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Anthelmintic activity of Arisaema franchetianum and Arisaema lobatum essential oils against Haemonchus contortus.

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ETHNOPHARMACOLOGICAL RELEVANCE: Arisaema franchetianum and Arisaema lobatum are two perennial plants native to China. Arisaema franchetianum is universally used to promote the subsidence of induration and swelling, quicken blood and relieve pains, and kill intestinal parasites in humans and animals. Arisaema lobatum is used to treat malaria, intestinal parasites, and snake and insect bites in humans and animals. The aim of this study was to determine the composition of the essential oils from Arisaema franchetianum and Arisaema lobatum and evaluate the anthelmintic effect against Haemonchus contortus. MATERIALS AND METHODS: Two oils were investigated by GC and GC-MS. The anthelmintic bioassay tests of Arisaema franchetianum and Arisaema lobatum essential oil, linalool and carvacrol were performed using egg hatch assay (EHA), larval development assay (LDA) and larval migration inhibition assay (LMIA). RESULTS: Fifty six components representing 96.88% of the Arisaema franchetianum oil and 64 components representing 96.88% of the Arisaema lobatum oil were identified. Carvacrol and linalool were found to be the major constituents of two oils. In the EHA, greater than 99% inhibition were observed with Arisaema franchetianum oil at 10mg/mL (CE50 1.63mg/mL) and Arisaema lobatum oil at 5 and 10mg/mL (CE50 0.48mg/mL). In the LDA, both oils induced complete inhibition at 10mg/mL, with the CE50 being 1.10mg/mL for Arisaema franchetianum oil and 0.73mg/mL for Arisaema lobatum oil. In the LMIA, the Arisaema franchetianum oil and Arisaema lobatum oil at best inhibited 74.1% and 95.6% of larval migration at 10mg/mL, respectively. Carvacrol exhibited similar activity to Arisaema lobatum essential oil and linalool did not show high activity in every assay. CONCLUSIONS: These data show for the first time that the essential oils obtained from Arisaema franchetianum or Arisaema lobatum had promising anthelmintic activity against Haemonchus contortus. Arisaema plant may offer an alternative source for the control of gastrointestinal nematodes of sheep and goats.

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Sciadopitysin protects osteoblast function via its antioxidant activity in MC3T3-E1 cells.

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Age-related osteoblast dysfunction is the main cause of age-related bone loss in both men and women. In the present study, the effect of sciadopitysin, a type of biflavonoids, on osteoblast function was investigated in osteoblastic MC3T3-E1 cells. Sciadopitysin caused a significant elevation of alkaline phosphatase activity, collagen synthesis, osteocalcin production, mineralization, and glutathione content in the cells (P<0.05). Sciadopitysin also decreased the production of tumor necrosis factor-a (TNF-α) induced by antimycin A, a mitochondrial electron transport inhibitor. We investigated the protective effects of sciadopitysin on antimycin A-induced toxicity in osteoblastic MC3T3-E1 cells. Exposure of MC3T3-E1 cells to antimycin A caused a significant reduction in osteoblast dysfunction. However, pretreatment with sciadopitysin prior to antimycin A exposure significantly reduced antimycin A-induced cell damage by preventing mitochondrial membrane potential dissipation, adenosine triphosphate (ATP) loss, reactive oxygen species (ROS) release, and nitrotyrosine increase, suggesting that sciadopitysin may be useful for protecting mitochondria against a burst of oxidative stress. Moreover, sciadopitysin increased phosphorylation of cAMP-response element-binding protein (CREB) inhibited by antimycin A. Our results demonstrate that sciadopitysin may reduce or prevent osteoblasts degeneration.

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In vitro binding affinities of a series of flavonoids for μ-opioid receptors. Antinociceptive effect of the synthetic flavonoid 3,3-dibromoflavanone in mice.

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The pharmacotherapy for the treatment of pain is an active area of investigation. There are effective drugs to treat this problem, but there is also a need to find alternative treatments free of undesirable side effects. In the present work the capacity of a series of flavonoids to bind to the μ opioid receptor was evaluated. The most active compound, 3,3-dibromoflavanone (31), a synthetic flavonoid, presented a significant inhibition of the binding of the selective μ opioid ligand [(3)H]DAMGO, with a Ki of 0.846 ± 0.263 μM. Flavanone 31 was further synthesized using a simple and cheap procedure with good yield. Its in vivo effects in mice, after acute treatments, were studied using antinociceptive and behavioral assays. It showed no sedative, anxiolytic, motor incoordination effects or inhibition of the gastrointestinal transit in mice at the doses tested. It evidenced antinociceptive activity on the acetic acid-induced nociception, hot plate and formalin tests (at 10 mg/kg and 30 mg/kg). The results showed that the 5-HT2 receptor and the adrenoceptors seem unlikely to be involved in its antinociceptive effects. Naltrexone, a nonselective opioid receptors antagonist, totally blocked compound 31 antinociceptive effects on the hot plate test, but naltrindole (δ opioid antagonist) and nor-binaltorphimine (κ opioid antagonist) did not. These findings demonstrated that 3,3-dibromoflavanone (31), at doses that did not interfere with the motor performance, exerted clear dose dependent antinociception when assessed in the chemical and thermal models of nociception in mice and it seems that its action is related to the activation of the μ opioid receptor.

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Trabecular bone adapts to long-term cyclic loading by increasing stiffness and normalization of dynamic morphometric rates.

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Bone has the ability to adapt to external loading conditions. Especially the beneficial effect of short-term cyclic loading has been investigated in a number of in vivo animal studies. The aim of this study was to assess the long-term effect (>10weeks) of cyclic mechanical loading on the bone microstructure, bone stiffness, and bone remodeling rates. Mice were subjected to cyclic mechanical loading at the sixth caudal vertebra with 8N or 0N (control) three times per week for a total period of 14weeks. Structural bone parameters were determined from in vivo micro-computed tomography (micro-CT) scans performed at week 0, 4, 6, 8, 10, 12, and 14. Mechanical parameters were derived from micro-finite element analysis. Dynamic bone morphometry was calculated using registration of serial micro-CT scans. Bone volume fraction and trabecular thickness increased significantly more for the loaded group than for the control group (p=0.006 and p=0.002 respectively). The trabecular bone microstructure adapted to the load of 8N in approximately ten weeks, indicated by the trabecular bone volume fraction, which increased from 16.7% at 0weeks to 21.6% at week 10 and only showed little change afterwards (bone volume fraction of 21.5% at 14weeks). Similarly bone stiffness - at the start of the experiment 649N/mm - reached 846N/mm at 10weeks in the loaded group and was maintained to the end of the experiment (850N/mm). At 4weeks the bone formation rate was 32% greater and the bone resorption rate 22% less for 8N compared to 0N. This difference was significantly reduced as the bone adapted to 8N, with 8N remodeling rates returning to the values of the 0N group at approximately 10weeks. Together these data suggest that once bone has adapted to a new loading state, the remodeling rates reduce gradually while maintaining bone volume fraction and stiffness.

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The extraction and analysis of cylindrospermopsin from human serum and urine.

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The naturally derived cyanotoxin, cylindrospermopsin (CYN), has been detected in freshwater systems worldwide and poses a threat to human health. The methods for the extraction and detection of this toxin in source water are well documented, but methods for CYN determination in exposed individuals have not been investigated. In this study, the extraction and detection of CYN from two different matrices, serum and urine, was explored. Both serum and urine matrices inherently produce interference with analytical analyses and require extensive clean-up. Methods for extraction of CYN from both matrices were developed and validated using fortified samples. Serum extraction included homogenization followed by protein precipitation and solid phase extraction (SPE). Urine samples were processed using filtration, pH manipulation, and SPE. Analyses using a commercially available enzyme-linked immunosorbent assay (ELISA) and liquid chromatography coupled with mass spectrometry (LC/MS/MS) were assessed. Matrix effects inhibited ELISA's use as a quantitative tool for both matrices. LC/MS/MS was determined to be the most effective and reproducible means to detect and quantify CYN. The method detection limits determined in this study using LC/MS/MS were 0.25 and 0.50 ng mL(-1) for serum and urine, respectively. This method can be used to test individuals exposed to blooms of cyanobacteria producing CYN.

