Input: The mean age of patients with joint involvement (8 +/- 2. 3 years) were considerably lower than the patients without joint involvement (10. 35 +/- 3. 04 years), and this was statistically significant (p = 0. 008).


Input: The most commonly involved joints were ankles and knees.


Input: Multiple joint involvements were most frequently observed in the M694V and M694I gene mutations (16. 7%).


Input: Conclusions: We use and recommend the bone scintigraphy in patients with FMF to determine the presence and distribution of arthritis, since bone scintigraphy is inexpensive, noninvasive, easy-to-use, and also is more sensitive in the diagnosis and distribution of arthritis than conventional radiological methods and clinical examination.


Input: Micro/nanostructured hyaluronic acid matrices with tuned swelling and drug release properties.


Input: Hyaluronic acid (HA) hydrogels were structured in the form of porous monoliths by means of the ice-segregation-induced self-assembly (ISISA) method coupled with freeze-drying.


Input: Physical and chemical parameters were explored in order to fine-tune the microstructure and the incidence on both swelling and dissolution behavior in aqueous media.


Input: Gentamicin-loaded HA matrices with tuned drug release properties were also prepared; their inherent properties and behavior in solution are discussed in the framework of thermal analysis and scanning electron microscopy inspection.

Gentamicin


Input: Antipsychotic drug effects in schizophrenia: a review of longitudinal FMRI investigations and neural interpretations.


Input: The evidence that antipsychotics improve brain function and reduce symptoms in schizophrenia is unmistakable, but how antipsychotics change brain function is poorly understood, especially within neuronal systems.


Input: In this review, we investigated the hypothesized normalization of the functional magnetic resonance imaging (fMRI) blood oxygen level dependent signal in the context of antipsychotic treatment.

oxygen


Input: First, we conducted a systematic PubMed search to identify eight fMRI investigations that met the following inclusion criteria: case-control, longitudinal design; pre-and post-treatment contrasts with a healthy comparison group; and antipsychotic-free or antipsychotic-naive patients with schizophrenia at the start of the investigation.


Input: We hypothesized that aberrant activation patterns or connectivity between patients with schizophrenia and healthy comparisons at the first imaging assessment would no longer be apparent or " normalize " at the second imaging assessment.


Input: The included studies differed by analysis method and fMRI task but demonstrated normalization of fMRI activation or connectivity during the treatment interval.


Input: Second, we reviewed putative mechanisms from animal studies that support normalization of the BOLD signal in schizophrenia.


Input: We provided several neuronal-based interpretations of these changes of the BOLD signal that may be attributable to long-term antipsychotic administration.


Input: Systematic review of the influence of antipsychotics on the blood oxygenation level-dependent signal of functional magnetic resonance imaging.


Input: Functional Magnetic Resonance Imaging (FMRI) is a non-invasive technique for brain mapping and mostly performed using changes of the blood-oxygen-level-dependent (BOLD)-signal.

oxygen


Input: It has been widely used to investigate patients with schizophrenia.


Input: Most of the studies examine patients treated with antipsychotic drugs, although little is known about the effects of these drugs on the BOLDsignal.


Input: Here we examined studies of patients with schizophrenia treated with different antipsychotics to address the question whether and to what extent antipsychotic drugs in themselves produce BOLD-signal changes.


Input: We performed a PubMed-search for the period from 1999 until January 2012 with the search items " schizophrenia " and " Magnetic Resonance Imaging " and " Antipsychotic Agents; or " Magnetic Resonance Imaging " and " Antipsychotic Agents "; or " schizophrenia " and " Antipsychotic Agents " and " FMRI ".


Input: We extracted articles that examined at least two patient groups with different treatments, or patients examined on different medications at different times and that provided information about drug effects.


Input: No common effect of antipsychotics on BOLD-signal was found.


Input: However, based on the results for different antipsychotics (haloperidol, olanzapine, quetiapine and risperidone) we found evidence that the affinity to the dopamine (DA) D (2)-receptor may influence BOLD-signal.

haloperidol

olanzapine

quetiapine

risperidone

dopamine


Input: Prostate cancer, miRNAs, metallothioneins and resistance to cytostatic drugs.


Input: MicroRNAs (miRNAs) translationally repressing their target messenger RNAs due to their gene-regulatory functions play an important but not unexpected role in a tumour development.


Input: More surprising are the findings that levels of various miRNAs are well correlated with presence of specific tumours and formation of metastases.


Input: Moreover, these small regulatory molecules play a role in the resistance of cancer cells to commonly used anti-cancer drugs, such as cisplatin, anthracyclines, and taxanes.

cisplatin

anthracyclines

taxanes


Input: In that respect, miRNAs become very attractive target for potential therapeutic interventions.


Input: Improvements in the sensitivity of miRNAs detection techniques led to discovery of circulating miRNAs which became very attractive non-invasive biomarker of cancer with a substantial predictive value.


Input: In this review, the authors focus on i) oncogenic and anti-tumour acting miRNAs, ii) function of miRNAs in tumour progression, iii) possible role of miRNAs in resistance to anticancer drugs, and iv) diagnostic potential of miRNAs for identification of cancer from circulating miRNAs with special emphasis on prostate cancer.


Input: Moreover, relationship between miRNAs and expression of metallothionein is discussed as a possible explanation of resistance against platinum based drugs.

platinum


Input: Ethanol modulates the neurovascular coupling.

Ethanol


Input: Despite some evidence of the underlying molecular mechanisms the neuronal basis of ethanol-induced effects on the neurovascular coupling that forms the BOLD (blood oxygenation level dependent) signal is poorly understood.

ethanol


Input: In a recent fMRI (functional magnetic resonance imaging) study monitoring ethanol-induced changes of the BOLD signal a reduction of the amplitude and a prolongation of the BOLD signal were observed.

ethanol


Input: However, the BOLD signal is assumed to consist of a complex superposition of different underlying signals.


Input: To gain insight how ethanol influences stimulus efficacy, oxygen extraction, transit time and vessel-related parameters the fMRI time series from the sensori-motor and the visual cortex were analyzed using the balloon model.

ethanol

oxygen


Input: The results show a region-dependent decrease of the stimulus efficacy to trigger a post-stimulus neurovascular response as well as a prolongation of the transit time through the venous compartment.


Input: Oxygen extraction, feedback mechanisms and other vessel-related parameters were not affected.

Oxygen


Input: The results may be interpreted as follows: the overall mechanisms of the neurovascular coupling are still acting well at the moderate ethanol level of about 0. 8 /1000 (in particular the vessel-related parts), but the potency to evoke a neurovascular response is already compromised most obviously in the supplementary motor area responsible for complex synchronizing and planning processes.

ethanol


Input: Perseverative behavior in rats with methamphetamine-induced neurotoxicity.

methamphetamine


Input: Methamphetamine induces monoamine depletions thought to contribute to cognitive and behavioral dysfunctions.

Methamphetamine


Input: Previously, we reported that methamphetamine-induced neurotoxicity is associated with impaired formation of stimulus-response associations.

methamphetamine


Input: Additionally, subjective observations suggested that behavioral flexibility might be affected.


Input: Thus, the present study examined whether methamphetamine neurotoxicity induces perseverative behavior.

methamphetamine


Input: Rats were pretreated with (+/-)-methamphetamine (4 x 10 mg/kg, 2-hr intervals) or saline.

(+/-)-methamphetamine


Input: Three weeks later, rats were trained to press a lever on one side of an operant chamber and then retrieve the reinforcer from a magazine on the opposite side until they reached criterion (> 50 reinforcers/30-min).


Input: After four consecutive sessions performing the task at criterion, rats were sacrificed and brains removed for monoamine determinations.


Input: Methamphetamine-pretreated rats had ~ 50% loss of striatal dopamine and prefrontal serotonin.

Methamphetamine

dopamine

serotonin


Input: Methamphetamine-and saline-pretreated rats were not different in the number of sessions required to reach criterion or in the total numbers of lever presses and/or head entries made across the four consecutive sessions at criterion-level performance.

Methamphetamine


Input: However, methamphetamine-pretreated rats earned fewer reinforcers, because they made extra lever-presses and head entries when they should have been retrieving the reinforcer or returning to the lever.

methamphetamine


Input: Latencies for methamphetamine-pretreated rats to switch between the two behaviors also were significantly slower than latencies for controls.

methamphetamine


Input: Interestingly, the degree of additional lever-presses negatively correlated with serotonin-transporter binding in the prefrontal cortex, even in saline-pretreated controls.

serotonin


Input: These data suggest that methamphetamine-induced partial monoamine toxicity is associated with perseveration and that the degree of perseveration may depend on serotonin innervation of the frontal cortex.

methamphetamine

serotonin


Input: Challenges and recommendations for obtaining chemical structures of industry-provided repurposing candidates.


Input: There is an expanding amount of interest directed at the repurposing and repositioning of drugs, as well as how in silico methods can assist these endeavors.


Input: Recent repurposing project tendering calls by the National Center for Advancing Translational Sciences (USA) and the Medical Research Council (UK) have included compound information and pharmacological data.


Input: However, none of the internal company development code names were assigned to chemical structures in the official documentation.


Input: This not only abrogates in silico analysis to support repurposing but consequently necessitates data gathering and curation to assign structures.


Input: Here, we describe the approaches, results and major challenges associated with this.


Input: High resolution fluorescence microscopy evidence on the transport of immunoglobulins.


Input: Differences between mammalian IgG, F (ab') 2 and avian IgY.


Input: We describe the subcellular localization of horse F (ab') (2) and IgG, and ostrich IgY labeled with fluorescein isothiocyanate (FITC) administered IV to mice.

fluorescein isothiocyanate

FITC


Input: We used wide field high sensitivity fluorescence microscopy deblurred by 3-dimensional blind deconvolution of kidney, liver, lungs and brain sections.


Input: Sections were obtained from mice sacrificed 15 min, 1 or 5 h after receiving FITC-immunoproteins, counter-stained with DAPI (4', 6'-diamidino-2-phenylindole) and Evans blue.

FITC

DAPI

4', 6'-diamidino-2-phenylindole

Evans blue


Input: FITC-IgG and its fractions are rapidly taken up and extravasated by vascular endothelium.

FITC


Input: FITC-IgG and FITC-F (ab') (2) appear to be quickly secreted by glomeruli endothelium and to be reabsorbed along all nephron segments.

FITC

FITC


Input: FITC-IgG and FITC-F (ab') (2) appeared 15 min after IV injection within bronchial, alveolar and bile duct epithelium.

FITC

FITC


Input: Hepatocytes were loaded with fluorescence after 15 min of administration.


Input: Fluorescence was absent from brain slices, except for the endothelium of some vessels in brain ventricles which appeared intensely fluorescent.


Input: Fluorescence appeared in intracellular vesicles which conferred the tissues a glowing foamy aspect for up to 5 h after inoculation.


Input: Arterial elastic layers were intensely green after horse FITC-Ig inoculation.

FITC


Input: Ostrich FITC-IgY behaved completely differently to horse Ig' s; only 1 h after injection it was possible to observe small brightly green scarce vesicles in vascular endothelium of arteries, interstitial kidney capillaries between nephron tubules and were also scarce in glomeruli endothelium; FITC-IgY appeared only in hepatic sinusoids in the liver.

