Input: In sum, this study adds to the body of research on the evolution of female sexual signals and how males may infer information from these cues.


Input: Organization of the BcgI restriction-modification protein for the transfer of one methyl group to DNA.

methyl


Input: The Type IIB restriction-modification protein BcgI contains A and B subunits in a 2: 1 ratio: A has the active sites for both endonuclease and methyltransferase functions while B recognizes the DNA.


Input: Like almost all Type IIB systems, BcgI needs two unmethylated sites for nuclease activity; it cuts both sites upstream and downstream of the recognition sequence, hydrolyzing eight phosphodiester bonds in a single synaptic complex.

phosphodiester


Input: This complex may incorporate four A (2) B protomers to give the eight catalytic centres (one per A subunit) needed to cut all eight bonds.


Input: The BcgI recognition sequence contains one adenine in each strand that can be N (6)-methylated.

adenine


Input: Although most DNA methyltransferases operate at both unmethylated and hemi-methylated sites, BcgI methyltransferase is only effective at hemi-methylated sites, where the nuclease component is inactive.


Input: Unlike the nuclease, the methyltransferase acts at solitary sites, functioning catalytically rather than stoichiometrically.


Input: Though it transfers one methyl group at a time, presumably through a single A subunit, BcgI methyltransferase can be activated by adding extra A subunits, either individually or as part of A (2) B protomers, which indicates that it requires an assembly containing at least two A (2) B units.

methyl


Input: The influence of diet on the gut microbiota.


Input: Diet is a major factor driving the composition and metabolism of the colonic microbiota.


Input: The amount, type and balance of the main dietary macronutrients (carbohydrates, proteins and fats) have a great impact on the large intestinal microbiota.

carbohydrates


Input: The human colon contains a dense population of bacterial cells that outnumber host cells 10-fold.


Input: Bacteroidetes, Firmicutes and Actinobacteria are the three major phyla that inhabit the human large intestine and these bacteria possess a fascinating array of enzymes that can degrade complex dietary substrates.


Input: Certain colonic bacteria are able to metabolise a remarkable variety of substrates whilst other species carry out more specialised activities, including primary degradation of plant cell walls.


Input: Microbial metabolism of dietary carbohydrates results mainly in the formation of short chain fatty acids and gases.

carbohydrates

fatty acids


Input: The major bacterial fermentation products are acetate, propionate and butyrate; and the production of these tends to lower the colonic pH.

acetate

propionate

butyrate


Input: These weak acids influence the microbial composition and directly affect host health, with butyrate the preferred energy source for the colonocytes.

butyrate


Input: Certain bacterial species in the colon survive by cross-feeding, using either the breakdown products of complex carbohydrate degradation or fermentation products such as lactic acid for growth.

carbohydrate

lactic acid


Input: Microbial protein metabolism results in additional fermentation products, some of which are potentially harmful to host health.


Input: The current' omic era promises rapid progress towards understanding how diet can be used to modulate the composition and metabolism of the gut microbiota, allowing researchers to provide informed advice, that should improve long-term health status.


Input: Anti-proliferative effect of (19Z)-halichondramide, a novel marine macrolide isolated from the sponge Chondrosia corticata, is associated with G2/M cell cycle arrest and suppression of mTOR signaling in human lung cancer cells.


Input: Five oxazole-containing macrolides isolated from the marine sponge Chondrosia corticata were evaluated for their anti-proliferative activity in a panel of human solid cancer cell lines.

oxazole


Input: (19Z)-Halichondramide ((19Z)-HCA), a novel trisoxazole-containing macrolide, exhibited the highest potency among the macrolides, with IC50 values in the submicro-molar ranges.

trisoxazole


Input: Prompted by the high potency of growth inhibition of cancer cells, we investigated the mechanism of action of the anti-proliferative activity of (19Z)-HCA in human A549 lung cancer cells.


Input: (19Z)-HCA induced cell cycle arrest in the G2/M phase, and this event was highly correlated with the expression of checkpoint proteins, including the up-regulation of p53 and GADD45 alpha and the down-regulation of cyclin B1, cyclin A, CDC2, and CDC25C.


Input: In addition, the growth inhibition by (19Z)-HCA was associated with the suppression of mTOR and its downstream effector molecules 4EBP1 and p70S6K.


Input: The modulation of mTOR signaling by (19Z)-HCA was found to be mediated by the regulation of upstream proteins, including the down-regulation of Akt and p38 MAPK and the up-regulation of AMPK.


Input: These data suggest the potential of (19Z)-HCA to serve as a candidate for cancer chemotherapeutic agents derived from marine organisms by virtue of arresting the cell cycle in the G2/M phase and the modulation of mTOR/AMPK signaling pathways.


Input: Effect of the disintegrin eristostatin on melanoma-natural killer cell interactions.


Input: Malignant melanoma is difficult to treat due to its resistance to chemotherapeutic regimens.


Input: Discovery of new pharmaceuticals with inhibitory potential can be helpful in the development of novel treatments.


Input: The snake venom disintegrin eristostatin, from the viper Eristicophis macmahoni, caused immunodeficient mice to be significantly protected from development of lung colonization when melanoma cells and the disintegrin were co-injected in vivo into the lateral tail vein compared to vehicle controls.


Input: Cytotoxicity assays suggested that eristostatin makes the melanoma cells a better target for lysis by human natural killer cells.


Input: Direct binding assays using atomic force microscopy showed eristostatin does specifically bind the surface of the six melanoma cell lines tested.


Input: Eristostatin binding was partially inhibited by the addition of soluble RGDS peptide, suggesting an integrin as one likely, but not the sole, binding partner.


Input: Studies done with melanoma cells on a culture dish and natural killer cells attached to a cantilever tip in atomic force microscopy showed four major populations of interactions which exhibited altered frequency and unbinding strength in the presence of eristostatin.


Input: A practical quantification method for Heinz bodies in birds applicable to rapid response field scenarios.


Input: Oil-induced oxidative injury to red blood cells results in Heinz body hemolytic anemia.


Input: Here, we evaluated three Heinz body staining techniques in brown pelican (Pelecanus occidentalis) blood.


Input: Using a range of in vitro acetylphenylhydrazine incubations, we validated a field-adapted technique against laboratory wet-mounts and verified the stability of this technique for one month following preparation.

acetylphenylhydrazine


Input: Employing this technique during petrochemical spill responses allows for delays between sample collection and analysis.


Input: Effects-based marine ecological risk assessment at a polychlorinated biphenyl-contaminated site in Saglek, Labrador, Canada.

polychlorinated biphenyl


Input: Although the presence and distribution of polychlorinated biphenyls (PCBs) in Arctic marine environments has been well documented, the implications for the health of biota are poorly understood.

polychlorinated biphenyls

PCBs


Input: In the present study, multiple lines of evidence, including site-specific effects data, were used to assess PCB-related risks to marine biota at a contaminated military site in Saglek Bay, Labrador, Canada, from 1997 to 1999.

PCB


Input: Risks were evaluated for three components of the ecosystem: benthic invertebrates, a bottom-feeding fish (shorthorn sculpin, Myoxocephalus scorpius), and a diving seabird (black guillemot, Cepphus grylle).


Input: Average sediment PCB concentrations exceeded the Canadian interim sediment quality guideline level by 41-fold.

PCB


Input: However, sediment toxicity testing and a benthic community survey showed no evidence of adverse effects.


Input: In contrast, shorthorn sculpin and black guillemot PCB exposures (measured as sum of 55 congeners) were elevated enough to pose risks to survival or reproduction.

PCB


Input: Based on the collective evidence, the authors estimated that risks were posed by sediment PCB concentrations greater than 77 ng/g dry weight for black guillemots and 750 ng/g dry weight for shorthorn sculpins.

PCB


Input: The present study, along with two parallel studies, provided information to support the management decisions concerning potential remedial action on the contaminated sediments.


Input: This ecological risk assessment describes the steps and rationale taken to evaluate the risk posed by an area of PCB-contaminated marine sediments in an otherwise relatively pristine northern coastal environment.

PCB


Input: Metabolically competent human skin models: activation and genotoxicity of benzo [a] pyrene.

benzo [a] pyrene


Input: The polycyclic aromatic hydrocarbon (PAH) benzo [a] pyrene (BP) is metabolized into a complex pattern of BP derivatives, among which the ultimate carcinogen (+)-anti-BP-7, 8-diol-9, 10-epoxide (BPDE) is formed to certain extents.

polycyclic aromatic hydrocarbon

PAH

benzo [a] pyrene

(+)-anti-BP-7, 8-diol-9, 10-epoxide

BPDE


Input: Skin is frequently in contact with PAHs and data on the metabolic capacity of skin tissue toward these compounds are inconclusive.

PAHs


Input: We compared BP metabolism in excised human skin, commercially available in vitro 3D skin models and primary 2D skin cell cultures, and analyzed the metabolically catalyzed occurrence of seven different BP follow-up products by means of liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).


Input: All models investigated were competent to metabolize BP, and the metabolic profiles generated by ex vivo human skin and skin models were remarkably similar.


Input: Furthermore, the genotoxicity of BP and its derivatives was monitored in these models via comet assays.


Input: In a full-thickness skin, equivalent BP-mediated genotoxic stress was generated via keratinocytes.


Input: Cultured primary keratinocytes revealed a level of genotoxicity comparable with that of direct exposure to 50-100 nM of BPDE.

BPDE


Input: Our data demonstrate that the metabolic capacity of human skin ex vivo, as well as organotypic human 3D skin models toward BP, is sufficient to cause significant genotoxic stress and thus cutaneous bioactivation may potentially contribute to mutations that ultimately lead to skin cancer.


Input: Response to variable light intensity in photoacclimated algae and cyanobacteria exposed to atrazine.

atrazine


Input: Atrazine is frequently detected in freshwater ecosystems exposed to agricultural waste waters and runoffs worldwide and it can affect non-target organisms (mainly photoautotrophic) and modify community structure.

Atrazine


Input: Meanwhile, light environment is known to vary between aquatic ecosystems, but also before and during the exposure to atrazine and these variations may modify the sensitivity to atrazine of photoautotroph organisms.

atrazine

atrazine


Input: In this study, 10 species of phytoplankton (chlorophytes, baccilariophytes and cyanophytes) acclimated to low or high light intensities were exposed to atrazine and light of different intensities to compare their combined effect.

atrazine


Input: Our data showed that chlorophytes and baccilariophytes were more resistant to atrazine compared to cyanophytes for all light conditions.

atrazine


Input: Atrazine was found to inhibit Phi' (M), Psi (0), P (M) and non-photochemical quenching for all species indicating an effect on electron transport, primary production and photoregulation processes.