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Developmental toxicity and estrogenic potency of zearalenone in zebrafish (Danio rerio).

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Zearalenone (ZEA, F2) is one of the most common mycotoxins and the only known mycoestrogen. It enters the food and feed chain from contaminated cereals and infiltrates into sewage or natural waters posing potential threat to exposed livestock, wildlife and humans. Therefore evaluation of its biological effects is of international importance. We performed toxicological tests on zebrafish (Danio rerio) larvae and adults. Developmental toxicity was assessed by an extended (5 days) fish embryo toxicity test (FET). Effects of early ZEA exposure were concentration-dependent with LC50 and LC10 values of 893 and 335μg/L. In larvae exposed to 500μg/L and above, ZEA induced similar phenotype to has (heart-and soul) showing defects in heart and eye development and upward curvature of the body axis. From 250μg/L at 72hpf the gap in the melanophore streak at the base of the tail fin was missing and the fin fold was abnormal, suggesting disturbance in the development of the adult tail fin primordium. Estrogenic potency was measured on the basis of Vitellogenin (Vtg) protein (adults) levels and relative abundance of vitellogenin-1 mRNA (vtg-1) (larvae and adults). qRT-PCR in larvae proved to be sufficient substitute to adult tests and sensitive enough to detect ZEA in 0.1μg/L concentrations, that is close to levels observed in wastewaters. Developmental defects reveal that besides direct estrogenic effects, zearalenone might interact with other ontogenic pathways.

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Controlled electrochemical deposition and transformation of hetero-nanoarchitectured electrodes for energy storage.

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A review of electrochemically synthesized nanomaterials with different controllable architectures for electrochemical energy storage devices is shown. It is demonstrated that these nano-architectures can be created either by electrodeposition or by the electrochemical transformation of materials. Electrochemical synthesis is presented here as it provides intimate contact between the electrode and current collector and also promotes an electronic pathway for all materials to be connected to the circuit. Although still in their infancy, electrosynthesized nano-architectures show promise to be used in future electrochemical energy storage devices as utilization of this method bypasses the need for bulky conductive additives and electrochemically inactive binders. Furthermore, electrochemical transformations can be used to create additional architectural features or change the chemical make-up of the electrode. This review is meant to show the creativity of current science when it comes to these nano-architectured electrodes. It is organized by technique used for synthesis including hard template, soft template, and template-free synthesis along with electrochemical transformation techniques.

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Effects of intravenous nicotine on prepulse inhibition in smokers and non-smokers: relationship with familial smoking.

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RATIONALE: The reinforcing properties of nicotine may be, in part, derived from its ability to enhance certain forms of cognitive processing. Several animal and human studies have shown that nicotine increases prepulse inhibition (PPI) of the startle reflex. However, it remains unclear whether these effects are related to smoking susceptibility. OBJECTIVES: The current study examined the effects of intravenously delivered nicotine on PPI in smokers and non-smokers, as well as its association with a quantitative index of familial smoking. METHODS: The sample consisted of 30 non-smokers and 16 smokers, who completed an initial assessment, followed on a separate day by a laboratory assessment of PPI prior to and following each of two intravenous nicotine infusions. Separate doses were used in smoker and non-smoker samples. RESULTS: Analyses indicated that both nicotine infusions acutely enhanced PPI among non-smokers, and this enhancement was positively related to the degree of smoking among first and second-degree relatives. Smokers also displayed PPI enhancement after receiving the first infusion, but this effect was unrelated to familial smoking. CONCLUSIONS: These data suggest that the PPI paradigm may have utility as an endophenotype for cognitive processes which contribute to smoking risk.

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Ventral tegmental area α6β2 nicotinic acetylcholine receptors modulate phasic dopamine release in the nucleus accumbens core.

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RATIONALE: Phasic dopamine (DA) signaling underlies reward learning. Cholinergic and glutamatergic inputs into the ventral tegmental area (VTA) are crucial for modulating burst firing activity and subsequent phasic DA release in the nucleus accumbens (NAc), but the specific VTA nicotinic receptor subtypes that regulate phasic DA release have not been identified. OBJECTIVE: The goal was to determine the role of VTA N-methyl-D-aspartate receptors (NMDARs) and specific subtypes of nicotinic acetylcholine receptors (nAChRs) in regulating phasic DA release in the NAc core. METHODS: Fast-scan cyclic voltammetry in anesthetized rats was combined with intra-VTA micro-infusion to evaluate the ability of glutamatergic and cholinergic drugs to modulate stimulated phasic DA release in the NAc core. RESULTS: VTA NMDAR blockade with AP-5 decreased, while VTA NMDAR activation with NMDA increased NAc peak phasic DA release. Intra-VTA administration of the nonspecific nAChR antagonist mecamylamine produced a persistent decrease in phasic DA release. Infusion of the α6-selective antagonist α-conotoxin MII (α-ctx MII) produced a robust, but transient decrease in phasic DA, whereas infusion of selective doses of either the α4β2-selective antagonist, dihydro-beta-erythroidine, or the α7 antagonist, methyllycaconitine, had no effect. Co-infusion of AP-5 and α-ctx MII produced a similar phasic DA decrease as either drug alone, with no additive effect. CONCLUSIONS: The results suggest that VTA α6β2 nAChRs, but not α4β2 or α7 nAChRs, regulate phasic DA release in the NAc core and that VTA α6β2 nAChRs and NMDA receptors act at a common site or target to regulate NAc phasic DA signaling.

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The Value of Expression of M2-PK and VEGF in Patients with Advanced Gastric Cancer.

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Glycolytic pyruvate kinase isoenzyme type M2 (M2-PK) plays a key role in tumor metabolism and energy production. Vascular endothelial growth factor (VEGF) is critical in regulating angiogenesis which is an essential process required for tumor growth and metastasis. These two genes may function in accordance with tumor development. The purpose of this study was to investigate the relationship between the expression of M2-PK and VEGF, and their association with clinicopathological features in patients with advanced gastric cancer. Expression of M2-PK and VEGF were examined in 142 cases of paraffin-embedded tissue blocks from patients with advanced gastric cancer. M2-PK expression was found to strongly correlate with that of VEGF (r = 0.718). In addition, expression of M2-PK and VEGF correlates with tumor size (p = 0.0001, and p = 0.0017, respectively), depth of invasion (p = 0.0024, and p = 0.0261, respectively), and lymph node metastasis (p = 0.036, and p = 0.028, respectively). The high expression levels of M2-PK and VEGF may indicate poor prognosis in patients with advanced gastric cancer.

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Effects of Soil Trace Elements on Longevity Population in China.

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Based on background concentrations of elements in soils and the sixth population census data of China, this study discussed the distribution characteristics of soil elements and longevity population at province level in China. Percentages of the aging population are high in Southwest China and the eastern coastal region but low in western and northwestern regions. Provinces in South and Southwest China gain a high level of longevity, while the northern part of China has a low level of longevity. The background concentration of Se in soil has a significant positive correlation with longevity index, while Ba and Ni have a significant negative correlation with longevity indexes. By regression analysis, longevity index C/100,000 can be expressed as C/100,000 = 1.679-0.205 Ni + 0.413 Co + 0.006 Se (with R (2) = 0.402 and p < 0.01), C/65+ can be expressed as C/65+=3.425-0.262 Ni + 0.435 Co + 0.006 Se (with R (2) = 0.369 and p < 0.01).