FITC

FITC


Input: No IgY was seen in bronchial and alveolar endothelium, in bile ducts or in hepatocytes.


Input: Systemic effects induced by the venom of the snake Bothrops caribbaeus in a murine model.


Input: Snakebite envenoming by Bothrops caribbaeus, an endemic viperid from the Lesser Antillean island of Saint Lucia, is clinically characterized by local tissue damage and systemic thrombosis that can lead to cerebral, myocardial or pulmonary infarctions and venous thromboses.


Input: Systemic effects (lethality, pulmonary hemorrhage, thrombocytopenia and coagulopathy) induced by intravenous (i. v.) administration of B. caribbaeus venom were studied in mice.


Input: The role of snake venom metalloproteinases (SVMPs) in these systemic alterations was assessed by inhibition with the chelating agent calcium disodium ethylenediaminetetraacetic acid (CaNa (2) EDTA).

calcium disodium ethylenediaminetetraacetic acid

CaNa (2) EDTA


Input: A snake C-type lectin-like (snaclec) and a type P-III hemorrhagic SVMP were isolated and characterized from this venom, and the effect of venom and the isolated snaclec on human platelet aggregation was studied in vitro.


Input: Results indicate that SVMPs play an important role in the overall toxicity of B. caribbaeus venom, being responsible for systemic hemorrhage and lethality, but not thrombocytopenia, whereas the isolated snaclec is involved in the thrombocytopenic effect.


Input: Both venom and snaclec induce platelet aggregation/agglutination.


Input: Moreover, the snaclec binds directly to glycoprotein Ib (GPIb) and induces agglutination in washed fixed platelets.


Input: On the other hand, B. caribbaeus venom hydrolyzed fibrinogen in vitro and induced a partial drop of fibrinogen levels with an increase in fibrin/fibrinogen degradation products (FDP) levels in vivo.


Input: The negative result for D-dimer (DD) in plasma is consistent with the lack of microscopic evidence of pulmonary thrombosis and endothelial cell damage.


Input: Likewise, no increments in plasma sE-selectin levels were detected.


Input: The absence of thrombosis in this murine model suggests that this effect may be species-specific.


Input: The impact of oxytocin administration and maternal love withdrawal on event-related potential (ERP) responses to emotional faces with performance feedback.

oxytocin


Input: This is the first experimental study on the effect of oxytocin administration on the neural processing of facial stimuli conducted with female participants that uses event-related potentials (ERPs).

oxytocin


Input: Using a double-blind, placebo-controlled within-subjects design, we studied the effects of 16 IU of intranasal oxytocin on ERPs to pictures combining performance feedback with emotional facial expressions in 48 female undergraduate students.

oxytocin


Input: Participants also reported on the amount of love withdrawal they experienced from their mothers.


Input: Vertex positive potential (VPP) and late positive potential (LPP) amplitudes were more positive after oxytocin compared to placebo administration.

oxytocin


Input: This suggests that oxytocin increased attention to the feedback stimuli (LPP) and enhanced the processing of emotional faces (VPP).

oxytocin


Input: Oxytocin heightened processing of the happy and disgusted faces primarily for those reporting less love withdrawal.

Oxytocin


Input: Significant associations with LPP amplitude suggest that more maternal love withdrawal relates to the allocation of attention toward the motivationally relevant combination of negative feedback with a disgusted face.


Input: Nanobody-albumin nanoparticles (NANAPs) for the delivery of a multikinase inhibitor 17864 to EGFR overexpressing tumor cells.


Input: A novel, EGFR-targeted nanomedicine has been developed in the current study.


Input: Glutaraldehyde crosslinked albumin nanoparticles with a size of approximately 100nm were loaded with the multikinase inhibitor 17864-L (x)-a platinum-bound sunitinib analogue-which couples the drug to methionine residues of albumin and is released in a reductive environment.

Glutaraldehyde

platinum

sunitinib

methionine


Input: Albumin nanoparticles were surface-coated with bifunctional polyethylene glycol 3500 (PEG) and a nanobody-the single variable domain of an antibody-(Ega1) against the epidermal growth factor receptor (EGFR).

polyethylene glycol

PEG


Input: EGa1-PEG functionalized nanoparticles showed a 40-fold higher binding to EGFR-positive 14C squamous head and neck cancer cells in comparison to PEGylated nanoparticles.

PEG


Input: 17864-L (x) loaded EGa1-PEG nanoparticles were internalized by clathrin-mediated endocytosis and ultimately digested in lysosomes.

PEG


Input: The intracellular routing of EGa1 targeted nanoparticles leads to a successful release of the kinase inhibitor in the cell and inhibition of proliferation whereas the non-targeted formulations had no antiproliferative effects on 14C cells.


Input: The drug loaded targeted nanoparticles were as effective as the free drug in vitro.


Input: These results demonstrate that multikinase inhibitor loaded nanoparticles are interesting nanomedicines for the treatment of EGFR-positive cancers.


Input: Ex vivo permeation characteristics of venlafaxine through sheep nasal mucosa.

venlafaxine


Input: Venlafaxine, a dual acting antidepressant is a new therapeutic option for chronic depression.

Venlafaxine


Input: Depression is a common mental disorder associated with the abnormalities in neuronal transport in the brain.


Input: Since the nose-to-brain pathway has been indicated for delivering drugs to the brain, we analyzed the transport of venlafaxine through sheep nasal mucosa.

venlafaxine


Input: Transmucosal permeation kinetics of venlafaxine were examined using sheep nasal mucosa mounted onto static vertical Franz diffusion cells.

venlafaxine


Input: Nasal mucosa was treated with venlafaxine in situ gel (100 mu l; 1% w/v) for 7h.

venlafaxine


Input: Amount of venlafaxine diffused through mucosa was measured using validated RP-HPLC method.

venlafaxine


Input: After the completion of the study histopathological investigation of mucosa was carried out.


Input: Ex vivo studies through sheep nasal mucosa showed sustained diffusion of venlafaxine with 66. 5% permeation in 7h.

venlafaxine


Input: Transnasal transport of venlafaxine followed a non-Fickian diffusion process.

venlafaxine


Input: Permeability coefficient and steady state flux were found to be 21. 11 x 10 (-3) cmh (-1) and 21. 118 mu g cm (-2) h (-1) respectively.


Input: Cumulative amount permeated through mucosa at 7h was found to be 664. 8 mu g through an area of 3. 14 cm (2).


Input: Total recovery of venlafaxine at the end of the permeation study was 87. 3% of initial dose distributed (i) at the mucosal surface (208. 4 mu g; 20. 8%) and (ii) through mucosa (664. 8 mu g; 66. 5%).

venlafaxine


Input: Histopathological examinations showed no significant adverse effects confirming that the barrier function of nasal mucosa remains unaffected even after treatment with venlafaxine in situ gel.

venlafaxine


Input: Permeation through sheep nasal mucosa using in situ gel demonstrated a harmless nasal delivery of venlafaxine, providing new dimension to the treatment of chronic depression.

venlafaxine


Input: Transferrin conjugation does not increase the efficiency of liposomal Foscan during in vitro photodynamic therapy of oesophageal cancer.

Foscan


Input: Photodynamic therapy (PDT) is based on the delivery of photocytotoxic agents to a target tissue, followed by irradiation.


Input: In order to increase the efficiency of PDT in oesophageal cancer therapy, polyethylene glycol (PEG)-grafted, transferrin (Tf)-conjugated liposome formulations of 5, 10, 15, 20-tetra (m-hydroxyphenyl) chlorin (Foscan), a second-generation photosensitiser, were prepared.

polyethylene glycol

PEG

5, 10, 15, 20-tetra (m-hydroxyphenyl) chlorin

Foscan


Input: Expression of transferrin receptors (CD71) in the oesophageal cancer cell line, OE21, was confirmed by immunoblot and confocal laser scanning microscopy.


Input: The anti-proliferative effect of Foscan liposomes was evaluated and compared with plain formulations (i. e., without Tf) as well as with free drug.

Foscan


Input: In addition, the intracellular accumulation was studied using high content analysis.


Input: Surprisingly, delivering Foscan by transferrin-conjugated PEG-liposomes to oesophageal cancer cells did not improve the photocytotoxicity or the intracellular accumulation of Foscan when compared to unmodified liposomes or indeed free photosensitiser.

Foscan

PEG

Foscan


Input: Tf-targeted drugs and drug delivery systems have shown improved the therapy of many cancers.


Input: Our study, however, did not corroborate these findings.


Input: If this is due to the tumour type, the choice of in vitro model or the delivery systems remains to be confirmed.


Input: A novel approach to improve the pharmacokinetic properties of 8-chloro-adenosine by the dual combination of lipophilic derivatisation and liposome formulation.


Input: 8-Chloro-adenosine (8CA) has shown promise in hematologic and solid tumor models and is in a phase I clinical trial.


Input: However, 8CA is intensively metabolized shortly after i. v. administration, with a t (1/2 beta) of approximately 1h.


Input: Many carriers have failed to encapsulate 8CA efficiently.


Input: To improve its pharmacokinetic properties, 8-chloro-adenosine-5'-O-stearate (8CAS), a lipophilic octadecanoyl analogue of 8CA, was synthesized and incorporated into pegylated liposomes.

octadecanoyl


Input: The liposomes, comprising egg phosphatidylcholine, cholesterol and poly (ethylene glycol) 2000-distearoyl phosphatidylethanolamine (PEG-DSPE), had mean diameters of approximately 100 nm and an entrapment efficiency of 69-86%.

phosphatidylcholine

cholesterol

poly (ethylene glycol)

distearoyl phosphatidylethanolamine

PEG-DSPE


Input: MTT assays showed that the cytotoxicity of 8CAS and its pegylated liposomes (8CAS-PL) were retained, with IC (50) values of 1. 0 mu M and 1. 9 mu M at 72 h on MCF-7 cells, respectively, slightly higher than that of 8CA (0. 6 mu M).

MTT


Input: Pharmacokinetic studies in rats after i. v. injection showed that both 8CAS and 8 CAS-PL had increased elimination half-lives (t (1/2), 128. 4, 249. 2 vs. 74. 7 min), decreased clearance rates (Cl, 0. 0135, 0. 00875 vs. 0. 2398 L/min/kg) and increased area under the concentration-time curve (AUC (0-infinity), 741. 4, 1163. 6 vs. 42. 0 mg min/L) compared to 8CA.


Input: No obvious hematological toxicity was seen for Kunming mice receiving i. v. 8CA or 8CAS-PL at a dosage of 10mg/kg daily.


Input: These results indicate that the lipophilic derivation of 8CA and the incorporation of 8CAS is an effective strategy to improve the bioavailability of 8CA.


Input: Mucoadhesive multiparticulate patch for the intrabuccal controlled delivery of lidocaine.

lidocaine


Input: The aim of the present study was to prepare and evaluate patches for the controlled release of lidocaine in the oral cavity.

lidocaine


Input: Mucoadhesive buccal patches, containing 8 mg/cm (2) lidocaine base, were formulated and developed by solvent casting method technique, using a number of different bio-adhesive and film-forming semi-synthetic and synthetic polymers (Carbopol, Poloxamer, different type Methocel) and plasticizers (PEG 400, triethyl citrate); the patches were evaluated for bioadhesion, in vitro drug release and permeation using a modified Franz diffusion cell.

lidocaine

Carbopol

Poloxamer

PEG 400

triethyl citrate


Input: A lidocaine/Compritol solid dispersion in the form of microspheres, embedded inside the patch, alone or together with free lidocaine, was also examined to prolong the drug release.

lidocaine

Compritol

lidocaine


Input: The effects of the composition were evaluated considering a number of technological parameters and the release of the drug.