Atrazine


Input: These data also indicate a higher sensitivity of Psi (0) (average Psi (0)-EC (50) of 91 +/- 11 nM or 19. 6 +/- 0. 9 mu gL (-1)) compared to Phi' (M) (average Phi' (M)-EC (50) of 217 +/- 19 nM or 46. 8 +/- 4. 1 mu gL (-1)) and suggest that photoregulation processes activated in presence of light decrease the effect of atrazine.

atrazine


Input: We also showed that increasing light intensity decreased Phi' (M)-EC (50) in both low (except baccilariophytes) and high light acclimated conditions.


Input: Despite this similarity, most species acclimated to high light were found to have higher or similar Phi' (M)-EC (50) compared to low light acclimated cells and thus, were less sensitive to atrazine in low light and high light environments.

atrazine


Input: We concluded that an increase in the plastoquinone pool induced by acclimation to high light decreased the sensitivity to atrazine in phytoplankton and we hypothesized that the effect observed was the result of a dilution of atrazine toxicity through increased binding site availability (quinones) combined with increased photoregulation processes capacity.

plastoquinone

atrazine

atrazine

quinones


Input: Short duration of diabetes and disuse of sulfonylurea have any association with insulin cessation of the patients with type 2 diabetes in a clinical setting in Japan (JDDM 30).

sulfonylurea


Input: Insulin therapy is often required to achieve good glycemic control for the patients with type 2 diabetes mellitus (T2DM), while protraction of glycemic control without insulin therapy may be preferable for patients.


Input: To determine the characteristics of and therapeutic regimen in outpatients with T2DM who were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan by a case-control study.


Input: The present study was performed on 928 patients with T2DM who started insulin therapy in 2007.


Input: Data regarding age, sex, body mass index, duration of diabetes, HbA1c, postprandial plasma glucose, plasma fasting C-peptide immunoreactivity and treatment modality were compared between patients who were able to stop insulin therapy and those who continued with insulin.

glucose


Input: Of the 928 patients, 37 had stopped insulin therapy within 1 year.


Input: In the patients who stopped insulin therapy, the duration of diabetes was significantly shorter and the daily insulin dosage at initiation and the prevalence of sulfonylurea pretreatment significantly lower compared with patients who continued on insulin.

sulfonylurea


Input: In conclusion, almost 4% of T2DM patients were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan.


Input: Shorter duration of diabetes and disuse of sulfonylureas prior to insulin may associate with stopping insulin therapy as a near-normoglycemic remission in outpatients with T2DM in Japan.

sulfonylureas


Input: RBFOX2 is an important regulator of mesenchymal tissue-specific splicing in both normal and cancer tissues.


Input: Alternative splicing provides a critical and flexible layer of regulation intervening in many biological processes to regulate the diversity of proteins and impact cell phenotype.


Input: To identify alternative splicing differences that distinguish epithelial from mesenchymal tissues, we have investigated hundreds of cassette exons using a high-throughput reverse transcription-PCR (RT-PCR) platform.


Input: Extensive changes in splicing were noted between epithelial and mesenchymal tissues in both human colon and ovarian tissues, with many changes from mostly one splice variant to predominantly the other.


Input: Remarkably, many of the splicing differences that distinguish normal mesenchymal from normal epithelial tissues matched those that differentiate normal ovarian tissues from ovarian cancer.


Input: Furthermore, because splicing profiling could classify cancer cell lines according to their epithelial/mesenchymal characteristics, we used these cancer cell lines to identify regulators for these specific splicing signatures.


Input: By knocking down 78 potential splicing factors in five cell lines, we provide an extensive view of the complex regulatory landscape associated with the epithelial and mesenchymal states, thus revealing that RBFOX2 is an important driver of mesenchymal tissue-specific splicing.


Input: Design, synthesis and anticancer activity of N (3), N (11)-bis (2-hydroxyethyl)-14-aryl-14H-dibenzo [a, j] xanthenes-3, 11-dicarboxamide.

N (3), N (11)-bis (2-hydroxyethyl)-14-aryl-14H-dibenzo [a, j] xanthenes-3, 11-dicarboxamide


Input: A series of novel N (3), N (11)-bis (2-hydroxyethyl)-14-aryl-14H-dibenzo [a, j] xanthenes-3, 11-dicarboxamide, three N (3), N (11)-bis (2-hydroxyethyl)-14-aryl-14H-dibenzo [a, j] xanthene-3, 11-dimethanamine derivatives and their intermediates 14-aryl-14H-dibenzo [a, j] xanthenes-3, 11-dicarboxylic acid, were synthesized, and the structures of which were characterized by (1) H-NMR, (13) C-NMR, high resolution (HR)-MS, and IR spectra.

N (3), N (11)-bis (2-hydroxyethyl)-14-aryl-14H-dibenzo [a, j] xanthenes-3, 11-dicarboxamide

N (3), N (11)-bis (2-hydroxyethyl)-14-aryl-14H-dibenzo [a, j] xanthene-3, 11-dimethanamine

14-aryl-14H-dibenzo [a, j] xanthenes-3, 11-dicarboxylic acid

(1) H

(13) C


Input: The antitumor activities of these molecules were evaluated on five cancer cell lines.


Input: The results of in vitro assay against human hepatocellular carcinoma cell lines (SK-HEP-1 and HepG2 and SMMC-7721 cells), acute promyelocytic leukemia NB4 cells and uterine cervix cancer HeLa cells, show several compounds to be endowed with cytotoxicity in micromolar to submicromolar range.


Input: The carboxamide derivatives 6c and 6e exhibitted good inhibition on NB4 cancer cells, and the IC (50) values of which were 0. 82 micro M and 0. 96 micro M, respectively, much lower than 5. 01 micro M of the positive control As (2) O (3).

carboxamide

As (2) O (3)


Input: Flow cytometric analysis results revealed that compounds 6e and 6f may induce tumor cell apoptosis.


Input: Synthesis and quantitative structure-activity relationships of selective BCRP inhibitors.


Input: The breast cancer resistance protein (BCRP/ABCG2) is a member of the ABC transporter superfamily.


Input: This protein has a number of physiological functions, including protection of the human body from xenobiotics.


Input: The overexpression of BCRP in certain tumor cell lines causes cross-resistance against various drugs used in chemotherapeutic treatment.


Input: In a previous work we showed that a new class of compounds derived from XR9576 (tariquidar) selectively inhibits BCRP.

tariquidar


Input: In this work we synthesized more members of this class, with modification on the second and third aromatic rings.


Input: The inhibitory activities against BCRP and P-gp were assayed using a Hoechst 33342 assay for BCRP and a calcein AM assay for P-gp.

Hoechst 33342


Input: Finally, quantitative structure-activity relationships for both aromatic rings were established.


Input: The results obtained show the importance of the electron density on the third aromatic ring, influenced by substituents, pointing to interactions with aromatic residues of the protein binding site.


Input: In the second aromatic ring the activity of compounds is influenced by the steric volume of the substituents.


Input: Reduction of helical content by insertion of a disulfide bond leads to an antimicrobial peptide with decreased hemolytic activity.

disulfide


Input: CAPs off to the S-S bond: Application of a strategy involving the introduction of intramolecular disulfide bonds to amphipathic cationic antimicrobial peptides (CAPs) led to decreased alpha-helicity and hydrophobicity.

S-S

disulfide


Input: The mutant peptides were observed to have significantly increased (250-fold) minimum hemolytic concentrations while maintaining MIC values against E. coli, affording more therapeutically selective CAPs.


Input: Hepatic Cyp2d and Cyp26a1 mRNAs and activities are increased during mouse pregnancy.


Input: There is considerable evidence that drug disposition is altered during human pregnancy and based on probe drug studies, CYP2D6 activity increases during human pregnancy.


Input: The aim of this study was to determine whether the changes of CYP2D6 activity observed during human pregnancy could be replicated in the mouse, and explore possible mechanisms of increased CYP2D6 activity during pregnancy.


Input: Cyp2d11, Cyp2d22, Cyp2d26 and Cyp2d40 mRNA was increased (P < 0. 05) on gestational days (GD) 15 and 19 compared with the non-pregnant controls.


Input: There was no change (P > 0. 05) in Cyp2d9 and Cyp2d10 mRNA.


Input: In agreement with the increased Cyp2d mRNA, Cyp2d-mediated dextrorphan formation from dextromethorphan was increased 2. 7-fold (P < 0. 05) on GD19 (56. 8 +/- 39. 4 pmol/min/mg protein) when compared with the non-pregnant controls (20. 8 +/- 11. 2 pmol/min/mg protein).

dextrorphan

dextromethorphan


Input: An increase in Cyp26a1 mRNA (10-fold) and retinoic acid receptor (Rar) beta mRNA (2. 8-fold) was also observed during pregnancy.

retinoic acid


Input: The increase in Cyp26a1 and Rar beta mRNA during pregnancy indicates increased retinoic acid signaling in the liver during pregnancy.

retinoic acid


Input: A putative retinoic acid response element was identified within the Cyp2d40 promoter and the mRNA of Cyp2d40 correlated (P < 0. 05) with Cyp26a1 and Rar beta.

retinoic acid


Input: These results show that Cyp2d mRNA is increased during mouse pregnancy the and mouse may provide a suitable model to investigate the mechanisms underlying the increased clearance of CYP2D6 probes observed during human pregnancy.


Input: Our findings also suggest that retinoic acid signaling in the liver is increased during pregnancy, which may have broader implications to energy homeostasis in the liver during pregnancy.

retinoic acid


Input: Susceptibility to fatty acid-induced beta-cell dysfunction is enhanced in prediabetic diabetes-prone biobreeding rats: a potential link between beta-cell lipotoxicity and islet inflammation.

fatty acid


Input: beta-Cell lipotoxicity is thought to play an important role in the development of type 2 diabetes.


Input: However, no study has examined its role in type 1 diabetes, which could be clinically relevant for slow-onset type 1 diabetes.


Input: Reports of enhanced cytokine toxicity in fat-laden islets are consistent with the hypothesis that lipid and cytokine toxicity may be synergistic.


Input: Thus, beta-cell lipotoxicity could be enhanced in models of autoimmune diabetes.


Input: To determine this, we examined the effects of prolonged free fatty acids elevation on beta-cell secretory function in the prediabetic diabetes-prone BioBreeding (dp-BB) rat, its diabetes-resistant BioBreeding (dr-BB) control, and normal Wistar-Furth (WF) rats.

fatty acids


Input: Rats received a 48-h iv infusion of saline or Intralipid plus heparin (IH) (to elevate free fatty acid levels ~ 2-fold) followed by hyperglycemic clamp or islet secretion studies ex vivo.

fatty acid


Input: IH significantly decreased beta-cell function, assessed both by the disposition index (insulin secretion corrected for IH-induced insulin resistance) and in isolated islets, in dp-BB, but not in dr-BB or WF, rats, and the effect of IH was inhibited by the antioxidant N-acetylcysteine.