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Glomerular Filtration Rate Equations Overestimate Creatinine Clearance in Older Individuals Enrolled in the Baltimore Longitudinal Study on Aging: Impact on Renal Drug Dosing.

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OBJECTIVES: To evaluate the performance of kidney function estimation equations and to determine the frequency of drug dose discordance in an older population. DESIGN: Cross-sectional analysis of data from community-dwelling volunteers randomly selected from the Baltimore Longitudinal Study of Aging from January 1, 2005, to December 31, 2010. SUBJECTS: A total of 269 men and women with a mean ± SD age of 81 ± 6 years, mean serum creatinine concentration (Scr ) of 1.1 ± 0.4 mg/dl, and mean 24-hour measured creatinine clearance (mClcr ) of 53 ± 13 ml/minute. MEASUREMENTS AND MAIN RESULTS: Kidney function was estimated by using the following equations: Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The performance of each equation was assessed by measuring bias and precision relative to mClcr . Dose calculation errors (discordance) were determined for 10 drugs requiring renal dosage adjustments to avoid toxicity when compared with the dosages approved by the Food and Drug Administration. The CG equation was the least biased estimate of mClcr . The MDRD and CKD-EPI equations were significantly positively biased compared with CG (mean ± SD 34 ± 20% and 22 ± 15%, respectively, p<0.001) and mClcr (29 ± 47% and 18 ± 40%, respectively, p<0.001). Rounding low Scr values (less than 1.0 mg/dl) up to an arbitrary value of 1.0 mg/dl resulted in CG values (44 ± 10 ml/minute) that were significantly lower than mClcr (56 ± 12 ml/minute, p<0.001) and CG (56 ± 15 ml/minute, p<0.001). The MDRD and CKD-EPI equations had median dose discordance rates of 28.6% and 22.9%, respectively. CONCLUSION: The MDRD and CKD-EPI equations significantly overestimated creatinine clearance (mClcr and CG) in elderly individuals. This leads to dose calculation errors for many drugs, particularly in individuals with severe renal impairment. Thus equations estimating glomerular filtration rate should not be substituted in place of the CG equation in older adults for the purpose of renal dosage adjustments. In addition, the common practice of rounding or replacing low Scr values with an arbitrary value of 1.0 mg/dl for use in the CG equation should be avoided. Additional studies that evaluate alternative eGFR equations in the older populations that incorporate pharmacokinetic and pharmacodynamic outcomes measures are needed.

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Multiple Site-Selective Insertions of Noncanonical Amino Acids into Sequence-Repetitive Polypeptides.

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A simple and efficient method is described for the introduction of noncanonical amino acids at multiple, defined sites within recombinant polypeptide sequences. Escherichia coli MRA30, a bacterial host strain with attenuated activity of release factor 1 (RF1), was assessed for its ability to support incorporation of a diverse range of noncanonical amino acids in response to multiple encoded amber (TAG) codons within genes derived from superfolder GFP and an elastin-mimetic protein polymer. Suppression efficiency and protein yield depended on the identity of the orthogonal aminoacyl-tRNA synthetase/tRNA(CUA) pair and the noncanonical amino acid. Elastin-mimetic protein polymers were prepared in which noncanonical amino acid derivatives were incorporated at up to 22 specific sites within the polypeptide sequence with high substitution efficiency. The identities and positions of the variant residues were confirmed by mass spectrometric analysis of the full-length polypeptides and proteolytic cleavage fragments from thermolysin digestion. The data suggest that this multisite suppression approach permits the preparation of protein-based materials in which novel chemical functionalities can be introduced at precisely defined positions within the polypeptide sequence.

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Studying the effect of antioxidants on cytogenetic manifestations of solvent exposure in paint industry.

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OBJECTIVE: To investigate the antioxidant role in reversing cytogenetic changes caused by solvent exposure in paint industry.Subjects and METHODS: A prospective controlled clinical trial was performed on 39 workers exposed to solvents and 39 workers not exposed to solvents by supplying a mixture of antioxidant vitamins (A, C, E and selenium) and the after effects of such regimen were analyzed. Environmental monitoring was carried out for air concentrations of different solvents at workplace. Exposed group was cytogenetically tested before and after giving the mixture of antioxidant vitamins for 1 month duration. RESULTS: Frequency of chromosomal aberrations (CAs) and the mean of sister chromatid exchanges (SCEs) were statistically significantly higher among exposed workers than among controls. After the supplementation of antioxidants, there was a statistically significant decrease in the frequency of CAs, and 88% abnormal levels of SCEs were back to normal levels. CONCLUSION: Antioxidant supplementation decreases the frequency of CAs and SCEs among exposed workers.

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Pirimicarb-based formulation-induced genotoxicity and cytotoxicity in the fresh water fish Cnesterodon decemmaculatus (Jenyns, 1842) (Pisces, Poeciliidae).

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We analyzed the aspects of lethality, genotoxicity, and cytotoxicity in the ten spotted live-bearer exposed under laboratory conditions to the pirimicarb-based formulation Patton Flow(®) (50% active ingredient (a.i.)). Acute effects were evaluated using different end points for lethality, genotoxicity, and cytotoxicity. Median lethal concentration (LC50) estimation was employed as a bioassay for lethality, whereas micronucleus (MN) induction and alterations in erythrocyte/erythroblast frequency were used as end points for genotoxicity and cytotoxicity, respectively. Results demonstrated an LC5096h value of 88 mg/L. Patton Flow(®) increased the MN frequency in fish erythrocytes after 48 h of exposure at a concentration of 66 mg/L, whereas a concentration range of 22-66 mg/L was able to exert the same genotoxic effect at 96 h of treatment. Furthermore, cytotoxicity was also observed by alterations in erythrocyte/erythroblast frequencies within the concentration range of 22-66 mg/L, regardless of the exposure time. Our current observations provide evidence that Patton Flow(®) (50% a.i.) should be considered a clear lethal, cytotoxic, and genotoxic agent on Cnesterodon decemmaculatus. Thus, repeated applications of this carbamic insecticide can enter the aquatic environment and exert deleterious effects on aquatic organisms other than the evaluated species C. decemmaculatus.

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1,1-Diphenyl,2-picrylhydrazyl free radical scavenging, bactericidal, fungicidal and leishmanicidal properties of Teucrium stocksianum.

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In the present study, we evaluated the pharmacological and toxicological effects of Teucrium stocksianum. The crude extract of T. stocksianum (Ts.Cr) and its subsequent organic fractions: n-hexane (Ts.Hex), chloroform (Ts.CHCl3) and ethyl acetate (Ts.EtAc) exhibited 1,1-diphenyl,2-picrylhydrazyl free radical scavenging activity with different potencies. Ts.EtAc was found to be most potent. Ts.Cr, Ts.Hex, Ts.CHCl3 and Ts.EtAc showed significant bactericidal activity against Escherichia coli, Staphylococcus aureus, Salmonella typhi, Shigella flexneri and Bacillus subtilis at their extent. Ts.Cr, Ts.Hex, Ts.CHCl3 and Ts.EtAc displayed fungicidal action against Aspergillus niger, Aspergillus flavus, Aspergillus fumigatus and Fusarium solani at various minimum inhibitory concentrations. Ts.Cr and Ts.EtAc exhibited marked inhibition of Leishmania tropica growth, observed after 48 and 96 hrs of treatment. These data indicate that the T. stocksianum methanolic extract and its resultant fractions possess antioxidant, antibacterial, antifungal and antileishmanial activities. Thus, the present research unearths the scientific base for T. stocksianum medicinal application as antioxidant and antimicrobial agents.

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Effect of paraoxonase 1 192 Q/R polymorphism on paraoxonase and acetylcholinesterase enzyme activities in Turkish population exposed to organophosphate.

