol-3-one, and also fifteen 1, 3, 4-oxathiazol-2-one molecules in order for potency comparison and structure-activity relationship elucidation since their antibacterial effects on the virulent strains were not evaluated before.

3H-1, 2, 4-dithiazol-3-one

1, 3, 4-oxathiazol-2-one


Input: All the compounds were assessed for antitubercular activities on the virulent H37Rv strain by a serial dilution method.


Input: Among the tested compounds, 3H-1, 2, 4-dithiazol-3-one compound 4n was found to be the most active with a lowest MIC (90) value of 1 mu g/mL.

3H-1, 2, 4-dithiazol-3-one


Input: Furthermore, the cytotoxicities of all the compounds against normal human liver cell line L02 were determined by an MTT method.

MTT


Input: Compound 4n displayed a lower inhibitory ratio than HT1171 at the concentration of 100 mu M, indicating its better safety profile.


Input: Toxicity assessment on trophoblast cells for some environment polluting chemicals and 17 beta-estradiol.

17 beta-estradiol


Input: The identification of reproductive toxicants is a major scientific challenge for human health.


Input: We investigated the effects of a selected group of environmental polluting chemicals mostly provided with estrogenic activity on the human trophoblast cell lines BeWo and HTR-8/SVneo.


Input: Cells were exposed for 24h to various concentrations (from 0. 1 pM to 1 mM) of atrazine (ATR), diethylstilbestrol (DES), para-nonylphenol (p-NP), resveratrol (RES) and 17 beta-estradiol (E2) and assayed for cell viability and human beta-Chorionic Gonadotropin (beta-hCG) secretion.

atrazine

ATR

diethylstilbestrol

DES

para-nonylphenol

p-NP

resveratrol

RES

17 beta-estradiol


Input: Decrease of cell viability as respect to control, vehicle-treated, cultures was obtained for all chemicals in the concentration range of 1 mu M-1 mM in both cell types.


Input: A parallel decrease of beta-hCG secretion was observed in BeWo cells, at 1 mu M-1 mM concentrations, with the only exception of ATR which caused an increase at concentrations up to 1mM.

ATR


Input: beta-hCG release was also unexpectedly inhibited by ATR, DES, p-NP and RES at non-toxic (pM-nM) concentrations.

ATR

DES

p-NP

RES


Input: These findings raise concern about the negative, potential effects of various environmental polluting chemicals on pregnancy success and fetal health.


Input: Electronic and EPR spectra of the species involved in [W10O32] 4-photocatalysis.

[W10O32] 4-


Input: A relativistic DFT investigation.


Input: The decatungstate anion [W (10) O (32)] (4-) is widely used as a photocatalyst in different transformations, during which it undergoes one-electron reduction to [W (10) O (32)] (5-), possibly protonated; the bi-reduced species [W (10) O (32)] (6-) is obtained by ensuing disproportionation.

[W (10) O (32)] (4-)

[W (10) O (32)] (5-)

[W (10) O (32)] (6-)


Input: Relativistic DFT calculations were used to predict the UV-VIS spectra and EPR parameters of all such species.


Input: Differentiating factors between erythropoiesis-stimulating agents: an update to selection for anaemia of chronic kidney disease.


Input: Erythropoiesis-stimulating agents (ESAs) have become a hallmark of anaemia therapy in patients with chronic kidney disease (CKD).


Input: Although different ESAs are available for the treatment of renal anaemia, each nephrologist should select a single ESA for an individual patient.


Input: Epoetin alfa and epoetin beta have been used 1-3 times weekly but extended-interval dosing up to every 4 weeks is also effective in a substantial majority of CKD patients.


Input: However, the epoetin dose necessary to achieve or maintain target haemoglobin (Hb) levels increases substantially as the dosing interval increases.


Input: Subcutaneous administration of short-acting ESAs is more effective than the intravenous route of administration.


Input: Darbepoetin alfa and the continuous erythropoietin receptor activator (CERA) have been developed as a treatment for anaemia with extended administration intervals (every 2 weeks and every 4 weeks, respectively).


Input: Dose requirements for these long-acting ESAs are independent of the route of administration.


Input: Patents of short-acting ESAs have expired, which has opened the field for biosimilars.