Input: All the formulations tested offer a variety of drug release mechanisms, obtaining a quick or delayed or prolonged anesthetic local activity with simple changes of the formulation parameters.


Input: Immunotoxic effects of oil sands-derived naphthenic acids to rainbow trout.

naphthenic acids


Input: Naphthenic acids are the major organic constituents in waters impacted by oil sands.

Naphthenic acids


Input: To investigate their immunotoxicity, rainbow trout (Oncorhynchus mykiss) were injected with naphthenic acids extracted from aged oil sands tailings water.

naphthenic acids


Input: In two experiments, rainbow trout were injected intraperitoneally with 0, 10, or 100 mg/kg of naphthenic acids, and sampled after 5 or 21 d.

naphthenic acids


Input: Half of the fish from the 21 d exposure were co-exposed to inactivated Aeromonas salmonicida (A. s.) to induce an immune response.


Input: A positive control experiment was conducted using an intraperitoneal injection of 100 mg/kg of benzo [a] pyrene, a known immune suppressing compound.

benzo [a] pyrene


Input: T-lymphocytes, B-lymphocytes, thrombocytes, and myeloid cells were counted in blood and lymphatic tissue using flow cytometry.


Input: In the 5d exposure, there was a reduction in blood leucocytes and spleen thrombocytes at the 100 mg/kg dose.


Input: However, at 21 d, leucocyte populations showed no effects of exposure with the exception that spleen thrombocyte populations increase at the 100 mg/kg dose.


Input: In the 21 d exposure, B-and T-lymphocytes in blood showed a significant Dose x A. s. interaction, indicating stimulated blood cell proliferation due to naphthenic acids alone as well as due to A. s.

naphthenic acids


Input: Naphthenic acid injections did not result in elevated bile fluorescent metabolites or elevated hepatic EROD activity.

Naphthenic acid


Input: In contrast to naphthenic acids exposures, as similar dose of benzo [a] pyrene caused a significant decrease in B-and T-lymphocyte absolute counts in blood and relative B-lymphocyte counts in spleen.

naphthenic acids

benzo [a] pyrene


Input: Results suggest that the naphthenic acids may act via a generally toxic mechanism rather than by specific toxic effects on immune cells.

naphthenic acids


Input: The specific interaction of the photosensitizer methylene blue with acetylcholinesterase provides a model system for studying the molecular consequences of photodynamic therapy.

methylene blue


Input: The photosensitizer, methylene blue (MB), generates singlet oxygen ((1) O2) that irreversibly inhibits Torpedo californica acetylcholinesterase (TcAChE).

methylene blue

oxygen


Input: In the dark MB inhibits reversibly, binding being accompanied by a bathochromic shift that can be used to show its displacement by other reversible inhibitors binding to the catalytic' anionic' subsite (CAS), the peripheral' anionic' subsite (PAS), or bridging them.


Input: Data concerning both reversible and irreversible inhibition are here reviewed.


Input: MB protects TcAChE from thermal denaturation, and differential scanning calorimetry reveals a ~ 8 degrees C increase in the denaturation temperature.


Input: The crystal structure of the MB/TcAChE complex reveals a single MB stacked against W279 in the PAS, pointing down the gorge towards the CAS.


Input: The intrinsic fluorescence of the irreversibly inhibited enzyme displays new emission bands that can be ascribed to N'-formylkynurenine (NFK); this was indeed confirmed using anti-NFK antibodies.

N'-formylkynurenine

NFK

NFK


Input: Mass spectroscopy revealed that two Trp residues, Trp84 in the CAS, and Trp279 in the PAS, were the only Trp residues, out of a total of 14, significantly modified by photo-oxidation, both being converted to NFK.

Trp

Trp

NFK


Input: In the presence of competitive inhibitors that displace MB from the gorge, their modification is completely prevented.


Input: Thus, photo-oxidative damage caused by MB involves targeted release of (1) O2 by the bound photosensitizer within the aqueous milieu of the active-site gorge.


Input: Purification and structural characterisation of phospholipase A1 (Vespapase, Ves a 1) from Thai banded tiger wasp (Vespa affinis) venom.


Input: The Thai banded tiger wasp (Vespa affinis) is one of the most dangerous vespid species in Southeast Asia, and stinging accidents involving this species still cause fatalities.


Input: In the present study, four forms of V. affinis phospholipase A (1) were identified through a proteomics approach.


Input: Two of these enzymes were purified by reverse-phase chromatography, and their biochemical properties were characterised.


Input: These enzymes, designated Ves a 1s, are not glycoproteins and exist as 33441. 5 and 33474. 4 Da proteins, which corresponded with the 34-kDa band observed via SDS-PAGE.


Input: The thermal stabilities of these enzymes were stronger than snake venom.


Input: Using an in vivo assay, no difference was found in the toxicities of the different isoforms.


Input: Furthermore, the toxicity of these enzymes does not appear to be correlated with their PLA (1) activity.


Input: The cDNAs of the full-length version of Ves a 1s revealed that the Ves a 1 gene consists of a 1005-bp ORF, which encodes 334 amino acid residues, and 67-and 227-bp 5' and 3' UTRs, respectively.

amino acid


Input: The two isoforms are different by three nucleotide substitutions, resulting in the replacement of two amino acids.

nucleotide

amino acids


Input: Through sequence alignment, these enzymes were classified as members of the pancreatic lipase family.


Input: The structural modelling of Ves a 1 used the rat pancreatic lipase-related protein 2 (1bu8A) as a template because it has PLA (1) activity, which demonstrated that this enzyme belongs to the alpha/beta hydrolase fold family.


Input: The Ves a 1 structure, which is composed of seven alpha-helixes and eleven beta-strands, contains the beta-strand/epsilon Ser/alpha-helix structural motif, which contains the Gly-X-Ser-X-Gly consensus sequence.

Gly

Ser

Gly


Input: The typical surface structures that play important roles in substrate selectivity (the lid domain and the beta 9 loop) were shortened in the Ves a 1 structure, which suggests that this enzyme may only exhibit phospholipase activity.


Input: Moreover, the observed insertion of proline into the lid domain of the Ves a 1 structure is rare.

proline


Input: We therefore propose that this proline residue might be involved in the stability and activity of Ves a 1s.

proline


Input: Analysis of mammalian alcohol dehydrogenase 5 (ADH5): characterisation of rat ADH5 with comparisons to the corresponding human variant.

alcohol


Input: Alcohol dehydrogenase 5 (ADH5) is a member of the mammalian alcohol dehydrogenase family of yet undefined functions.

Alcohol

alcohol


Input: ADH5 was first identified at the DNA level in human and deer mouse.


Input: A rat alcohol dehydrogenase structure of similar type has been isolated at the cDNA level using human ADH5 as a screening probe, where the rat cDNA structure displayed several atypical properties.

alcohol


Input: mRNA for rat ADH5 was found in multiple tissues, especially in the kidney.


Input: In vitro translation experiments indicated that rat ADH5 is expressed as efficiently as ADH1 and furthermore, rat ADH5 was readily expressed in COS cells fused to Green Fluorescent Protein.


Input: However, no soluble ADH5 protein could be heterologously expressed in Escherichia coli cells with expression systems successfully used for other mammalian ADHs, including fused to glutathione-S-transferase.

glutathione

S


Input: Molecular modelling of the enzyme indicated that the protein does not fold in a productive way, which can be the explanation why no stable and active ADH5 has been isolated.


Input: These results indicate that ADH5, while readily expressed at the mRNA level, does not behave similarly to other mammalian ADHs investigated.


Input: The results, in vitro and in silico, suggest an unstable ADH5 structure, which can explain for why no active and stable protein can be isolated.


Input: Further possibilities are conceivable: the ADH5 protein may have to interact with a stabiliser, or the gene is actually a pseudogene.


Input: Combining multiple autosomal introns for studying shallow phylogeny and taxonomy of Laurasiatherian mammals: Application to the tribe Bovini (Cetartiodactyla, Bovidae).


Input: Mitochondrial sequences are widely used for species identification and for studying phylogenetic relationships among closely related species or populations of the same species.


Input: However, many studies of mammals have shown that the maternal history of the mitochondrial genome can be discordant with the true evolutionary history of the taxa.


Input: In such cases, the analyses of multiple nuclear genes can be more powerful for deciphering interspecific relationships.


Input: Here, we designed primers for amplifying 13 new exon-primed intron-crossing (EPIC) autosomal loci for studying shallow phylogeny and taxonomy of Laurasiatherian mammals.


Input: Three criteria were used for the selection of the markers: gene orthology, a PCR product length between 600 and 1200 nucleotides, and different chromosomal locations in the bovine genome.


Input: Positive PCRs were obtained from different species representing the orders Carnivora, Cetartiodactyla, Chiroptera, Perissodactyla and Pholidota.


Input: The newly developed markers were analyzed in a phylogenetic study of the tribe Bovini (the group containing domestic and wild cattle, bison, yak, African buffalo, Asian buffalo, and saola) based on 17 taxa and 18 nuclear genes, representing a total alignment of 13, 095 nucleotides.


Input: The phylogenetic results were compared to those obtained from analyses of the complete mitochondrial genome and Y chromosomal genes.


Input: Our analyses support a basal divergence of the saola (Pseudoryx) and a sister-group relationship between yak and bison.


Input: These results contrast with recent molecular studies but are in better agreement with morphology.


Input: The comparison of pairwise nucleotide distances shows that our nuDNA dataset provides a good signal for identifying taxonomic levels, such as species, genera, subtribes, tribes and subfamilies, whereas the mtDNA genome fails because of mtDNA introgression and higher levels of homoplasy.


Input: Accordingly, we conclude that the genus Bison should be regarded as a synonym of Bos, with the European bison relegated to a subspecies rank within Bos bison.


Input: We compared our molecular dating estimates to the fossil record in order to propose a biogeographic scenario for the evolution of Bovini during the Neogene.


Input: Biomimetic diversity-oriented synthesis of benzannulated medium rings via ring expansion.


Input: Nature has exploited medium-sized 8-to 11-membered rings in a variety of natural products to address diverse and challenging biological targets.


Input: However, owing to the limitations of conventional cyclization-based approaches to medium-ring synthesis, these structures remain severely underrepresented in current probe and drug discovery efforts.


Input: To address this problem, we have established an alternative, biomimetic ring expansion approach to the diversity-oriented synthesis of medium-ring libraries.


Input: Oxidative dearomatization of bicyclic phenols affords polycyclic cyclohexadienones that undergo efficient ring expansion to form benzannulated medium-ring scaffolds found in natural products.

bicyclic phenols

polycyclic cyclohexadienones


Input: The ring expansion reaction can be induced using three complementary reagents that avoid competing dienone-phenol rearrangements and is driven by rearomatization of a phenol ring adjacent to the scissile bond.

dienone-phenol

phenol


Input: Cheminformatic analysis of the resulting first-generation library confirms that these molecules occupy chemical space overlapping with medium-ring natural products and distinct from that of synthetic drugs and drug-like libraries.