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Organophosphate (OP) compounds are the most commonly used pesticide groups and they are commercially used in the market for local and industrial purposes. Paraoxonase 1 (PON1) enzyme plays an important role in biotransformation of OP compounds, which shows toxic effects via inhibiting the acetylcholinesterase (AChE). The aim of this study was to determine the effects of PON1 gene polymorphism and its effects on PON and AChE enzyme activities in individuals who were exposed to organophosphorus insecticides due to occupational reasons, and to profile the probability of susceptibility to organophosphorus compounds. For this purpose, 54 individuals who were exposed to OPs and 54 healthy unrelated controls were studied. First, PON1 and AChE enzyme activities were measured. Second, PON1 192 Q/R polymorphism was determined by standard polymerase chain reaction-restriction fragment length polymorphism technique. When the PON1 192 Q/R polymorphism was compared with PON1 enzyme activities, statistically significant association was found in both OP-exposed and control groups (p < 0.05). PON1 192 R(+) (QR + RR genotypes) genotype carriers had higher PON1 activities than 192 R(-) (QQ) genotype carriers. On the other hand, results were statistically analyzed in terms of AChE enzyme activities and there were statistically significant differences only in the OP-exposed group (p < 0.05). The mean AChE concentration in the OP-exposed group was determined as 33.79 ± 6.84 U/g haemoglobin (Hb) for PON1 192 R(+) carriers and 30.37 ± 7.62 U/g Hb for PON1 192 R(+) carriers. As a conclusion, PON1 and AChE activities were increasing according to the genotypes found in individuals having been exposed to OPs at a chronic level; 192 R(+) > 192 R(-), respectively.

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Structural Determinants of Agonist Efficacy at the Glutamate Binding Site of NMDA Receptors.

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NMDA receptors are ligand-gated ion channels assembled from GluN1 and GluN2 subunits. We utilized a series of N-hydroxypyrazole-5-glycine (NHP5G) partial agonists at the GluN2 glutamate binding site as tools to study activation of GluN1/GluN2A and GluN1/GluN2D NMDA receptor subtypes. We show using two-electrode voltage-clamp electrophysiology, fast-application patch-clamp, and single channel recordings that propyl- and ethyl-substituted NHP5G agonists have a broad range of agonist efficacies relative to the full agonist glutamate (<1%-72%). Crystal structures of the agonist binding domains (ABDs) of GluN2A and GluN2D do not reveal any differences in the overall domain conformation induced by binding of the full agonist glutamate or the partial agonist propyl-NHP5G, which is strikingly different from ABD structures of AMPA and kainate receptors bound to full and partial agonists. Subsequent evaluation of relative NHP5G agonist efficacy at GluN2A-GluN2D chimeric subunits implicates the amino-terminal domain (ATD) as a strong determinant of agonist efficacy, suggesting that interdomain interactions between the ABD and the ATD may be a central element in controlling the manner by which agonist binding leads to channel opening. We propose that variation in the overall receptor conformation, which is strongly influenced by the nature of interdomain interactions in resting and active states, mediates differences in agonist efficacy and partial agonism at the GluN2 subunits.

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Microfluidic affinity and ChIP-seq analyses converge on a conserved FOXP2-binding motif in chimp and human, which enables the detection of evolutionarily novel targets.

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The transcription factor forkhead box P2 (FOXP2) is believed to be important in the evolution of human speech. A mutation in its DNA-binding domain causes severe speech impairment. Humans have acquired two coding changes relative to the conserved mammalian sequence. Despite intense interest in FOXP2, it has remained an open question whether the human protein's DNA-binding specificity and chromatin localization are conserved. Previous in vitro and ChIP-chip studies have provided conflicting consensus sequences for the FOXP2-binding site. Using MITOMI 2.0 microfluidic affinity assays, we describe the binding site of FOXP2 and its affinity profile in base-specific detail for all substitutions of the strongest binding site. We find that human and chimp FOXP2 have similar binding sites that are distinct from previously suggested consensus binding sites. Additionally, through analysis of FOXP2 ChIP-seq data from cultured neurons, we find strong overrepresentation of a motif that matches our in vitro results and identifies a set of genes with FOXP2 binding sites. The FOXP2-binding sites tend to be conserved, yet we identified 38 instances of evolutionarily novel sites in humans. Combined, these data present a comprehensive portrait of FOXP2's-binding properties and imply that although its sequence specificity has been conserved, some of its genomic binding sites are newly evolved.

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Self-Assembly and Near Perfect Macroscopic Alignment of Fluorescent Triangulenium Salt in Spin Cast Thin Films on PTFE.

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Highly fluorescent, discotic trioxatriangulenium dyes were aligned by simple spin casting on substrates with friction transferred PTFE layers. The fluorescent crystalline thin films show near perfect macroscopic alignment on centimeter large areas directly from spin casting. Gracing Incidence X-ray Diffraction (GIXD) unambiguously allowed to determine a long range order unit cell as well as its orientation with respect to the PTFE fibers. Further analysis of the X-ray data, in conjunction with polarized absorption spectroscopy, suggest a lamellar packing model with alternating layers of alkyl chains and ionic dyes oriented parallel to the substrate. This structure results in a highly anisotropic electrostatic potential around the cationic chromophore, causing significant shifts in energy and orientation of the optical transitions. Thus, the optical properties of the material are, to a large extent, controlled by the position of the otherwise inert PF6- counter ions. The bright fluorescence from the films is also polarized parallel to the PTFE alignment layer. Doping of the thin films with fluorescent energy acceptor traps shows that efficient exciton migration takes place in the thin films. The excellent exciton transfer capabilities, in conjunction with the perfect alignment, might be of interest in future applications in solar energy harvesting or as thin film sensors.

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How Selective Are the New Guidelines for Treatment of Subclinical Hypothyroidism for Patients with Thyrotropin Levels At or Below 10 mIU/L?

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Background: By consensus, a thyrotropin (TSH) level persistently >10 mIU/L is an indication for the treatment of subclinical hypothyroidism (SCH). Controversy exists regarding patients whose TSH level is elevated but <10 mIU/L. Recently, the American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists (AACE) published their position about factors that should be considered in the decision on treating SCH. This study evaluated the frequency of these factors among adult (non-pregnant) women with SCH whose TSH levels are ≤10 mIU/L. Methods: The presence of the conditions that should be considered for the treatment of SCH according to ATA and AACE was evaluated in 252 women who were diagnosed with SCH and had TSH levels ≤10 mIU/L. Pregnant women were excluded. Results: Antithyroperoxidase antibodies (TPOAbs) were detected in 137 (54.3%) women. A high cardiovascular risk was observed in 43 (17%) women. Eighty (31.7%) women who were not at high cardiovascular risk presented at least one classical risk factor (arterial hypertension, elevated level of low-density lipoprotein-cholesterol or low level of high-density lipoprotein-cholesterol, smoking, or first-degree family history of premature coronary artery disease). At least one symptom or sign of hypothyroidism that could not be explained by another condition was observed in 180 (71.4%) women. Two hundred thirty-two (92%) women had positive TPOAbs, or at least one classical cardiovascular risk factor, or at least one symptom or sign of hypothyroidism. Conclusions: According to the new ATA and AACE guidelines, L-T4 therapy would be considered for 92% of women with SCH and TSH ≤10 mIU/L.

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NMDA receptors and memory encoding.