Input: Epoetin biosimilars approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) have been shown to have a comparable efficacy and safety profile to their originators.


Input: An alarming increase in pure red cell aplasia (PRCA) in Thailand with follow-on epoetins manufactured in Asia (but also those manufactured in Latin America) indicates that stringent country-specific approval and pharmacovigilance protocols for ESAs manufactured in non-North American and non-EU European countries are urgently needed.


Input: Two PRCA cases occurring with subcutaneous HX575 (one certain, one likely) indicate that chances of inducing a more immunogenic product are unpredictable, even with a biosimilar epoetin approved under the EMA biosimilar approval pathway.


Input: Phase III clinical trials with peginesatide, a pegylated synthetic peptide-based ESA without any homology to erythropoietin raised safety concerns in non-dialysis CKD patients but not in dialysis patients.


Input: Subcutaneous bortezomib: in multiple myeloma.

bortezomib


Input: A subcutaneous formulation of bortezomib is now indicated in the EU and the US for the treatment of patients with multiple myeloma.

bortezomib


Input: This article reviews pharmacological, therapeutic efficacy and tolerability data relevant to the utilization of subcutaneous bortezomib (Velcade ((R))) in the treatment of patients with multiple myeloma.

bortezomib

Velcade


Input: In a randomized, nonblind, phase III study, subcutaneous bortezomib was noninferior to intravenous bortezomib in the treatment of adults with relapsed multiple myeloma, as determined by the overall response rate after four cycles of therapy (primary endpoint).

bortezomib

bortezomib


Input: No significant differences between the subcutaneous and intravenous bortezomib formulations were observed in the median time to first response, median progression-free survival, median time to progression and 1-year overall survival.

bortezomib


Input: Compared with intravenous bortezomib, subcutaneous bortezomib confers a significant advantage with respect to the incidence of peripheral neuropathy (all grades, grade >= 2 and grade >= 3).

bortezomib

bortezomib


Input: As a consequence, it provides a new treatment option for patients with multiple myeloma, particularly those with pre-existing neuropathy or at a high risk of developing peripheral neuropathy.


Input: Local deposition of anisotropic nanoparticles using scanning electrochemical microscopy (SECM).


Input: We demonstrate localized electrodeposition of anisotropic metal nanoobjects, namely Au nanorods (GNR), on indium tin oxide (ITO) using scanning electrochemical microscopy (SECM).

Au

indium tin oxide

ITO


Input: A gold microelectrode was the source of the gold ions whereby double pulse chronoamperometry was employed to generate initially Au seeds which were further grown under controlled conditions.

Au


Input: The distance between the microelectrode and the ITO surface as well as the different experimental parameters (electrodeposition regime, solution composition and temperature) were optimized to produce faceted gold seeds with the required characteristics (size and distribution).

ITO


Input: Colloidal chemical synthesis was successfully exploited for better understanding the role of the surfactant and different additives in breaking the crystallographic symmetry and anisotropic growth of GNR.


Input: Experiments performed in a conventional three-electrode cell revealed the most appropriate electrochemical conditions allowing high yield synthesis of nanorods with well-defined shape as well as nanocubes and bipyramids.


Input: Synthesis of long-circulating, backbone degradable HPMA copolymer-doxorubicin conjugates and evaluation of molecular-weight-dependent antitumor efficacy.

HPMA

doxorubicin


Input: Backbone degradable, linear, multiblock N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-doxorubicin (DOX) conjugates are synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization followed by chain extension via thiol-ene click reaction.

N-(2-hydroxypropyl) methacrylamide

HPMA

doxorubicin

DOX

thiol


Input: The examination of molecular-weight-dependent antitumor activity toward human ovarian A2780/AD carcinoma in nude mice reveals enhanced activity of multiblock, second-generation, higher molecular weight conjugates when compared with traditional HPMA copolymer-DOX conjugates.

HPMA

DOX


Input: The examination of body weight changes during treatment indicates the absence of non-specific adverse effects.


Input: Structure prediction of binary pernitride MN2 compounds (M = Ca, Sr, Ba, La, and Ti).

pernitride MN2

Ca

Sr

Ba

La

Ti


Input: Metal-pernitride compounds belong to a class of chemical systems in which both the complex ions and the non-bonding electrons may play roles in the formation of their modified crystalline structures.