N-acetylcysteine


Input: Furthermore, IH significantly increased islet cytokine mRNA and plasma cytokine levels (monocyte chemoattractant protein-1 and IL-10) in dp-BB, but not in dr-BB or WF, rats.


Input: All dp-BB rats had mononuclear infiltration of islets, which was absent in dr-BB and WF rats.


Input: In conclusion, the presence of insulitis was permissive for IH-induced beta-cell dysfunction in the BB rat, which suggests a link between beta-cell lipotoxicity and islet inflammation.


Input: Ablation of Egr2-positive cells in male mouse anterior pituitary leads to atypical isolated GH deficiency.


Input: In this study, we have investigated the expression and function of the transcription factor early growth response factor 2 (Egr2)/Krox20 in the developing anterior pituitary.


Input: Egr2 is initially expressed in all differentiating hormonal cells types, but its expression is mostly restricted to the somatotroph lineage after birth.


Input: Egr2 knockout results in anterior pituitary hypoplasia.


Input: However, the analysis of a conditional mutant demonstrates that this phenotype does not originate from a lack of Egr2 expression in the pituitary.


Input: Using an Egr2 allele driving a Cre-activable toxin gene, we performed a genetic ablation of Egr2-positive cells in the pituitary.


Input: During the postnatal period, this ablation leads to specific and progressive depletion of the somatotroph population, creating a novel model of early-onset isolated GH deficiency (GHD).


Input: Mutant animals were subjected to a complete metabolic analysis, revealing atypical and expected features.


Input: Consistent with an adult-onset isolated GHD model, mutant animals are hypoglycemic and display increased insulin sensitivity and glucose clearance.

glucose


Input: This latter phenotype is in contrast to the glucose intolerance observed in another early-onset GHD model.

glucose


Input: Surprisingly, increased insulin sensitivity is not accompanied by a modified balance between fat and lean tissues, but by reduced metabolic adaptability between glucose and lipid oxidation conditions.

glucose


Input: This suggests that the relationship between these metabolic features and insulin sensitivity should be reconsidered.


Input: In conclusion, our mutant may be a valuable genetic model with which to study the effects of long-term GH deficiency, in conditions of normal pancreatic function and unaffected balance between fat and glucose metabolism.

glucose


Input: Assembly of subtype 1 influenza neuraminidase is driven by both the transmembrane and head domains.


Input: Neuraminidase (NA) is one of the two major influenza surface antigens and the main influenza drug target.


Input: Although NA has been well characterized and thought to function as a tetramer, the role of the transmembrane domain (TMD) in promoting proper NA assembly has not been systematically studied.


Input: Here, we demonstrate that in the absence of the TMD, NA is synthesized and transported in a predominantly inactive state.


Input: Substantial activity was rescued by progressive truncations of the stalk domain, suggesting the TMD contributes to NA maturation by tethering the stalk to the membrane.


Input: To analyze how the TMD supports NA assembly, the TMD was examined by itself.


Input: The NA TMD formed a homotetramer and efficiently trafficked to the plasma membrane, indicating the TMD and enzymatic head domain drive assembly together through matching oligomeric states.


Input: In support of this, an unrelated strong oligomeric TMD rescued almost full NA activity, whereas the weak oligomeric mutant of this TMD restored only half of wild type activity.


Input: These data illustrate that a large soluble domain can force assembly with a poorly compatible TMD; however, optimal assembly requires coordinated oligomerization between the TMD and the soluble domain.


Input: Membrane domains and the " lipid raft " concept.


Input: The bulk structure of biological membranes consists of a bilayer of amphipathic lipids.


Input: According to the fluid mosaic model proposed by Singer and Nicholson, the glycerophospholipid bilayer is a two-dimensional fluid construct that allows the lateral movement of membrane components.

glycerophospholipid


Input: Different types of lateral interactions among membrane components can take place, giving rise to multiple levels of lateral order that lead to highly organized structures.


Input: Early observations suggested that some of the lipid components of biological membranes may play active roles in the creation of these levels of order.


Input: In the late 1980s, a diverse series of experimental findings collectively gave rise to the lipid raft hypothesis.


Input: Lipid rafts were originally defined as membrane domains, i. e., ordered structures created as a consequence of the lateral segregation of sphingolipids and differing from the surrounding membrane in their molecular composition and properties.

sphingolipids


Input: This definition was subsequently modified to introduce the notion that lipid rafts correspond to membrane areas stabilized by the presence of cholesterol within a liquid-ordered phase.

cholesterol


Input: During the past two decades, the concept of lipid rafts has become extremely popular among cell biologists, and these structures have been suggested to be involved in a great variety of cellular functions and biological events.


Input: During the same period, however, some groups presented experimental evidence that appeared to contradict the basic tenets that underlie the lipid raft concept.


Input: The concept is currently being re-defined, with greater consistency regarding the true nature and role of lipid rafts.


Input: In this article we will review the concepts, criticisms, and the novel confirmatory findings relating to the lipid raft hypothesis.


Input: Regulation of G protein-coupled receptor kinases by phospholipids.


Input: G protein coupled-receptor (GPCR) kinases (GRKs) initiate the deactivation of GPCRs by phosphorylating their cytoplasmic loops and C-terminal tails.


Input: They are regulated not only by allosteric interactions with activated GPCRs, but also by the membrane environment itself.


Input: Herein we describe how the various GRKs are recruited to lipid bilayers and, where evident, how specific anionic phospholipids help regulate their activity.


Input: Using crystal structures representing each of the three vertebrate GRK subfamilies, we map the lipid binding sites in order to better understand how these enzymes are oriented at the cell surface.


Input: This analysis suggests that GRKs bind lipid and active GPCRs in a coordinated manner.


Input: Membrane lipids in the function of serotonin and adrenergic receptors.

serotonin


Input: G-protein coupled receptors (GPCRs) are the largest class of molecules involved in signal transduction across membranes, and represent major targets in the development of novel drug candidates in all clinical areas.


Input: Since GPCRs are integral membrane proteins, interaction of membrane lipids such as cholesterol and sphingolipids with GPCRs constitutes an emerging area of research in contemporary biology.

cholesterol

sphingolipids


Input: Cholesterol and sphingolipids represent important lipid components of eukaryotic membranes and play a crucial role in a variety of cellular functions.

Cholesterol

sphingolipids


Input: In this review, we highlight the role of these vital lipids in the function of two representative GPCRs, the serotonin (1A) receptor and the adrenergic receptor.

serotonin


Input: We believe that development in deciphering molecular details of the nature of GPCR-lipid interaction would lead to better insight into our overall understanding of GPCR function in health and disease.


Input: GPR55 and its interaction with membrane lipids: comparison with other endocannabinoid-binding receptors.


Input: A number of integral membrane G protein-coupled receptors (GPCRs) share common structural features (including palmytoilated aminoacid residues and consensus sequences specific for interaction with cholesterol) that allow them to interact with lipid rafts, membrane cholesterol-rich microdomains able to regulate GPCR signalling and functions.

palmytoilated aminoacid

cholesterol

cholesterol


Input: Among GPCRs, type-1 and type-2 cannabinoid receptors, the molecular targets of endocannabinoids (eCBs), control many physiological and pathological processes through the activation of several signal transduction pathways.


Input: Recently, the orphan GPR55 receptor has been proved to be activated by many eCBs, thus leading to the hypothesis that it might be the " type-3 " cannabinoid receptor.


Input: While the biological activity of eCBs and the influence of membrane lipids on their functions are rather well established, information regarding GPR55 is still scarce and often controversial.


Input: Based on this background, here we shall review current data about GPR55 pharmacology and signalling, highlighting its involvement in several pathophysiological conditions.


Input: We shall also outline the structural features that allow GPR55 to interact with cholesterol and to associate with lipid rafts; how the latter lipid microdomains impact the biological activity of GPR55 is also addressed, as well as their potential for the discovery of new therapeutics useful for the treatment of those human diseases that might be associated with alterations of GPR55 activity.

cholesterol


Input: 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation.

2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin

oxygen


Input: Chloracne is commonly observed in humans exposed to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD); yet, the mechanism of toxicity is not well understood.

2, 3, 7, 8-tetrachlorodibenzo-p-dioxin

TCDD


Input: Using normal human epidermal keratinocytes, we investigated the mechanism of TCDD-mediated enhancement of epidermal differentiation by integrating functional genomic, metabolomic, and biochemical analyses.

TCDD


Input: TCDD increased the expression of 40% of the genes of the epidermal differentiation complex found on chromosome 1q21 and 75% of the genes required for de novo ceramide biosynthesis.

TCDD

ceramide


Input: Lipid analysis demonstrated that eight of the nine classes of ceramides were increased by TCDD, altering the ratio of ceramides to free fatty acids.

ceramides

TCDD

ceramides

fatty acids


Input: TCDD decreased the expression of the glucose transporter, SLC2A1, and most of the glycolytic transcripts, followed by decreases in glycolytic intermediates, including pyruvate.

TCDD

glucose

pyruvate


Input: NADH and Krebs cycle intermediates were decreased, whereas NAD (+) was increased.

NADH

NAD (+)


Input: Mitochondrial glutathione (GSH) reductase activity and the GSH/glutathione disulfide ratio were decreased by TCDD, ultimately leading to mitochondrial dysfunction, characterized by decreased inner mitochondrial membrane potential and ATP production, and increased production of the reactive oxygen species (ROS), hydrogen peroxide.

glutathione

GSH

GSH

glutathione disulfide

TCDD

ATP

oxygen

hydrogen peroxide


Input: Aryl hydrocarbon receptor (AHR) antagonists blocked the response of many transcripts to TCDD, and the endpoints of decreased ATP production and differentiation, suggesting regulation by the AHR.

Aryl hydrocarbon

TCDD

ATP


Input: Cotreatment of cells with chemical antioxidants or the enzyme catalase blocked the TCDD-mediated acceleration of keratinocyte cornified envelope formation, an endpoint of terminal differentiation.

TCDD


Input: Thus, TCDD-mediated ROS production is a critical step in the mechanism of this chemical to accelerate keratinocyte differentiation.

TCDD


Input: Delta 9-tetrahydrocannabinol impairs the inflammatory response to influenza infection: role of antigen-presenting cells and the cannabinoid receptors 1 and 2.

Delta 9-tetrahydrocannabinol


Input: Delta (9)-tetrahydrocannabinol (Delta (9)-THC) has potent immune modulatory properties and can impair pathogen-induced immune defenses, which in part have been attributed to ligation of the cannabinoid receptors 1 (CB (1)) and 2 (CB (2)).

Delta (9)-tetrahydrocannabinol

Delta (9)-THC


Input: Most recently, dendritic cells (DC) were identified for their potential to enhance influenza-induced immunopathology in mice lacking CB (1) and CB (2) (CB (1) (-/-) CB (2) (-/-)).


Input: This study focused on the modulation of the inflammatory immune response to influenza by Delta (9)-THC and the role of CB (1) and/or CB (2) as receptor targets for Delta (9)-THC.

