Input: Cyclin-dependent kinase 9/cyclin T, the protein kinase heterodimer that constitutes positive transcription elongation factor b, is a well-validated target for treatment of several diseases, including cancer and cardiac hypertrophy.


Input: In order to aid inhibitor design and rationalize the basis for CDK9 selectivity, we have studied the CDK-binding properties of six different members of a 4-(thiazol-5-yl)-2-(phenylamino) pyrimidine-5-carbonitrile series that bind to both CDK9/cyclin T and CDK2/cyclin A.

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


Input: We find that for a given CDK, the melting temperature of a CDK/cyclin/inhibitor complex correlates well with inhibitor potency, suggesting that differential scanning fluorimetry (DSF) is a useful orthogonal measure of inhibitory activity for this series.


Input: We have used DSF to demonstrate that the binding of these compounds is independent of the presence or absence of the C-terminal tail region of CDK9, unlike the binding of the CDK9-selective inhibitor 5, 6-dichlorobenzimidazone-1-beta-d-ribofuranoside (DRB).

C

5, 6-dichlorobenzimidazone-1-beta-d-ribofuranoside

DRB


Input: Finally, on the basis of 11 cocrystal structures bound to CDK9/cyclin T or CDK2/cyclin A, we conclude that selective inhibition of CDK9/cyclin T by members of the 4-(thiazol-5-yl)-2-(phenylamino) pyrimidine-5-carbonitrile series results from the relative malleability of the CDK9 active site rather than from the formation of specific polar contacts.

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


Input: Development of new cathepsin B inhibitors: combining bioisosteric replacements and structure-based design to explore the structure-activity relationships of nitroxoline derivatives.

nitroxoline


Input: Human cathepsin B has many house-keeping functions, such as protein turnover in lysosomes.


Input: However, dysregulation of its activity is associated with numerous diseases, including cancers.


Input: We present here the structure-based design and synthesis of new cathepsin B inhibitors using the cocrystal structure of 5-nitro-8-hydroxyquinoline in the cathepsin B active site.


Input: A focused library of over 50 compounds was prepared by modifying positions 5, 7, and 8 of the parent compound nitroxoline.

nitroxoline


Input: The kinetic parameters and modes of inhibition were characterized, and the selectivities of the most promising inhibitors were determined.


Input: The best performing inhibitor 17 was effective in cell-based in vitro models of tumor invasion, where it significantly abrogated invasion of MCF-10A neoT cells.


Input: These data show that we have successfully explored the structure-activity relationships of nitroxoline derivatives to provide new inhibitors that could eventually lead to compounds with clinical usefulness against the deleterious effects of cathepsin B in cancer progression.

nitroxoline


Input: Adverse events associated with mTOR inhibitors.


Input: INTRODUCTION: The mTOR (mechanistic target of rapamycin, formerly known as mammalian target of rapamycin) kinase is centrally involved in the regulation of cell growth and metabolism in response to intra-and extracellular energetic stimuli and growth factors.

rapamycin

rapamycin


Input: The importance of mTOR in health and diseases has fueled the development of molecules that inhibit mTOR signaling, including rapalogs (sirolimus, temsirolimus, everolimus and deforolimus), which complex with FK506-binding protein 12 (FK-BP12) to inhibit mTOR complex 1 (MTORC1) activity in an allosteric manner, or the more recent ATP-competitive mTOR inhibitors (mTORi), which target the catalytic site of the enzyme.

sirolimus

temsirolimus

everolimus

deforolimus

ATP


Input: However, clinical development of these mTORi has revealed that these drugs produced numerous side effects that could be serious and/or debilitating.


Input: Despite pharmacological efforts to develop drugs with an improved safety profile, these side effects are often unpredictable and may frequently preclude the efficiency of mTORi.


Input: AREAS COVERED: The objective of this review is to perform a comprehensive survey of the safety profiles of various rapalog-based therapies from the available clinical literature.


Input: The authors will discuss the potential mechanisms of these therapies, taking into account the knowledge of the biological pathways regulated by mTOR.


Input: EXPERT OPINION: A better prevention and management of mTORi-related side effects requires the identification of alterations in related biological pathways that will help to delineate therapeutic targets.


Input: Dependence of QSAR models on the selection of trial descriptor sets: a demonstration using nanotoxicity endpoints of decorated nanotubes.


Input: Little attention has been given to the selection of trial descriptor sets when designing a QSAR analysis even though a great number of descriptor classes, and often a greater number of descriptors within a given class, are now available.


Input: This paper reports an effort to explore interrelationships between QSAR models and descriptor sets.


Input: Zhou and co-workers (Zhou et al., Nano Lett. 2008, 8 (3), 859-865) designed, synthesized, and tested a combinatorial library of 80 surface modified, that is decorated, multi-walled carbon nanotubes for their composite nanotoxicity using six endpoints all based on a common 0 to 100 activity scale.

carbon


Input: Each of the six endpoints for the 29 most nanotoxic decorated nanotubes were incorporated as the training set for this study.


Input: The study reported here includes trial descriptor sets for all possible combinations of MOE, VolSurf, and 4D-fingerprints (FP) descriptor classes, as well as including and excluding explicit spatial contributions from the nanotube.


Input: Optimized QSAR models were constructed from these multiple trial descriptor sets.


Input: It was found that (a) both the form and quality of the best QSAR models for each of the endpoints are distinct and (b) some endpoints are quite dependent upon 4D-FP descriptors of the entire nanotube-decorator complex.


Input: However, other endpoints yielded equally good models only using decorator descriptors with and without the decorator-only 4D-FP descriptors.


Input: Lastly, and most importantly, the quality, significance, and interpretation of a QSAR model were found to be critically dependent on the trial descriptor sets used within a given QSAR endpoint study.


Input: Towards a balanced value business model for personalized medicine: an outlook.


Input: Novel targeted drugs, mainly in oncology, have commanded substantial price premiums in the recent past.


Input: Consequently, the attention of pharmaceutical companies has shifted away from the traditional low-price and high-volume blockbuster business model to drugs that command high, and sometimes extremely high, prices in limited markets defined by targeted patient populations.


Input: This model may have already passed its zenith, as the impact of more and more high-priced drugs coming to market substantially increases their combined burden on payors and public health finances.


Input: This article introduces a new' balanced value' business model for personalized medicine, leveraging the emerging opportunities to reduce drug development cost and time for targeted therapies.


Input: This model allows pharmaceutical companies to charge prices for targeted therapy below the likely future thresholds for payors' willingness to pay, at the same time preserving attractive margins for the drug developers.


Input: Improving clinical trial sampling for future research-an international approach: outcomes and next steps from the DIA future use sampling workshop 2011.


Input: Clinical trial samples collected for pharmacogenomic and future research are vital resources for the development of safe and effective drugs, yet collecting adequate, representative sample sets in global trials is challenging.


Input: The Drug Information Association (DIA) sponsored a workshop on future use sampling in September 2011, bringing together experts from regulatory agencies, academia and industry to discuss challenges to future use sample collection and identify actions to improve collection.


Input: Several common themes and associated action items emerged, including the need for international guidance on the collection of samples for future research; additional discussion related to coding, scope of research, and return of research results; and additional education about pharmacogenomic/future research and the importance of long-term storage of specimens.


Input: Expanding the number of' druggable' targets: non-enzymes and protein-protein interactions.


Input: Following sequencing and assembly of the human genome, the preferred methods for identification of new drug targets have changed dramatically.


Input: Modern tactics such as genome-wide association studies (GWAS) and deep sequencing are fundamentally different from the pharmacology-guided approaches used previously, in which knowledge of small molecule ligands acting at their cellular targets was the primary discovery engine.


Input: A consequence of the' target-first, pharmacology-second' strategy is that many predicted drug targets are non-enzymes, such as scaffolding, regulatory or structural proteins, and their activities are often dependent on protein-protein interactions (PPIs).


Input: These types of targets create unique challenges to drug discovery efforts because enzymatic turnover cannot be used as a convenient surrogate for compound potency.


Input: Moreover, it is often challenging to predict how ligand binding to non-enzymes might affect changes in protein function and/or pathobiology.


Input: Thus, in the postgenomic era, targets might be strongly implicated by molecular biology-based methods, yet they often later earn the designation of' undruggable'.


Input: Can the scope of available targets be widened to include these promising, but challenging, non-enzymes?


Input: In this review, we discuss advances in high-throughput screening (HTS) technology and chemical library design that are emerging to deal with these challenges.


Input: Antibody-drug conjugates for the treatment of cancer.


Input: With over 20 antibody-drug conjugates in clinical trials as well as a recently FDA-approved drug, it is clear that this is becoming an important and viable approach for selectively delivering highly cytotoxic agents to tumor cells while sparing normal tissue.


Input: This review discusses the critical aspects for this approach with an emphasis on the properties of the linker between the antibody and the cytotoxic payload that are required for an effective antibody-drug conjugate.


Input: Different linkers are illustrated with attention focused on (i) the specifics of attachment to the antibody, (ii) the polarity of the linker, (iii) the trigger on the linker that initiates cleavage from the drug, and (iv) the self-immolative spacer that liberates the active payload.


Input: Future directions in the field are proposed.


Input: Peptide scanning for studying structure-activity relationships in drug discovery.


Input: Peptide-based therapeutics have grown in importance over the last few decades.


Input: Furthermore, peptides have been extensively used as lead compounds in the drug discovery process to investigate the nature of chemical space required for molecular recognition and activity at a variety of targets.


Input: This critical commentary reviews scanning techniques, which employ natural and non-proteinogenic amino acids to facilitate understanding of structural requirements for peptide biological activity.

amino acids


Input: The value of sequence analysis by such methods is highlighted by examples, in which the elements for peptide affinity and activity have been elucidated and employed to prepare peptidomimetic leads for drug development.


Input: Neurochemical control of rapid stress-induced changes in brain aromatase activity.


Input: In the male brain, the medial preoptic nucleus (POM) is known to be a critical relay for the activation of sexual behaviour, with the aromatisation of testosterone into 17 beta-oestradiol (E2) playing a key role.

testosterone

17 beta-oestradiol


Input: Acute stress has been shown to differentially modulate the aromatase enzyme in this and other brain nuclei in a sex-specific manner.


Input: In POM specifically, stress induces increases in aromatase activity (AA) that are both rapid and reversible.


Input: How the physiological processes initiated during an acute stress response mediate sex-and nuclei-specific changes in AA and which stress response hormones are involved remains to be determined.


Input: By examining the relative effects of corticosterone (CORT), arginine vasotocin (AVT, the avian homologue to arginine vasopressin) and corticotrophin-releasing factor (CRF), the present study aimed to define the hormone profile regulating stress-induced increases in AA in the POM.

corticosterone

CORT

arginine vasotocin

AVT

arginine vasopressin


Input: We found that CORT, AVT and CRF all appear to play some role in these changes in the male brain.

CORT

AVT


Input: In addition, these effects occur in a targeted manner, such that modulation of the enzyme by these hormones only occurs in the POM rather than in all aromatase-expressing nuclei.


Input: Similarly, in the female brain, the experimental effects were restricted to the POM but only CRF was capable of inducing the stress-like increases in AA.