Metal-pernitride


Input: To investigate this issue, the energy landscapes of pernitrides of metals with different maximum valence (M = Ca, Sr, Ba, La, and Ti) were globally explored on the ab initio level at standard and high pressures, thereby yielding possible (meta) stable modifications in these systems together with information on how the landscape changed as function of the valence of the metal cation.

pernitrides

Ca

Sr

Ba

La

Ti


Input: For all of the systems in which no compounds had been synthesized so far, we predicted the existence of kinetically stable modifications that should, in principle, be experimentally accessible.


Input: In particular, TiN2 should crystallize in a new structure type, TiN2-I.


Input: Inhibition pathways of the potent organophosphate CBDP with cholinesterases revealed by X-ray crystallographic snapshots and mass spectrometry.

organophosphate CBDP


Input: Tri-o-cresyl-phosphate (TOCP) is a common additive in jet engine lubricants and hydraulic fluids suspected to have a role in aerotoxic syndrome in humans.

Tri-o-cresyl-phosphate

TOCP


Input: TOCP is metabolized to cresyl saligenin phosphate (CBDP), a potent irreversible inhibitor of butyrylcholinesterase (BChE), a natural bioscavenger present in the bloodstream, and acetylcholinesterase (AChE), the off-switch at cholinergic synapses.

TOCP

cresyl saligenin phosphate

CBDP


Input: Mechanistic details of cholinesterase (ChE) inhibition have, however, remained elusive.


Input: Also, the inhibition of AChE by CBDP is unexpected, from a structural standpoint, i. e., considering the narrowness of AChE active site and the bulkiness of CBDP.

CBDP

CBDP


Input: In the following, we report on kinetic X-ray crystallography experiments that provided 2. 7-3. 3 A snapshots of the reaction of CBDP with mouse AChE and human BChE.

CBDP


Input: The series of crystallographic snapshots reveals that AChE and BChE react with the opposite enantiomers and that an induced-fit rearrangement of Phe297 enlarges the active site of AChE upon CBDP binding.

CBDP


Input: Mass spectrometry analysis of aging in either H (2) (16) O or H (2) (18) O furthermore allowed us to identify the inhibition steps, in which water molecules are involved, thus providing insights into the mechanistic details of inhibition.

H (2) (16) O

H (2) (18) O


Input: X-ray crystallography and mass spectrometry show the formation of an aged end product formed in both AChE and BChE that cannot be reactivated by current oxime-based therapeutics.

oxime


Input: Our study thus shows that only prophylactic and symptomatic treatments are viable to counter the inhibition of AChE and BChE by CBDP.

CBDP


Input: From isolated metaatoms to photonic metamaterials: evolution of the plasmonic near-field.


Input: Metamaterials are artificial media which can provide optical properties not available from natural materials.


Input: These properties often result from the resonant excitation of plasmonic modes in the metallic building blocks (" metaatoms ") of the metamaterial.


Input: Electromagnetic interactions between the metaatoms significantly modify the resonances of the individual metaatoms and influence the optical properties of the whole metamaterial.


Input: To better understand these interactions, we study in this Letter the evolution of the plasmonic near-field in the course of the transition from an isolated metaatom, in our case a split-ring resonator (SRR), to a photonic metamaterial via electron energy-loss spectroscopy.


Input: For small SRR ensembles, we observe the formation of discrete optical bright and dark modes due to coupling of the metaatoms.


Input: Large SRR arrays reveal a quasi-continuum of modes in the interior and distinct edge modes at the boundaries of the array.


Input: Our experimental results are in excellent agreement with numerical calculations.


Input: Single molecule characterization of the interactions between amyloid-beta peptides and the membranes of hippocampal cells.


Input: Oligomers of the 40 and 42 residue amyloid-beta peptides (A beta 40 and A beta 42) have been implicated in the neuronal damage and impaired cognitive function associated with Alzheimer' s disease.


Input: However, little is known about the specific mechanisms by which these misfolded species induce such detrimental effects on cells.