Delta (9)-THC

Delta (9)-THC


Input: C57Bl/6 (wild type) and CB (1) (-/-) CB (2) (-/-) mice were administered Delta (9)-THC (75 mg/kg) surrounding the intranasal instillation of A/PR/8/34 influenza virus.

Delta (9)-THC


Input: Three days post infection (dpi), Delta (9)-THC broadly decreased expression levels of mRNA induced by the innate immune response to influenza, suppressed the percentage of interferon-gamma (IFN-gamma)-producing CD4 (+) and interleukin-17-producing NK1. 1 (+) cells, and reduced the influx of antigen-presenting cells (APC), including inflammatory myeloid cells and monocytes/macrophages, into the lung in a CB (1)-and/or CB (2)-dependent manner.

Delta (9)-THC


Input: Delta (9)-THC had little effect on the expression of CD86, major histocompatibility complex I (MHC I), and MHC II by APC isolated from the lung.

Delta (9)-THC


Input: In vitro studies demonstrated that lipopolysaccharide (LPS)-induced maturation was suppressed by Delta (9)-THC in bone marrow-derived DC (bmDC).

Delta (9)-THC


Input: Furthermore, antigen-specific IFN-gamma production by CD8 (+) T cells after coculture was reduced by Delta (9)-THC treatment of bmDC in a CB (1)-and/or CB (2)-dependent manner.

Delta (9)-THC


Input: Collectively, these studies suggest that Delta (9)-THC potently suppresses myeloid cell immune function, in a manner involving CB (1) and/or CB (2), thereby impairing immune responses to influenza infection.

Delta (9)-THC


Input: Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature.


Input: Hungry bone syndrome (HBS) refers to the rapid, profound, and prolonged hypocalcaemia associated with hypophosphataemia and hypomagnesaemia, and is exacerbated by suppressed parathyroid hormone (PTH) levels, which follows parathyroidectomy in patients with severe primary hyperparathyroidism (PHPT) and preoperative high bone turnover.


Input: It is a relatively uncommon, but serious adverse effect of parathyroidectomy.


Input: We conducted a literature search of all available studies reporting a' hungry bone syndrome' in patients who had a parathyroidectomy for PHPT, to identify patients at risk and address the pitfalls in their management.


Input: The severe hypocalcaemia is believed to be due to increased influx of calcium into bone, due to the sudden removal of the effect of high circulating levels of PTH on osteoclastic resorption, leading to a decrease in the activation frequency of new remodelling sites and to a decrease in remodelling space, although there is no good documentation for this.

calcium


Input: Various risk factors have been suggested for the development of HBS, including older age, weight/volume of the resected parathyroid glands, radiological evidence of bone disease and vitamin D deficiency.

vitamin D


Input: The syndrome is reported in 25-90% of patients with radiological evidence of hyperparathyroid bone disease vs only 0-6% of patients without skeletal involvement.


Input: There is insufficient data-based evidence on the best means to treat, minimise or prevent this severe complication of parathyroidectomy.


Input: Treatment is aimed at replenishing the severe calcium deficit by using high doses of calcium supplemented by high doses of active metabolites of vitamin D.

calcium

calcium

vitamin D


Input: Adequate correction of magnesium deficiency and normalisation of bone turnover are required for resolution of the hypocalcaemia which may last for a number of months after successful surgery.

magnesium


Input: Preoperative treatment with bisphosphonates has been suggested to reduce post-operative hypocalcaemia, but there are to date no prospective studies addressing this issue.

bisphosphonates


Input: Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome.


Input: Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA.


Input: This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant-negative lamin A protein, known as progerin.


Input: Here we show that primary HGPS skin fibroblasts experience genome-wide correlated alterations in patterns of H3K27me3 deposition, DNA-lamin A/C associations, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains.


Input: We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells.


Input: Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin-lamina interactions.


Input: These changes may result in transcriptional misregulation and eventually trigger the global loss of spatial chromatin compartmentalization in late passage HGPS fibroblasts.


Input: Dynorphin-still an extraordinarily potent opioid peptide.


Input: This issue of Molecular Pharmacology is dedicated to Dr. Avram Goldstein, the journal' s founding editor and one of the leaders in the development of modern pharmacology.


Input: This article focuses on his contributions to the discovery of the dynorphins and evidence that members of this family of opioid peptides are endogenous agonists for the kappa opioid receptor.


Input: In his original publication describing the purification and sequencing of dynorphin A, Avram described this peptide as " extraordinarily potent " (" dyn " from the Greek, dynamis = power and " orphin " for endogenous morphine peptide).


Input: The name originally referred to its high affinity and great potency in the bioassay that was used to follow its activity during purification, but the name has come to have a second meaning: studies of its physiologic function in brain continue to provide powerful insights to the molecular mechanisms controlling mood disorders and drug addiction.


Input: During the 30 years since its discovery, we have learned that the dynorphin peptides are released in brain during stress exposure.


Input: After they are released, they activate kappa opioid receptors distributed throughout the brain and spinal cord, where they trigger cellular responses resulting in different stress responses: analgesia, dysphoria-like behaviors, anxiety-like responses, and increased addiction behaviors in experimental animals.


Input: Avram predicted that a detailed molecular analysis of opiate drug actions would someday lead to better treatments for drug addiction, and he would be gratified to know that subsequent studies enabled by his discovery of the dynorphins resulted in insights that hold great promise for new treatments for addiction and depressive disorders.


Input: Development of solid lipid nanoparticles (SLNs) of lopinavir using hot self nano-emulsification (SNE) technique.

lopinavir


Input: Solid lipid nanoparticles (SLNs) of poor orally bioavailable drug lopinavir were prepared using hot self nano-emulsification (SNE) technique.

lopinavir


Input: Hot isotropic mixture of stearic acid, poloxamer and polyethylene glycol was spontaneously self nano-emulsify in hot water and SLNs were formed with subsequent rapid cooling.

stearic acid

poloxamer

polyethylene glycol


Input: Self nano-emulsification ability of stearic acid, poloxamer and polyethylene glycol mixture was assessed by ternary phase diagram study.

stearic acid

poloxamer

polyethylene glycol


Input: Optimized SLNs were having particle size of 180. 6 +/- 2. 32 nm (PDI = 0. 133 +/- 0. 001), 91. 5 +/- 1. 3% entrapment efficiency and zeta potential of-13. 4 +/- 0. 56 mV.


Input: SLNs were evaluated by transmission electron microscopy (TEM) and atomic force microscopy (AFM) for morphological study.


Input: Further, Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) of SLNs were also performed for checking solid state characterization.


Input: Higher oral bioavailability was found for lopinavir loaded SLNs in comparison to bulk lopinavir due to higher lymphatic drug transport (p < 0. 05).

lopinavir

lopinavir


Input: Results indicate that SLNs of higher fatty acids can be successfully prepared by hot SNE technique.

fatty acids


Input: Retinal drug delivery using eyedrop preparations of poly-L-lysine-modified liposomes.

poly-L-lysine


Input: The purpose of this study was to develop surface-modified liposomes that enhance the efficiency of eye drop drug delivery to the retina.


Input: Various molecular weights and concentrations of the water-soluble cationic polymer poly-L-lysine (PLL) were used to modify the surface of submicronized (100 nm) liposomes.

poly-L-lysine

PLL


Input: Physicochemical properties of surface-modified liposomes were determined in vitro, and the efficiency of drug delivery to the retina was investigated in vivo.


Input: Using coumarin-6 as a model drug and fluorescent marker, we show that liposome surface modification by PLL dramatically increased delivery to mouse retina segments after eye drop administration.

PLL


Input: However, when PLL of high molecular weight (> 30, 000) was used at higher concentrations (> 0. 05%), aggregation of surface-modified liposomes increased particle size and hampered distribution to inner ocular tissues.

PLL


Input: As a result, the efficiency of drug delivery of these aggregated surface-modified liposomes was the same as unmodified liposomes.


Input: The optimal molecular weight and concentration of PLL in drug-delivering liposomes were 15, 000-30, 000 and 0. 005%, respectively.

PLL


Input: Under these conditions, PLL-modified liposomes were not cytotoxic in corneal or conjunctival cells.

PLL


Input: In conclusion, surface-modified liposomes have great potential as effective retinal drug delivery carriers in eye drop formulations.


Input: Amino acid derivatives as transdermal permeation enhancers.

Amino acid


Input: Transdermal permeation enhancers are compounds that temporarily decrease skin barrier properties to promote drug flux.


Input: In this study, we investigated enhancers with amino acids (proline, sarcosine, alanine, beta-alanine, and glycine) attached to hydrophobic chain (s) via a biodegradable ester link.

amino acids

proline

sarcosine

alanine

beta-alanine

glycine

ester


Input: The double-chain lipid-like substances displayed no enhancing effect, whereas single-chain substances significantly increased skin permeability.


Input: The proline derivative l-Pro2 reached enhancement ratios of up to 40 at 1% concentration, which is higher than that of the well-established and standard enhancers Azone, DDAIP, DDAK, and Transkarbam 12.

proline

Azone

DDAIP

DDAK

Transkarbam 12


Input: No stereoselectivity was observed.


Input: l-Pro2 acted synergistically with propylene glycol.

propylene glycol


Input: Infrared studies revealed that l-Pro2 forms a separate liquid ordered phase in the stratum corneum lipids and has no significant effect on proteins.


Input: l-Pro2 action was at least partially reversible as measured by skin electrical impedance.


Input: Toxicity in keratinocyte (HaCaT) and fibroblast (3T3) cell lines showed IC (50) values ranging from tens to hundreds of mu M, which is comparable with standard enhancers.


Input: Furthermore, l-Pro2 was rapidly decomposed in plasma.


Input: In vivo transdermal absorption studies in rats confirmed the enhancing activity of l-Pro2 and suggested its negligible skin toxicity and minimal effect on transepidermal water loss.


Input: These properties make l-Pro2 a promising candidate for potential clinical use.


Input: The onset of antineutrophil cytoplasmic antibody-associated vasculitis immediately after methimazole was switched to propylthiouracil in a woman with Graves' disease who wished to become pregnant.

methimazole

propylthiouracil


Input: Propylthiouracil (PTU) is recommended as a first-line antithyroid drug (ATD) during first trimester organogenesis in pregnancy because recent evidence suggests that methimazole (MMI) may be associated with congenital anomalies.

Propylthiouracil

PTU

methimazole

MMI


Input: However, PTU more commonly causes myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which usually occurs during prolonged treatment, compared with MMI.

PTU

MMI


Input: We report a case of MPO-ANCA-associated vasculitis in a 35-year-old woman with Graves' disease.


Input: Although her thyroid function could be maintained euthyroid by MMI, her ATD was switched to PTU because she wished to become pregnant.