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It is humbling to think that 30 years have passed since the paper by Collingridge, Kehl and McLennan showing that one of Jeff Watkins most interesting compounds, R-2-amino-5-phosphonopentanoate (d-AP5), blocked the induction of long-term potentiation in vitro at synapses from area CA3 of the hippocampus to CA1 without apparent effect on baseline synaptic transmission (Collingridge et al., 1983). This dissociation was one of the key triggers for an explosion of interest in glutamate receptors, and much has been discovered since that collectively contributes to our contemporary understanding of glutamatergic synapses - their biophysics and subunit composition, of the agonists and antagonists acting on them, and their diverse functions in different networks of the brain and spinal cord. It can be fairly said that Collingridge et al.'s (1983) observation was the stimulus that has led, on the one hand, to structural biological work at the atomic scale describing the key features of NMDA receptors that enables their coincidence function to happen; and, on the other, to work with whole animals investigating the contributions that calcium signalling via this receptor can have on rhythmical activities controlled by spinal circuits, memory encoding in the hippocampus (the topic of this article), visual cortical plasticity, sensitization in pain, and other functions. In this article, I lay out how my then interest in long-term potentiation (LTP) as a model of memory enabled me to recognise the importance of Collingridge et al.'s discovery - and how I and my colleagues endeavoured to take things forward in the area of learning and memory. This is in some respects a personal story, and I tell it as such. The idea that NMDA receptor activation is essential for memory encoding, though not for storage, took time to develop and to be accepted. Along the way, there have been confusions, challenges, and surprises surrounding the idea that activation of NMDA receptors can trigger memory. Some of these are described and how they have been addressed and resolved. Last, I touch on some new directions of interest with respect to the functional role of the NMDA receptor in cognition. This article is part of a Special Issue entitled 'GluR-dep synaptic plasticity'.

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Scientific evidence for traditional claim of antiobesity activity of Tecomella undulata bark.

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ETHNOPHARMACOLOGICAL RELEVANCE: The bark of Tecomella undulata is traditionally claimed in the treatment of various disease ailments including obesity and cancer. Till now there are no studies about anti obesity activity of Tecomella undulata bark. AIM OF THE STUDY: The present study was aimed to establish a scientific evidence for anti obesity efficiency of ethyl acetate extract of Tecomella undulata bark (EATUB). Further to standardize the active fractions of EATUB using different biomarkers. MATERIALS AND METHODS: We investigated activity of EATUB fractions (F1-F7) using 3T3-L1 fibroblasts. Further, F1-mediated effects were characterized by determining mRNA and protein levels of SIRT1, one of the key targets for the treatment of obesity, using semi quantitative RT-PCR (sqRT-PCR) and western blot analysis. The consequences of modulation of SIRT1 on mRNA and protein levels of various adipogenesis mediators like PPARγ, C/EBPα, E2F1, leptin, adiponectin and LPL were also studied. In-vivo studies were performed using High Fat Diet (HFD) obese mice. RESULTS: Our data showed that compared to controls, preadipocytes and adipocytes incubated with F1 exhibited a significant decrease in adipogenesis and lipogenesis. In addition, sqRT-PCR and western blot analysis showed significant increase in SIRT1 and adiponectin levels and decrease in PPARγ, C/EBPα, E2F1, leptin and LPL levels in preadipocytes and adipocytes. In-vivo studies of F1 in HFD induced obese mice showed significant improvement in lipid profile and glucose levels. The bioactive fraction (F1) was determined to possess 4.95% of ferulic acid. CONCLUSION: Thus, our findings signified the beneficial effects of Tecomella undulata bark in pharmacologic interventions related to obesity and metabolic disorders. Ferulic acid and rutin are being reported and quantified for the first time from the bark of Tecomella undulata.

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Cytotoxic effects of amphetamine mixtures in primary hepatocytes are severely aggravated under hyperthermic conditions.

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Amphetamine consumers are often, deliberately or not, polydrug abusers. Predicting combination effects based on concentration-response analysis of individual components is a valid strategy for accurate toxicological assessment of mixtures. We previously reported that joint effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and three other often co-ingested amphetamines (methamphetamine, 4-methylthyoamphetamine and D-amphetamine) could be predicted by the concentration addition (CA) model in HepG2 cells. We sought to further evaluate the relevance of these findings by extending these studies to a cell model that more closely mimics the in vivo situation. Detailed cytotoxic information of the four individual amphetamines on primary rat hepatocytes was recorded by the MTT assay, at 37°C and 40.5°C, simulating the rise in body temperature that could be induced following amphetamine intake. Mixture expectations were calculated using CA and independent action (IA) models. At 37°C, concentration-dependent cytotoxicity occurred for the drugs individually and combined. Mixture effects were accurately predicted by the CA model, while the IA model underestimated cytotoxicity. At 40.5°C these cytotoxic effects were aggravated. Our findings provide evidence of the increased risks associated with the abuse of amphetamine mixtures, especially during hyperthermia, emphasising the need to increase awareness of misinformed users who believe these drugs are safe.

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Receiver Operating Characteristic Analysis of HLA, CTLA4, and Insulin Genotypes for Type 1 Diabetes.

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OBJECTIVEThis study assessed the ability to distinguish between type 1 diabetes-affected individuals and their unaffected relatives using HLA and single nucleotide polymorphism (SNP) genotypes.RESEARCH DESIGN AND METHODSEight models, ranging from only the high-risk DR3/DR4 genotype to all significantly associated HLA genotypes and two SNPs mapping to the cytotoxic T-cell-associated antigen-4 gene (CTLA4) and insulin (INS) genes, were fitted to high-resolution class I and class II HLA genotyping data for patients from the Type 1 Diabetes Genetics Consortium collection. Pairs of affected individuals and their unaffected siblings were divided into a "discovery" (n = 1,015 pairs) and a "validation" set (n = 318 pairs). The discriminating performance of various combinations of genetic information was estimated using receiver operating characteristic (ROC) curve analysis.RESULTSThe use of only the presence or absence of the high-risk DR3/DR4 genotype achieved very modest discriminating ability, yielding an area under the curve (AUC) of 0.62 in the discovery set and 0.59 in the validation set. The full model, which included HLA information from the class II loci DPB1, DRB1, DQB1, selected alleles from HLA class I loci A and B, and SNPs from the CTLA4 and INS genes, increased the AUC to 0.74 in the discovery set and to 0.71 in the validation set. A cost-effective alternative is proposed, using genotype information equivalent to typing four SNPs (DR3, DR4-DQB1*03:02, CTLA-4, and INS), which achieved an AUC of 0.72 in the discovery set and 0.69 in the validation set.CONCLUSIONSGenotyping data sufficient to tag DR3, DR4-DQB1*03:02, CTLA4, and INS was shown to distinguish between subjects with type 1 diabetes and their unaffected siblings adequately to achieve clinically utility to identify children in multiplex families to be considered for early intervention.

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Cuf2 boosts the transcription of APC/C activator Fzr1 to terminate the meiotic division cycle.

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The number of nuclear divisions in meiosis is strictly limited to two. Although the precise mechanism remains unknown, this seems to be achieved by adjusting the anaphase-promoting complex/cyclosome (APC/C) activity to degrade cyclin. Here, we describe a fission yeast cuf2 mutant that enters into a third nuclear division cycle, represented by ectopic spindle assembly and abnormal chromosome segregation. Cuf2 is a meiotic transcription factor, and its critical target is fzr1(+)/mfr1(+), which encodes a meiotic APC/C activator. fzr1Δ also enters a third nuclear division. Thus, Cuf2 ensures termination of the M-phase cycle by boosting Fzr1 expression to generate functional gametes.

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Intracellular trafficking of solid lipid nanoparticles and their distribution between cells through tunneling nanotubes.

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The intracellular fate of nanosized drug delivery systems is still not well understood. Various internalization pathways have been discovered, but knowledge of their intracellular trafficking is still incomplete. The aim of this study was to examine the internalization, pathways, and positioning taken by solid lipid nanoparticles (SLNs) in cells. SLNs were fluorescence labeled with a newly synthesized fluorescent probe, 14-DACA. The probe was strongly incorporated into the nanoparticle core under the influence of its long lipophilic chain, enabling superior visualization of SLNs under complex and dynamic intracellular conditions. The intracellular distribution of SLNs was studied qualitatively using a co-localization technique and quantitatively using fluorescence intensity profiles. SLNs were seen inside the cells as distinct bright blue dots that underwent dynamic movement and were finally positioned in the proximity of the nucleus. A few SLNs were shown to be present in mitochondria and between actin filaments, but none in the cell nucleus or lysosomes. SLNs are here reported to be present in tunneling nanotubes (TNTs), which could be a new route of SLN transfer between cells. More TNTs were observed in cells treated with SLNs. The presence of TNTs was additionally confirmed by atomic force microscopy analysis, which indicated that treated cells were more rough than control cells. Detailed investigation of the subcellular localization of SLNs and the evidence for their transfer and distribution via TNTs to the cells, which are not in direct contact with the source of SLNs, are important for understanding the mechanism of targeted drug delivery. Understanding the possible intercellular distribution of SLNs via TNTs can significantly influence approaches to treating organelle-specific diseases.