Input: In this work, we use single-molecule imaging techniques to examine the initial interactions between A beta monomers and oligomers and the membranes of live cells.


Input: This highly sensitive method enables the visualization of individual A beta species on the cell surface and characterization of their oligomerization state, all at biologically relevant, nanomolar concentrations.


Input: The results indicate that oligomers preferentially interact with cell membranes, relative to monomers and that the oligomers become immobilized on the cell surface.


Input: Additionally, we observe that the interaction of A beta species with the cell membrane is inhibited by the presence of ATP-independent molecular chaperones.

ATP


Input: This study demonstrates the power of this methodology for characterizing the interactions between protein aggregates and the membranes of live neuronal cells at physiologically relevant concentrations and opens the door to quantitative studies of the cellular responses to potentially pathogenic oligomers.


Input: Thyroid hormone levels within reference range are associated with heart rate, cardiac structure and function in middle-aged men and women.

Thyroid hormone


Input: Background Triiodothyronine (T3) has many effects on the heart and marked changes in cardiac function and structure occur in patients with (subclinical) thyroid disease.

Triiodothyronine


Input: We investigated whether between-subject variation in thyroid hormone levels within the euthyroid range is also associated with heart rate and echocardiographic heart function and structure.

thyroid hormone


Input: Methods Subjects were selected from the Asklepios study (n = 2524), a population-representative random sample between 35 and 55 yrs, free from overt cardiovascular disease at baseline.


Input: Analyses were restricted to 2078 subjects (1013 women and 1065 men), not using antihypertensive or thyroid medication nor having anti-TPO levels above clinical cut-off or TSH levels outside the reference range.


Input: All subjects were phenotyped in-depth and underwent comprehensive echocardiography, including diastolic evaluation.


Input: Thyroid function parameters were determined by automated electrochemiluminescence.


Input: Results Heart rate was robustly positively associated with (quartiles of) (F) T3, both in subjects with TSH levels within reference (0. 27-4. 2 micro U/l) as in narrow TSH-range (0. 5-2. 5 micro U/l) (p <= 0. 0001).


Input: (F) T3 was negatively associated with LV (left ventricular) end-diastolic volume but positively with relative wall thickness.


Input: TT3 was associated with enhanced ventricular contraction (as assessed by tissue Doppler imaging).


Input: FT4, FT3 and TT3 were positively associated with late ventricular filling, and TT3 was associated with early ventricular filling.


Input: Conclusion We have demonstrated a strong positive association between thyroid hormone levels within the euthyroid range and heart rate, and more subtle effects on cardiac function and structure.

thyroid hormone


Input: More specifically, we suggest smaller LV cavity size (with increased relative wall thickness), an enhanced atrial and ventricular contraction and LV relaxation with higher circulating thyroid hormones.

thyroid hormones


Input: These results illustrate that variation of thyroid hormone levels even within the reference range exerts effects on the heart.

thyroid hormone


Input: Disorder imposed limits of mono-and bilayer graphene electronic modification using covalent chemistry.

graphene


Input: A central question in graphene chemistry is to what extent chemical modification can control an electronically accessible band gap in monolayer and bilayer graphene (MLG and BLG).

graphene

graphene


Input: Density functional theory predicts gaps in covalently functionalized graphene as high as 2 eV, while this approach neglects the fact that lattice symmetry breaking occurs over only a prescribed radius of nanometer dimension, which we label the S-region.

graphene


Input: Therefore, high chemical conversion is central to observing this band gap in transport.


Input: We use an electrochemical approach involving phenyl-diazonium salts to systematically probe electronic modification in MLG and BLG with increasing functionalization for the first time, obtaining the highest conversion values to date.

phenyl-diazonium salts


Input: We find that both MLG and BLG retain their relatively high conductivity after functionalization even at high conversion, as mobility losses are offset by increases in carrier concentration.


Input: For MLG, we find that band gap opening as measured during transport is linearly increased with respect to the I (D)/I (G) ratio but remains below 0. 1 meV in magnitude for SiO (2) supported graphene.