Input: Two new chromone glycosides from Drynaria fortunei.

chromone glycosides


Input: Two new chromone glycosides, drynachromoside A (1), drynachromoside B (2), along with three known flavanones, 5, 7, 3', 5'-tetrahydroxy-flavanone (3), 5, 7, 3', 5'-tetrahydroxy-flavanone-7-O-beta-d-glucopyranoside (4), and 5, 7, 3', 5'-tetrahydroxy-flavanone-7-O-neohesperidoside (5), were isolated from the dry rhizomes of Drynaria fortunei by means of bio-active screening.

chromone glycosides

drynachromoside A

drynachromoside B

flavanones

5, 7, 3', 5'-tetrahydroxy-flavanone

5, 7, 3', 5'-tetrahydroxy-flavanone-7-O-beta-d-glucopyranoside

5, 7, 3', 5'-tetrahydroxy-flavanone-7-O-neohesperidoside


Input: The two former compounds were elucidated on the basis of physico-chemical property and spectroscopic data.


Input: The osteoblastic proliferation activities of these flavonoids were evaluated by the method of MTT.

flavonoids

MTT


Input: The results showed that compound 1 exhibited the biochemical effects on the proliferation of MC3T3-E1 cells, while Compound 2 showed inhibitory effects against MC3T3-E1 cells.


Input: Effects of the extracts and an active compound curcumenone isolated from Curcuma zedoaria rhizomes on alcohol-induced drunkenness in mice.

curcumenone

alcohol


Input: The Curcuma zedoaria rhizome has been used traditionally to treat gastrointestinal diseases as an aromatic stomachic drug, and this is currently used to treat alcohol-induced loss of appetite and nausea in Japan.

alcohol


Input: We examined the effects of various fractions and isolated compounds on alcohol-induced drunkenness and blood alcohol concentrations in mice.

alcohol

alcohol


Input: The 30% ethanol-extract (1000mg/kg) of C. zedoaria rhizome prevented drunkenness 60 and 120min after 40% alcohol administration.

ethanol

alcohol


Input: The n-hexane-soluble fraction (300mg/kg) and an isolated compound (3, 10 or 30mg/kg) prevented drunkenness at 30, 60 or 120min.

n-hexane


Input: The extract, n-hexane-soluble fraction and isolated compound reduced the elevation in blood alcohol concentrations 30 and 60min after 40% alcohol administration.

n-hexane

alcohol

alcohol


Input: The isolated compound (10 and 30mg/kg) enhanced liver ADH activity 30 and 60min after 40% alcohol administration.

alcohol


Input: The compound was identified as curcumenone by a direct comparison of (1) H-and (13) C-NMR spectral data.

curcumenone

(1) H

(13) C


Input: In conclusion, the protective effect of the C. zedoaria extract on drunkenness might be due to an active substance, curcumenone, and decreases in the elevation of blood alcohol concentrations through increased liver alcohol dehydrogenase activity.

curcumenone

alcohol

alcohol


Input: Nitrogen dioxide at the air-water interface: trapping, absorption, and solvation in the bulk and at the surface.

Nitrogen dioxide


Input: The interaction of NO (2) with water surfaces in the troposphere is of major interest in atmospheric chemistry.

NO (2)


Input: We examined an initial step in this process, the uptake of NO (2) by water through the use of molecular dynamics simulations.

NO (2)


Input: An NO (2)-H (2) O intermolecular potential was obtained by fitting to high-level ab initio calculations.

NO (2)

H (2) O


Input: We determined the binding of NO (2)-H (2) O to be about two times stronger than that previously calculated.

NO (2)

H (2) O


Input: From scattering simulations of an NO (2) molecule interacting with a water slab we observed that the majority of the scattering events resulted in outcomes in which the NO (2) molecule became trapped at the surface or in the interior of the water slab.

NO (2)

NO (2)


Input: Typical surface-trapped/adsorbed and bulk-solvated/absorbed trajectories were analyzed to obtain radial distribution functions and the orientational propensity of NO (2) with respect to the water surface.

NO (2)


Input: We observed an affinity of the nitrogen atom for the oxygen in water, rather than hydrogen-bonding which was rare.

nitrogen

oxygen

hydrogen


Input: The water solvation shell was less tight for the bulk-absorbed NO (2) than for the surface-adsorbed NO (2).

NO (2)

NO (2)


Input: Adsorbed NO (2) demonstrated a marked orientational preference, with the oxygens pointing into the vacuum.

NO (2)

oxygens


Input: Such behavior is expected for a mildly hydrophobic and surfactant molecule like NO (2).

NO (2)


Input: Estimates based on our results suggest that at high NO (2) concentrations encountered, for example, in some sampling systems, adsorption and reaction of NO (2) at the surface may contribute to the formation of gas-phase HONO.

NO (2)

NO (2)

HONO


Input: Liver-specific disruption of the murine glucagon receptor produces alpha-cell hyperplasia: evidence for a circulating alpha-cell growth factor.


Input: Glucagon is a critical regulator of glucose homeostasis; however, mechanisms regulating glucagon action and alpha-cell function and number are incompletely understood.

glucose


Input: To elucidate the role of the hepatic glucagon receptor (Gcgr) in glucagon action, we generated mice with hepatocyte-specific deletion of the glucagon receptor.


Input: Gcgr (Hep) (-/-) mice exhibited reductions in fasting blood glucose and improvements in insulin sensitivity and glucose tolerance compared with wild-type controls, similar in magnitude to changes observed in Gcgr (-/-) mice.

glucose

glucose


Input: Despite preservation of islet Gcgr signaling, Gcgr (Hep) (-/-) mice developed hyperglucagonemia and alpha-cell hyperplasia.


Input: To investigate mechanisms by which signaling through the Gcgr regulates alpha-cell mass, wild-type islets were transplanted into Gcgr (-/-) or Gcgr (Hep) (-/-) mice.


Input: Wild-type islets beneath the renal capsule of Gcgr (-/-) or Gcgr (Hep) (-/-) mice exhibited an increased rate of alpha-cell proliferation and expansion of alpha-cell area, consistent with changes exhibited by endogenous alpha-cells in Gcgr (-/-) and Gcgr (Hep) (-/-) pancreata.


Input: These results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase alpha-cell proliferation independent of direct pancreatic input.


Input: Identification of novel factors regulating alpha-cell proliferation and mass may facilitate the generation and expansion of alpha-cells for transdifferentiation into beta-cells and the treatment of diabetes.


Input: HLA-A * 24 is an independent predictor of 5-year progression to diabetes in autoantibody-positive first-degree relatives of type 1 diabetic patients.


Input: We investigated whether HLA-A * 24 typing complements screening for HLA-DQ and for antibodies (Abs) against insulin, GAD, IA-2 (IA-2A), and zinc transporter-8 (ZnT8A) for prediction of rapid progression to type 1 diabetes (T1D).

zinc


Input: Persistently Ab (+) siblings/offspring (n = 288; aged 0-39 years) of T1D patients were genotyped for HLA-DQA1-DQB1 and HLA-A * 24 and monitored for development of diabetes within 5 years of first Ab (+).


Input: HLA-A * 24 (P = 0. 009), HLA-DQ2/DQ8 (P = 0. 001), and positivity for IA-2A +/- ZnT8A (P < 0. 001) were associated with development of T1D in multivariate analysis.


Input: The 5-year risk increased with the number of the above three markers present (n = 0: 6%; n = 1: 18%; n = 2: 46%; n = 3: 100%).


Input: Positivity for one or more markers identified a subgroup of 171 (59%) containing 88% of rapid progressors.


Input: The combined presence of HLA-A * 24 and IA-2A (+) +/- ZnT8A (+) defined a subgroup of 18 (6%) with an 82% diabetes risk.


Input: Among IA-2A (+) +/- ZnT8A (+) relatives, identification of HLA-A * 24 carriers in addition to HLA-DQ2/DQ8 carriers increased screening sensitivity for relatives at high Ab-and HLA-inferred risk (64% progression; P = 0. 002).


Input: In conclusion, HLA-A * 24 independently predicts rapid progression to T1D in Ab (+) relatives and complements IA-2A, ZnT8A, and HLA-DQ2/DQ8 for identifying participants in immunointervention trials.


Input: Comparison of the structural characteristics of Cu (2 +)-bound and unbound alpha-syn12 peptide obtained in simulations using different force fields.

Cu (2 +)

alpha-syn12 peptide


Input: The effects of Cu (2 +) binding and the utilization of different force fields when modeling the structural characteristics of alpha-syn12 peptide were investigated.

Cu (2 +)

alpha-syn12 peptide


Input: To this end, we performed extensive temperature replica exchange molecular dynamics (T-REMD) simulations on Cu (2 +)-bound and unbound alpha-syn12 peptide using the GROMOS 43A1, OPLS-AA, and AMBER03 force fields.

Cu (2 +)

alpha-syn12 peptide


Input: Each replica was run for 300 ns.


Input: The structural characteristics of alpha-syn12 peptide were studied based on backbone dihedral angle distributions, free-energy surfaces obtained with different reaction coordinates, favored conformations, the formation of different Turn structures, and the solvent exposure of the hydrophobic residues.

alpha-syn12 peptide


Input: The findings show that AMBER03 prefers to sample helical structures for the unbound alpha-syn12 peptide and does not sample any beta-hairpin structure for the Cu (2 +)-bound alpha-syn12 peptide.

alpha-syn12 peptide

Cu (2 +)

alpha-syn12 peptide


Input: In contrast, the central structure of the major conformational clusters for the Cu (2 +)-bound and unbound alpha-syn12 peptide according to simulations performed using the GROMOS 43A1 and OPLS-AA force fields is a beta-hairpin with Turn (9-6).

Cu (2 +)

alpha-syn12 peptide


Input: Cu (2 +) can also promote the formation of the beta-hairpin and increase the solvent exposure of hydrophobic residues, which promotes the aggregation of alpha-syn12 peptide.

Cu (2 +)

alpha-syn12 peptide


Input: This study can help us to understand the mechanisms through which Cu (2 +) participates in the fibrillation of alpha-syn12 peptide at the atomic level, which in turn represents a step towards elucidating the nosogenesis of Parkinson' s disease.

Cu (2 +)

alpha-syn12 peptide


Input: CB (1) receptor allosteric modulators display both agonist and signaling pathway specificity.


Input: We have previously identified allosteric modulators of the cannabinoid CB (1) receptor (Org 27569, PSNCBAM-1) that display a contradictory pharmacological profile: increasing the specific binding of the CB (1) receptor agonist [(3) H] CP55940 but producing a decrease in CB (1) receptor agonist efficacy.

Org 27569

[(3) H] CP55940


Input: Here we investigated the effect one or both compounds in a broad range of signaling endpoints linked to CB (1) receptor activation.


Input: We assessed the effect of these compounds on CB (1) receptor agonist-induced [(35) S] GTP gamma S binding, inhibition, and stimulation of forskolin-stimulated cAMP production, phosphorylation of extracellular signal-regulated kinases (ERK), and beta-arrestin recruitment.

[(35) S] GTP gamma S

forskolin

cAMP


Input: We also investigated the effect of these allosteric modulators on CB (1) agonist binding kinetics.


Input: Both compounds display ligand dependence, being significantly more potent as modulators of CP55940 signaling as compared with WIN55212 and having little effect on [(3) H] WIN55212 binding.