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Ubiquitous trisulfur radical anion: fundamentals and applications in materials science, electrochemistry, analytical chemistry and geochemistry.

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The trisulfur radical anion [S3]˙(-) is well-known from inorganic chemistry textbooks as the blue chromophore in ultramarine blues in which this highly reactive species is trapped in a zeolitic framework. Recent findings have revealed that [S3]˙(-) has a multi-faceted role in a variety of media, including alkali metal-sulfur batteries, aqueous solutions at high temperatures and pressures, and ionic liquids; it has also been used to detect trace amounts of water in organic solvents. This tutorial review illustrates how various physical techniques are used to identify a reactive species in solution and shows how elucidation of electronic structures can be used to explain spectroscopic and structural properties. Examples of the function of [S3]˙(-) in materials science, electrochemistry, analytical chemistry and geochemistry are used to illustrate the widespread influence of this fundamentally important triatomic sulfur species.

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COMPLETE ARTIFICIAL SALIVA ALTERS EXPRESSION OF PROINFLAMMATORY CYTOKINES IN HUMAN DERMAL FIBROBLASTS.

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Complete artificial saliva (CAS) is a saliva substitute often used as a vehicle for test articles, including smokeless tobacco products. In the course of a study employing normal adult human dermal fibroblasts (HDFa) as a model in vitro, we discovered that CAS as a vehicle introduced a significant change in the expression of proinflammatory cytokines. To determine the effects of CAS on gene expression, real-time quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) gene array analysis was used. Results indicate that robust changes in the expression of the proinflammatory cytokine interleukin 8 (IL8) and the vascular cell adhesion molecule 1 (VCAM1) occur within 5 hours of exposure to CAS. To determine whether CAS also alters cytokine release into the culture media, cytometric bead array (CBA) assays for human inflammatory cytokines were performed. Analysis shows that CAS induced the release of IL8 and interleukin 6 (IL6). This study focused on determining which components in CAS were responsible for the proinflammatory response in HDFa. The following components were investigated: α-amylase, lysozyme, acid phosphatase, and urea. Results demonstrated that enzymatically active α-amylase induced gene expression for proinflammatory cytokines IL8, IL6, tumor necrosis factor-α (TNFα), and interleukin 1α (IL1α), and for VCAM1. Therefore, it is important to carefully evaluate the "vehicle effects" of CAS and its components in in vitro toxicology research.

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Simple and Rapid Synthesis of Magnetite/Hydroxyapatite Composites for Hyperthermia Treatments via a Mechanochemical Route.

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This paper presents a simple method for the rapid synthesis of magnetite/hydroxyapatite composite particles. In this method, superparamagnetic magnetite nanoparticles are first synthesized by coprecipitation using ferrous chloride and ferric chloride. Immediately following the synthesis, carbonate-substituted (B-type) hydroxyapatite particles are mechanochemically synthesized by wet milling dicalcium phosphate dihydrate and calcium carbonate in a dispersed suspension of magnetite nanoparticles, during which the magnetite nanoparticles are incorporated into the hydroxyapatite matrix. We observed that the resultant magnetite/hydroxyapatite composites possessed a homogeneous dispersion of magnetite nanoparticles, characterized by an absence of large aggregates. When this material was subjected to an alternating magnetic field, the heat generated increased with increasing magnetite concentration. For a magnetite concentration of 30 mass%, a temperature increase greater than 20 K was achieved in less than 50 s. These results suggest that our composites exhibit good hyperthermia properties and are promising candidates for hyperthermia treatments.

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A Detailed Experimental and Theoretical Study into the Properties of C60 Dumbbell Junctions.

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A combined experimental and theoretical investigation is carried out into the electrical transport across a fullerene dumbbell one-molecule junction. The newly designed molecule comprises two C60 s connected to a fluorene backbone via cyclopropyl groups. It is wired between gold electrodes under ambient conditions by pressing the tip of a scanning tunnelling microscope (STM) onto one of the C60 groups. The STM allows us to identify a single molecule before the junction is formed through imaging, which means unambiguously that only one molecule is wired. Once lifted, the same molecule could be wired many times as it was strongly fixed to the tip, and a high conductance state close to 10(-2) G0 is found. The results also suggest that the relative conductance fluctuations are low as a result of the low mobility of the molecule. Theoretical analysis indicates that the molecule is connected directly to one electrode through the central fluorene, and that to bind it to the gold fully it has to be pushed through a layer of adsorbates naturally present in the experiment.

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Extracellular Electron Transfer across Bacterial Cell Membranes via a Cytocompatible Redox-Active Polymer.

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A redox-active phospholipid polymer with a phospholipid-mimicking structure (2-methacryloyloxyethyl phosphorylcholine; MPC) was synthesized to construct a biocompatible electron mediator between bacteria and an electrode. In this study, a copolymer of MPC and vinylferrocene [VF; poly(MPC-co-VF)] (PMF) is synthesized. When PMF is added to cultures of the bacterial species Escherichia coli (Gram negative) and Lactobacillus plantarum (Gram positive), which have different cell wall structures, a catalytic current mediated by PMF is observed. In addition, growth curves and live/dead assays indicate that PMF does not decrease metabolic activity or cell viability. These results indicate that PMF mediates extracellular electron transfer across bacterial cell membranes without associated cytotoxicity.

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PICK1 Deficiency Impairs Secretory Vesicle Biogenesis and Leads to Growth Retardation and Decreased Glucose Tolerance.

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Secretory vesicles in endocrine cells store hormones such as growth hormone (GH) and insulin before their release into the bloodstream. The molecular mechanisms governing budding of immature secretory vesicles from the trans-Golgi network (TGN) and their subsequent maturation remain unclear. Here, we identify the lipid binding BAR (Bin/amphiphysin/Rvs) domain protein PICK1 (protein interacting with C kinase 1) as a key component early in the biogenesis of secretory vesicles in GH-producing cells. Both PICK1-deficient Drosophila and mice displayed somatic growth retardation. Growth retardation was rescued in flies by reintroducing PICK1 in neurosecretory cells producing somatotropic peptides. PICK1-deficient mice were characterized by decreased body weight and length, increased fat accumulation, impaired GH secretion, and decreased storage of GH in the pituitary. Decreased GH storage was supported by electron microscopy showing prominent reduction in secretory vesicle number. Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance. PICK1 localized in cells to immature secretory vesicles, and the PICK1 BAR domain was shown by live imaging to associate with vesicles budding from the TGN and to possess membrane-sculpting properties in vitro. In mouse pituitary, PICK1 co-localized with the BAR domain protein ICA69, and PICK1 deficiency abolished ICA69 protein expression. In the Drosophila brain, PICK1 and ICA69 co-immunoprecipitated and showed mutually dependent expression. Finally, both in a Drosophila model of type 2 diabetes and in high-fat-diet-induced obese mice, we observed up-regulation of PICK1 mRNA expression. Our findings suggest that PICK1, together with ICA69, is critical during budding of immature secretory vesicles from the TGN and thus for vesicular storage of GH and possibly other hormones. The data link two BAR domain proteins to membrane remodeling processes in the secretory pathway of peptidergic endocrine cells and support an important role of PICK1/ICA69 in maintenance of metabolic homeostasis.