SiO (2)

graphene


Input: The largest transport band gap obtained in a suspended, highly functionalized (I (D)/I (G) = 4. 5) graphene is about 1 meV, lower than our theoretical predictions considering the quantum interference effect between two neighboring S-regions and attributed to its population with midgap states.

graphene


Input: On the other hand, heavily functionalized BLG (I (D)/I (G) = 1. 8) still retains its signature dual-gated band gap opening due to electric-field symmetry breaking.


Input: We find a notable asymmetric deflection of the charge neutrality point (CNP) under positive bias which increases the apparent on/off current ratio by 50%, suggesting that synergy between symmetry breaking, disorder, and quantum interference may allow the observation of new transistor phenomena.


Input: These important observations set definitive limits on the extent to which chemical modification can control graphene electronically.

graphene


Input: 5-((1-Aroyl-1H-indol-3-yl) methylene)-2-thioxodihydropyrimidine-4, 6 (1H, 5H)-diones as potential anticancer agents with anti-inflammatory properties.

5-((1-Aroyl-1H-indol-3-yl) methylene)-2-thioxodihydropyrimidine-4, 6 (1H, 5H)-diones


Input: A series of novel 5-((1-aroyl-1H-indol-3-yl) methylene)-2-thioxodihydropyrimidine-4, 6 (1H, 5H)-diones (3a-z) have been evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines.

5-((1-aroyl-1H-indol-3-yl) methylene)-2-thioxodihydropyrimidine-4, 6 (1H, 5H)-diones


Input: Compound 3k exhibited the most potent growth inhibition against melanoma MDA-MB-435 cells (GI (50) = 850 nM), against leukemia SR cancer cells (GI (50) = 1. 45 mu M), and OVCAR-3 (GI (50) = 1. 26 mu M) ovarian cancer cell lines.


Input: The structurally related compound 3s had a GI (50) value of 1. 77 mu M against MDA-MB-435 cells.


Input: The N-naphthoyl analogue 3t had GI (50) values of 1. 30 and 1. 91 mu M against HOP-92 non-small cell lung cancer and MDA-MB-435 melanoma cell lines, respectively.

N

naphthoyl


Input: The related analogue 3w had GI (50) values of 1. 09 mu M against HOP-92 non-small cell lung cancer cell lines.


Input: Interestingly, docking of the two active molecules 3k and 3w into the active site of COX-2 indicates that these compounds are COX-2 ligands with strong hydrophobic and hydrogen bonding interactions.

hydrogen


Input: Thus, compounds 3k, 3t, 3s, and 3w constitute a new class of anticancer/anti-inflammatory agents that may have unique potential for cancer therapy.


Input: Impact of cooking and handling conditions on furanic compounds in breaded fish products.

furanic


Input: This study evaluates the influence of cooking and handling conditions on the quantity of furanic compounds (furan, 2-furfural, furfuryl alcohol, 2-pentylfuran, 5-hydroxymethylfurfural) in breaded fish products.

furanic

furan

furfuryl alcohol


Input: Oven-baking and reheating in the microwave lead to low furanic compounds formation in comparison with deep-frying.

furanic


Input: The use of olive oil for deep-frying promoted higher levels of furanic compounds than sunflower oil.

furanic


Input: The amounts of these compounds diminished as the temperature and time of deep-frying decreased as well as after a delay after deep-frying.


Input: Thus, the generation of furanic compounds can be minimized by adjusting the cooking method and conditions, such as using an electric oven, deep-frying in sunflower oil at 160 degrees C during 4min, or waiting 10min after cooking.

furanic


Input: However, these conditions that reduce furanic compounds levels also reduce the content of volatile compounds related to the aroma and flavour of fried foods.

furanic


Input: In this sense, new efforts should be done to reduce the formation of furanic compounds without being detrimental to the volatile profile.

furanic


Input: Shifting from the single to the multitarget paradigm in drug discovery.


Input: Increasing evidence that several drug compounds exert their effects through interactions with multiple targets is boosting the development of research fields that challenge the data reductionism approach.


Input: In this article, we review and discuss the concepts of drug repurposing, polypharmacology, chemogenomics, phenotypic screening and high-throughput in vivo testing of mixture-based libraries in an integrated manner.


Input: These research fields offer alternatives to the current paradigm of drug discovery, from a one target-one drug model to a multiple-target approach.