PTU


Input: The patient presented with flu-like symptoms 8 days after starting PTU and developed hemoptysis and dyspnea at 22 days.

PTU


Input: Her MPO-ANCA titer was 21 ELISA units (EUs) before PTU treatment but increased to 259 EUs at 22 days after PTU treatment.

PTU

PTU


Input: Her clinical condition improved with the discontinuation of PTU and with immunosuppressive therapy.

PTU


Input: This case indicated that MPO-ANCA vasculitis occurred within several weeks after the initiation of PTU and that this side effect could be caused by the change from MMI to PTU.

PTU

MMI

PTU


Input: Thus, our clinical observation suggests that patients treated with PTU should be carefully monitored for MPO-ANCA titers and variable manifestations of MPO-ANCA-associated vasculitis regardless of the period of administration.

PTU


Input: RNApathwaysDB--a database of RNA maturation and decay pathways.


Input: Many RNA molecules undergo complex maturation, involving e. g. excision from primary transcripts, removal of introns, post-transcriptional modification and polyadenylation.


Input: The level of mature, functional RNAs in the cell is controlled not only by the synthesis and maturation but also by degradation, which proceeds via many different routes.


Input: The systematization of data about RNA metabolic pathways and enzymes taking part in RNA maturation and degradation is essential for the full understanding of these processes.


Input: RNApathwaysDB, available online at http://iimcb. genesilico. pl/rnapathwaysdb, is an online resource about maturation and decay pathways involving RNA as the substrate.


Input: The current release presents information about reactions and enzymes that take part in the maturation and degradation of tRNA, rRNA and mRNA, and describes pathways in three model organisms: Escherichia coli, Saccharomyces cerevisiae and Homo sapiens.


Input: RNApathwaysDB can be queried with keywords, and sequences of protein enzymes involved in RNA processing can be searched with BLAST.


Input: Options for data presentation include pathway graphs and tables with enzymes and literature data.


Input: Structures of macromolecular complexes involving RNA and proteins that act on it are presented as' potato models' using DrawBioPath-a new javascript tool.


Input: Protein-polyanion interactions for the controlled release of monoclonal antibodies.


Input: The objective of the present study was to investigate ionic interactions between alginate and a monoclonal antibody (mAb1) and to utilize those interactions for the sustained release of mAb1.


Input: The existence of ionic interactions between alginate and mAb1 was strongly reflected by their rheological behavior.


Input: A 3-4 times increase in storage modulus (G') was observed by addition of 30 mg/mL mAb1 to a 20 mg/mL alginate solution.


Input: This increase was strongly dependent on pH and ionic strength.


Input: In vitro release studies revealed a marked pH-dependence of release rates and the reversibility of alginate-mAb1 complexation under physiological conditions.


Input: Two alginate-mAb1 sustained release formulations were developed by an internal gelation technique using CaCO (3) and CaHPO (4) as calcium sources for physical cross-linking.

CaCO (3)

CaHPO (4)

calcium


Input: The CaCO (3) formulation provided a stable pH-environment, optimally suited for pH-sensitive proteins.

CaCO (3)


Input: CaHPO (4) led to a lower pH and stronger alginate-mAb1 interactions.

CaHPO (4)


Input: The CaHPO (4) cross-linked alginate released mAb1 over a period of 10-15 days.

CaHPO (4)


Input: The long release period and changes in viscoelastic properties of alginate, when being mixed with mAb1, indicate the incorporation of mAb1 molecules into a mixed network with alginate.


Input: The results of this study demonstrate that ionic interactions between polyanions and mAb1 are present and that they can be exploited for sustained release delivery of mAb1.


Input: Effects of antipsychotics on the BDNF in schizophrenia.


Input: Brain-derived neurotropic factor (BDNF) is involved in the development of the brain, and likely influences the neuroplasticity in schizophrenia.


Input: BDNF is also believed to interact with other neurotransmitter systems implicated in schizophrenia, such as dopamine, glutamate, serotonin and GABA.

dopamine

glutamate

serotonin

GABA


Input: Therefore, BDNF is a candidate gene for schizophrenia.


Input: In past decades, the blood (serum or plasma) BDNF protein levels and BDNF gene alleles and genotypes to the clinical features of schizophrenia, such as age of onset, clinical subtypes, symptom severity, and drug response, have been evaluated among different populations.


Input: However, the results are still inconsistent.


Input: Further, different drugs have been reported to have different effects on BDNF protein levels.


Input: A cross-sectional survey revealed that serum BDNF levels in chronic schizophrenic patients treated with clozapine exceeded those of patients treated with risperidone or with typical antipsychotics.

clozapine

risperidone


Input: In recent times, BDNF epigenetic studies have also been conducted in clinical studies of schizophrenia to address the question of why patients with the same gene genotype and alleles have different clinical presentations.


Input: In addition, the effects of different antipsychotic drugs on gene methylation and protein acetylation have also been reported.


Input: In conclusion, more data are needed regarding BDNF in the brain and in peripheral blood, including protein levels, single nucleotide polymorphisms, epigenetic regulation, and clinical data in order to understand the role of BDNF in schizophrenia.


Input: Facilitative effect of serotonin (1A) receptor agonists on cognition in patients with schizophrenia.

serotonin


Input: Disturbances of cognitive function are considered to largely affect the outcome in patients with schizophrenia.


Input: There is much attention to the role of psychotropic compounds acting on serotonin (5-HT) receptors in ameliorating cognitive deficits of the disease.

serotonin


Input: Among the 5-HT receptor subtypes, the 5-HT (1A) receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence.


Input: The neural network underlying the ability of 5-HT (1A) agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and gamma-aminobutyric acid neurons.

dopamine

glutamate

gamma-aminobutyric acid


Input: Recent advances of electrophysiological measures, such as event-related potentials, have provided insights into facilitative effects on cognition of some atypical antipsychotic drugs or related compounds acting directly or indirectly on 5-HT (1A) receptors.


Input: These considerations are expected to promote the development of novel therapeutics for the betterment of functional outcome in people suffering from schizophrenia.


Input: Neurobiological basis of dyskinetic effects induced by antipsychotics: the contribution of animal models.


Input: Tardive dyskinesia (TD) is a movement disorder characterized by abnormal involuntary facial movements induced by chronic therapy with classical antipsychotic medications.


Input: Currently, there is no satisfactory pharmacotherapy for TD, which represents a major limitation to therapy with classical antipsychotics.


Input: In order to develop or optimize therapies for TD, and to develop new APDs with lower indices of motor side effects, the pathology underlying TD must first be understood.


Input: The use of animal models has been used to further this objective.


Input: Here, we review different preparations that have been used to model TD and discuss the contribution of neuroimaging studies conducted in these models.


Input: Studies in animal models have lead to several hypotheses of TD pathology, although none has yet emerged as the ultimate underlying cause of this syndrome.


Input: We discuss alterations in functional indices, neuron and synapse morphology and changes in specific neurotransmitter systems that have been described in animal models of TD, and outline how these findings have contributed to our understanding of antipsychotic-induced dyskinesias.


Input: We conclude that several non-mutually exclusive theories of TD are supported by animal studies, including increases in oxidative stress leading to structural and functional changes in specific neurotransmitter systems.


Input: Elucidating the mechanisms underlying TD neuropathology partly through the use of animal models will lead to the development of APDs with superior side effect profiles or more effective therapies for TD.


Input: Abnormal striatal dopamine transmission in schizophrenia.

dopamine


Input: Despite numerous revisions and reformulations, dopamine (DA) hypothesis of schizophrenia remains a pivotal neurochemical hypothesis of this illness.

dopamine


Input: The aim of this review is to expose and discuss findings from positron emission tomography (PET) or single-photon-emission computed tomography (SPECT) studies investigating DA function in the striatum of medicated, drug-naive or drug-free patients with schizophrenia and in individuals at risk compared with healthy volunteers.


Input: DA function was studied at several levels: i) at a presynaptic level where neuroimaging studies investigating DOPA uptake capacity clearly show an increase of DA synthesis in patients with schizophrenia; ii) at a synaptic level where neuroimaging studies investigating dopamine transporter availability (DAT) does not bring any evidence of dysfunction; iii) and finally, neuroimaging studies investigating DA receptor density show a mild increase of D2 receptor density in basic condition and, an hyperreactivity of DA system in dynamic condition.

DOPA

dopamine


Input: These results are discussed regarding laterality, sub-regions of striatum and implications for the at-risk population.


Input: Striatal DA abnormalities are now clearly demonstrated in patients with schizophrenia and at risk population and could constitute an endophenotype of schizophrenia.


Input: Subtle sub-clinical striatal DA abnormalities in at risk population could be a biomarker of transition from a vulnerability state to the expression of frank psychosis.


Input: Proton magnetic resonance spectroscopy changes after antipsychotic treatment.


Input: Proton magnetic resonance spectroscopy ((1) H MRS) enables the observation of brain function in vivo.

(1) H


Input: Several brain metabolites can be measured by the means of (1) H MRS: N-acetylaspartate (NAA), choline containing compounds (Cho), myo-inositol (mI) and glutamate (Glu), glutamine (Gln) and GABA (together as Glx complex or separately).

N-acetylaspartate

NAA

choline

myo-inositol

glutamate

Glu

glutamine

Gln

GABA


Input: (1) H MRS measures have been found to be abnormal in psychotic disorders such as schizophrenia.

(1) H


Input: Here we specifically review the influence exerted by antipsychotic drugs on brain metabolism, as detected by (1) H MRS.

(1) H


Input: We systematically reviewed the available literature and uncovered 27 studies, 16 before-after treatment and 11 cross-sectional.


Input: Most of them addressed the effects of antipsychotics in schizophrenia and mainly focusing on NAA alterations.

NAA


Input: Follow up studies indicated antipsychotic drugs may act by increasing NAA levels in selected brain areas (the frontal lobe and thalamus), especially during the short-time observation.

NAA


Input: This phenomenon seems to vanish after longer observation.


Input: Other studies indicated that glutamate measures are decreasing along with the duration of the disease, suggesting both a neurodegenerative process present in schizophrenic brain as well as an influence of antipsychotics.

glutamate


Input: The above results were reviewed according to the most recent theories in the field accounting for the impact of antipsychotics (1) HMRS measures.

(1) HMRS


Input: The next frontier in composite tissue allotransplantation.


Input: Solid organ transplantations became a clinical option in the 1950s.


Input: The hand allograft was the pioneer of composite tissue allotransplantation (CTA), successfully started near the end of the last century despite arguments over the practicality and methods.


Input: Since then, CTA such as hand and face has continued to progress from the theoretical to clinical reality.


Input: The treatment principles, drug combinations, and mechanisms of the immunosuppression medications on which contemporary transplant surgeries have been based continue to develop as researchers and physicians gain more experience in the CTA field.


Input: It could be argued that the ethical issues associated with CTA have prevented evolution of the field rather than surgical or technical skill.