Input: These data further demonstrate the high degree of specificity (nuclei-, sex-and hormone-specific effects) in this system, highlighting the complexity of the stress-aromatase link and suggesting modes through which the nongenomic modulation of this enzyme can result in targeted, rapid changes in local oestrogen concentrations.

oestrogen


Input: Assessment of the usefulness of the murine cytotoxic T cell line CTLL-2 for immunotoxicity screening by transcriptomics.


Input: A toxicogenomics approach was applied to assess the usefulness of the mouse cytotoxic T cell line CTLL-2 for in vitro immunotoxicity testing.


Input: CTLL-2 cells were exposed for 6 h to two model immunotoxic compounds: (1) the mycotoxin deoxynivalenol (DON, 1 and 2 mu M), a ribotoxic stress inducer, and (2) the organotin compound tributyltin oxide (TBTO, 100 and 200 nM), an endoplasmic reticulum (ER) stress inducer.

deoxynivalenol

DON

organotin

tributyltin oxide

TBTO


Input: Effects on whole-genome mRNA expression were assessed by microarray analysis.


Input: The biological interpretation of the microarray data indicated that TBTO (200 nM) induced genes involved in T cell activation, ER stress, NF kappa B activation and apoptosis, which agreed very well with results obtained before on TBTO exposed Jurkat cells and mouse primary thymocytes.

TBTO

TBTO


Input: Remarkably, DON (2 mu M) downregulated genes involved in T cell activation, ER stress and apoptosis, which is opposite to results obtained before for DON-exposed Jurkat cells and mouse primary thymocytes.

DON

DON


Input: Furthermore, the results for DON in CTLL-2 cells are also opposite to the results obtained for TBTO in CTLL-2 cells.

DON

TBTO


Input: In agreement with the lack of induction of ER stress and apoptosis, viability assays showed that CTLL-2 cells are much more resistant to the toxicity of DON than Jurkat cells and primary thymocytes.

DON


Input: We propose that CTLL-2 cells lack the signal transduction that induces ER stress and apoptosis in response to ribotoxic stress.


Input: Based on the results for TBTO and DON, the CTLL-2 cell line does not yield an added value for immunotoxicity compared to the human Jurkat T cell line.

TBTO

DON


Input: Effect of lactation on postpartum cardiac function of pregnancy-associated hypertensive mice.


Input: Preeclampsia is a serious complication during pregnancy, and recent epidemiological studies indicate the association between preeclampsia and cardiac morbidity and mortality during the postpartum period.


Input: Although the risk of cardiovascular diseases in the postpartum period is affected by lactation, its role in maternal heart with a history of preeclampsia remains unclear.


Input: In this study, we investigated postpartum change in cardiac remodeling and function of pregnancy-associated hypertensive (PAH) mice with and without lactation.


Input: The systolic blood pressure was increased in PAH mice at day 19 of gestation (E19) and was reduced to normal levels in both lactating and nonlactating (NL) groups in the postpartum period.


Input: Histological analyses revealed that cardiac hypertrophy and macrophage infiltration in PAH mice at E19 were improved in both lactating and NL groups at 4 weeks postpartum (4W-PP), while marked fibrosis remained.


Input: Increased mRNA expression of profibrotic genes and proinflammatory cytokines in PAH mice at E19 was significantly reduced in both lactating and NL groups at 4W-PP.


Input: Echocardiographic analysis found no significant differences in fractional shortening between PAH mice and C57BL/6J mice at E19.


Input: On the other hand, at 4W-PP, NL PAH mice showed normal fractional shortening, but lactating PAH mice exhibited significant decreases in cardiac contractility compared with NL PAH mice.


Input: These results show that cardiac remodeling induced by hypertension during pregnancy are improved in the postpartum period except fibrosis, whereas lactation induces cardiac contractile dysfunction in mice with a history of pregnancy-associated hypertension.


Input: Focal adhesion size uniquely predicts cell migration.


Input: Focal adhesions are large protein complexes organized at the basal surface of cells, which physically connect the extracellular matrix to the cytoskeleton and have long been speculated to mediate cell migration.


Input: However, whether clustering of these molecular components into focal adhesions is actually required for these proteins to regulate cell motility is unclear.


Input: Here we use quantitative microscopy to characterize descriptors of focal adhesion and cell motility for mouse embryonic fibroblasts and human fibrosarcoma cells, across a wide range of matrix compliance and following genetic manipulations of focal adhesion proteins (vinculin, talin, zyxin, FAK, and paxilin).


Input: This analysis reveals a tight, biphasic gaussian relationship between mean size of focal adhesions (not their number, surface density, or shape) and cell speed.


Input: The predictive power of this relationship is comprehensively validated by disrupting nonfocal adhesion proteins (alpha-actinin, F-actin, and myosin II) and subcellular organelles (mitochondria, nuclear DNA, etc.) not known to affect either focal adhesions or cell migration.


Input: This study suggests that the mean size of focal adhesions robustly and precisely predicts cell speed independently of focal adhesion surface density and molecular composition.-Kim, D.-H., Wirtz, D.


Input: Focal adhesion size uniquely predicts cell migration.


Input: Formation and infrared absorption of protonated naphthalenes (1-C10H9 + and 2-C10H9 +) and their neutral counterparts in solid para-hydrogen.

protonated naphthalenes

1-C10H9 +

2-C10H9 +

para-hydrogen


Input: Protonated naphthalene (C (10) H (9) (+)) and its neutral counterparts (hydronaphthyl radicals, C (10) H (9)) are important intermediates in the reactions of aromatic compounds and in understanding the unidentified infrared (IR) emissions from interstellar media.

Protonated naphthalene

C (10) H (9) (+)

hydronaphthyl

C (10) H (9)


Input: We report the IR spectra of 1-C (10) H (9) (+), 2-C (10) H (9) (+), 1-C (10) H (9), and 2-C (10) H (9) trapped in solid para-hydrogen (p-H (2)); the latter three are new.

1-C (10) H (9) (+)

2-C (10) H (9) (+)

1-C (10) H (9)

2-C (10) H (9)

para-hydrogen

p-H (2)


Input: These species were produced upon electron bombardment of a mixture of naphthalene (C (10) H (8)) and p-H (2) during matrix deposition.

naphthalene

C (10) H (8)

p-H (2)


Input: The intensities of IR features of 1-C (10) H (9) (+) decreased after the matrix was maintained in darkness for 19 h, whereas those of 1-C (10) H (9) and 2-C (10) H (9) increased.

1-C (10) H (9) (+)

1-C (10) H (9)

2-C (10) H (9)


Input: Irradiation of this matrix sample with light at 365 nm diminished lines of 1-C (10) H (9) (+) and 2-C (10) H (9) and enhanced lines of 1-C (10) H (9) and 2-C (10) H (9) (+); the latter species was unstable and converted to 1-C (10) H (9) (+) in less than 30 min and 2-C (10) H (9) was converted to 1-C (10) H (9) at 365 nm.

1-C (10) H (9) (+)

2-C (10) H (9)

1-C (10) H (9)

2-C (10) H (9) (+)

1-C (10) H (9) (+)

2-C (10) H (9)

1-C (10) H (9)


Input: Observed wavenumbers and relative intensities of these species agree satisfactorily with the anharmonic vibrational wavenumbers and IR intensities predicted with the B3PW91/6-311 + + G (2d, 2p) method.


Input: Compared with spectra recorded previously with IR photodissociation of Ar-tagged C (10) H (9) (+) or IR multiphoton dissociation of C (10) H (9) (+), our method has the advantages of producing high-resolution IR spectra with a wide spectral coverage, true IR intensity and excellent ratio of signal to noise; both protonated species and their neutral counterparts are produced with little interference from other fragments.

Ar

C (10) H (9) (+)

C (10) H (9) (+)


Input: With these advantages, the IR spectra of 1-C (10) H (9) (+), 2-C (10) H (9) (+), 1-C (10) H (9), and 2-C (10) H (9) are here clearly characterized.

1-C (10) H (9) (+)

2-C (10) H (9) (+)

1-C (10) H (9)

2-C (10) H (9)


Input: Identification of multiple binding sites for substrate transport in bovine organic anion transporting polypeptide 1a2.


Input: Organic anion transporting polypeptides (OATP) have been extensively recognized as key determinants of absorption, distribution, metabolism, and excretion of various drugs because of their broad substrate specificity, wide tissue distribution, and the involvement of drug-drug interaction.


Input: As the first cloned human OATP, OATP1A2 has been found to transport a wide spectrum of endogenous and exogenous compounds.


Input: Bovine Oapt1a2 shared high homology with the human transporter and is considered as its functional ortholog.


Input: In the present study, we expressed bovine Oatp1a2 in human embryonic kidney 293 cells and found that, unlike human OATP1A2, the transport of estrone-3-sulfate (E-3-S) exhibited biphasic saturation kinetics.


Input: The K (m) values are 0. 25 +/- 0. 08 and 46. 6 +/- 18. 5 micro M, and V (max) values were 24. 5 +/- 4. 4 and 375 +/- 142 pmol/mg protein/min for high-and low-affinity sites, respectively, suggesting the presence of multiple binding sites.


Input: Further study on other Oatp1a2 substrates showed that the high affinity component for E-3-S is responsible for the interaction with taurocholate, bromsulphthalein, and rifampicin and is sensitive to proton concentration change, whereas the low affinity binding site is only involved in the binding of the antitumor drug methotrexate and had no response to change of pH.

taurocholate

bromsulphthalein

rifampicin

methotrexate


Input: Bamboo salt has in vitro anticancer activity in HCT-116 cells and exerts anti-metastatic effects in vivo.


Input: Bamboo salt is a traditional food widely used in Korea.


Input: The in vitro anticancer effects of this salt were evaluated in HCT-116 human colon cancer cells using a 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyltetrazolium bromide (MTT) assay.

3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyltetrazolium bromide

MTT


Input: A 1% salt concentration of bamboo salt baked nine times (9 x) inhibited the growth of HCT-116 cells by 53%, which was higher than salt baked three times (3 x) or once (1 x; 44% and 41%, respectively) and much higher than solar sea salt (Korean sea salt) and purified salt (22% and 18%, respectively).


Input: To elucidate the inhibitory mechanisms underlying the anticancer effect of the salt samples in cancer cells, expression of genes associated with apoptosis, inflammation, and metastasis was measured with reverse transcription-polymerase chain reaction and Western blotting.


Input: Bamboo salt (9 x) significantly induced apoptosis in cancer cells (P <. 05) by upregulating Bax, caspase-9, and caspase-3, and downregulating Bcl-2.


Input: The expression of genes associated with inflammation (NF-kappa B, iNOS, and COX-2) was significantly downregulated (P <. 05) by 9 x bamboo salt, demonstrating its anti-inflammatory properties.


Input: The 9 x bamboo salt also exerted a greater anti-metastatic effect on cancer cells than the other salts as demonstrated by decreased mRNA expression of MMP genes and increased expression of tissue inhibitors of metalloproteinases, which was confirmed by the inhibition of tumor metastasis induced in colon 26-M3. 1 cells in BALB/c mice.


Input: In contrast, purified and solar salts increased metastasis in the mice.

solar salts


Input: Our results demonstrated that 9 x bamboo salt had the most potent in vitro anticancer effect, induced apoptosis, had anti-inflammatory activities, and exerted in vivo anti-metastatic effects.