Input: Furthermore, the goals of lead identification are being expanded accordingly to identify not only' key' compounds that fit with a single-target' lock', but also' master key' compounds that favorably interact with multiple targets (i. e. operate a set of desired locks to gain access to the expected clinical effects).


Input: Impaired fertility and FSH synthesis in gonadotrope-specific Foxl2 knockout mice.


Input: Impairments in pituitary FSH synthesis or action cause infertility.


Input: However, causes of FSH dysregulation are poorly described, in part because of our incomplete understanding of mechanisms controlling FSH synthesis.


Input: Previously, we discovered a critical role for forkhead protein L2 (FOXL2) in activin-stimulated FSH beta-subunit (Fshb) transcription in immortalized cells in vitro.


Input: Here, we tested the hypothesis that FOXL2 is required for FSH synthesis in vivo.


Input: Using a Cre/lox approach, we selectively ablated Foxl2 in murine anterior pituitary gonadotrope cells.


Input: Conditional knockout (cKO) mice developed overtly normally but were subfertile in adulthood.


Input: Testis size and spermatogenesis were significantly impaired in cKO males.


Input: cKO females exhibited reduced ovarian weight and ovulated fewer oocytes in natural estrous cycles compared with controls.


Input: In contrast, ovaries of juvenile cKO females showed normal responses to exogenous gonadotropin stimulation.


Input: Both male and female cKO mice were FSH deficient, secondary to diminished pituitary Fshb mRNA production.


Input: Basal and activin-stimulated Fshb expression was similarly impaired in Foxl2 depleted primary pituitary cultures.


Input: Collectively, these data definitively establish FOXL2 as the first identified gonadotrope-restricted transcription factor required for selective FSH synthesis in vivo.


Input: The endocrine disrupting chemical tolylfluanid alters adipocyte metabolism via glucocorticoid receptor activation.

tolylfluanid


Input: Glucocorticoid signaling plays a critical role in regulating energy metabolism.


Input: Emerging data implicate environmental endocrine-disrupting chemicals as contributors to the obesity and diabetes epidemics.


Input: Previous studies have shown that the phenylsulfamide fungicide tolylfluanid (TF) augments glucocorticoid receptor (GR)-dependent luciferase expression in 3T3-L1 preadipocytes while modulating insulin action in primary murine and human adipocytes.

phenylsulfamide

tolylfluanid


Input: Studies were performed to interrogate glucocorticoid signaling in primary adipocytes exposed to TF.


Input: TF mimicked the gene transcription profile of the murine glucocorticoid corticosterone (Cort).

corticosterone

Cort


Input: Cellular fractionation assays demonstrated that TF treatment promoted the activating serine phosphorylation of GR, augmenting its cytoplasmic-to-nuclear translocation as well as its enrichment at glucocorticoid response elements on the glucocorticoid-induced leucine zipper gene promoter.

serine

leucine


Input: After acute treatment, Cort or TF promoted insulin receptor substrate-1 (IRS-1) gene and protein expression.

Cort


Input: Either treatment also enriched GR binding at an identified glucocorticoid response element in the IRS-1 gene.


Input: TF or Cort each increased insulin-stimulated lipogenesis, an effect resulting from increased lipogenic gene expression and enhanced insulin-stimulated dephosphorylation of acetyl-coenzyme A carboxylase.

Cort

acetyl-coenzyme A


Input: The augmentation of insulin-stimulated lipogenesis was mediated through a specific enhancement of Akt phosphorylation at T308.


Input: These findings support modulation of IRS-1 levels as a mechanism for glucocorticoid-mediated changes in insulin action in primary adipocytes.


Input: Albeit with less affinity than Cort, in silico analysis suggests that TF can interact with the ligand binding pocket of GR.

Cort


Input: Collectively, these studies identify TF as a structurally unique environmental glucocorticoid.


Input: Glucocorticoid signaling may thus represent a novel pathway by which environmental toxicants promote the development of metabolic diseases.