[(3) H] WIN55212


Input: Org 27569 displays biased antagonism whereby it inhibits: agonist-induced guanosine 5'-O-(3-[(35) S] thio) triphosphate ([(35) S] GTP gamma S) binding, simulation (G alpha (s)-mediated), and inhibition (G alpha (i)-mediated) of cAMP production and beta-arrestin recruitment.

Org 27569

guanosine 5'-O-(3-[(35) S] thio) triphosphate

[(35) S] GTP gamma S

cAMP


Input: In contrast, it acts as an enhancer of agonist-induced ERK phosphorylation.


Input: Alone, the compound can act also as an allosteric agonist, increasing cAMP production and ERK phosphorylation.

cAMP


Input: We find that in both saturation and kinetic-binding experiments, the Org 27569 and PSNCBAM-1 appeared to influence only orthosteric ligand maximum occupancy rather than affinity.

Org 27569


Input: The data indicate that the allosteric modulators share a common mechanism whereby they increase available high-affinity CB (1) agonist binding sites.


Input: The receptor conformation stabilized by the allosterics appears to induce signaling and also selectively traffics orthosteric agonist signaling via the ERK phosphorylation pathway.


Input: Plasma ghrelin is positively associated with body fat, liver fat and milk fat content but not with feed intake of dairy cows after parturition.


Input: Ghrelin is a gastrointestinal peptide hormone that is present in blood mostly in a non-posttranslationally modified form, with a minor proportion acylated at Ser (3).

Ser


Input: Both ghrelin forms were initially assigned a role in the control of food intake but there is accumulating evidence for their involvement in fat allocation and utilization.


Input: We investigated changes in the ghrelin system in dairy cows, exhibiting differences in body fat mobilization and fatty liver, from late pregnancy to early lactation.


Input: Sixteen dairy cows underwent liver biopsy and were retrospectively grouped based on high (H) or low (L) liver fat content post-partum.


Input: Both groups had a comparable feed intake in week-6 (before parturition) and week 2 (after parturition).


Input: Only before parturition was preprandial total ghrelin concentration higher in L than in H cows and only after parturition was the basal plasma concentration of non-esterified fatty acids higher in H than in L cows.

fatty acids


Input: Both before and after parturition, H cows had higher preprandial plasma concentrations of acyl ghrelin, a higher acyl: total ghrelin ratio, lower plasma triacylglyceride concentrations and a lower respiratory quotient compared with L cows.

acyl

acyl

triacylglyceride


Input: These group differences could not be attributed to an allelic variant of the acyl ghrelin receptor.

acyl


Input: Rather, the ratio of acyl: total ghrelin correlated with several aspects of fat metabolism and with respiratory quotient but not with feed intake.

acyl


Input: These results show that endogenous ghrelin forms are associated with fat allocation, fatty liver, and utilization of fat during the periparturient period.


Input: 1, 25-Dihydroxyvitamin D3 upregulates leptin expression in mouse adipose tissue.

1, 25-Dihydroxyvitamin D3


Input: Leptin is an adipose tissue-derived hormone that plays a critical role in energy homeostasis.


Input: Vitamin D has been shown to regulate energy metabolism, but the relationship between vitamin D and leptin is unclear.

Vitamin D

vitamin D


Input: Leptin expression and secretion was reduced in vitamin D receptor (VDR)-null mice and increased in transgenic (Tg) mice overexpressing the VDR in adipocytes; however, as leptin is mainly determined by fat mass, it is unclear whether the vitamin D hormone directly regulates leptin expression.

vitamin D

vitamin D


Input: To address this question, we determined the effect of vitamin D on leptin expression in vivo and ex vivo.

vitamin D


Input: One-week treatment of WT mice with the vitamin D analog RO-27-5646 led to a significant increase in adipose leptin mRNA transcript and serum leptin levels.

vitamin D


Input: Moreover, in adipose tissue cultures, 1, 25-dihydroxyvitamin D markedly stimulated mRNA expression and secretion of leptin, but not resistin, in adipose tissues obtained from WT mice, but not from VDR-null mice, and leptin upregulation induced by 1, 25-dihydroxyvitamin D was more robust in adipose tissues obtained from VDR Tg mice compared with WT mice.

1, 25-dihydroxyvitamin D

1, 25-dihydroxyvitamin D


Input: These data demonstrate that 1, 25-dihydroxyvitamin D stimulates adipose leptin production in a VDR-dependent manner, suggesting that vitamin D may affect energy homeostasis through direct regulation of leptin expression.

1, 25-dihydroxyvitamin D

vitamin D


Input: Suramin decreases injury and improves regeneration of ethanol-induced steatotic partial liver grafts.

Suramin

ethanol


Input: Steatotic grafts are excluded for use in partial liver transplantation (LT) because of the increased risk of primary nonfunction.


Input: This study investigated the effects of suramin, a polysulfonated naphthylurea, on the outcome of steatotic partial LT.

suramin

polysulfonated naphthylurea


Input: Rat livers were harvested after acute ethanol treatment (6 g/kg, intragastric administration), reduced in size to =~ 1/3, and transplanted.

ethanol


Input: Serum alanine aminotransferase (ALT) and total bilirubin levels as well as hepatic necrosis and apoptosis were significantly higher after transplantation of fatty partial grafts (FPG) than lean partial grafts (LPG).

alanine

bilirubin


Input: Suramin (5 mg/kg, i. p.) decreased ALT by =~ 60%, hyperbilirubinemia by 75%, necrosis by 83%, and apoptosis by 70% after FPG transplantation.

Suramin


Input: Hepatic cellular 5-bromo-2'-deoxyuridine (BrdU) incorporation increased to 28% in LPG but was only 2% in FPG at 48 hours, and the mitotic index increased to 7% in LPG but was only 0. 2% in FPG, indicating suppressed regeneration in FPG.

BrdU


Input: Suramin increased BrdU incorporation and the mitotic index to 43% and 9%, respectively, in FPG.

Suramin

BrdU


Input: All FPG recipients died within 5 days.


Input: Suramin recovered survival of FPG to 62%.

Suramin


Input: Tumor necrosis factor-alpha (TNF-alpha) mRNA was 2. 2-fold higher in FPG than in LPG and was associated with activation of caspase-8 and caspase-3 in FPG.


Input: Suramin decreased TNF-alpha and caspase activation in FPG.

Suramin


Input: Transforming growth factor-beta (TGF-beta), phospho-Smad2/3 and p21Cip1 were significantly higher in FPG than in LPG and suramin blocked TGF-beta formation and its down-stream signaling pathway.

phospho

suramin


Input: Taken together, suramin improves the outcome of FPG transplantation, most likely by inhibition of TNF-alpha and TGF-beta formation.

suramin


Input: Ecological risk assessment in the context of global climate change.


Input: Changes to sources, stressors, habitats, and geographic ranges; toxicological effects; end points; and uncertainty estimation require significant changes in the implementation of ecological risk assessment (ERA).


Input: Because of the lack of analog systems and circumstances in historically studied sites, there is a likelihood of type III error.


Input: As a first step, the authors propose a decision key to aid managers and risk assessors in determining when and to what extent climate change should be incorporated.


Input: Next, when global climate change is an important factor, the authors recommend seven critical changes to ERA.


Input: First, develop conceptual cause-effect diagrams that consider relevant management decisions as well as appropriate spatial and temporal scales to include both direct and indirect effects of climate change and the stressor of management interest.


Input: Second, develop assessment end points that are expressed as ecosystem services.


Input: Third, evaluate multiple stressors and nonlinear responses-include the chemicals and the stressors related to climate change.


Input: Fourth, estimate how climate change will affect or modify management options as the impacts become manifest.


Input: Fifth, consider the direction and rate of change relative to management objectives, recognizing that both positive and negative outcomes can occur.


Input: Sixth, determine the major drivers of uncertainty, estimating and bounding stochastic uncertainty spatially, temporally, and progressively.


Input: Seventh, plan for adaptive management to account for changing environmental conditions and consequent changes to ecosystem services.


Input: Good communication is essential for making risk-related information understandable and useful for managers and stakeholders to implement a successful risk-assessment and decision-making process.


Input: Topoisomerase I inhibitor evodiamine acts as an antibacterial agent against drug-resistant Klebsiella pneumoniae.

evodiamine


Input: Topoisomerase inhibitors have been developed in a variety of clinical applications.


Input: We investigated the inhibitory effect of evodiamine on E. coli topoisomerase I, which may lead to an anti-bacterial effect.

evodiamine


Input: Evodiamine inhibits the supercoiled plasmid DNA relaxation that is catalyzed by E. coli topoisomerase I, and computer-aided docking has shown that the Arg161 and Asp551 residues of topoisomerase I interact with evodiamine.

Evodiamine

evodiamine


Input: We investigated the bactericidal effect of evodiamine against multidrug-resistant Klebsiella pneumoniae.

evodiamine


Input: Evodiamine showed a significantly lower minimal inhibitory concentration value (MIC 128 micro g/mL) compared with antibiotics (> 512 micro g/mL) against the clinical isolate of K. pneumoniae.

Evodiamine


Input: The results suggested that evodiamine is a potential agent against drug-resistant bacteria.

evodiamine


Input: Derivation of a benchmark for freshwater ionic strength.


Input: Because increased ionic strength has caused deleterious ecological changes in freshwater streams, thresholds for effects are needed to inform resource-management decisions.


Input: In particular, effluents from surface coal mining raise the ionic strength of receiving streams.

coal


Input: The authors developed an aquatic life benchmark for specific conductance as a measure of ionic strength that is expected to prevent the local extirpation of 95% of species from neutral to alkaline waters containing a mixture of dissolved ions in which the mass of SO (4) 2-+ HCO (3)->= Cl (-).

SO (4) 2-

HCO (3)-

Cl (-)


Input: Extirpation concentrations of specific conductance were estimated from the presence and absence of benthic invertebrate genera from 2, 210 stream samples in West Virginia.


Input: The extirpation concentration is the 95th percentile of the distribution of the probability of occurrence of a genus with respect to specific conductance.


Input: In a region with a background of 116 micro S/cm, the 5th percentile of the species sensitivity distribution of extirpation concentrations for 163 genera is 300 micro S/cm.


Input: Because the benchmark is not protective of all genera and protects against extirpation rather than reduction in abundance, this level may not fully protect sensitive species or higher-quality, exceptional waters.


Input: Hypoxia-response element (HRE)-directed transcriptional regulation of the rat lysyl oxidase gene in response to cobalt and cadmium.

lysyl

cobalt

cadmium


Input: Lysyl oxidase (LO) catalyzes crosslink of collagen, elastin, and histone H1, stabilizing the extracellular matrix and cell nucleus.

Lysyl


Input: This enzyme displays dual functions for tumorigenesis, i. e., as a tumor suppressor inactivating the ras oncogene and as a tumor promoter enhancing malignant cell metastasis.


Input: To elucidate LO transcriptional regulation, we have cloned the 804 base pair region upstream of the translation start site (ATG) of the rat LO gene with the maximal promoter activity.


Input: Computer analysis indicated that at least four hypoxia-response element (HRE) consensuses (5'-ACGTG-3') exist in the cloned LO promoter.


Input: Treatment of rat lung fibroblasts (RFL6) with CoCl2 (Co, 10-100 mu M), a chemical hypoxia reagent, enhanced LO mRNA expression and promoter activities.