Input: Additionally, the anticancer, anti-inflammatory, and anti-metastatic effects of the 1 x and 3 x bamboo salts were stronger than those of the purified and solar salts.

solar salts


Input: Iodine-129 microdosing for protein and peptide drug development: erythropoietin as a case study.


Input: BACKGROUND: Microdosing is a technique for studying the behavior of compounds in vivo at 1/100th of the dose of a test substance calculated, based on animal data, to yield a pharmacologic effect.


Input: In microdosing, use is made of accelerator MS (AMS).


Input: In this study, we investigated whether (129) I-labeling of proteins with subsequent AMS measurements is a suitable method to perform microdose studies with therapeutic proteins.

(129) I


Input: We used erythropoietin (EPO) as a case study.


Input: RESULTS: In an animal study with (129) I-labeled EPO in Han-Wistar rats, an increase of (129) I-EPO is observed after dose administration.

(129) I

(129) I


Input: The half-life was found to be 2 and 5. 5 h for two different EPOs.


Input: These results are in accordance with expected values.


Input: CoNCLUSION: Although further research is required, (129) I-labeling of proteins seems a feasible method for AMS microdose studies with peptide and protein drugs, such as biosimilars.

(129) I


Input: Structural-Functional Studies of Burkholderia cenocepaciad-Glycero-beta-d-manno-heptose 7-Phosphate Kinase (HldA) and Characterization of Inhibitors with Antibiotic Adjuvant and Antivirulence Properties.

Glycero-beta-d-manno-heptose 7-Phosphate


Input: As an essential constituent of the outer membrane of Gram-negative bacteria, lipopolysaccharide contributes significantly to virulence and antibiotic resistance.


Input: The lipopolysaccharide biosynthetic pathway therefore serves as a promising therapeutic target for antivirulence drugs and antibiotic adjuvants.


Input: Here we report the structural-functional studies of d-glycero-beta-d-manno-heptose 7-phosphate kinase (HldA), an absolutely conserved enzyme in this pathway, from Burkholderia cenocepacia.

d-glycero-beta-d-manno-heptose 7-phosphate


Input: HldA is structurally similar to members of the PfkB carbohydrate kinase family and appears to catalyze heptose phosphorylation via an in-line mechanism mediated mainly by a conserved aspartate, Asp270.

carbohydrate

heptose

aspartate


Input: Moreover, we report the structures of HldA in complex with two potent inhibitors in which both inhibitors adopt a folded conformation and occupy the nucleotide-binding sites.

nucleotide


Input: Together, these results provide important insight into the mechanism of HldA-catalyzed heptose phosphorylation and necessary information for further development of HldA inhibitors.

heptose


Input: Application of a liquid chromatography-electrospray mass spectrometry (LC/MS) method to the biodistribution and excretion studies of novel 5'-chloro-2, 3-didehydroindolo (2', 3': 2, 3) betulinic acid (DRF-4012) in tumour-bearing mice.

5'-chloro-2, 3-didehydroindolo (2', 3': 2, 3) betulinic acid


Input: Novel betulinic acid derivative 5'-chloro-2, 3-didehydroindolo [2', 3': 2, 3] betulinic acid (DRF-4012) is a new effective lupane type triterpenes with greater anticancer activity and efficacy than betulinic acid and currently under advanced preclinical investigation phase.

betulinic acid

5'-chloro-2, 3-didehydroindolo [2', 3': 2, 3] betulinic acid

lupane

triterpenes

betulinic acid


Input: In this study, a sensitive and rapid liquid chromatography-electrospray mass spectrometric (LC/MS) method has been developed for the determination of DRF-4012 in tumour-bearing mice plasma, urine, feces and tissues (liver, brain, lungs, heart, spleen, stomach, thigh muscle, kidneys, urinary bladder, small intestine and tumour).


Input: Biodistribution and excretion studies were performed for DRF-4012 nanoparticle (30 mg/kg body weight) after intravenous (i. v.) injection in tumour-bearing mice.


Input: DRF-4012 rapidly distributed throughout the body.


Input: After 0. 5 h, tumour showed the second highest concentration, which was nearly half of the liver.


Input: After 4 and 24 h, the highest concentration of DRF-4012 was found in tumour indicating its retention in tumour site for a longer time.


Input: Excretion studies revealed that very low amount of unchanged DRF-4012 was observed in urine and primarily excreted through fecal route.


Input: This study may be useful to explain the manner in which DRF-4012 can inhibit tumour growth without apparent toxicity and preclinical/clinical evaluation of this potential antitumour agent.


Input: Characterization of in vitro metabolites of luotonin A in human liver microsomes using electrospray/tandem mass spectrometry.

luotonin A


Input: The pharmacological activity of luotonin A varies, depending on the type of functional group and the site of derivatization.

luotonin A


Input: To understand the in vivo efficacy of luotonin A, the in vitro metabolism of luotonin A was investigated in human liver microsomes and recombinant cDNA-expressed cytochromeP450 (CYP).

luotonin A

luotonin A


Input: Incubation of luotonin A with pooled human liver microsomes in the presence of NADPH-generating system resulted in the formation of four metabolites and the structures of each metabolite were tentatively characterized on the basis of electrospray tandem mass spectra.

luotonin A

NADPH


Input: The main metabolic pathway of luotonin A in human liver microsomes was hydroxylation, resulting in the generation of two mono-hydroxyl metabolites (M1 and M2) and two di-hydroxyl metabolites (M3 and M4).

luotonin A

mono-hydroxyl

di-hydroxyl


Input: CYP1A2 was primarily involved in hydroxylation of the quinolone moiety (M1 andM3), while CYP3A4 was mainly responsible for hydroxylation of the quinazoline moiety of luotonin A (M2 and M4) in human liver microsomes.

quinolone

quinazoline

luotonin A


Input: Evaluation of low background liquid scintillation counter for non-clinical ADME studies.


Input: 1. The performance of low background (BG) liquid scintillation counter (LSC) was evaluated for practical purposes of non-clinical drug absorption, distribution, metabolism and excretion (ADME) studies.


Input: The measurement conditions for the radioactivity for low BG LSC were investigated and metabolite profiling in rat plasma after single oral administration of (14) C-labeled compounds was performed.

(14) C


Input: Metabolite profiling was also conducted using conventional LSC and accelerator mass spectrometer (AMS), and the performances of these measuring instruments were compared.


Input: 2. The established measurement conditions showed good linearity of the calibration curve over the concentration range from 3 to 300 dpm/vial.


Input: Metabolite profiling using low BG LSC for the plasma samples diluted to 5-55 times was comparable to that using conventional LSC for the undiluted plasma samples.


Input: Meanwhile, metabolite profiling using AMS for the plasma samples diluted to 250-2000 times was comparable to that using conventional LSC.


Input: 3. These results suggest that the application of low BG LSC is one of the useful tools for non-clinical ADME studies and that it is possible to select conventional LSC, low BG LSC or AMS for radioactivity measurement by considering the specific radioactivity of the compounds and the predicted concentrations of radioactivity in biological samples in ADME studies.


Input: The effects of kisspeptin in human reproductive function-therapeutic implications.


Input: Kisspeptin is a 54-amino acid peptide which is encoded by the KiSS-1 gene and activates the G protein-coupled receptor GPR54.

amino acid


Input: Evidence suggests that this system is a key regulator of mammalian and human reproduction.


Input: Animal studies have shown that GPR54-deficient mice have abnormal sexual development.


Input: Central and peripheral administration of kisspeptin stimulates the hypothalamic-pituitary-gonadal (HPG) axis whilst pre-administration of a gonadotrophin releasing hormone (GnRH) antagonist abolishes this effect.

gonadotrophin releasing hormone

GnRH


Input: In humans, inactivating GPR54 mutations cause normosmic hypogonadotrophic hypogonadism whilst activation of GPR54 signalling is associated with premature puberty.


Input: In healthy human volunteers, the acute intravenous administration of kisspeptin potently increases plasma luteinising hormone (LH) levels and significantly increases plasma follicle stimulating hormone (FSH) and testosterone without side effects in both males and in females particularly in the preovulatatory phase of the menstrual cycle.

testosterone


Input: In infertility due to hypothalamic amenorrhoea acute administration of kisspeptin results in stimulation of reproductive hormones.


Input: The kisspeptin/GPR54 system therefore appears to play an important role in the regulation of reproduction in humans.


Input: Hence kisspeptin has potential as a novel tool for the manipulation of the HPG axis and treatment of infertility in humans.


Input: This review discusses the evidence highlighting kisspeptin' s key role in human reproduction.


Input: Construction and Characterization of Molecular Nonwoven Fabrics Consisting of Cross-Linked Poly (gamma-methyl-l-glutamate).

Poly (gamma-methyl-l-glutamate)


Input: Molecular nonwoven fabrics in the form of ultrathin layer-by-layer (LbL) helical polymer films with covalent cross-linking were assembled on substrates by an alternate ester-amide exchange reaction between poly (gamma-methyl l-glutamate) (PMLG) and cross-linking agent ethylene diamine or 4, 4'-diamino azobenzene.

ester

amide

poly (gamma-methyl l-glutamate)

PMLG

ethylene diamine

4, 4'-diamino azobenzene


Input: The regular growth of helical monolayers without excessive adsorption and the formation of amide bonds were confirmed by ultraviolet-visible (UV-vis) spectrophotometry, quartz crystal microbalance (QCM), ellipsometry, and infrared reflection-absorption spectroscopy (IR-RAS) measurements.

amide

quartz


Input: Nanostructures with high uniformity and ultrathin films with few defects formed by helical rod segments of PMLG were characterized by atomic force microscopy (AFM) and Kelvin probe force microscopy (KFM).

PMLG


Input: Dating an impressive Neotropical radiation: Molecular time estimates for the Sigmodontinae (Rodentia) provide insights into its historical biogeography.


Input: With about 400 living species and 82 genera, rodents of the subfamily Sigmodontinae comprise one of the most diverse and more broadly distributed Neotropical mammalian clades.


Input: There has been much debate on the origin of the lineage or the lineages of sigmodontines that entered South America, the timing of entrance and different aspects of further diversification within South America.


Input: The ages of divergence of the main lineages and the crown age of the subfamily were estimated by using sequences of the interphotoreceptor retinoid binding protein and cytochrome b genes for a dense sigmodontine and muroid sampling.

retinoid


Input: Bayesian inference using three fossil calibration points and a relaxed molecular clock estimated a middle Miocene origin for Sigmodontinae (~ 12Ma), with most tribes diversifying throughout the Late Miocene (6. 9-9. 4Ma).


Input: These estimates together results of analyses of ancestral area reconstructions suggest a distribution for the most recent common ancestor of Sigmodontinae in Central-South America and a South American distribution for the most recent common ancestor of Oryzomyalia.


Input: Fragile X syndrome: from targets to treatments.


Input: Fragile X syndrome (FXS) is one of the most prevalent and well-studied monogenetic causes of intellectual disability and autism and, although rare, its high penetrance makes it a desirable model for the study of neurodevelopmental disorders more generally.


Input: Indeed recent studies suggest that there is functional convergence of a number of genes that are implicated in intellectual disability and autism indicating that an understanding of the cellular and biochemical dysfunction that occurs in monogenic forms of these disorders are likely to reveal common targets for therapeutic intervention.