Input: Perfluoroalkylated compounds induce cell death and formation of reactive oxygen species in cultured cerebellar granule cells.

oxygen


Input: The present communication investigates the effects of different perfluoroalkylated compounds (PFCs) on formation of reactive oxygen species (ROS) and cell death in cultured cerebellar granule cells.

oxygen


Input: This allows direct comparison with similar effects found for other environmental contaminants like polychlorinated biphenyls and brominated flame-retardants.

polychlorinated biphenyls


Input: The increase in ROS formation and cell death was assayed using the fluorescent probe 2, 7-dichlorofluorescin diacetate (DCFH-DA) and the trypan blue exclusion assay.

2, 7-dichlorofluorescin diacetate

DCFH-DA

trypan blue


Input: The effects of the PFCs were structure dependent.


Input: Cell death was induced at relatively low concentrations by perfluorooctyl sulfonate (PFOS), perfluorooctane sulfonylamide (PFOSA) and the fluorotelomer alcohol 1H, 1H, 2H, 2H-perfluorodecanol (FTOH 8: 2) with EC (50)-values of 62 +/- 7. 6, 13 +/- 1. 8 and 15 +/- 4. 2 mu M (mean +/- SD) respectively.

perfluorooctyl sulfonate

PFOS

perfluorooctane sulfonylamide

PFOSA

fluorotelomer alcohol 1H, 1H, 2H, 2H-perfluorodecanol

FTOH 8: 2


Input: PFOS, perfluorooctanoic acid (PFOA) and PFOSA induced a concentration dependent increase in ROS formation with EC (50)-values of 27 +/- 9. 0, 25 +/- 11 and 57 +/- 19 mu M respectively.

PFOS

perfluorooctanoic acid

PFOA

PFOSA


Input: Reduced cell viability and ROS formation were observed at concentration level close to what is found in serum of occupationally exposed workers.


Input: The effect of PFCs on ROS formation and cell viability was compared with other halogenated compounds and future investigations should emphasize effects of mixtures and how physical chemical properties of the compounds influence their toxicity.


Input: Drug shortages: the cycle of quantity and quality.


Input: Shortages of pharmaceutical drugs pose a serious and growing threat to public health.


Input: Although the number of drugs in shortage in the United States in any given year is very small, the number of prescription drug shortages in the country nearly tripled between 2005 and 2010.


Input: Drug shortages are becoming more severe as well as more frequent.


Input: The affected medicines include cancer treatments, anesthesia drugs, and other drugs that are critical to the treatment and prevention of serious diseases and life-threatening conditions.


Input: (The White House, Office of the Press Secretary, Executive Order 13588-Reducing Prescription Drug Shortages (http://www. whitehouse. gov/the-press-office/2011/10/31/executive-order-reducing-prescription-drug-shortages)).


Input: Membrane tethered bursicon constructs as heterodimeric modulators of the Drosophila G protein-coupled receptor rickets.


Input: The study of complex heterodimeric peptide ligands has been hampered by a paucity of pharmacological tools.


Input: To facilitate such investigations, we have explored the utility of membrane tethered ligands (MTLs).


Input: Feasibility of this recombinant approach was explored with a focus on Drosophila bursicon, a heterodimeric cystine-knot protein that activates the G protein-coupled receptor rickets (rk).

cystine


Input: Rk/bursicon signaling is an evolutionarily conserved pathway in insects required for wing expansion, cuticle hardening, and melanization during development.


Input: We initially engineered two distinct MTL constructs, each composed of a type II transmembrane domain, a peptide linker, and a C terminal extracellular ligand that corresponded to either the alpha or beta bursicon subunit.

C


Input: Coexpression of the two complementary bursicon MTLs triggered rk-mediated signaling in vitro.


Input: We were then able to generate functionally active bursicon MTLs in which the two subunits were fused into a single heterodimeric peptide, oriented as either alpha-beta or beta-alpha.


Input: Carboxy-terminal deletion of 32 amino acids in the beta-alpha MTL construct resulted in loss of agonist activity.

Carboxy

amino acids


Input: Coexpression of this construct with rk inhibited receptor-mediated signaling by soluble bursicon.


Input: We have thus generated membrane-anchored bursicon constructs that can activate or inhibit rk signaling.


Input: These probes can be used in future studies to explore the tissue and/or developmental stage-dependent effects of bursicon in the genetically tractable Drosophila model organism.