Co


Input: Overexpression of LO was associated with upregulation of hypoxia-inducible factor (HIF)-1 alpha at mRNA levels in cobalt (Co)-treated cells.

cobalt

Co


Input: Thus, LO is a hypoxia-responsive gene.


Input: Dominant negative-HIF-1 alpha inhibited LO promoter activities stimulated by Co.

Co


Input: Electrophoretic mobility shift, oligonucleotide competition, and in vitro translated HIF-1 alpha binding assays indicated that only one HRE mapped at-387/-383 relative to ATG was functionally active among four consensuses.


Input: Site-directed mutation of this HRE significantly diminished the Co-induced and LO promoter-directed expression of the reporter gene.

Co


Input: Cadmium (Cd), an inducer of reactive oxygen species, inhibited HIF-1 alpha mRNA expression and HIF-1 alpha binding to the LO gene in Co-treated cells as revealed by RT-PCR and ChIP assays, respectively.

Cadmium

Cd

oxygen

Co


Input: Thus, modulation of the HRE activity by Co and Cd plays a critical role in LO gene transactivation.

Co

Cd


Input: Identifying protein interaction subnetworks by a bagging Markov random field-based method.


Input: Identification of differentially expressed subnetworks from protein-protein interaction (PPI) networks has become increasingly important to our global understanding of the molecular mechanisms that drive cancer.


Input: Several methods have been proposed for PPI subnetwork identification, but the dependency among network member genes is not explicitly considered, leaving many important hub genes largely unidentified.


Input: We present a new method, based on a bagging Markov random field (BMRF) framework, to improve subnetwork identification for mechanistic studies of breast cancer.


Input: The method follows a maximum a posteriori principle to form a novel network score that explicitly considers pairwise gene interactions in PPI networks, and it searches for subnetworks with maximal network scores.


Input: To improve their robustness across data sets, a bagging scheme based on bootstrapping samples is implemented to statistically select high confidence subnetworks.


Input: We first compared the BMRF-based method with existing methods on simulation data to demonstrate its improved performance.


Input: We then applied our method to breast cancer data to identify PPI subnetworks associated with breast cancer progression and/or tamoxifen resistance.

tamoxifen


Input: The experimental results show that not only an improved prediction performance can be achieved by the BMRF approach when tested on independent data sets, but biologically meaningful subnetworks can also be revealed that are relevant to breast cancer and tamoxifen resistance.

tamoxifen


Input: G4LDB: a database for discovering and studying G-quadruplex ligands.


Input: The G-quadruplex ligands database (G4LDB, http://www. g4ldb. org) provides a unique collection of reported G-quadruplex ligands to streamline ligand/drug discovery targeting G-quadruplexes.


Input: G-quadruplexes are guanine-rich nucleic acid sequences in human telomeres and gene promoter regions.

guanine

nucleic acid


Input: There is a growing recognition for their profound roles in a wide spectrum of diseases, such as cancer, diabetes and cardiovascular disease.


Input: Ligands that affect the structure and activity of G-quadruplexes can shed light on the search for G-quadruplex-targeting drugs.


Input: Therefore, we built the G4LDB to (i) compile a data set covering various physical properties and 3D structure of G-quadruplex ligands; (ii) provide Web-based tools for G-quadruplex ligand design; and (iii) to facilitate the discovery of novel therapeutic and diagnostic agents targeting G-quadruplexes.


Input: G4LDB currently contains > 800 G-quadruplex ligands with ~ 4000 activity records, which, to our knowledge, is the most extensive collection of its kind.


Input: It offers a user friendly interface that can meet a variety of data inquiries from researchers.


Input: For example, ligands can be searched for by name, molecular properties, structures, ligand activities and so on.


Input: Building on the reported data, the database also provides an online ligand design module that can predict ligand binding affinity in real time.


Input: Laminar silk scaffolds for aligned tissue fabrication.


Input: 3D-biomaterial scaffolds with aligned architecture are of vital importance in tissue regeneration.


Input: A generic method is demonstrated to produce aligned biomaterial scaffolds using the physics of directional ice freezing.


Input: Homogeneously aligned 3D silk scaffolds with high porosity and alignment are prepared.


Input: The method can be adapted to a wide range of polymers and is devoid of any chemical reactions, thus avoiding potential complications associated with by-products.


Input: Mechanical properties and cellular responses with chondrocytes and bone-marrow-derived hMSCs are studied, assessing survival, proliferation, and differentiation.


Input: In vivo tests suggest biocompatibility of the matrices for future tissue engineering applications, specifically in areas where high cellular alignment is needed.


Input: Enantiomeric discrimination of isoxazoline fused beta-amino acid derivatives using (18-crown-6)-2, 3, 11, 12-tetracarboxylic acid as a chiral NMR solvating agent.

isoxazoline

beta-amino acid

(18-crown-6)-2, 3, 11, 12-tetracarboxylic acid


Input: (18-Crown-6)-2, 3, 11, 12-tetracarboxylic acid is a useful chiral NMR solvating agent for isoxazoline-fused beta-amino acid derivatives.

(18-Crown-6)-2, 3, 11, 12-tetracarboxylic acid

isoxazoline

beta-amino acid


Input: Isoxazoline substrates are analyzed as their hydrochloride salts in methanol-d (4).

Isoxazoline

hydrochloride

methanol


Input: The crown ether and substrate associate through the formation of three hydrogen bonds between the protonated amine and crown ether oxygen atoms.

hydrogen

amine

crown ether oxygen


Input: Enantiomeric discrimination is observed for two or more resonances of every substrate.


Input: At least one of these resonances is free of overlap with other resonances in the spectrum and has large enough enantiomeric discrimination to enable the determination of enantiomeric purity.


Input: 2D COSY methods can be used to identify additional resonances that exhibit enantiomeric discrimination in the NMR spectrum.


Input: Effects of mutated pregnancy-associated plasma protein-a on atherosclerotic lesion development in mice.


Input: Pregnancy-associated plasma protein-A (PAPP-A) is a large multidomain metalloprotease involved in cleavage of IGF binding protein (IGFBP)-4 and-5 thereby causing release of bioactive IGF.


Input: Individual domains of PAPP-A have been characterized in vitro, including the metzincin proteolytic domain important for IGFBP proteolytic activity, short consensus repeats critical for cell surface association, and Lin-12/Notch repeat module demonstrated to determine IGFBP substrate specificity.


Input: To test the hypothesis that specific cleavage of IGFBP-4 by PAPP-A in close proximity to the cell surface is required for development of lesions in a murine model of atherosclerosis, the following PAPP-A transgenic (Tg) mice were generated: Tg (E483A), which lacks all PAPP-A proteolytic activity; Tg (D1499A), which selectively lacks proteolytic activity against IGFBP-4; and Tg (K1296A/K1316A), in which cell surface binding is compromised.


Input: Following cross-breeding with apolipoprotein E (ApoE) knockout (KO) mice, ApoE KO/Tg mice were fed a high-fat diet to promote aortic lesion development.


Input: Lesion area was increased 2-fold in aortas from ApoE KO/Tg wild-type compared with ApoE KO mice (P < 0. 001).


Input: However, there was no significant increase in the lesion area in any of the ApoE KO/Tg mutant mice.


Input: We conclude that PAPP-A proteolytic activity is required for the lesion-promoting effect of PAPP-A and that its specificity must be directed against IGFBP-4.


Input: Furthermore, our data demonstrate that cleavage of IGFBP-4 at a distance from the cell surface, and hence from the IGF receptor, is not effective in promoting the development of the atherosclerotic lesions.


Input: Thus, PAPP-A exerts its effect while bound to the cell surface in vivo.


Input: Does catch and release affect the mating system and individual reproductive success of wild Atlantic salmon (Salmo salar L.)?


Input: In this study, we documented the breeding system of a wild population of Atlantic salmon (Salmo salar L.) by genetically sampling every returning adult and assessed the determinants of individual fitness.


Input: We then quantified the impacts of catch and release (C & R) on mating and reproductive success.


Input: Both sexes showed high variance in individual reproductive success, and the estimated standardized variance was higher for males (2. 86) than for females (0. 73).


Input: We found a weak positive relationship between body size and fitness and observed that fitness was positively correlated with the number of mates, especially in males.


Input: Mature male parr sired 44% of the analysed offspring.


Input: The impact of C & R on the number of offspring was size dependent, as the reproductive success of larger fish was more impaired than smaller ones.


Input: Also, there was an interactive negative effect of water temperature and air exposure time on reproductive success of C & R salmon.


Input: This study improves our understanding of the complex reproductive biology of the Atlantic salmon and is the first to investigate the impact of C & R on reproductive success.


Input: Our study expands the management toolbox of appropriate C & R practices that promote conservation of salmon populations and limit negative impacts on mating and reproductive success.


Input: Effective targeting of A beta to macrophages by sonochemically prepared surface-modified protein microspheres.


Input: Imbalanced homeostasis and oligomerization of the amyloid-beta (A beta) peptide in the brain are hallmarks of Alzheimer' s disease (AD).


Input: Microglia and macrophages play a critical role in the etiology of AD either by clearing A beta from the brain or inducing inflammation.


Input: Recent evidence suggests that clearance of A beta by microglia/macrophages via the phagocytic pathway is defective in AD, which can contribute to the accumulation of A beta in the brain.


Input: We have recently demonstrated that protein microspheres modified at their surface with multiple copies of an A beta-recognition motif can strongly bind A beta, inhibit its aggregation, and directly reduce its toxicity by sequestering it from the medium.


Input: Here, we describe how microsphere-bound A beta can stimulate microglial cells and be phagocytosed through a mechanism that is distinct from that of A beta removal and, thus, contribute to the clearance of A beta, even by defective microglial cells.


Input: The phagocytosis was most effective, with microspheres having a diameter of < 1 mu m.


Input: The introduction of polyethylene glycol to the surface of the microspheres changed the kinetics of the phagocytosis.

polyethylene glycol


Input: Moreover, while aggregated A beta induced a significant inflammatory response that was manifested by the release of TNF-alpha, the microsphere-bound A beta dramatically reduced the amount of cytokine released from microglial cells.


Input: Diversity patterns of uncultured Haptophytes unravelled by pyrosequencing in Naples Bay.


Input: Haptophytes are a key phylum of marine protists, including ~ 300 described morphospecies and 80 morphogenera.


Input: We used 454 pyrosequencing on large subunit ribosomal DNA (LSU rDNA) fragments to assess the diversity from size-fractioned plankton samples collected in the Bay of Naples.


Input: One group-specific primer set targeting the LSU rDNA D1/D2 region was designed to amplify Haptophyte sequences from nucleic acid extracts (total DNA or RNA) of two size fractions (0. 8-3 or 3-20 mu m) and two sampling depths [subsurface, at 1 m, or deep chlorophyll maximum (DCM) at 23 m].

chlorophyll


Input: 454 reads were identified using a database covering the entire Haptophyta diversity currently sequenced.


Input: Our data set revealed several hundreds of Haptophyte clusters.


Input: However, most of these clusters could not be linked to taxonomically known sequences: considering OTUs (97%) (clusters build at a sequence identity level of 97%) on our global data set, less than 1% of the reads clustered with sequences from cultures, and less than 12% clustered with reference sequences obtained previously from cloning and Sanger sequencing of environmental samples.