Input: Fundamental research into FXS has provided a wealth of information about how the loss of function of the fragile X mental retardation protein results in biochemical, anatomical and physiological dysfunction leading to the discovery of interventions that correct many of the core pathological phenotypes associated with animal models of FXS.


Input: Most promisingly such strategies have led to development of drugs that are now in clinical trials.


Input: This review highlights how progress in understanding disorders such as FXS has led to a new era in which targeted molecular treatment towards neurodevelopmental disorders is becoming a reality.


Input: This article is part of the Special Issue entitled' Neurodevelopmental Disorders'.


Input: Genipin stimulates glucose transport in C2C12 myotubes via an IRS-1 and calcium-dependent mechanism.

Genipin

glucose

calcium


Input: Genipin, a compound derived from Gardenia jasminoides Ellis fruits, has been used over the years in traditional Chinese medicine to treat symptoms of type 2 diabetes.

Genipin


Input: However, the molecular basis for its antidiabetic effect has not been fully revealed.


Input: In this study, we investigated the effects of genipin on glucose uptake and signaling pathways in C (2) C (12) myotubes.

genipin

glucose


Input: Our study demonstrates that genipin stimulated glucose uptake in a time-and dose-dependent manner.

genipin

glucose


Input: The maximal effect was achieved at 2 h with a concentration of 10 mu M.


Input: In myotubes, genipin promoted glucose transporter 4 (GLUT4) translocation to the cell surface, which was observed by analyzing their distribution in subcellular membrane fraction, and increased the phosphorylation of insulin receptor substrate-1 (IRS-1), AKT, and GSK3 beta.

genipin

glucose


Input: Meanwhile, genipin increased ATP levels, closed K (ATP) channels, and then increased the concentration of calcium in the cytoplasm in C (2) C (12) myotubes.

genipin

ATP

K

ATP

calcium


Input: Genipin-stimulated glucose uptake could be blocked by both the PI3-K inhibitor wortmannin and calcium chelator EGTA.

Genipin

glucose

wortmannin

calcium

EGTA


Input: Moreover, genipin increases the level of reactive oxygen species and ATP in C (2) C (12) myotubes.

genipin

oxygen

ATP


Input: These results suggest that genipin activates IRS-1, PI3-K, and downstream signaling pathway and increases concentrations of calcium, resulting in GLUT4 translocation and glucose uptake increase in C (2) C (12) myotubes.

genipin

calcium

glucose


Input: Electrophoresis of randomly and vertically embedded graphene nanosheets in activated carbon film as a counter electrode for dye-sensitized solar cells.

graphene

carbon


Input: A new approach has been developed to randomly and vertically embed the graphene nanosheets (GNs) in the activated carbon (AC) film in an applied electric field.

graphene

carbon


Input: The activated carbon (AC) nanoparticles in suspension during electrophoresis play an important role in supporting the GNs perpendicular to the FTO (fluorine-doped tin oxide) glass.

carbon

FTO

fluorine-doped tin oxide


Input: Insufficient amount of AC nanoparticles might result in a deposition of GNs parallel to the FTO glass, leading to incomplete utilization of the surface area accessible to electrolyte ions.

FTO


Input: An AC cathode with randomly and vertically embedded GNs facilitated electrolyte penetration and electron conduction.


Input: The photoelectron conversion efficiency of the cell was increased to 7. 50% by employing the AC cathode with randomly and vertically embedded GNs.


Input: Heterogeneous oxidation of a phosphocholine on synthetic sea salt by ozone at room temperature.

phosphocholine

ozone


Input: The ozonolysis of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) adsorbed on salt mixtures as models for sea-salt particles was studied in real time using diffuse reflection infrared Fourier transform spectrometry (DRIFTS) at room temperature with and without added water vapor.

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

POPC


Input: The salt substrates were a mixture of MgCl (2). 6H (2) O with NaCl or a commercially available synthetic sea salt.

MgCl (2). 6H (2) O

NaCl


Input: Ozone concentrations ranged from (0. 25 to 3. 9) x 10 (13) molecules cm (-3) (0. 1-1. 6 ppm).

Ozone


Input: The major products identified by FTIR and confirmed using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry were the secondary ozonide (SOZ) and a phospholipid aldehyde and carboxylic acid formed by scission of the double bond.

secondary ozonide

SOZ

aldehyde

carboxylic acid


Input: The reaction probabilities for the two substrates were similar, gamma = (6-7) x 10 (-7), with an estimated overall uncertainty of a factor of two.


Input: The presence of water vapor decreased the yield of SOZ relative to the products formed by C [double bond, length as m-dash] C scission, but also increased the availability of the double bond for reaction, particularly on the less hygroscopic commercial sea-salt substrate.

SOZ

C

C


Input: Thus, water not only affects the mechanisms and products, but also the structure of the phospholipid on the salt in a manner that affects its reactivity.


Input: The results of these studies suggest that the reactivity and products of oxidation of unsaturated phospholipids on sea-salt particles in air will be very sensitive to the nature and phase of the substrate, the amount of water present, and whether there is phase separation between the organics and the inorganic salt mixture.


Input: Prediction of (TiO2) x (Cu2O) y alloys for efficient photoelectrochemical water splitting.

(TiO2) x (Cu2O) y


Input: The formation of (TiO (2)) (x) (Cu (2) O) (y) solid-solutions is investigated using a global optimization evolutionary algorithm.

(TiO (2)) (x) (Cu (2) O) (y)


Input: First-principles calculations based on density functional theory are then used to gain insight into the electronic properties of these alloys.


Input: We find that: (i) Ti and Cu in (TiO (2)) (x) (Cu (2) O) (y) alloys have similar local environments as in bulk TiO (2) and Cu (2) O except for (TiO (2)) (Cu (2) O) which has some trigonal-planar Cu ions.

Ti

Cu

(TiO (2)) (x) (Cu (2) O) (y)

TiO (2)

Cu (2) O

TiO (2)

Cu (2) O

Cu


Input: (ii) The predicted optical band gaps are around 2. 1 eV (590 nm), thus having much better performance in the absorption of visible light compared with both binary oxides.

oxides


Input: (iii) (TiO (2)) (2) (Cu (2) O) has the lowest formation energy amongst all studied alloys and the positions of its band edges are found to be suitable for solar-driven water splitting applications.

(TiO (2)) (2) (Cu (2) O)


Input: pH tuning of DNA translocation time through organically functionalized nanopores.


Input: Controlling DNA translocation speed is critically important for nanopore sequencing as free electrophoretic threading is far too rapid to resolve individual bases.


Input: A number of promising strategies have been explored in recent years, largely driven by the demands of next-generation sequencing.


Input: Engineering DNA-nanopore interactions (known to dominate translocation dynamics) with organic coatings is an attractive method as it does not require sample modification, processive enzymes, or complicated and expensive fabrication steps.


Input: In this work, we show for the first time 4-fold tuning of unfolded, single-file translocation time through small, amine-functionalized solid-state nanopores by varying the solution pH in situ.

amine


Input: Additionally, we develop a simple analytical model based on electrostatic interactions to explain this effect which will be a useful tool in designing future devices and experiments.


Input: Visualization and virtual screening of the chemical universe database GDB-17.


Input: The chemical universe database GDB-17 contains 166. 4 billion molecules of up to 17 atoms of C, N, O, S, and halogens obeying rules for chemical stability, synthetic feasibility, and medicinal chemistry.

C

N

O

S

halogens


Input: GDB-17 was analyzed using 42 integer value descriptors of molecular structure which we term " Molecular Quantum Numbers " (MQN).


Input: Principal component analysis and representation of the (PC1, PC2)-plane provided a graphical overview of the GDB-17 chemical space.


Input: Rapid ligand-based virtual screening (LBVS) of GDB-17 using the city-block distance CBD (MQN) as a similarity search measure was enabled by a hashed MQN-fingerprint.


Input: LBVS of the entire GDB-17 and of selected subsets identified shape similar, scaffold hopping analogs (ROCS > 1. 6 and T (SF) < 0. 5) of 15 drugs.


Input: Over 97% of these analogs occurred within CBD (MQN) <= 12 from each drug, a constraint which might help focus advanced virtual screening.


Input: An MQN-searchable 50 million subset of GDB-17 is publicly available at www. gdb. unibe. ch.


Input: Tailorable cell culture platforms from enzymatically cross-linked multifunctional poly (ethylene glycol)-based hydrogels.

poly (ethylene glycol)


Input: As stem-cell-based therapies rapidly advance toward clinical applications, there is a need for cheap, easily manufactured, injectable gels that can be tailored to carry stem cells and impart function to such cells.


Input: Herein we describe a process for making hydrogels composed of hydroxyphenyl propionic acid (HPA) conjugated, branched poly (ethylene glycol) (PEG) via an enzyme mediated, oxidative cross-linking method.

hydroxyphenyl propionic acid

HPA

poly (ethylene glycol)

PEG


Input: Functionalization of the branched PEG with HPA at varying degrees of substitution was confirmed via attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and (1) H NMR.

PEG

HPA

(1) H


Input: The versatility of this hydrogel system was exemplified through variations in the degree of HPA substitution, polymer concentration, and the concentration of cross-linking reagents (horseradish peroxidase and H (2) O (2)), which resulted in a range of mechanical properties and gelation kinetics for these gels.

HPA

H (2) O (2)


Input: Cross-linking of the PEG-HPA conjugate with a recombinantly produced Fibronectin fragment (Type III domains 7-10) encouraged attachment and spreading of human mesenchymal stem cells (hMSCs) when assessed in both two-dimensional and three-dimensional formats.

PEG-HPA


Input: Interestingly, when encapsulated in both nonfunctionalized and functionalized cross-linked PEG-HPA gels, MSCs showed good viability over all time periods assessed.

PEG-HPA


Input: With tunable gelation kinetics and mechanical properties, these hydrogels provide a flexible in vitro cell culture platform that will likely have significant utility in tissue engineering as an injectable delivery platform for cells to sites of tissue damage.


Input: Discovery of a new series of [1, 2, 4] triazolo [4, 3-a] quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors.

[1, 2, 4] triazolo [4, 3-a] quinoxalines


Input: The synthesis, preliminary evaluation and structure-activity relationship (SAR) of a series of 1-aryl-4-methyl [1, 2, 4] triazolo [4, 3-a] quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors are described.

1-aryl-4-methyl [1, 2, 4] triazolo [4, 3-a] quinoxalines


Input: From this investigation compound 31 was identified, showing good combined potency, acceptable brain uptake and high selectivity for both PDE2 and PDE10 enzymes.


Input: Compound 31 was subjected to a microdosing experiment in rats, showing preferential distribution in brain areas where both PDE2 and PDE10 are highly expressed.


Input: These promising results may drive the further development of highly potent combined PDE2/PDE10 inhibitors, or even of selective inhibitors of PDE2 and/or PDE10.


Input: Discovering gene-environment interactions in Glioblastoma through a comprehensive data integration bioinformatics method.


Input: Glioblastoma multiforme (GBM) is the most common and aggressive type of human brain tumor.


Input: Although considerable efforts to delineate the underlying pathophysiological pathways have been made during the last decades, only very limited progress on treatment have been achieved because molecular pathways that drive the aggressive nature of GBM are largely unknown.