Input: In addition, our success in generating functionally diverse bursicon MTLs offers promise that such technology can be broadly applied to other complex ligands, including the family of mammalian cystine-knot proteins.


Input: Exploring resources for intrafamilial communication of cancer genetic risk: we still need to talk.


Input: While the importance of intrafamilial communication of hereditary cancer risk has been acknowledged, the factors that promote and act as barriers to patients disclosing their information to their families are complex and emerging.


Input: This raises the question: How are patients guided in practice to contemplate intrafamilial communication?


Input: Focusing on breast cancer, we conducted an exploratory study examining current resources supporting patients and health-care professionals, and isolated the messages surrounding intrafamilial communication of cancer risk.


Input: We find the duty for health-care professionals to counsel patients regarding intrafamilial communication is acknowledged to varying degrees by multiple actors in the cancer care delivery landscape, including health-care professional associations, health service organizations, and patient groups.


Input: A range of medical, psychosocial, and other factors underlying intrafamilial communication are acknowledged in messages to patients.


Input: Patients, however, are often referred to a single group of health-care professionals to discuss their diverse and complex needs.


Input: At the same time, messages aimed at patients appear to place the emphasis on barriers that could exist for patients contemplating intrafamilial communication, while highlighting the benefits families derive from such communication.


Input: Taken together, this points to a lack of coherence within materials directed to patients and suggests the need to do coordinated research among stakeholders to address two related issues: (1) determining who are the actors best positioned to send messages surrounding intrafamilial communication to patients and (2) addressing the content of messages conveyed in patient materials. European Journal of Human Genetics advance online publication, 23 January 2013; doi: 10. 1038/ejhg. 2012. 286.


Input: Induction of heat shock protein 70 ameliorates ultraviolet-induced photokeratitis in mice.


Input: Acute ultraviolet (UV) B exposure causes photokeratitis and induces apoptosis in corneal cells.


Input: Geranylgeranylacetone (GGA) is an acyclic polyisoprenoid that induces expression of heat shock protein (HSP) 70, a soluble intracellular chaperone protein expressed in various tissues, protecting cells against stress conditions.

Geranylgeranylacetone

GGA

acyclic polyisoprenoid


Input: We examined whether induction of HSP70 has therapeutic effects on UV-photokeratitis in mice.


Input: C57 BL/6 mice were divided into four groups, GGA-treated (500 mg/kg/mouse) and UVB-exposed (400 mJ/cm2), GGA-untreated UVB-exposed (400 mJ/cm2), GGA-treated (500 mg/kg/mouse) but not exposed and naive controls.

GGA

GGA

GGA


Input: Eyeballs were collected 24 h after irradiation, and corneas were stained with hematoxylin and eosin (H & amp; E) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL).

hematoxylin

eosin

dUTP


Input: HSP70, reactive oxygen species (ROS) production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) and protein kinase B (Akt) expression were also evaluated.

oxygen


Input: Irradiated corneal epithelium was significantly thicker in the eyes of mice treated with GGA compared with those given the vehicle alone (p < 0. 01).

GGA


Input: Significantly fewer TUNEL-positive cells were observed in the eyes of GGA-treated mice than controls after irradiation (p < 0. 01).

GGA


Input: Corneal HSP70 levels were significantly elevated in corneas of mice treated with GGA (p < 0. 05).

GGA


Input: ROS signal was not affected by GGA.

GGA


Input: NF-kappa B activation was reduced but phospho-(Ser/Ther) Akt substrate expression was increased in corneas after irradiation when treated with GGA.

Ser

Ther

GGA


Input: GGA-treatment induced HSP70 expression and ameliorated UV-induced corneal damage through the reduced NF-kappa B activation and possibly increased Akt phosphorilation.

GGA


Input: NMR crystallography of alpha-poly (L-lactide).

alpha-poly (L-lactide)


Input: A complementary approach that combines NMR measurements, analysis of X-ray and neutron powder diffraction data and advanced quantum mechanical calculations was employed to study the alpha-polymorph of L-polylactide.

L-polylactide


Input: Such a strategy, which is known as NMR crystallography, to the best of our knowledge, is used here for the first time for the fine refinement of the crystal structure of a synthetic polymer.