Input: Thus, we highlighted a large uncharacterized environmental genetic diversity, which clearly shows that currently cultivated species poorly reflect the actual diversity present in the natural environment.


Input: Haptophyte community appeared to be significantly structured according to the depth.


Input: The highest diversity and evenness were obtained in samples from the DCM, and samples from the large size fraction (3-20 mu m) taken at the DCM shared a lower proportion of common OTUs (97%) with the other samples.


Input: Reads from the species Chrysoculter romboideus were notably found at the DCM, while they could be detected at the subsurface.


Input: The highest proportion of totally unknown OTUs (97%) was collected at the DCM in the smallest size fraction (0. 8-3 mu m).


Input: Overall, this study emphasized several technical and theoretical barriers inherent to the exploration of the large and largely unknown diversity of unicellular eukaryotes.


Input: The octadecaneuropeptide stimulates somatolactin release from cultured goldfish pituitary cells.


Input: The present study aimed to investigate the distribution of the octadecaneuropeptide (ODN) in the goldfish brain and to look for a possible effect of ODN on somatolactin (SL) release from pituitary cells.


Input: A discrete population of ODN-immunoreactive neurones was localised in the lateral part of the nucleus lateralis tuberis.


Input: These neurones sent projections through the neurohypophyseal tract towards the neurohypophysis, and nerve fibres were seen in the close vicinity of SL-producing cells in the pars intermedia.


Input: Incubation of cultured goldfish pituitary cells with graded concentrations of ODN (10 (-9)-10 (-5) m) induced a dose-dependent stimulation of SL-beta, but not SL-alpha, release.


Input: ODN-evoked SL release was blocked by the metabotrophic endozepine receptor antagonist cyclo (1-8) [DLeu (5)] OP but was not affected by the central-type benzodiazepine receptor antagonist flumazenil.

cyclo (1-8) [DLeu (5)] OP

benzodiazepine

flumazenil


Input: ODN-induced SL release was suppressed by treatment with the phospholipase C (PLC) inhibitor U-73122 but not with the protein kinase A (PKA) inhibitor H-89.


Input: These results indicate that, in fish, ODN produced by hypothalamic neurones acts as a hypophysiotrophic neuropeptide stimulating SL release.


Input: The effect of ODN is mediated through a metabotrophic endozepine receptor positively coupled to the PLC/inositol 1, 4, 5-trisphosphate/protein kinase C-signalling pathway.

inositol 1, 4, 5-trisphosphate


Input: Metal-mediated targeting in the body.


Input: Metal ions are important for many biological processes and are steadily available in the human body.


Input: Metal concentrations can be extremely high in diseased areas of various pathological conditions.


Input: Some synthetic and natural drugs need to be activated by metal ions as prodrugs.


Input: In this review, we provide a few examples to illustrate how metal ions activate and mediate drug targeting in the body.


Input: This knowledge may be helpful for the development of more effective drugs and pharmaceutical formulations.


Input: The serotonin receptor 7 promotes neurite outgrowth via ERK and Cdk5 signaling pathways.

serotonin


Input: Serotonergic neurotransmission is mediated by at least 14 subtypes of 5-HT receptors.


Input: Among these, the CNS serotonin receptor 7 (5-HTR7) is involved in diverse physiological processes.

serotonin


Input: Here we show that treatment of murine striatal and cortical neuronal cultures with 5-HTR7 agonists (8-OH-DPAT and LP-211) significantly enhances neurite outgrowth.


Input: This effect is abolished by the selective 5-HTR7 antagonist SB-269970, by the ERK inhibitor U0126, by the cyclin-dependent kinase 5 (Cdk5) inhibitor roscovitine, as well as by cycloheximide, an inhibitor of protein synthesis.

roscovitine

cycloheximide


Input: These data indicate that 5-HTR7 activation stimulates extensive neurite elongation in CNS primary cultures, subserved by ERK and Cdk5 activation, and de novo protein synthesis.


Input: Two-dimensional (2D) gel electrophoresis coupled to Western blot analyses reveals both qualitative and quantitative expression changes in selected cytoskeletal proteins, following treatment of striatal primary cultures with LP-211.


Input: In particular, the 34 kDa isoform of MAP1B is selectively expressed in stimulated cultures, consistent with a role of this protein in tubulin polymerization and neurite elongation.


Input: In summary, our results show that agonist-dependent activation of the endogenous 5-HTR7 in CNS neuronal primary cultures stimulates ERK-and Cdk5-dependent neurite outgrowth, sustained by modifications of cytoskeletal proteins.


Input: These data support the hypothesis that the 5-HTR7 might play a crucial role in shaping neuronal morphology and behaviorally relevant neuronal networks, paving the way to new approaches able to modulate CNS connectivity.


Input: Differential modulation of retinal ganglion cell light responses by orthosteric and allosteric metabotropic glutamate receptor 8 compounds.

glutamate


Input: To investigate the role of mGluR8 in modulating the synaptic responses of retinal ganglion cells, we used a recently identified positive allosteric modulator of mGluR8, AZ12216052 (AZ) and the mGluR8-specific orthosteric agonist (S)-3, 4-dicarboxyphenylglycine (DCPG).

(S)-3, 4-dicarboxyphenylglycine

DCPG


Input: These agents were applied to whole-cell voltage-clamped ganglion cells from an isolated, superfused mouse retina preparation.


Input: DCPG reduced OFF-ganglion cell excitatory currents, whereas AZ enhanced the peak excitatory currents in ON-, OFF-, and ON-OFF-ganglion cells.

DCPG


Input: The effects on ganglion cell inhibitory currents were more varied.


Input: The effects of the allosteric modulator were stronger for bright stimuli than for dim stimuli, consistent with receptor stimulation by endogenous glutamate being stronger during bright light stimulation and with mGluR8 receptors mainly being localized away from glutamate release sites, immuno-labeled with VGLUT1.

glutamate

glutamate


Input: The differential sensitivity of ganglion cell light responses to DCPG and AZ supports multiple sites where mGluR8 modulates the light responses of ganglion cells.

DCPG


Input: Early life exposure to air pollution: how bad is it?


Input: Increasing concentrations of air pollution have been shown to contribute to an enormity of adverse health outcomes worldwide, which have been observed in clinical, epidemiological, and animal studies as well as in vitro investigations.


Input: Recently, studies have shown that air pollution can affect the developing fetus via maternal exposure, resulting in preterm birth, low birth weight, growth restriction, and potentially adverse cardiovascular and respiratory outcomes.


Input: This review will provide a summary of the harmful effects of air pollution exposure on the developing fetus and infant, and suggest potential mechanisms to limit the exposure of pregnant mothers and infants to air pollution.


Input: On scaffold hopping: challenges in the discovery of sulfated small molecules as mimetics of glycosaminoglycans.


Input: The design of sulfated, small, nonsaccharide molecules as modulators of proteins is still in its infancy as standard drug discovery tools such as library of diverse sulfated molecules and in silico docking and scoring protocol have not been firmly established.


Input: Databases, such as ZINC, contain too few sulfate-containing nonsaccharide molecules, which severely limits the identification of new hits.

ZINC

sulfate


Input: Lack of a generally applicable protocol for scaffold hopping limits the development of sulfated small molecules as synthetic mimetics of the highly sulfated glycosaminoglycans.


Input: We explored a sequential ligand-based (LBVS) and structure-based virtual screening (SBVS) approach starting from our initial discovery of monosulfated benzofurans to discover alternative scaffolds as allosteric modulators of thrombin, a key coagulation enzyme.

monosulfated benzofurans


Input: Screening the ZINC database containing nearly 1 million nonsulfated small molecules using a pharmacophore developed from the parent sulfated benzofurans followed by a genetic algorithm-based dual-filter docking and scoring screening identified a group of 10 promising hits, of which three top-scoring hits were synthesized.

ZINC

sulfated benzofurans


Input: Each was found to selectively inhibit human alpha-thrombin suggesting the possibility of this approach for scaffold hopping.


Input: Michaelis-Menten kinetics showed allosteric inhibition mechanism for the best molecule and human plasma studies confirmed good anticoagulation potential as expected.


Input: Our simple sequential LBVS and SBVS approach is likely to be useful as a general strategy for identification of sulfated small molecules hits as modulators of glycosaminoglycan-protein interactions.


Input: The perirhinal cortex of rats: an intricate area for microinfusion of anticonvulsants against soman-induced seizures.


Input: Microinfusion of anticonvulsants into the perirhinal cortex through 1 guide cannula in each hemisphere only invades a small area of this seizure controlling site in rats exposed to soman.


Input: The purpose of the present study was to examine whether infusions made through 2 cannulas in each perirhinal cortex may produce more efficacious anticonvulsant action against soman intoxication than the use of 1 cannula only in rats infused with the ionotropic antagonists procyclidine and caramiphen or the metabotropic glutamate modulators DCG-IV and MPEP.

procyclidine

caramiphen

glutamate

DCG-IV

MPEP


Input: The results showed that the mere presence of indwelling double cannulas caused proconvulsant effect in response to subsequent systemic administration of soman.


Input: Both the control and caramiphen groups with double cannulas had significantly shorter latencies to seizure onset than the corresponding groups with single cannula.

caramiphen


Input: Procyclidine resulted in anticonvulsant efficacy, even in rats with double cannulas.

Procyclidine


Input: In rats that received twin infusions of DCG-IV or MPEP, the anticonvulsant impact was very high, inasmuch as a majority of the rats in each group was protected against seizure activity.

DCG-IV

MPEP


Input: Drugs possessing powerful anticonvulsant potency can apparently counteract the proconvulsant effect of double cannulas, and some can even gain enhanced anticonvulsant capacity when invading a larger area of the perirhinal cortex.


Input: Perirhinal EEG recordings (electrodes in indwelling cannulas) in a separate set of rats not exposed to soman or drugs showed no differences in basal electrical activity (total power 0. 5-25Hz or the theta band 4-12Hz) between groups with single or double cannulas.


Input: The intrinsic excitability and synaptic connectivity of the perirhinal cortex may be associated with the proconvulsant impact observed in rats with double cannulas when exposed to soman.


Input: Placental concentrations of mercury, lead, cadmium, and arsenic and the risk of neural tube defects in a Chinese population.

mercury

cadmium

arsenic


Input: To examine whether in utero exposure to mercury (Hg), cadmium (Cd), lead (Pb) and arsenic (As) is associated with an elevated neural tube defects (NTDs) risk, placental concentrations of total Hg, Cd, Pb and As were measured with an inductively coupled plasma mass spectrometer (ICP-MS) in 36 anencephaly and 44 spina bifida cases as well as in 50 healthy controls.

mercury

Hg

cadmium

Cd

Pb

arsenic

As

Hg

Cd

Pb

As


Input: The median Hg concentration in the NTD cases (2. 25 ng/g) was higher than that of the controls (1. 16 ng/g).

Hg


Input: The odds ratio (OR) for an Hg concentration above the median was 8. 80 (95% CI 3. 80-20. 36) for the NTD cases.


Input: NTD risks increased for the second and third high levels of the concentrations, with ORs of 2. 70 (95% CI 1. 13-6. 43) and 18. 20 (95% CI 5. 45-60. 73), respectively.


Input: Therefore, higher placental levels of Hg are associated with an elevated risk of NTDs.