Input: Recent studies have emphasized the importance of environmental factors and the role of gene-environment interactions (GEI) in the development of GBM.


Input: Factors such as small sample sizes and study costs have limited the conduct of GEI studies in brain tumors however.


Input: Additionally, advances in high-throughput microarrays have produced a wealth of information concerning molecular biology of glioma.


Input: In particular, microarrays have been used to obtain genetic and epigenetic changes between normal non-tumor tissue and glioma tissue.


Input: Due to the relative rarity of gliomas, microarray data for these tumors is often the product of small studies, and thus pooling this data becomes desirable.


Input: To address the challenge of small sample sizes and GEI study difficulties, we introduce a comprehensive bioinformatics method using genetic variations (copy number variations and small-scale variations) and environmental data integration that links with Glioblastoma (GEG) to identify: (1) genes that interact with chemicals and have genetic variants linked to the development of GBM, (2) important pathways that may be influenced by environmental exposures (or endogenous chemicals), and (3) genes with variants in GBM that have been understudied in relation to GBM development.


Input: The first step in our GEG method identified genes responsive to environmental exposures using the Environmental Genome Project, Comparative Toxicology, and Seattle SNPs databases.


Input: These environmentally responsive genes were then compared to a curated list of genes containing copy number variation and/or mutations in GBM.


Input: This comparison produced a list of genes responsive to the environment and important to GBM that was then further analyzed using gene networking tools such as RSpider, Cytoscape, and DAVID.


Input: Using this GEG bioinformatics method we were able to identify 173 genes with the potential to be involved in GEI that may be important to the development of GBM.


Input: Sixty five of these environmentally responsive genes have not been reported as important to GBM development, despite several of them having substantial potential for response to chemicals and subsequent disease related actions.


Input: The main biological functions of these 173 genes include signaling by Nerve Growth Factor, DNA Repair, Integrin Cell Surface Interactions, Biological Oxidations, Apoptosis, Synaptic Transmission, Cell Cycle Checkpoints, and Arachidonic Acid Metabolism.

Arachidonic Acid


Input: Importantly, some of these functions have been implicated in the development of several cancers, including glioma.


Input: In summary, our GEG bioinformatics approach revealed potential gene-environment interactions, and generated new data for hypothesis generation, in GBM.


Input: Central nervous system damage due to acute paraquat poisoning: an experimental study with rat model.

paraquat


Input: Paraquat (PQ) is a common herbicide and PQ poisoning is a major medical problem in Asia.

Paraquat


Input: However, few studies have focused on the acute neurotoxic changes caused by PQ.


Input: Here we report the acute neurotoxicological findings of rats treated with lethal dose of PQ.


Input: In substantia nigra (SN) and striatum we found obvious microglia (labeled by Iba-1) activation within one week.


Input: In SN and hippocampus, we detected increased oxidative stress in the neurons based on NeuN/8-OHdG immunofluorescence double labeling and laser cofocal microscopy.


Input: Moreover, we provided ultrastructural evidences of astrocyte edema and neurons apoptosis in rat brain by electron microscopy.


Input: Further studies will be needed with non-lethal dose of PQ to confirm these results and demonstrate the direct CNS toxicity of PQ.


Input: The uptake and distribution of selenium in three aquatic plants grown in Se (IV) solution.

selenium

Se (IV)


Input: The uptake of Se (IV) by Myriophyllum spicatum, Ceratophyllum demersum and Potamogeton perfoliatus, and the effects of Se (IV) on their physiological and biochemical characteristics were studied.

Se (IV)

Se (IV)


Input: Plants were cultivated outdoors under semi-controlled conditions in water solution containing Na selenite (20 mu g Se L (-1) and 10 mg Se L (-1)).

Na selenite

Se

Se


Input: The higher concentration of Se lowered the photochemical efficiency of PSII in all species studied, while the lower concentration had no effect on any species.

Se


Input: The higher concentration of Se lowered respiratory potential in M. spicatum.

Se


Input: The response of M. spicatum and C. demersum to Se (IV) regarding chlorophylls was variable, however in the majority of cases, there was a trend of increasing the amount of chlorophylls, while in P. perfoliatus the amount of chlorophyll a decreased.

Se (IV)

chlorophylls

chlorophylls

chlorophyll a


Input: The concentration of Se in plants cultured in 10 mg Se (IV) L (-1) ranged from 436 to 839 mu g Se g (-1) DM in M. spicatum, 319 to 988 mu g Se g (-1) DM in C. demersum and 310 to 661 mu g Se g (-1) DM in P. perfoliatus.

Se

Se (IV)

Se

Se

Se


Input: The amount of soluble Se compounds in enzyme extracts of high Se treatment was 27% in M. spicatum, 41% in C. demersum and 35% in P. perfoliatus.

Se

Se


Input: Se compounds were determined using HPLC-ICP-MS.

Se


Input: It was observed that the applied Se (IV) was mainly transformed to insoluble Se.

Se (IV)

Se


Input: Qalibra: a general model for food risk-benefit assessment that quantifies variability and uncertainty.


Input: The EU project BRAFO proposed a framework for risk-benefit assessment of foods, or changes in diet, that present both potential risks and potential benefits to consumers (Hoekstra et al., 2012a).


Input: In higher tiers of the BRAFO framework, risks and benefits are integrated quantitatively to estimate net health impact measured in DALYs or QALYs (disability-or quality-adjusted life years).


Input: This paper describes a general model that was developed by a second EU project, Qalibra, to assist users in conducting these assessments.


Input: Its flexible design makes it applicable to a wide range of dietary questions involving different nutrients, contaminants and health effects.


Input: Account can be taken of variation between consumers in their diets and also other characteristics relevant to the estimation of risk and benefit, such as body weight, gender and age.


Input: Uncertainty in any input parameter may be quantified probabilistically, using probability distributions, or deterministically by repeating the assessment with alternative assumptions.


Input: Uncertainties that are not quantified should be evaluated qualitatively.


Input: Outputs produced by the model are illustrated using results from a simple assessment of fish consumption.


Input: More detailed case studies on oily fish and phytosterols are presented in companion papers.

phytosterols


Input: The model can be accessed as web-based software at www. qalibra. eu.


Input: Shikonin induces programmed necrosis-like cell death through the formation of receptor interacting protein 1 and 3 complex.

Shikonin


Input: An alternative cell demise programmed necrosis has also been proposed when apoptotic machinery is impaired or blocked during tumor necrosis factor alpha (TNF alpha) stimulation.


Input: Shikonin (SKN), an herbal extract from the Chinese plant, has been reported to induce either apoptosis or necrosis depending on cell types or its concentrations.

Shikonin

SKN


Input: In this presentation, SKN caused cell death of NIH3T3 in a dose-dependent manner.

SKN


Input: Intriguingly, SKN-mediated cell death was in part protected by necrostatin-1 (Nec-1), a specific inhibitor of programmed necrosis, but not zVAD a pan-caspase inhibitor.

SKN


Input: SKN directly mediated cell death via receptor interacting protein1 and 3 (RIP1-RIP3) complex formation, which is required for TNF alpha-mediated programmed necrosis.

SKN


Input: Additionally, SKN-caused cell death was reversed by a reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) whereas TNF alpha-mediated necrosis was successfully protected by butylated hydroxyanisole (BHA), implying that ROS may be differentially derived from death inducing agents.

SKN

oxygen

N-acetylcysteine

NAC

butylated hydroxyanisole

BHA


Input: Concurrently with the protective effect of the ROS scavenger or Nec-1 on TNF alpha or SKN, the RIP1-RIP3 complex was significantly affected in the presence of those agents.


Input: Here, it is highlighted that SKN as well as TNF alpha can directly mediate cell death via a pronecrotic complex, but ROS were generated via different routes depending on cell death-inducing agents.

SKN


Input: Comparative analysis of genetic toxicity of antiretroviral combinations in somatic cells of Drosophila melanogaster.


Input: Nucleoside reverse-transcriptase inhibitor (NRTI) drugs are a major component of highly-active antiretroviral therapy (HAART).

Nucleoside


Input: NRTI combinations have been demonstrated as producing a sustained reduction in plasma viremia with an increased CD4 count, thereby showing clear clinical benefits.


Input: Therefore, the secondary effects caused by the combination of two NRTIs, mainly those related to amplification of genotoxic effects, due to increased risk of DNA damage caused by these drugs, should be carefully examined.


Input: We employed the standard version of the wing SMART in Drosophila melanogaster to obtain more detailed knowledge about the genotoxic profile of NRTI combinations of AZT + ddI, AZT + 3TC and AZT + d4T.

AZT

ddI

AZT

AZT


Input: Our results showed that all combinations increased the frequencies of induction of mutant spots.


Input: The combinations AZT + ddI and AZT + 3TC were shown to induce recombination rates ranging from 86. 38% to 98. 36% while AZT + d4T showed a large discrepancy between recombination and mutation percentages.

AZT

ddI

AZT

AZT


Input: The combination index demonstrated that 3TC and d4T produced antagonism while ddI showed synergistic effects in combination with AZT.

ddI

AZT


Input: New enzymatic assay for the AKR1C enzymes.


Input: The imbalance in expression of the human aldo-keto reductases AKR1C1-AKR1C3 is related to different hormone dependent and independent cancers and some other diseases.


Input: The AKR1C1-3 enzymes thus represent emerging targets for the development of new drugs.


Input: Currently, various enzymatic assays are used in the search for AKR1C inhibitors, and consequently the results of different research groups are not necessarily comparable.


Input: During our recent search for AKR1C inhibitors, we found a cyclopentanol derivative (2-(4-chlorobenzylidene) cyclopentanol, CBCP-ol) and its respective cyclopentanone counterpart (2-(4-chlorobenzylidene) cyclopentanone, CBCP-one) that acted as AKR1C substrates.

cyclopentanol

2-(4-chlorobenzylidene) cyclopentanol

CBCP-ol

cyclopentanone

2-(4-chlorobenzylidene) cyclopentanone

CBCP-one


Input: We determined the kinetic parameters KM, kcat and kcat/KM for oxidation of CBCP-ol and reduction of CBCP-one by AKR1C enzymes in the presence of NAD (+)/NADP (+) and NADH/NADPH, respectively.

CBCP-ol

CBCP-one

NAD (+)

NADP (+)

NADH

NADPH


Input: The catalytic efficiencies for the oxidation of CBCP-ol in the presence of NAD (+) or NADP (+) were in general higher when compared to the catalytic efficiencies for reduction of CBCP-one in the presence of NADH or NADPH.

CBCP-ol

NAD (+)

NADP (+)

CBCP-one

NADH

NADPH


Input: When NADPH was used, as compared to NADH, the reductions of CBCP-one by AKR1C1, AKR1C2 and AKR1C3 were 14-, 51-and 31-fold more efficient, respectively.

NADPH

NADH

CBCP-one


Input: When comparing to oxidations of the well-known artificial substrates, 1-acenaphthenol and S-tetralol, we observed similar catalytic efficiencies as for CBCP-ol oxidation with NAD (+) and NADP (+).

S-tetralol

CBCP-ol

NAD (+)

NADP (+)


Input: The comparison of CBCP-one reduction with NADPH to reductions of physiological substrates revealed in general higher efficiencies, except for reduction of 9-cis-retinaldehyde by AKR1C3.