Input: This is particularly true for allo-head and body reconstruction (AHBR).


Input: How can leaders in the field of CTA develop a model that would satisfy ethical concerns?


Input: Bolstered by recent successes in the field, is it time to traverse the next frontier?


Input: Can AHBR ever be a feasible option in the clinical setting?


Input: The reader will be provided with a brief history of CTA from theory to research to clinical practice.


Input: A concise description of AHBR as it pertains to the critical procedure (i. e., surgery design) will also be discussed.


Input: Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of Tuberous Sclerosis Complex.

rapamycin


Input: Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder caused by mutation in either Tsc1 or Tsc2 genes that leads to the hyper activation of the mTOR pathway, a key signalling pathway for synaptic plasticity.


Input: TSC is characterized by benign tumors arising in different organs and severe neuropsychiatric symptoms, such as epilepsy, intellectual disability, autism, anxiety and depressive behaviour.


Input: Rapamycin is a potent inhibitor of mTOR and its efficacy in treating epilepsy and neurological symptoms remains elusive.

Rapamycin


Input: In a mouse model in which Tsc1 has been deleted in embryonic telencephalic neural stem cells, we analyzed anxiety-and depression-like behaviour by elevated-plus maze (EPM), open-field test (OFT), forced-swim test (FST) and tail-suspension test (TST), after chronic administration of rapamycin.

rapamycin


Input: In addition, spectral analysis of background EEG was performed.


Input: Rapamycin-treated mutant mice displayed a reduction in anxiety-and depression-like phenotype, as shown by the EPM/OFT and FST, respectively.

Rapamycin


Input: These results were inline with EEG power spectra outcomes.


Input: The same effects of rapamycin were observed in wild-type mice.

rapamycin


Input: Notably, in heterozygous animals we did not observe any EEG and/or behavioural variation after rapamycin treatment.

rapamycin


Input: Together these results suggest that both TSC1 deletion and chronic rapamycin treatment might have a role in modulating behaviour and brain activity, and point out to the potential usefulness of background EEG analysis in tracking brain dysfunction in parallel with behavioural testing.

rapamycin


Input: Novel antitussive strategies.


Input: Acute and chronic cough represent one of the most common symptoms of medical importance but effective pharmacotherapy is, to all intents and purposes, absent.


Input: Numerous initiatives targeting the recently discovered tussive pathways are in progress.


Input: Here, we review the current antitussive armamentarium and provide an update on the novel strategies and compounds in development.


Input: Clinical risk factors, bone density and fall history in the prediction of incident fracture among men and women.


Input: The FRAX (tr) algorithm uses clinical risk factors (CRF) and bone mineral density (BMD) to predict fracture risk but does not include falls history in the calculation.


Input: Using results from the Hertfordshire Cohort Study, we examined the relative contributions of CRFs, BMD and falls history to fracture prediction.


Input: We studied 2299 participants at a baseline clinic that included completion of a health questionnaire and anthropometric data.


Input: A mean of 5. 5years later (range 2. 9-8. 8years) subjects completed a postal questionnaire detailing fall and fracture history.


Input: In a subset of 368 men and 407 women, bone densitometry was performed using a Hologic QDR 4500 instrument.


Input: There was a significantly increased risk of fracture in men and women with a previous fracture.


Input: A one standard deviation drop in femoral neck BMD was associated with a hazards ratio (HR) of incident fracture (adjusted for CRFs) of 1. 92 (1. 04-3. 54) and 1. 77 (1. 16-2. 71) in men and women respectively.


Input: A history of any fall since the age of 45years resulted in an unadjusted HR of fracture of 7. 31 (3. 78-14. 14) and 8. 56 (4. 85-15. 13) in men and women respectively.


Input: In a ROC curve analysis, the predictive capacity progressively increased as BMD and previous falls were added into an initial model using CRFs alone.


Input: Falls history is a further independent risk factor for fracture.


Input: Falls risk should be taken into consideration when assessing whether or not to commence medication for osteoporosis and should also alert the physician to the opportunity to target falls risk directly.


Input: Season linked responses to fine and quasi-ultrafine Milan PM in cultured cells.


Input: Exposure to urbane airborne particulate matter (PM) is related to the onset and exacerbation of cardiovascular and respiratory diseases.


Input: The fine (PM1), and quasi-ultrafine (PM0. 4) Milan particles collected during different seasons have been characterised and the biological effects on human epithelial lung A549, monocytes THP-1 cells and their co-culture, evaluated and compared with the results obtained on the PM10 and PM2. 5 fractions.


Input: Chemical composition and transmission electron microscopy (TEM) analysis of PM0. 4 showed that this fraction was very similar to PM1 for biological responses and dimension.


Input: All the winter fractions increased within 1h the level of reactive oxygen species (ROS), while only summer PM2. 5 had this effect on A549 cells.

oxygen


Input: The phosphorylation of H2AX (gamma H2AX), a marker of double strand DNA breaks (DSBs), was increased by all the winter fractions on A549 and THP-1 cells while summer PM samples did not induced this effect.


Input: PM0. 4 and PM1 biological effects are partly similar and related to the season of sampling, with effects on ROS and DNA damage induced only by winter PM fractions.


Input: The winter PM damaging effect on DNA correlates with the presence of organic compounds.


Input: Effects of molecular weight on permeability and microstructure of mixed ethyl-hydroxypropyl-cellulose films.

ethyl-hydroxypropyl


Input: Films of ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC) can be used for extended release coatings in oral formulations.

ethyl

hydroxypropyl


Input: The permeability and microstructure of free EC/HPC films with 30% w/w HPC were studied to investigate effects of EC molecular weight.


Input: Phase separation during film spraying and subsequent HPC leaching after immersion in aqueous media cause pore formation in such films.


Input: It was found that sprayed films were porous throughout the bulk of the films after water immersion.


Input: The molecular weight affected HPC leaching, pore morphology and film permeability; increasing the molecular weight resulted in decreasing permeability.


Input: A model to distinguish the major factors contributing to diffusion retardation in porous films showed that the trend in permeability was determined predominantly by factors associated with the geometry and arrangement of pores, independent of the diffusing species.


Input: The film with the highest molecular weight did, however, show an additional contribution from pore wall/permeant interactions.


Input: In addition, rapid drying and increasing molecular weight resulted in smaller pores, which suggest that phase separation kinetics affects the final microstructure of EC/HPC films.


Input: Thus, the molecular weight influences the microstructural features of pores, which are crucial for mass transport in EC/HPC films.


Input: TGF-beta as a therapeutic target in high grade gliomas-promises and challenges.


Input: Transforming growth factor-beta (TGF-beta) is a cytokine with a key role in tissue homeostasis and cancer.


Input: TGF-beta elicits both tumor suppressive and tumor promoting functions during cancer progression, in a wide range of cancers.


Input: Here, we review the tumor promoting function of TGF-beta and its possible promise as a therapeutic target in high grade gliomas, including glioblastoma multiforme (GBM), a disease with very poor prognosis.


Input: TGF-beta signaling is highly active in high grade gliomas and elevated TGF-beta activity has been associated with poor clinical outcome in this deadly disease.


Input: Common features of GBMs include fast cell proliferation, invasion into normal brain parenchyma, hypoxia, high angiogenic-and immunosuppressive activity, characteristics that all have been linked to activation of the TGF-beta pathway.


Input: TGF-beta signaling has also been connected with the cancer stem cell (CSC) phenotype in GBM.


Input: CSCs represent a subset of GBM cells thought to be responsible for tumor initiation, progression and relapse of disease.


Input: Following the description of these different properties of TGF-beta signaling and the underlying mechanisms identified thus far, the promise of TGF-beta targeted therapy in malignant gliomas is discussed.


Input: Several drugs targeting TGF-beta signaling have been developed that showed potent antitumor activity in preclinical models.


Input: A number of agents are currently evaluated in early clinical studies in glioma patients.


Input: Available results of these studies are highlighted and a perspective on the promise of TGF-beta-targeted therapy is given.


Input: Gene expression analysis by ESTs sequencing of the Brazilian frog Phyllomedusa nordestina skin glands.


Input: The subfamily Phyllomedusinae has attracted a great interest of many researchers mainly due to the high diversity of these frog species and plethora of pharmacological activities frequently observed for their skin secretions.


Input: Despite of this fact, mainly for new species, limited information is available regarding the molecular composition of these skin secretions and the cellular components involved in their production.


Input: Phyllomedusa nordestina is a recently described Brazilian frog species also popularly known as' tree-frogs'.


Input: Aiming at contributing to the biological knowledge of this species, we show here the gene expression profile of this frog skin secretion using a global ESTs analysis of a cDNA library.


Input: The marked aspect of this analysis revealed a significant higher transcriptional level of the opioid peptide dermorphins in P. nordestina skin secretion than in Phyllomedusa hypochondrialis, which is its closest related species, belonging both to the same phylogenetic group.


Input: Precursors of bioactive peptides as dermaseptins, phylloseptins, tryptophyllins, and bradykinin-like peptideswere also found in this library.

bradykinin


Input: Transcripts encoding proteins related to ordinary cellular functions and pathways were also described.


Input: Some of them are chiefly involved in the production of the skin secretion.


Input: Taken together, the data reported here constitute a contribution to the characterization of the molecular diversity of gene-encoded polypeptides with potential possibility of pharmacological exploitation.


Input: The transcriptional composition of the skin secretion may also help to give the necessary support for the definition of P. nordestina as a new species, which actually relies basically on frog morphological characteristics and geographical distribution.


Input: Aldehyde dehydrogenases: from eye crystallins to metabolic disease and cancer stem cells.

Aldehyde


Input: The aldehyde dehydrogenase (ALDH) superfamily is composed of nicotinamide adenine dinucleotide (phosphate) (NAD (P) (+))-dependent enzymes that catalyze the oxidation of aldehydes to their corresponding carboxylic acids.

aldehyde

nicotinamide adenine dinucleotide (phosphate)

NAD (P) (+)

aldehydes

carboxylic acids


Input: To date, 24 ALDH gene families have been identified in the eukaryotic genome.


Input: In addition to aldehyde metabolizing capacity, ALDHs have additional catalytic (e. g. esterase and reductase) and non-catalytic activities.

aldehyde


Input: The latter include functioning as structural elements in the eye (crystallins) and as binding molecules to endobiotics and xenobiotics.


Input: Mutations in human ALDH genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases.

aldehyde


Input: Most recently ALDH polymorphisms have been associated with gout and osteoporosis.


Input: Aldehyde dehydrogenase enzymes also play important roles in embryogenesis and development, neurotransmission, oxidative stress and cancer.

Aldehyde


Input: This article serves as a comprehensive review of the current state of knowledge regarding the ALDH superfamily and the contribution of ALDHs to various physiological and pathophysiological processes.