Hg


Input: Telomere length and dynamics predict mortality in a wild longitudinal study.


Input: Explaining variation in life expectancy between individuals of the same age is fundamental to our understanding of population ecology and life history evolution.


Input: Variation in the length and rate of loss of the protective telomere chromosome caps has been linked to cellular lifespan.


Input: Yet, the extent to which telomere length and dynamics predict organismal lifespan in nature is still contentious.


Input: Using longitudinal samples taken from a closed population of Acrocephalus sechellensis (Seychelles warblers) studied for over 20 years, we describe the first study into life-long adult telomere dynamics (1-17 years) and their relationship to mortality under natural conditions (n = 204 individuals).


Input: We show that telomeres shorten with increasing age and body mass, and that shorter telomeres and greater rates of telomere shortening predicted future mortality.


Input: Our results provide the first clear and unambiguous evidence of a relationship between telomere length and mortality in the wild, and substantiate the prediction that telomere length and shortening rate can act as an indicator of biological age further to chronological age when exploring life history questions in natural conditions.


Input: Merit of quinacrine in the decrease of ingested sulfite-induced toxic action in rat brain.

quinacrine

sulfite


Input: We aimed at investigating the effects of sulfite-induced lipid peroxidation and apoptosis mediated by secretory phospholipase A2 (sPLA2) on somatosensory evoked potentials (SEP) alterations in rats.

sulfite


Input: Thirty male albino Wistar rats were randomized into three experimental groups as follows; control (C), sodium metabisulfite treated (S), sodium metabisulfite + quinacrine treated (SQ).

sodium metabisulfite

sodium metabisulfite

quinacrine


Input: Sodium metabisulfite (100 mg/kg/day) was given by gastric gavage for 5 weeks and 10 mg/kg/day quinacrine was applied as a single dose of intraperitoneal injection for the same period.

Sodium metabisulfite

quinacrine


Input: The latencies of SEP components were significantly prolonged in the S group and returned to control levels following quinacrine administration.

quinacrine


Input: Plasma-S-sulfonate level was increased in S and SQ groups.

S

sulfonate


Input: TBARS levels in the S group were significantly higher than those detected in controls.


Input: Quinacrine significantly decreased brain TBARS levels in the SQ group compared with the S group.

Quinacrine


Input: Quinacrine treatment did not have an effect on the increased sPLA2 level of the sulfite administered group.

Quinacrine

sulfite


Input: Immunohistochemistry showed that sulfite caused an increase in caspase-3 and TUNEL positive cells, restored to control levels via quinacrine administration.

sulfite

quinacrine


Input: This study showed that sPLA2 might play a role in ingested sulfite-induced SEP alterations, oxidative stress, apoptotic cell death and DNA damage in the brain.

sulfite


Input: Bone hemodynamic responses to changes in external pressure.


Input: Adequate blood supply and circulation to the bones is required to maintain a healthy skeleton.


Input: Inadequate blood perfusion is associated with numerous bone pathologies and a decrease in bone mineral density, yet bone hemodynamics remains poorly understood.


Input: This study aims to 1) quantify bone hemodynamic responses to changes in external pressure, and 2) identify the predominant mechanisms regulating bone hemodynamic responses to pressure changes.


Input: Photoplethysmography was used to measure bone and skin perfusion in response to changes in external pressure.


Input: Single-limb pressure chamber experiments were performed over a pressure range of-50 to + 50mmHg.


Input: Bone perfusion is decreased at all negative pressures, and larger decrements in perfusion are observed at the more extreme pressure differences.


Input: At positive pressures we observed an initial increase in perfusion followed by activation of intramuscular pressure receptors at + 30mmHg, which overrides the initial response and results in decreased perfusion at the highest positive pressure levels.


Input: The myogenic effect is observed and is shown to be the predominant control mechanism in bone over a wide range of pressure exposures.


Input: Greater understanding of these hemodynamic mechanisms may be important in developing new drugs and therapies to treat various bone disorders.


Input: Nanostructural transformations during the reduction of hollow and porous nickel oxide nanoparticles.

nickel oxide


Input: Size-dependent nanostructural transformations occurring during the H (2)-mediated reduction of hollow and porous NiO nanoparticles were investigated for controlled nanoparticle sizes of ~ 10 to 100 nm.

H (2)

NiO


Input: Transmission electron microscopy reveals that the location and number of reduction sites strongly depend on the nanoparticle size and structure.


Input: Excited-state proton coupled charge transfer modulated by molecular structure and media polarization.


Input: Charge and proton transfer reactions in the excited states of organic dyes can be coupled in many different ways.


Input: Despite the complementarity of charges, they can occur on different time scales and in different directions of the molecular framework.


Input: In certain cases, excited-state equilibrium can be established between the charge-transfer and proton-transfer species.


Input: The interplay of these reactions can be modulated and even reversed by variations in dye molecular structures and changes of the surrounding media.


Input: With knowledge of the mechanisms of these processes, desired rates and directions can be achieved, and thus the multiple emission spectral features can be harnessed.


Input: These features have found versatile applications in a number of cutting-edge technological areas, particularly in fluorescence sensing and imaging.


Input: How do the electrical properties of graphene change with its functionalization?

graphene


Input: Functionalization of graphene is essential to interface it with other moieties to expand the scope of its electrical/electronic applications.

graphene


Input: However, chemical functionalization and/or molecular interactions on graphene sensitively modulate its electrical properties.

graphene


Input: To evaluate and take advantage of the properties of functionalized graphene, it is important to understand how its electrical attributes (such as carrier scattering, carrier concentration, charge polarity, quantum-capacitance enhanced doping, energy levels, transport mechanisms, and orbital hybridization of energy-bands) are influenced by a change in carbon' s structural conformation, hybridization state, chemical potential, local energy levels, and dopant/interface coupling induced via functionalization or molecular interactions.

graphene

carbon


Input: Here, a detailed and integrated model describes factors influencing these electrical characteristics of functionalized graphene (covalent bonds, adsorption, pi-pi bonds, and lattice incorporation).

graphene


Input: The electrical properties are governed via three mechanisms: (a) conversion of carbon' s hybridized state, (b) dipole interactions enhanced via quantum capacitance, and (c) orbital hybridization with an interfacing molecule.

carbon


Input: A few graphenic materials are also identified where further studies are essential to understand the effect of their functionalization.


Input: Global cerebral ischemia: synaptic and cognitive dysfunction.


Input: Cardiopulmonary arrest is one of the leading causes of death and disability, primarily occurring in the aged population.


Input: Numerous global cerebral ischemia animal models induce neuronal damage similar to cardiac arrest.


Input: These global cerebral ischemia models range from vessel occlusion to total cessation of cardiac function, both of which have allowed for the investigation of this multifaceted disease and detection of numerous agents that are neuroprotective.


Input: Synapses endure a variety of alterations after global cerebral ischemia from the resulting excitotoxicity and have been a major target for neuroprotection; however, neuroprotective agents have proven unsuccessful in clinical trials, as neurological outcomes have not displayed significant improvements in patients.


Input: A majority of these neuroprotective agents have specific neuronal targets, where the success of future neuroprotective agents may depend on non-specific targets and numerous cognitive improvements.


Input: This review focuses on the different models of global cerebral ischemia, neuronal synaptic alterations, synaptic neuroprotection and behavioral tests that can be used to determine deficits in cognitive function after global cerebral ischemia.


Input: Minocycline mediated mitochondrial cytoprotection: premises for therapy of cerebrovascular and neurodegenerative diseases.

Minocycline


Input: In the last decades, emerging molecular targets for ischemic neuroprotection and regeneration have been postulated.


Input: This fact allowed that classical drugs with well established therapeutic applications might be used in cerebrovascular diseases as well as neurodegenerative diseases.


Input: Minocycline is a commonly used antibiotic of the tetracycline family (7-dimethylamino-6-dimethyl-6-deoxytetracycline) which reveals cytoprotective capability and potential use in treatment of different diseases.

Minocycline

tetracycline

7-dimethylamino-6-dimethyl-6-deoxytetracycline


Input: Here, we discuss the literature concerning minocycline.

minocycline


Input: The available data indicate that the antibiotic has multi-faceted effects on cell functions and, consequently, a number of clinical properties that are useful and/or could be useful for treatment of different diseases including bacterial infections, cancer, autoimmune disorders, ischemia as well as neurodegenerative and psychiatric diseases.


Input: Thus, application of minocycline as a therapeutic agent is the subject of clinical trials for various diseases.

minocycline


Input: It is also evident that minocycline-mediated cytoprotection, including neuroprotection, is an important aspect of its clinical application.

minocycline


Input: Here, we have reviewed the basis of the minocycline activity as well as different studies indicating that minocycline can be used as potential therapeutic agent in both cerebrovascular and neurodegenerative diseases in human.

minocycline

minocycline


Input: Neuroprotection & mechanism of ethanol in stroke and traumatic brain injury therapy: new prospects for an ancient drug.

ethanol


Input: Effective efforts to screen for agents that protect against the devastating effects of stroke have not produced viable results thus far.


Input: As a result this article reviews the possible role of ethanol as a neuroprotective agent in stroke and traumatic brain injury (TBI).

ethanol


Input: Previous studies have associated ethanol consumption with a decreased risk of ischemic stroke, suggesting a neuroprotective mechanism.


Input: The translation of this clinical knowledge into basic science research with the goal of new therapy for acute stroke patients remains in its initial stages.


Input: In a recent study involving rats, we have shown that ethanol administration, in the correct dose after stroke onset, protects against ischemia-induced brain injury.

ethanol


Input: The purpose of this paper is to discuss ethanol' s neuroprotective properties in stroke when consumed as a preconditioning agent, in TBI with a positive blood alcohol content, and finally in stroke treatment, with the goal of using post-ischemia ethanol (PIE) therapy to ameliorate brain damage in the future.

ethanol

ethanol


Input: Getting in shape: controlling peptide bioactivity and bioavailability using conformational constraints.


Input: Chemical biologists commonly seek out correlations between the physicochemical properties of molecules and their behavior in biological systems.


Input: However, a new paradigm is emerging for peptides in which conformation is recognized as the primary determinant of bioactivity and bioavailability.


Input: This review highlights an emerging body of work that directly addresses how a peptide' s conformation controls its biological effects, cell penetration, and intestinal absorption.


Input: Based on this work, the dream of mimicking the potency and bioavailability of natural product peptides is getting closer to reality.


Input: New 2-(aryloxy)-3-phenylpropanoic acids as peroxisome proliferator-activated receptor alpha/gamma dual agonists able to upregulate mitochondrial carnitine shuttle system gene expression.

2-(aryloxy)-3-phenylpropanoic acids

carnitine


Input: The preparation of a series of 2-(aryloxy)-3-phenylpropanoic acids, resulting from the introduction of different substituents into the biphenyl system of the previously reported peroxisome proliferator-activated receptor alpha/gamma (PPAR alpha/gamma) dual agonist 1, allowed the identification of new ligands with higher potency on PPAR alpha and fine-tuned moderate PPAR gamma activity.

2-(aryloxy)-3-phenylpropanoic acids

biphenyl


Input: For the most promising stereoisomer (S)-16, X-ray and calorimetric studies in PPAR gamma revealed, at high ligand concentration, the presence of two molecules simultaneously bound to the receptor.