CBCP-one

NADPH


Input: This NADPH-dependent reduction of CBCP-one was then used to re-evaluate inhibitory potencies of the known inhibitors of the target AKR1C3 and the anti-target AKR1C2, medroxyprogesterone acetate and ursodeoxycholic acid, respectively, showing Ki constants similar to the reported values.

NADPH

CBCP-one

medroxyprogesterone acetate

ursodeoxycholic acid


Input: Our data thus confirm that the new enzymatic assays with two cyclopentane substrates CBP-ol and CBP-one, and especially reduction of CBCP-one with NADPH, are appropriate for the evaluation of AKR1C inhibitors.

cyclopentane

CBP-ol

CBP-one

CBCP-one

NADPH


Input: Effects of p53 knockout on ochratoxin A-induced genotoxicity in p53-deficient gpt delta mice.

ochratoxin A


Input: Ochratoxin A (OTA) is a mycotoxin produced by fungal species and is carcinogenic targeting the S3 segment of the renal proximal tubules in rodents.

Ochratoxin A

OTA


Input: We previously reported that exposure of gpt delta rats to OTA induced both mutations in the red/gam gene (Spi (-)), suggesting large deletion mutations, and fluctuations in genes transcribed by p53 in the kidneys, which were associated with DNA double-strand break (DSB) repair, particularly homologous recombination (HR) repair.

OTA


Input: In the present study, to investigate the effects of p53 knockout on OTA-induced mutagenicity, apoptosis, and karyomegaly in renal tubular cells, p53-proficient and p53-deficient gpt delta mice were given 1 and 5mg/kg of OTA for 4 weeks.

OTA

OTA


Input: Significant increases in Spi (-) mutant frequencies (MFs) were observed in the kidneys of p53-deficient gpt delta mice given 5 mg/kg of OTA, but not in the kidneys of p53-proficient gpt delta mice given the same dose.

OTA


Input: There were no changes in gpt MFs in both genotypes of mice treated with OTA.

OTA


Input: Western blotting analysis demonstrated that p53 protein levels in the kidneys of p53-proficient mice given OTA were significantly increased compared with the control.

OTA


Input: Incidences of apoptosis and karyomegaly in not only the outer stripe of outer medulla but also the cortex were significantly higher in p53-deficient at 5mg/kg than in p53-proficient gpt delta mice at same dose, which had no change in the cortex, the inner stripe of outer stripe, and the inner medulla.


Input: Given that p53 regulates HR repair in DSBs, these results suggest that OTA may promote large deletion mutations in the process of HR repair for DSBs.

OTA


Input: Additionally, the lower incidence of karyomegaly and apoptosis found in the p53-proficient gpt delta mice suggests that these phenomena may arise from OTA-induced DNA damage.

OTA


Input: Sex hormones and mental rotation: an intensive longitudinal investigation.


Input: The present study used an intensive longitudinal design to examine whether mental rotation performance varies according to a monthly cycle in both males and females and whether these variations are related to variations in progesterone, estradiol, and testosterone levels.

progesterone

estradiol

testosterone


Input: We collected reaction time and accuracy data for 10 males and seven females each workday over eight weeks using 136 pairs of mental rotation stimuli/day, and measured sexual hormones concentrations in the saliva twice a week.


Input: A mixed linear model statistical analysis revealed that all females and seven males showed significant cycle effects in mental rotation performance.


Input: The female cycle showed an amplitude that was twice as large compared with the amplitude found in males.


Input: For males and females, estradiol and testosterone were significantly linearly and quadratically related to interindividual variation in performance at the beginning of the study (progesterone was linearly related to performance for females).

estradiol

testosterone

progesterone


Input: The association between testosterone and performance differed across sexes: for males, it had an inverse U-shape, for females it was U-shaped.

testosterone


Input: Towards the end of the study, none of the hormones were significantly related to performance anymore.


Input: Thus, the relationship between hormones and mental rotation performance disappeared with repeated testing.


Input: Only estradiol levels were significantly elevated at the lowest point of the cycle in mental rotation performance in females.

estradiol


Input: In conclusion, in this intensive longitudinal study spanning two months, a monthly cycle in mental rotation performance was found among both males and females, with a larger cycle' s amplitude for females.


Input: Effects of oxygen and glucose deprivation on synaptic transmission in rat dentate gyrus: role of A (2A) adenosine receptors.

oxygen

glucose

adenosine


Input: The hippocampus is comprised of two distinct subfields that show different responses to hypoxic-ischemic brain injury: the CA1 region is particularly susceptible whereas the dentate gyrus (DG) is quite resistant.


Input: Our aim was to determine the synaptic and proliferative response of the DG to severe oxygen and glucose deprivation (OGD) in acute rat hippocampal slices and to investigate the contribution of A (2A) adenosine receptor antagonism to recovery of synaptic activity after OGD.

oxygen

glucose

adenosine


Input: Extracellular recordings of field excitatory post-synaptic potentials (fEPSPs) in granule cells of the DG in brain slices prepared from male Wistar rats were used.


Input: A 9-min OGD is needed in the DG to always induce the appearance of anoxic depolarization (AD) and the irreversible block of synaptic activity, as recorded up to 24 h from the end of the insult, whereas only 7-min OGD is required in the CA1 region.


Input: Selective antagonism of A (2A) adenosine receptors by ZM241385 significantly prevents or delays the appearance of AD and protects from the irreversible block of neurotransmission induced by 9-min OGD in the DG.

adenosine


Input: The effects of 9-min OGD on proliferation and maturation of cells localized in the subgranular zone of DG in slices prepared from 5-bromo-2'-deoxyuridine (BrdU) treated rats was investigated.

BrdU


Input: Slices were further incubated with an immature neuronal marker, doublecortin (DCX).


Input: The number of BrdU (+) cells was significantly decreased 6 h after 9-min OGD and this effect was antagonized by ZM241385.

BrdU (+)


Input: After 24 h from the end of 9-min OGD, the number of BrdU (+) cells returned to that found before OGD and increased arborization of tertiary dendrites of DCX (+) cells was observed.

BrdU (+)


Input: The adenosine A (2A) antagonist ZM241385 protects from synaptic failure and from decreased proliferation of immature neuronal cells at a precocious time after OGD.

adenosine


Input: Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans.

paraxanthine

caffeine


Input: Caffeine induces locomotor activation by its ability to block adenosine receptors.

Caffeine

adenosine


Input: Caffeine is metabolized to several methylxanthines, with paraxanthine being the main metabolite in humans.

Caffeine

methylxanthines

paraxanthine


Input: In this study we show that in rats paraxanthine has a stronger locomotor activating effect than caffeine or the two other main metabolites of caffeine, theophylline and theobromine.

paraxanthine

caffeine

caffeine

theophylline

theobromine


Input: As previously described for caffeine, the locomotor activating doses of paraxanthine more efficiently counteract the locomotor depressant effects of an adenosine A (1) than an adenosine A (2A) receptor agonist.

caffeine

paraxanthine

adenosine

adenosine


Input: In drug discrimination experiments in rats trained to discriminate a maximal locomotor activating dose of caffeine, paraxanthine, unlike theophylline, generalized poorly to caffeine suggesting the existence of additional mechanisms other than adenosine antagonism in the behavioral effects of paraxanthine.

caffeine

paraxanthine

theophylline

caffeine

adenosine

paraxanthine


Input: Pretreatment with the nitric oxide inhibitor N (G)-nitro-l-arginine methyl ester (l-NAME) reduced the locomotor activating effects of paraxanthine, but not caffeine.

nitric oxide

N (G)-nitro-l-arginine methyl ester

l-NAME

paraxanthine

caffeine


Input: On the other hand, pretreatment with the selective cGMP-preferring phosphodiesterase PDE9 inhibitor BAY 73-6691, increased locomotor activity induced by caffeine, but not paraxanthine.

cGMP

BAY 73-6691

caffeine

paraxanthine


Input: Ex vivo experiments demonstrated that paraxanthine, but not caffeine, can induce cGMP accumulation in the rat striatum.

paraxanthine

caffeine

cGMP


Input: Finally, in vivo microdialysis experiments showed that paraxanthine, but not caffeine, significantly increases extracellular levels of dopamine in the dorsolateral striatum, which was blocked by l-NAME.

paraxanthine

caffeine

dopamine

l-NAME


Input: These findings indicate that inhibition of cGMP-preferring PDE is involved in the locomotor activating effects of the acute administration of paraxanthine.

cGMP

paraxanthine


Input: The present results demonstrate a unique psychostimulant profile of paraxanthine, which might contribute to the reinforcing effects of caffeine in humans.

paraxanthine

caffeine


Input: Site-specific modulation of brain glucocorticoid receptor and corticotropin-releasing hormone expression using lentiviral vectors.


Input: The glucocorticoid receptor (GR) and corticotropin-releasing hormone (CRH) are important molecular regulators of an individual' s ability to respond to stressful stimuli in an adaptive manner.


Input: Impaired signaling of both GR and CRH often leads to dysfunction of the hypothalamic-pituitary-adrenal axis, which underlies the etiology of many affective disorders such as anxiety and depression.


Input: Studies focusing on how GR and CRH influence the stress response are limited as they generalize to broad brain regions, thus hindering identification of how specific CNS nuclei contribute to maladaptive stress responses.


Input: Our objective is to distinguish the site-specific involvement of GR and CRH in limbic regions involved in the stress response.


Input: With that intent, we use lentiviral (LV) vectors in combination with transgenic mouse lines, enabling us to modify expression of GR or CRH in a very localized manner.


Input: This paper describes the generation of several distinct LV vectors and transgenic mice models that will help further elucidate the site-specific actions of GR and CRH.


Input: The molecular mystique of tetrodotoxin.

tetrodotoxin


Input: In many respects tetrodotoxin (TTX) is the quintessential natural toxin.

tetrodotoxin

TTX


Input: It is unequivocally toxic to mammals with LD (50) values for mice in the range of 10 mu g/kg (intraperitoneal), 16 mu g/kg (subcutaneous), and 332 mu g/kg (oral) (Kao, 1966).


Input: Its biothreat status is recognized by its listing as a " Select Agent " by the US Department of Health and Human Services which includes regulated agents " determined to have the potential to pose a severe threat to both human and animal health " (http://www. selectagents. gov/).


Input: It has a well-defined cellular target (i. e., NaV channels) and pharmacological mode of action (i. e., block of nerve and muscle action potentials), and it is an indispensable chemical tool in neuroscience.


Input: It is widely distributed in marine and terrestrial ecosystems where it plays a role in the chemical ecology of predator-prey relationships and drives evolutionary selection of TTX-resistance (Hanifin, 2010; Williams, 2010; Zimmer and Ferrer, 2007).

TTX


Input: Lastly, TTX has acquired a certain mystique in scientific lore attributable to many fascinating aspects of its natural history and molecular interactions as presented in selected summary below.

TTX


Input: Additional information may be found in other excellent reviews (Fozzard and Lipkind, 2010; Kao, 1966; Lee and Ruben, 2008; Narahashi, 2001, 2008).


Input: Glast-expressing progenitor cells contribute to heterotopic ossification.


Input: Heterotopic ossification (HO), acquired or hereditary, is the formation of true bone outside the normal skeleton.


Input: Although the lineages of cells contributing to bone formation during normal development are well defined, the precise lineages of cells that contribute to HO are not clear.