Input: Biochemical and molecular mechanisms of N-acetyl cysteine and silymarin-mediated protection against maneb-and paraquat-induced hepatotoxicity in rats.

N-acetyl cysteine

paraquat


Input: Oxidative stress is one of the major players in the pathogenesis of maneb (MB) and paraquat (PQ)-induced disorders.

paraquat


Input: N-acetyl cysteine (NAC), a glutathione (GSH) precursor and silymarin (SIL), a naturally occurring antioxidant, encounter oxidative stress-mediated cellular damage.

N-acetyl cysteine

NAC

glutathione

GSH


Input: The present study was aimed to investigate the effects of NAC and SIL against MB and/or PQ-induced hepatotoxicity in rats.

NAC


Input: The levels of hepatotoxicity markers-alanine aminotransaminase (ALT), aspartate aminotransaminase (AST) and total bilirubin, histological changes, oxidative stress indices, phase I and phase II xenobiotic metabolizing enzymes-cytochrome P450 (CYP) and glutathione S-transferase (GST) and pro-inflammatory molecules-inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) were measured in animals treated with MB and/or PQ in the presence or absence of NAC and SIL.

alanine

aspartate

bilirubin

glutathione S

nitric oxide

NAC


Input: MB and/or PQ augmented ALT, AST, total bilirubin, lipid peroxidation and nitrite contents and catalytic activities of superoxide dismutase and glutathione peroxidase however, the GSH content was attenuated.

bilirubin

nitrite

superoxide

glutathione

GSH


Input: NAC and SIL restored the above-mentioned alterations towards basal levels but the restorations were more pronounced in SIL treated groups.

NAC


Input: Similarly, MB and/or PQ-mediated histopathological symptoms and changes in the catalytic activities/expressions of CYP1A2, CYP2E1, iNOS, TNF-alpha, and IL-1 beta were alleviated by NAC and SIL.

NAC


Input: Conversely, MB and/or PQ-induced GSTA4-4 expression/activity was further increased by NAC/SIL and glutathione reductase activity was also increased.

NAC

glutathione


Input: The results obtained thus suggest that NAC and SIL protect MB and/or PQ-induced hepatotoxicity by reducing oxidative stress, inflammation and by modulating xenobitic metabolizing machinery and SIL seems to be more effective.

NAC


Input: Renal biomarker changes associated with hyaline droplet nephropathy in rats are time and potentially compound dependent.


Input: Alpha 2u-globulin mediated hyaline droplet nephropathy (HDN) is a male rat specific lesion induced when a compound or metabolite binds to alpha 2u-globulin.


Input: The objective of this study was to investigate if the newer and more sensitive renal biomarkers would be altered with HDN as well as be able to distinguish between HDN and oxidative stress-induced kidney injury.


Input: Rats were dosed orally for 7 days to determine (1) if HDN (induced by 2-propanol or D-limonene) altered the newer renal biomarkers and not BUN or creatinine, (2) if renal biomarkers could distinguish between HDN and oxidative stress-induced kidney injury (induced by potassium bromate), (3) sensitivity of HDN-induced renal biomarker changes relative to D-limonene dose, and (4) reversibility of HDN and renal biomarkers, using vehicle or 300 mg/kg/day D-limonene with 7 days of dosing and necropsies scheduled over the period of Days 8-85.

D-limonene

creatinine

potassium bromate

D-limonene

D-limonene


Input: HDN-induced renal biomarker changes in male rats were potentially compound specific: (1) 2-propanol induced mild HDN without increased renal biomarkers, (2) potassium bromate induced moderate HDN with increased clusterin, and (3) D-limonene induced marked HDN with increased alpha GST, mu GST and albumin.

potassium bromate

D-limonene


Input: Administration of potassium bromate did not result in oxidative stress-induced kidney injury, based on histopathology and renal biomarkers creatinine and BUN.

potassium bromate


Input: The compound D-limonene induced a dose dependent increase in HDN severity and renal biomarker changes without altering BUN, creatinine or NAG: (1) minimal induction of HDN and no altered biomarkers at 10 mg/kg/day, (2) mild induction of HDN with increased alpha GST and mu GST at 50 mg/kg/day and (3) marked induction of HDN with increased alpha GST, mu GST and albumin at 300 mg/kg/day.

D-limonene

creatinine


Input: HDN induced by D-limonene was reversible, but with a variable renal biomarker pattern over time: Day 8 there was increased alpha GST, mu GST and albumin; on Day 15 increased clusterin, albumin and Kim-1.

D-limonene


Input: In summary, HDN altered the newer and more sensitive renal biomarkers in a time and possibly compound dependent manner.


Input: Severe growth deficiency is associated with STAT5b mutations that disrupt protein folding and activity.


Input: The first genetic defect in human signal transducer and activator of transcription (STAT) 5b was identified in an individual with profound short stature and GH insensitivity, immune dysfunction, and severe pulmonary disease, and was caused by an alanine to proline substitution (A630P) within the Src homology-2 (SH2) domain.

alanine

proline


Input: STAT5b (A630P) was found to be an inactive transcription factor based on its aberrant folding, diminished solubility, and propensity for aggregation triggered by its misfolded SH2 domain.


Input: Here we have characterized the second human STAT5b amino acid substitution mutation in an individual with similar pathophysiological features.

amino acid


Input: This single nucleotide transition, predicted to change phenyalanine 646 to serine (F646S), also maps to the SH2 domain.

nucleotide

phenyalanine

serine


Input: Like STAT5b (A630P), STAT5b (F646S) is prone to aggregation, as evidenced by its detection in the insoluble fraction of cell extracts, the presence of dimers and higher-order oligomers in the soluble fraction, and formation of insoluble cytoplasmic inclusion bodies in cells.


Input: Unlike STAT5b (A630P), which showed minimal GH-induced tyrosine phosphorylation and no transcriptional activity, STAT5b (F646S) became tyrosine phosphorylated after GH treatment and could function as a GH-activated transcription factor, although to a substantially lesser extent than STAT5b (WT).

tyrosine

tyrosine


Input: Biochemical characterization demonstrated that the isolated SH2 domain containing the F646S substitution closely resembled the wild-type SH2 domain in secondary structure, but exhibited reduced thermodynamic stability and altered tertiary structure that were intermediate between STAT5b (A630P) and STAT5b (WT).


Input: Homology-based structural modeling suggests that the F646S mutation disrupts key hydrophobic interactions and may also distort the phosphopeptide-binding face of the SH2 domain, explaining both the reduced thermodynamic stability and impaired biological activity.


Input: FOXO1 controls thyroid cell proliferation in response to TSH and IGF-I and is involved in thyroid tumorigenesis.


Input: TSH and insulin/IGF-I synergistically induce the proliferation of thyroid cells mainly through the cAMP and phosphatidylinositol 3-kinase (PI3K) pathways.

cAMP

phosphatidylinositol


Input: However, the events involved in this cooperative induction remain unknown, and molecules that are potentially controlled by both TSH and IGF-I are interesting candidates as integrators of both stimuli.


Input: The finding that the PI3K pathway is frequently activated in thyroid malignancies has attracted attention to this pathway in the thyroid field.


Input: One of the targets of PI3K is Forkhead box O (FoxO)-1, a widely expressed transcription factor involved in a variety of cellular processes such as differentiation, proliferation, and apoptosis.


Input: Here we show that FoxO1 is highly expressed in differentiated rat thyroid cells and human thyroid tissue compared with human thyroid tumor-derived cells and surgically removed thyroid tumors, in which its expression is reduced.


Input: In differentiated cells, TSH/cAMP treatment decreases FoxO1 mRNA and protein levels through proteasome activation, whereas both TSH and IGF-I control FoxO1 localization by promoting a rapid exclusion from the nucleus in an Akt-dependent manner.

cAMP


Input: FoxO1 can control p27 (KIP1) expression in differentiated and tumor cells of the thyroid.


Input: Furthermore, FoxO1 reexpression in tumor cells promotes a decrease in their proliferation rate, whereas FoxO1 interference in differentiated cells increases their proliferation.


Input: These data point to an important role of FoxO1 in mediating the effects of TSH and IGF-I on thyroid cell proliferation and provide a link between loss of FoxO1 expression and the uncontrolled proliferation of thyroid tumor cells.


Input: Gliotransmission and brain glucose sensing: critical role of endozepines.

glucose


Input: Hypothalamic glucose sensing is involved in the control of feeding behavior and peripheral glucose homeostasis, and glial cells are suggested to play an important role in this process.

glucose

glucose


Input: Diazepam-binding inhibitor (DBI) and its processing product the octadecaneuropeptide (ODN), collectively named endozepines, are secreted by astroglia, and ODN is a potent anorexigenic factor.

Diazepam


Input: Therefore, we investigated the involvement of endozepines in brain glucose sensing.

glucose


Input: First, we showed that intracerebroventricular administration of glucose in rats increases DBI expression in hypothalamic glial-like tanycytes.

glucose


Input: We then demonstrated that glucose stimulates endozepine secretion from hypothalamic explants.

glucose


Input: Feeding experiments indicate that the anorexigenic effect of central administration of glucose was blunted by coinjection of an ODN antagonist.

glucose


Input: Conversely, the hyperphagic response elicited by central glucoprivation was suppressed by an ODN agonist.


Input: The anorexigenic effects of centrally injected glucose or ODN agonist were suppressed by blockade of the melanocortin-3/4 receptors, suggesting that glucose sensing involves endozepinergic control of the melanocortin pathway.

glucose

glucose


Input: Finally, we found that brain endozepines modulate blood glucose levels, suggesting their involvement in a feedback loop controlling whole-body glucose homeostasis.

glucose

glucose


Input: Collectively, these data indicate that endozepines are a critical relay in brain glucose sensing and potentially new targets in treatment of metabolic disorders.

glucose


Input: A kinesin-mediated mechanism that couples centrosomes to nuclei.


Input: The M-type kinesin isoform, Kif9, has recently been implicated in maintaining a physical connection between the centrosome and nucleus in Dictyostelium discoideum.


Input: However, the mechanism by which Kif9 functions to link these two organelles remains obscure.


Input: Here we demonstrate that the Kif9 protein is localized to the nuclear envelope and is concentrated in the region underlying the centrosome point of attachment.


Input: Nuclear anchorage appears mediated through a specialized transmembrane domain located in the carboxyl terminus.

carboxyl


Input: Kif9 interacts with microtubules in in vitro binding assays and effects an endwise depolymerization of the polymer.


Input: These results suggest a model whereby Kif9 is anchored to the nucleus and generates a pulling force that reels the centrosome up against the nucleus.


Input: This is a novel activity for a kinesin motor, one important for progression of cells into mitosis and to ensure centrosome-nuclear parity in a multinuclear environment.


Input: Toxicity of forest fire retardant chemicals to stream-type chinook salmon undergoing parr-smolt transformation.


Input: Long-term fire retardants are used to prevent the spread of wildland fires.