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X-ray structure analysis of a solid solution of milbemycins A3 and A4.

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Site-specific and Far-Red Light-Activatable Prodrug of Combretastain A-4 Using Photo-Unclick Chemistry.

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Although tissue-penetrable light (red and NIR) has a great potential for spatiotemporally controlled release of therapeutic agents, it has been hampered because of the lack of chemistry translating the photonic energy to a cleavage of a chemical bond. Recently, we discovered that an aminoacrylate group could be cleaved to release parent drugs after oxidation by SO, and have called this "photo-unclick chemistry". We demonstrate its application to far-red light-activated prodrugs. A prodrug of combretastatin A-4 (CA4) was prepared, CMP-L-CA4: CMP (dithiaporphyrin, a photosensitizer) and L (aminoacrylate linker). Upon irradiation with 690 nm diode laser, the aminoacrylate linker of the prodrug was cleaved rapidly releasing CA4 (> 80% in 10 min) in CDCl3. In the tissue culture, it showed about a 6-fold increase in its IC50 in MCF-7 after the irradiation, most likely, because of the released CA4. Most significantly, CMP-L-CA4 had better antitumor efficacy in vivo than its non-cleavable (NC) analog, CMP-NCL-CA4. This is the first demonstration of the in vivo efficacy of the novel low-energy light-activatable prodrug using the photo-unclick chemistry.

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"Strange Kinetics" in the Temperature Dependence of Methionine Ligand Rebinding Dynamics in Cytochrome c.

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Temperature dependence of methionine ligand dissociation and rebinding dynamics in cytochrome c in aqueous solution has been studied using classical molecular dynamics simulation. Results are compared with previous study of rebinding dynamics at 300K in water in order to understand how the change of protein environment and the underlying protein energy landscape influence the dynamics. Rebinding dynamics at 77K, 180K, and 300K exhibits changes in both timescale and mechanism as the protein and solvent undergo a dynamic "glass transition." At each temperature, the rebinding dynamics yields a subset of trajectories that undergo fast rebinding as well as a subset of trajectories that undergo slower rebinding. At 300K in water, both a fast (4.0 ps) and slow (14.6 ps) rebinding is observed. While fast rebinding occurs from a "downward" (heme pointing) substate of the methionine, the slow rebinding involves interconversion between an "upward" substate, from which rebinding cannot occur, and the downward substate. At lower temperatures (77K and 180K) the upward dissociated substate was not observed due to the high barrier imposed by the "frozen" protein structure. However, a slow rebinding phase is observed at both 77K and 180K and is associated with a process of trapping in downward but "binding forbidden" substates with subsequent slow dynamical conversion to "binding competent" substates from which rebinding is relatively rapid. Distinctive rebinding dynamics at 77K and 180K suggest that different rebinding time scales are predetermined by the protein and solvent structural arrangement prior to photodissociation, which causes either fast rebinding (about 2ps) or slow (> 50ps) rebinding. Suggestions for future experiments to further probe the role of dynamic heterogeneity in the kinetics of methionine ligand binding in cytochrome c protein are proposed.

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(De)Lithiation Mechanism of Li/SeSx (x = 0-7) Batteries Determined by In-situ Synchrotron X-ray Diffraction and X-ray Absorption Spectroscopy.

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Electrical energy storage for transportation has going beyond the limit of converntional lithium-ion batteries currently. New material or new battery system development is an alternative approach to achieve the goal of new high energy storage system with energy densities five times or more greater. A series of SeSx-carbon ( x = 0-7) composite materials has been prepared and evaluated as the positive electrodes in secondary lithium cells with ether-based electrolyte. In-situ synchrotron high energy X-ray diffraction was utilized to investigate the crystalline phase transition during cell cycling. Complementary, in-situ Se K-edge X-ray absorption near edge structure analysis was used to track the evolution of the Se valence state for both crystalline and non-crystalline phases, including amorphous and electrolyte-dissolved phases in the (de)lithiation process. On the basis of these reuslts, a mechanism for the (de)lithiation process is proposed, where Se is reduced to the polyselenides, Li2Sen (n≥4), Li2Se2, and Li2Se sequentially during the lithiation, and Li2Se is oxidized to Se through Li2Sen (n≥4) during the delithiation. In addition, X-ray photoelectron spectroscopy and electrochemical impedance spectroscopy demonstrated the reversibility of the Li/Se system in ether-based electrolyte and the presence of side products in the carbonate-based electrolytes. For Li/SeS2 and Li/SeS7 cells, Li2Se and Li2S are the discharged products with the presence of Se only as the crystalline phase in the end of charge.

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The Governing Role of Surface Hydration in Ion Specific Adsorption to Silica - an AFM Based Account of the Hofmeister Universality and its Reversal.

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AFM measurements of the force acting between silica surfaces in the presence of varied alkali-chloride salts and pH's elucidate the origin of the Hofmeister adsorption series and its reversal. At low pH, electrostatics is shown to be insignificant. The preferential adsorption of Cs+ to the silica surface is traced to the weak hydration of neutral silanols and the resulting hydrophobic expulsion of weakly hydrated ions from bulk solution to the interface. The same interactions keep the strongly hydrated Li+ and Na+ in solution. As pH is increased, a tightly bound hydration layer forms on deprotonating silanols. Cs+ is correspondingly expelled from the surface and adsorption of small ions is encouraged. The deduced role of surface hydration is corroborated by hydration repulsion observed at high pH, surface over-charging at low pH, and data in other oxides.

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Fungal ABC Transporter-Associated Activity of Isoflavonoids from the Root Extract of Dalea formosa.

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New potential treatments for disseminated fungal infections are needed, especially for infections caused by the commonly drug-resistant pathogens Candida albicans and C. glabrata. These pathogens cause systemic candidiasis, a significant cause of mortality in immune-compromised patients. ABC transporters of the pleiotropic drug resistance subfamily, such as Cdr1p of C. albicans, play an important role in antifungal resistance and are potential bioassay targets for antifungal therapies against drug-resistant pathogens. We observed strong antifungal growth inhibitory activity in the methanol extract of Dalea formosa roots. This extract afforded six new isoflavonoids, sedonans A-F (1-6), a new but-2-enolide, 4'-O-methylpuerol A (7), and the new pterocarpan ent-sandwicensin (8). The structures and absolute configurations of these compounds were assigned using spectroscopic and chiroptical techniques. The direct antifungal activity of 1 against C. glabrata (MIC = 20 μM) was higher than that of fluconazole. Sedonans A-F and ent-sandwicensin were also active against Saccharomyces cerevisiae strains that express differing ABC transporter-associated resistance mechanisms but differed in their susceptibility to Cdr1p-mediated detoxification. A sedonan A (1)/ent-sandwicensin (8) combination exhibited synergistic growth inhibition. The results demonstrate that multiple crude extract compounds are differentially affected by efflux-mediated resistance and are collectively responsible for the observed bioactivity.

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A Chemometric Approach to Distribution of Selenium in Medicinal Plants Cultivated in Poland.

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Abstract The aim of this study was to evaluate the level of selenium (Se) in common raw plant materials (herbs, leaves, flowers, fruits, and roots) obtained from medicinal plants cultivated in Poland. Furthermore, the relationship between the morphological part of a plant and its species was examined, and the concentration of Se in it was measured. Spectrofluorimetric determination of Se in 148 samples of 44 plant species revealed that the majority of the plants contained Se at a level from several to several tens of μg/kg dry weight (d.w.). A relatively high Se concentration, in the order of 50 μg/kg d.w., was found in Majoranae herba, Crataegi fructus, and Lini semen. An especially high Se level, >100 μg/kg d.w., was found in only three plants-Equiseti herba, Farfarae folium, and Cichorii radix. Application of a nonparametric Kruskal-Wallis analysis of variance test indicates that the morphological variable influences the level of Se in the studied groups of raw plant materials. The mean concentration of Se in fruits differs significantly from that found in flowers and roots. However, there was no statistically significant difference between the Se content in herbs and leaves and its levels in fruits, flowers, and roots. Cluster analysis and principal component analysis calculations show that it is possible to relate the Se concentration in plant material to the plant species and botanical family of the medicinal plant in only a few cases. Analysis of average Se levels in the plant species showed that the plants belonging to the Apiaceae and Labiatae are more Se-rich than those belonging to Rosaceae botanical families.