Input: This study utilized Cre-lox based genetic lineage tracing to examine the contribution to HO of cells that expressed either FoxD1 or Glast.


Input: Both lineages contributed broadly to different normal tissues, and FoxD1-cre labeled cells contributed to normal bone formation.


Input: Despite the similarity in labeling patterns of normal tissues, and the significant contribution of FoxD1-cre labeled cells to normal bone, only Glast-creERT labeled progenitors contributed significantly to HO at all stages, suggesting that the cell populations that normally contribute to physiological bone formation, such as the Foxd1-cre labeled cells, may not participate in pathological HO.


Input: Further, identification of Glast-expressing cells as precursors that give rise to HO should help with the molecular targeting of this population both for the prevention and for the treatment of HO.


Input: Anti-tumor efficacy of chitosan-g-poly (ethylene glycol) nanocapsules containing docetaxel: anti-TMEFF-2 functionalized nanocapsules vs. non-functionalized nanocapsules.

poly (ethylene glycol)

docetaxel


Input: The development and evaluation of PEGylated chitosan (CS) nanocapsules (NCs) conjugated to a monoclonal antibody anti-TMEFF-2 (CS-PEG-anti-TMEFF-2 mAb NCs) for targeted delivery of docetaxel (DCX) is presented.

PEGylated

docetaxel

DCX


Input: CS-PEG-Biotin NCs, displaying biotin tags at their surface, were obtained and efficiently functionalized with an anti-TMEFF-2 mAb through a convenient avidin-biotin approach.

PEG

Biotin

biotin

biotin


Input: Cell cycle analysis after treatment with different DCX-loaded CS-PEG NC formulations indicated that the encapsulated drug remained fully active, showing a similar functional behavior to free DCX.

DCX

PEG

DCX


Input: In vivo efficacy studies using a non-small cell lung carcinoma xenograft revealed that CS-PEG-anti-TMEFF-2 NCs resulted as effective as free DCX (Taxotere (R)).

PEG

DCX

Taxotere


Input: Interestingly, differences on the pharmacodynamic behavior among the different DCX formulations were observed.

DCX


Input: Thus, while free DCX exhibited a fast and short effect on tumor volume reduction, CS-PEG-anti-TMEFF-2 mAb NCs showed a delayed and prolonged action, with no significant side effects of treatments.

DCX

PEG


Input: Phenylethanoid glycosides from the stems of Callicarpa peii (hemostatic drug).

Phenylethanoid glycosides


Input: Two new trisaccharide intermediates of phenylethanoid glycosides, peiioside A (1)/A (2) (1a/1b) and peiioside B (2), were isolated from the n-BuOH fraction of MeOH extract of the stems of Callicarpa peii H. T.

trisaccharide

phenylethanoid glycosides

peiioside A (1)/A (2)

peiioside B

n-BuOH

MeOH


Input: Chang, together with five biogenetic relevant known compounds 3-7.


Input: The structures of compounds 1 and 2 were elucidated by extensive spectroscopic methods (especially 2D-NMR techniques) and acid-catalyzed hydrolysis as O-alpha-l-rhamnopyranosyl-(1'' --> 3')-O-[beta-d-apiofuranosyl-(1''' --> 6')]-4'-O-[(E)-caffeoyl]-d-glucopyranoside] (1a/1b), 3, 4-dihydroxy-beta-phenylethoxy-O-[beta-d-apiofuranosyl-(1''' --> 6')-alpha-l-rhamnopyranosyl-(1'' --> 3')-O-beta-d-glucopyranoside] (2), respectively.

O-alpha-l-rhamnopyranosyl-(1'' --> 3')-O-[beta-d-apiofuranosyl-(1''' --> 6')]-4'-O-[(E)-caffeoyl]-d-glucopyranoside]

3, 4-dihydroxy-beta-phenylethoxy-O-[beta-d-apiofuranosyl-(1''' --> 6')-alpha-l-rhamnopyranosyl-(1'' --> 3')-O-beta-d-glucopyranoside]


Input: On the basis of the isolated compounds, a presumable biogenetic pathway of the biologically interesting phenylethanoid glycosides about forsythoside B (3) and acteoside (4) isolated from this species was proposed.

phenylethanoid glycosides

forsythoside B

acteoside


Input: Isolation of five related intermediates (1-2, 5-7) provided further support for the biogenetic path.


Input: This is the first report about phytochemical research on C. peii and the biogenetic hypothesis of forsythoside B and acteoside.

forsythoside B

acteoside


Input: Reducing effect of an extract of Phaseolus vulgaris on food intake in mice--focus on highly palatable foods.


Input: Different lines of experimental evidence indicate that treatment with extracts from and derivatives of Phaseolus vulgaris reduces intake of food, including highly palatable foods and beverages, in rats.


Input: The present study was designed to extend to mice these lines of evidence.


Input: To this end, CD1 mice were treated acutely with a standardized extract of P. vulgaris and then exposed to unlimited access to regular food pellets (Experiment 1) or 1-hour limited access to three different palatable foods/beverages, such as butter cookies (Experiment 2), a condensed-milk beverage (Experiment 3), and a chocolate-flavored beverage (Experiment 4).


Input: Treatment with P. vulgaris extract resulted in a significant reduction in the intake of regular food pellets, that was still evident 24h later, as well as of the three palatable nourishments.


Input: Together, these results (a) extend to mice several previous findings on the capacity of P. vulgaris extracts to suppress food intake in rats, (b) suggest that P. vulgaris extracts may interfere with the central mechanisms regulating appetite, food intake, palatability, and/or the rewarding and hedonic properties of food, and (c) P. vulgaris extracts may represent a potentially effective therapy for overeating, obesity, and food craving.


Input: Characterization of tyrosinase inhibitors in the twigs of Cudrania tricuspidata and their structure-activity relationship study.


Input: The twigs of Cudrania tricuspidata were found to show strong tyrosinase inhibitory activity, and further detailed component analysis resulted in the isolation of a new flavanol glucoside, (2S, 3S)-2, 3-trans-dihydromorin-7-O-beta-d-glucoside (1), plus twenty-seven known compounds (2-28).

flavanol glucoside

(2S, 3S)-2, 3-trans-dihydromorin-7-O-beta-d-glucoside


Input: Their structures were elucidated on the basis of ESI-MS and NMR spectral data.


Input: Among the isolated compounds, trans-dihydromorin (8), oxyresveratrol (9), and steppogenin (12) were found to exhibit significant tyrosinase inhibition activities.

trans-dihydromorin

oxyresveratrol

steppogenin


Input: Moreover, the structure-activity relationship of these isolated compounds was also discussed.


Input: Design, synthesis, inhibition studies, and molecular modeling of pepstatin analogues addressing different secreted aspartic proteinases of Candida albicans.

pepstatin


Input: The family of secreted aspartic proteinases is known as an important virulence factor of yeast infections by Candida albicans in particular, which is the most common fungal pathogen for humans with respect to systemic disease.


Input: Due to the continuing increase of drug resistant strains, these proteinases are currently considered as promising drug target candidates.


Input: Based on the known Sap2-substrate specificity data and X-ray analyses of Sap/inhibitor complexes, three libraries of inhibitors were designed and synthesized by modifying the structure of pepstatin A, a common non-selective aspartic proteinase inhibitor, at the P3, P2, or P2' position.

pepstatin A


Input: These novel inhibitors showed high inhibitory potencies for the isoenzymes Sap1, Sap3, Sap5 and Sap6.


Input: Then, the affinity and selectivity of the peptide ligands were investigated by molecular modeling, highlighting new key structural information for the design of potent and selective anti-virulence agents targeting Candida albicans.


Input: FluidFM as a lithography tool in liquid: spatially controlled deposition of fluorescent nanoparticles.


Input: The atomic force microscope (AFM) is a powerful instrument for nanolithography, which is well characterized in air where the deposition process is steered by capillary action.


Input: In contrast, AFM patterning has been seldom achieved in liquid, mostly via electrochemical deposition.


Input: This study investigates the pressure-controlled local deposition of nanoparticles in a liquid environment using a FluidFM.


Input: Fluorescent 25 nm polystyrene nanospheres were chosen as nanoobjects to be dispensed because they enable both the in situ monitoring of the process by optical microscopy and the ex situ high-resolution characterization of the pattern by e. g. scanning electron microscopy.

polystyrene


Input: The FluidFM microchannel was filled with an aqueous solution of negatively charged nanoparticles to be delivered onto a glass surface coated with a polycation.


Input: An overpressure in the internal fluidic circuit leads to the deposition of nanoparticle dots and lines under the tip, while the force control regulates the contact between the probe and the surface.


Input: The nanoparticle adsorption process depends both on applied pressure and contact time (respectively tip velocity) and can be described using the Langmuir approximation for the random sequential adsorption model.


Input: Moreover, we observed that the force setpoint, which does not influence the capillary-driven mechanism in air, indeed affects the hydrodynamic resistance at the tip aperture and therefore the volumetric flow.


Input: The described method demonstrates the potential of FluidFM in depositing nano-sized objects in liquid with nanometre precision.


Input: Both CpG methylation and activation-induced deaminase are required for the fragility of the human bcl-2 major breakpoint region: implications for the timing of the breaks in the t (14; 18) translocation.

CpG


Input: The t (14; 18) chromosomal translocation typically involves breakage at the bcl-2 major breakpoint region (MBR) to cause human follicular lymphoma.


Input: A theory to explain the striking propensity of the MBR breaks at three CpG clusters within the 175-bp MBR region invoked activation-induced deaminase (AID).

CpG


Input: In a test of that theory, we used here minichromosomal substrates in human pre-B cell lines.


Input: Consistent with the essential elements of the theory, we found that the MBR breakage process is indeed highly dependent on DNA methylation at the CpG sites and highly dependent on the AID enzyme to create lesions at peak locations within the MBR.

CpG


Input: Interestingly, breakage of the phosphodiester bonds at the AID-initiated MBR lesions is RAG dependent, but, unexpectedly, most are also dependent on Artemis.

phosphodiester


Input: We found that Artemis is capable of nicking small heteroduplex structures and is even able to nick single-base mismatches.


Input: This raises the possibility that activated Artemis, derived from the unjoined D to J (H) DNA ends at the IgH locus on chromosome 14, nicks AID-generated TG mismatches at methyl CpG sites, and this would explain why the breaks at the chromosome 18 MBR occur within the same time window as those on chromosome 14.

CpG


Input: Quantitative analysis of chromosome condensation in fission yeast.


Input: Chromosomes undergo extensive conformational rearrangements in preparation for their segregation during cell divisions.


Input: Insights into the molecular mechanisms behind this still poorly understood condensation process require the development of new approaches to quantitatively assess chromosome formation in vivo.


Input: In this study, we present a live-cell microscopy-based chromosome condensation assay in the fission yeast Schizosaccharomyces pombe.


Input: By automatically tracking the three-dimensional distance changes between fluorescently marked chromosome loci at high temporal and spatial resolution, we analyze chromosome condensation during mitosis and meiosis and deduct defined parameters to describe condensation dynamics.


Input: We demonstrate that this method can determine the contributions of condensin, topoisomerase II, and Aurora kinase to mitotic chromosome condensation.