Input: These products are normally applied by aircraft and are intended specifically for terrestrial application, but fire retardants have entered aquatic habitats by misapplication and/or accidental spills and have resulted in fish mortalities.


Input: The authors examined the toxicity of two fire retardant products, PHOS-CHEK 259F and LC-95A, to salmon undergoing parr-smolt transformation.

PHOS-CHEK 259F and LC-95A


Input: Yearling stream-type chinook salmon at the smolt stage were exposed to eight concentrations of each retardant in freshwater and a no-PHOS-CHEK control for 96 h to determine acute toxicity.


Input: Concentrations of the products that caused 50% mortality were 140. 5 and 339. 8 mg/L for 259F and LC-95A, respectively, and could occur during accidental drops into aquatic habitats.


Input: Damage to gill tissues seen in histopathological sections was attributed to fire retardant exposure.


Input: Un-ionized ammonia levels, from 259F, were sufficient to cause acute mortality; but additional factors, indicated by increased phagosome prevalence in the gills, might have contributed to mortality during LC-95A exposure.


Input: Seawater and disease challenges were performed to determine sublethal effects of product exposures on fish health.


Input: Although PHOS-CHEK exposure did not adversely affect chinook salmon' s susceptibility to Listonella anguillarum, exposure did significantly reduce seawater survival.


Input: Reduced salmon survival resulting from prior fire retardant exposure during their transition from freshwater rearing environments to seawater may decrease the abundance of salmon populations.


Input: A method for assessing the potential for confounding applied to ionic strength in central Appalachian streams.


Input: Causal relationships derived from field data are potentially confounded by variables that are correlated with both the cause and its effect.


Input: The present study presents a method for assessing the potential for confounding and applies it to the relationship between ionic strength and impairment of benthic invertebrate assemblages in central Appalachian streams.


Input: The method weighs all available evidence for and against confounding by each potential confounder.


Input: It identifies 10 types of evidence for confounding, presents a qualitative scoring system, and provides rules for applying the scores.


Input: Twelve potential confounders were evaluated: habitat, organic enrichment, nutrients, deposited sediments, pH, selenium, temperature, lack of headwaters, catchment area, settling ponds, dissolved oxygen, and metals.

selenium

oxygen


Input: One potential confounder, low pH, was found to be biologically significant and eliminated by removing sites with pH < 6.


Input: Other potential confounders were eliminated based on the weight of evidence.


Input: This method was found to be useful and defensible.


Input: It could be applied to other environmental assessments that use field data to develop causal relationships, including contaminated site remediation or management of natural resources.


Input: Substituent variation drives metal/monolayer/semiconductor junctions from strongly rectifying to ohmic behavior.


Input: An eight-orders of magnitude enhancement in current across Hg/X-styrene-Si junctions is caused by merely altering a substituent, X.

Hg

styrene

Si


Input: Interface states are passivated and, depending on X, the Si Schottky junction encompasses the full range from Ohmic to strongly rectifying.

Si


Input: This powerful electrostatic molecular effect has immediate implications for interface band alignment and sensing.


Input: Influence of silver doping on electron transport in thin films of PbSe nanocrystals.

silver

PbSe


Input: Field-effect transistors are fabricated from thin films of Ag-doped PbSe nanocrystals to analyze the influence of electronically active impurities on electrical transport in this important material for nanocrystal applications.

Ag-doped PbSe


Input: Data is collected as a function of nanocrystal size, dopant concentration, and temperature.


Input: Changes in the Fermi level and transport parameters indicate that Ag is acting as a p-type dopant (acceptor).

Ag


Input: New horizons for diagnostics and therapeutic applications of graphene and graphene oxide.

graphene

graphene oxide


Input: Graphene, a one-atom-thick two-dimensional (2D) layer of sp (2)-bonded carbon, has received worldwide attention owing to its extraordinary physical and chemical properties.

Graphene

carbon


Input: Recently, great efforts have been devoted to explore potential applications of graphene and its oxide in life science, especially in disease-related diagnostics, near-Infrared (NIR) phototherapy and imaging.

graphene


Input: Here we will introduce recent advances and new horizons in this area, and focus on the rising progress on NIR photothermal therapy for cancer and Alzheimer' s disease (AD), human telomerase detection, stem cell proliferation and differentiation on graphene substrate, diagnosis of cancer cell and related biomarkers, drug/nucleotide/peptide delivery and cell imaging, which have not been comprehensively reviewed.

graphene

nucleotide


Input: We hope to provide an outlook to the applications of graphene and its oxide, especially on the new horizons in this field, and inspire broader interests across various disciplines.

graphene


Input: SchistoDB: an updated genome resource for the three key schistosomes of humans.


Input: The new release of SchistoDB (http://SchistoDB. net) provides a rich resource of genomic data for key blood flukes (genus Schistosoma) which cause disease in hundreds of millions of people worldwide.


Input: SchistoDB integrates whole-genome sequence and annotation of three species of the genus and provides enhanced bioinformatics analyses and data-mining tools.


Input: A simple, yet comprehensive web interface provided through the Strategies Web Development Kit is available for the mining and visualization of the data.


Input: Genomic scale data can be queried based on BLAST searches, annotation keywords and gene ID searches, gene ontology terms, sequence motifs, protein characteristics and phylogenetic relationships.


Input: Search strategies can be saved within a user' s profile for future retrieval and may also be shared with other researchers using a unique web address.


Input: Combining quantum mechanical ligand conformation analysis and protein modeling to elucidate GPCR-ligand binding modes.


Input: SAR beyond protein-ligand interactions: By combining structure-affinity relationships, protein-ligand modeling studies, and quantum mechanical calculations, we show that ligand conformational energies and basicity play critical roles in ligand binding to the histamine H4 receptor, a GPCR that plays a key role in inflammation.

histamine


Input: Ras-dva is a novel Pit-1-and glucocorticoid-regulated gene in the embryonic anterior pituitary gland.


Input: Glucocorticoids play a role in functional differentiation of pituitary somatotrophs and lactotrophs during embryogenesis.


Input: Ras-dva was identified as a gene regulated by anterior neural fold protein-1/homeobox expressed in embryonic stem cells-1, a transcription factor known to be critical in pituitary development, and has an expression profile in the chicken embryonic pituitary gland that is consistent with in vivo regulation by glucocorticoids.


Input: The objective of this study was to characterize expression and regulation of ras-dva mRNA in the developing chicken anterior pituitary.


Input: Pituitary ras-dva mRNA levels increased during embryogenesis to a maximum on embryonic day (e) 18 and then decreased and remained low or undetectable after hatch.


Input: Ras-dva expression was highly enriched in the pituitary gland on e18 relative to other tissues examined.


Input: Glucocorticoid treatment of pituitary cells from mid-and late-stage embryos rapidly increased ras-dva mRNA, suggesting it may be a direct transcriptional target of glucocorticoids.


Input: A reporter construct driven by 4 kb of the chicken ras-dva 5'-flanking region, containing six putative pituitary-specific transcription factor-1 (Pit-1) binding sites and two potential glucocorticoid receptor (GR) binding sites, was highly activated in embryonic pituitary cells and up-regulated by corticosterone.

corticosterone


Input: Mutagenesis of the most proximal Pit-1 site decreased promoter activity in chicken e11 pituitary cells, indicating regulation of ras-dva by Pit-1.


Input: However, mutating putative GR binding sites did not substantially reduce induction of ras-dva promoter activity by corticosterone, suggesting additional DNA elements within the 5'-flanking region are responsible for glucocorticoid regulation.

corticosterone


Input: We have identified ras-dva as a glucocorticoid-regulated gene that is likely expressed in cells of the Pit-1 lineage within the developing anterior pituitary gland.


Input: The role of the carbohydrate response element-binding protein in male fructose-fed rats.

carbohydrate

fructose


Input: By 2030, nearly half of Americans will have nonalcoholic fatty liver disease.


Input: In part, this epidemic is fueled by the increasing consumption of caloric sweeteners coupled with an innate capacity to convert sugar into fat via hepatic de novo lipogenesis.

sugar


Input: In addition to serving as substrates, monosaccharides also increase the expression of key enzymes involved in de novo lipogenesis via the carbohydrate response element-binding protein (ChREBP).

monosaccharides

carbohydrate


Input: To determine whether ChREBP is a potential therapeutic target, we decreased hepatic expression of ChREBP with a specific antisense oligonucleotide (ASO) in male Sprague-Dawley rats fed either a high-fructose or high-fat diet.

fructose


Input: ChREBP ASO treatment decreased plasma triglyceride concentrations compared with control ASO treatment in both diet groups.

triglyceride


Input: The reduction was more pronounced in the fructose-fed group and attributed to decreased hepatic expression of ACC2, FAS, SCD1, and MTTP and a decrease in the rate of hepatic triglyceride secretion.

fructose

triglyceride


Input: This was associated with an increase in insulin-stimulated peripheral glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp.

glucose


Input: In contrast, ChREBP ASO did not alter hepatic lipid content or hepatic insulin sensitivity.


Input: Interestingly, fructose-fed rats treated with ChREBP ASO had increased plasma uric acid, alanine transaminase, and aspartate aminotransferase concentrations.

fructose

uric acid

alanine

aspartate


Input: This was associated with decreased expression of fructose aldolase and fructokinase, reminiscent of inherited disorders of fructose metabolism.

fructose

fructose


Input: In summary, these studies suggest that targeting ChREBP may prevent fructose-induced hypertriglyceridemia but without the improvements in hepatic steatosis and hepatic insulin responsiveness.

fructose


Input: Genetic requirements for Moraxella catarrhalis growth under iron-limiting conditions.

iron


Input: Iron sequestration by the human host is a first line defence against respiratory pathogens like Moraxella catarrhalis, which consequently experiences a period of iron starvation during colonization.

Iron

iron


Input: We determined the genetic requirements for M. catarrhalis BBH18 growth during iron starvation using the high-throughput genome-wide screening technology genomic array footprinting (GAF).

iron


Input: By subjecting a large random transposon mutant library to growth under iron-limiting conditions, mutants of the MCR _ 0996-rhlB-yggW operon, rnd, and MCR _ 0457 were negatively selected.

iron


Input: Growth experiments using directed mutants confirmed the GAF phenotypes with Delta yggW (putative haem-shuttling protein) and Delta MCR _ 0457 (hypothetical protein) most severely attenuated during iron starvation, phenotypes which were restored upon genetic complementation of the deleted genes.

iron


Input: Deletion of yggW resulted in similar attenuated phenotypes in three additional strains.


Input: Transcriptional profiles of Delta yggW and Delta MCR _ 0457 were highly altered with 393 and 192 differentially expressed genes respectively.


Input: In all five mutants, expression of nitrate reductase genes was increased and of nitrite reductase decreased, suggesting an impaired aerobic respiration.

nitrate

nitrite