Input: We furthermore show that the assay can identify proteins required for mitotic chromosome formation de novo by isolating mutants in condensin, DNA polymerase epsilon, and F-box DNA helicase I that are specifically defective in pro-/metaphase condensation.


Input: Thus, the chromosome condensation assay provides a direct and sensitive system for the discovery and characterization of components of the chromosome condensation machinery in a genetically tractable eukaryote.


Input: The conserved PHD1-PHD2 domain of ZFP-1/AF10 is a discrete functional module essential for viability in Caenorhabditis elegans.


Input: Plant homeodomain (PHD)-type zinc fingers play an important role in recognizing chromatin modifications and recruiting regulatory proteins to specific genes.

zinc


Input: A specific module containing a conventional PHD finger followed by an extended PHD finger exists in the mammalian AF10 protein, among a few others.


Input: AF10 has mostly been studied in the context of the leukemic MLL-AF10 fusion protein, which lacks the N-terminal PHD fingers of AF10.

N


Input: Although this domain of AF10 is the most conserved region of the protein, its biological significance has not been elucidated.


Input: In this study, we used genetic and biochemical approaches to examine the PHD1-PHD2 region of the Caenorhabditis elegans ortholog of AF10, zinc finger protein 1 (ZFP-1).

zinc


Input: We demonstrate that the PHD1-PHD2 region is essential for viability and that the first PHD finger contributes to the preferred binding of PHD1-PHD2 to lysine 4-methylated histone H3 tails.

lysine


Input: Moreover, we show that ZFP-1 localization peaks overlap with H3K4 methylation-enriched promoters of actively expressed genes genomewide and that H3K4 methylation is important for ZFP-1 localization to promoters in the embryo.


Input: We predict that the essential biological role of the PHD1-PHD2 module of ZFP-1/AF10 is connected to the regulation of actively expressed genes during early development.


Input: Interferon beta and glatiramer acetate therapy.

glatiramer acetate


Input: Interferon beta and glatiramer acetate have been mainstays of treatment in relapsingremitting multiple sclerosis for two decades.

glatiramer acetate


Input: Remarkable advances in our understanding of immune function and dysfunction as well as increasingly sophisticated clinical trial design have stemmed from efforts to better understand these drugs.


Input: In this chapter, we review the history of their development and elaborate on known and theorized mechanisms of action.


Input: We describe the pivotal clinical trials that have led to their widespread use.


Input: We evaluate the clinical use of the drugs including tolerability, side effects, and efficacy measures.


Input: Finally, we look to the future of interferon beta and glatiramer acetate in the context of an ever growing armamentarium of treatments for relapsing remitting multiple sclerosis.

glatiramer acetate


Input: Long-lasting inhibitory effect of apple and orange juices, but not grapefruit juice, on OATP2B1-mediated drug absorption.


Input: Enzyme-based grapefruit juice (GFJ)-drug interactions are mainly due to mechanism-based irreversible inhibition of metabolizing enzyme CYP3A4 by GFJ components, but the transporter organic anion transporting polypeptide (OATP) 2B1 is also a putative site of interaction between drugs and fruit juices (FJ) in the absorption process.


Input: Here we aimed to investigate the effect of preincubation with FJ on OATP2B1-mediated transport of drugs in vitro.


Input: When OATP2B1-expressing Xenopus oocytes were preincubated with GFJ, orange juice (OJ), or apple juice (AJ), AJ induced a remarkable decrease in OATP2B1-mediated estrone-3-sulfate uptake in a concentration-dependent manner (IC (50) = 1. 5%).


Input: A similar but less potent effect was observed with OJ (IC (50) = 21%), whereas GFJ had no effect.


Input: Similar results were obtained in preincubation studies using fexofenadine.

fexofenadine


Input: Preincubation with OJ and AJ resulted in time-dependent inhibition of OATP2B1.


Input: Again, AJ had the more potent effect; its action lasted for at least 240 minutes, suggesting that AJ irreversibly inhibits OATP2B1-mediated drug uptake.


Input: Kinetic analysis revealed that coincubation and preincubation with AJ reduced OATP2B1-mediated estrone-3-sulfate uptake via competitive and noncompetitive mechanisms, respectively.


Input: Thus, OATP2B1 is functionally impaired through both competitive and long-lasting inhibition mechanisms by AJ and OJ, but not GFJ.


Input: Interestingly, although GFJ but not AJ is able to irreversibly inhibit CYP3A4, in the case of OATP2B1, AJ but not GFJ has a long-lasting inhibitory effect.


Input: Accordingly, complex FJ-drug interactions may occur in vivo, and their clinical significance should be examined.


Input: Vicilin and the basic subunit of legumin are putative chickpea allergens.


Input: IgE-mediated reactions to food allergens constitute a major health problem in industrialized countries.


Input: Chickpea is consumed in Mediterranean countries, and reportedly associated with IgE-mediated hypersensitivity reactions.


Input: However, the nature of allergic reactions to chickpea has not been characterized.


Input: A serum pool from paediatric patients allergic to chickpeas was used to detect IgE-binding proteins from chickpea seeds by immunoassay and immunoblot inhibition assay.


Input: Protein samples enriched in chickpea legumin and vicilin were obtained by anion exchange chromatography, and were identified by mass spectrometric analysis.


Input: IgE-immunoassays of globulin fractions from chickpeas revealed that vicilin (50 kDa) and the basic subunit of legumin (20 kDa) were bound by IgE from patient sera.


Input: Pea and lentil protein extracts strongly inhibited the IgE binding to chickpea globulin.


Input: We speculate that vicilin and the basic subunit of legumin are major chickpea allergens.


Input: Also, the globulin fraction of chickpea likely cross-reacts with the allergenic proteins of pea and lentil.


Input: Antioxidant and immunomodulatory activity of selenium exopolysaccharide produced by Lactococcus lactis subsp. lactis.

selenium


Input: Exopolysaccharide (EPS) was isolated and purified from Lactococcus lactis subsp.


Input: Lactis culture broth.


Input: Selenium chloride oxide (SeCl (2) O) was added to the EPS to synthesize selenium-exopolysaccharide (Se-EPS).

Selenium chloride oxide

SeCl (2) O

selenium

Se


Input: The in vitro and in vivo antioxidant and in vivo immunomodulatory activity of EPS and Se-EPS were compared.

Se


Input: EPS and Se-EPS scavenged superoxide anions and hydroxyl radicals.

Se

superoxide

hydroxyl


Input: They also increased catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, while decreasing malondialdehyde (MDA) levels in serum and in the livers of mice.

superoxide

glutathione

GSH

malondialdehyde

MDA


Input: Se-EPS showed stronger in vitro and in vivo antioxidant activity than were shown by EPS.

Se


Input: The in vivo immunoenhancement activity of EPS and Se-EPS induced by cyclophosphamide (CY) treatment in immunosuppressed mice was researched.

Se

cyclophosphamide


Input: EPS and Se-EPS treatments increased macrophage phagocytosis, spleen and thymus indices and haemolytic complement activity (HC (50)).

Se


Input: Se-EPS showed stronger immunomodulatory activity than did EPS.

Se


Input: Apoptosis during postmortem conditioning and its relationship to duck meat quality.


Input: The aim of this work was to examine the relationship of skeletal muscle apoptosis and postmortem development of meat quality.


Input: Colour, cooking loss, myofibril fragmentation index (MFI) and shear force of duck breast and thigh meat postmortem were measured, and changes of positive nuclei were assessed with Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphophate nick end-labelling method (TUNEL).

deoxynucleotidyl

deoxyuridine triphosphophate


Input: Correlation analysis revealed that apoptosis were positively correlated with colour (L (*), a (*) and b (*)), cooking loss and MFI (P < 0. 05), while it is negatively correlated with shear force (P < 0. 05).


Input: Our results indicate the growing level of duck skeletal muscle cell apoptosis was associated with the postmortem development of meat quality traits such as meat colour, water holding capacity and tenderness.


Input: Biochemical characterisation of Alaska pollock, Pacific whiting, and threadfin bream surimi as affected by comminution conditions.


Input: Salt-soluble protein, surface reactive sulfhydryl content, and surface hydrophobicity of Alaska pollock, Pacific whiting, and threadfin bream surimi were characterised, as affected by various comminution conditions.

sulfhydryl


Input: Chopping time/temperatures were explored in consideration of their habitat temperatures.


Input: Salt-soluble protein (SSP) significantly decreased when chopping time was extended.


Input: Corresponding to our follow-up study, no relationship between SSP and gel texture was found.


Input: Surface hydrophobicity was inversely proportional to SSP concentration, indicating the unfolding of protein upon comminution.


Input: Alaska pollock surimi demonstrated aggregation during chopping at 10 and 20 degrees C, based on the surface hydrophobicity.


Input: Surface reactive sulfhydryl (SRSH) contents of the three fish species behaved differently.

sulfhydryl


Input: The SH groups were oxidized to disulphide bonds when higher chopping temperature was applied.

SH

disulphide


Input: As a result, increased SRSH content was not observed in Alaska pollock (10 and 20 degrees C chopping) and threadfin bream paste (25 and 30 degrees C chopping).


Input: Characterization of modified high-amylose maize starch-alpha-naphthol complexes and their influence on rheological properties of wheat starch.

alpha-naphthol


Input: Amylose can form inclusion complexes with diverse small molecules.


Input: Modified starch has different and unique properties compared with its native counterpart.


Input: In this study, chemically/enzymatically modified high-amylose maize starches were used to make inclusion complexes with alpha-naphthol, and the physical properties of complexes and their influences on the rheology of wheat starch were characterized.

alpha-naphthol


Input: The results showed that modification of starch had little influence on the wide angle X-ray diffraction pattern of complex (eightfold single helix), but did so on the complexation index and precipitation yield.


Input: Inclusion complexes with chemically modified starch showed a lower range of thermostability and recrystallization temperatures.


Input: Addition of complex considerably influenced the rheological properties of wheat starch, and the effect was dependent on the type of modified starch used.


Input: It may be concluded that starch inclusion complexes, with a range of properties and potential food applications, may be feasibly prepared by using diverse modified high-amylose maize starches.


Input: Retention of aroma compounds from Mentha piperita essential oil by cyclodextrins and crosslinked cyclodextrin polymers.


Input: In this paper, the controlled release of aroma compounds from cyclodextrins (CDs) and CD polymers was studied by multiple headspace extraction (MHE) experiments.


Input: Mentha piperita essential oil was obtained by Soxhlet extraction and identification of the major compounds was performed by GC-MS analysis.


Input: Menthol, menthone, pulegone and eucalyptol were identified as the major components.

Menthol

menthone

pulegone

eucalyptol


Input: Retention of standard compounds in the presence of different CDs and CD polymers has been realised by static headspace gas chromatography (SH-GC) at 25 degrees C in the aqueous or gaseous phase.


Input: Stability constants for standard compounds and for compounds in essential oil have been also determined with monomeric CD derivatives.


Input: The obtained results indicated the formation of a 1: 1 inclusion complex for all the studied compounds.


Input: Molecular modelling was used to investigate the complementarities between host and guest.


Input: This study showed that beta-CDs were the most versatile CDs and that beta-CD polymers could perform the controlled release of aroma compounds.

beta-CDs

beta-CD


Input: Effects of ozone microbubble treatment on removal of residual pesticides and quality of persimmon leaves.

ozone