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Non-destructive monitoring of creaming of oil-in-water emulsion-based formulations using magnetic resonance imaging.

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Abstract A non-destructive method for monitoring creaming of emulsion-based formulations is in great demand because it allows us to understand fully their instability mechanisms. This study was aimed at demonstrating the usefulness of magnetic resonance (MR) techniques, including MR imaging (MRI) and MR spectroscopy (MRS), for evaluating the physicochemical stability of emulsion-based formulations. Emulsions that are applicable as the base of practical skin creams were used as test samples. Substantial creaming was developed by centrifugation, which was then monitored by MRI. The creaming oil droplet layer and aqueous phase were clearly distinguished by quantitative MRI by measuring T1 and the apparent diffusion coefficient. Components in a selected volume in the emulsions could be analyzed using MRS. Then, model emulsions having different hydrophilic-lipophilic balance (HLB) values were tested, and the optimal HLB value for a stable dispersion was determined. In addition, the MRI examination enables the detection of creaming occurring in a polyethylene tube, which is commonly used for commercial products, without losing any image quality. These findings strongly indicate that MR techniques are powerful tools to evaluate the physicochemical stability of emulsion-based formulations. This study will make a great contribution to the development and quality control of emulsion-based formulations.

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Spectroscopic Study of the Light-Harvesting CP29 Antenna Complex of Photosystem II - Part I.

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Recent structural data revealed that the CP29 protein of higher plant Photosystem II (PSII) contains 13 chlorophylls (Chls) per complex [Pan et al., Nat. Struct. Mol. Biol. 2011, 18, 309], i.e., five Chls more than in the predicted CP29 homology-based structure model [Bassi et al., Proc. Natl. Acad. Sci. USA 1999, 96, 10056]. This lack of consensus presents a constraint on the interpretation of CP29 optical spectra and their underlying electronic structure. To address this problem, we present new low-temperature (5 K) absorption, fluorescence, and hole-burned (HB) spectra for CP29 proteins from spinach, which are compared with the previously reported data. We focus on excitation energy transfer (EET) and the nature of the lowest-energy state(s). We argue that CP29 proteins previously studied by HB spectroscopy lacked at least one Chl a molecule (i.e., a615 or a611), which along with Chl a612 contribute to the lowest energy state in more intact CP29, and one Chl b (most likely b607). This is why the low-energy state and fluorescence maxima reported by Pieper et al. [Photochem. Photobiol. 2000, 71, 574] were blueshifted by ~ 1 nm, the low-energy state appeared to be highly localized on a single Chl a molecule, and the position of the low-energy state was independent of burning fluence. In contrast, the position of the nonresonant HB spectrum shifts blue with increasing fluence in intact CP29, as this state is strongly contributed to by several pigments (i.e., a611, a612, a615 and a610). Zero-phonon hole widths obtained for the Chl b band at 638.5 nm (5 K) revealed two independent Chl b → Chl a EET times, i.e., 4 ± 0.5 ps and 0.4 ± 0.1 ps. The latter value is a factor of two faster than previously observed by HB spectroscopy and very similar to the one observed by Gradinaru et al. [J. Phys. Chem. B 2000, 104, 9330] in pump-probe experiments. EET time from 650 nm Chl b → Chl a and downward EET from Chl(s) a state(s) at 665 nm occurs in 4.9 ± 0.7 ps. These findings provide important constraints for excitonic calculations that are discussed in the accompanying paper (Part II).

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Group B Streptococcus pilus sortase regulation: a single mutation in the lid region induces pilin protein polymerization in vitro.

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Anti-allergic actions of rottlerin from Mallotus philippinensis in experimental mast cell-mediated anaphylactic models.

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Allergy is an acquired hypersensitivity reaction of the immune system mediated by cross-linking of the allergen-specific IgE-bound high-affinity IgE receptors, leading to immediate mast cell degranulation. Rottlerin is an active molecule isolated from Mallotus philippinensis, a medicinal plant used in Ayurvedic Medicine System for anti-allergic and anti-helminthic treatments. The present study investigated potential anti-allergic effects of rottlerin in animal models of IgE-dependent anaphylaxis and the anti-allergic mechanisms of action of rottlerin in mast cells. Anti-allergic actions of rottlerin were evaluated in passive cutaneous anaphylaxis and passive systemic anaphylaxis mouse models, and in anaphylactic contraction of bronchial rings isolated from sensitized guinea pigs. Direct mast cell-stabilizing effect of rottlerin was examined in RBL-2H3 mast cell line. Anti-allergic signaling mechanisms of action of rottlerin in mast cells were also examined. Rottlerin prevented IgE-mediated cutaneous vascular extravasation, hypothermia, elevation in plasma histamine level and tracheal tissue mast cell degranulation in mice in a dose-dependent manner. In addition, rottlerin suppressed ovalbumin-induced guinea pig bronchial smooth muscle contraction. Furthermore, rottlerin concentration-dependently blocked IgE-mediated immediate release of β-hexosaminidase from RBL-2H3 mast cells. Rottlerin was found to inhibit IgE-induced PLCγ1 and Akt phosphorylation, production of IP3 and rise in cytosolic Ca(2+) level in mast cells. We report here for the first time that rottlerin possesses anti-allergic activity by blocking IgE-induced mast cell degranulation, providing a foundation for developing rottlerin for the treatment of allergic asthma and other mast cell-mediated allergic disorders.

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Clock Gene Expression in the Liver of Streptozotocin-induced and Spontaneous Type 1 Diabetic Rats.

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Several investigations have shown a relation between diabetes and alterations of the liver circadian clock. We investigated the diurnal expression of clock genes and clock-controlled genes (CCGs) in 3-hour intervals for a 24-h period in the livers of male streptozotocin (STZ)-treated rats, male spontaneous type 1 diabetic LEW.1AR1-iddm (Iddm) rats, and Iddm rats treated for 10 days with insulin. Hepatic mRNA was extracted, and the relative expression of clock genes (Per1, Per2, Bmal1, Clock, Cry1), as well as CCGs (Dbp, E4bp4, RevErbα, Rorα, Pparγ), was analyzed by reverse transcription followed by real-time polymerase chain reaction. Diabetic STZ and Iddm rats, as well as insulin-substituted Iddm rats, exhibited a significant diurnal expression pattern of clock genes as determined by Cosinor analysis; however, the MESOR (midline estimating statistic of rhythm) of Bmal1, Per2, and Clock transcript expression was altered in Iddm and insulin-substituted Iddm rats. The hepatic expression of the CCGs Dbp and RevErbα revealed a diurnal rhythm in all investigated groups. Insulin administration to Iddm rats normalized the enhanced MESOR in the expression of Dbp, RevErbα, and E4bp4 to the levels of normoglycemic controls. Cosinor analysis indicated no diurnal rhythm of Pparγ expression in the livers of diabetic STZ or Iddm rats or in those of insulin-substituted Iddm rats. Also, insulin substitution could not reverse the decreased MESOR of Pparγ expression in Iddm rats. In consequence of the diabetic disease, changes in the expression of clock genes and CCGs suggest alterations in the hepatic peripheral clock mechanism.

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Studies on the Himbert Intramolecular Arene/Allene Diels-Alder Cycloaddition. Mechanistic Studies and Expansion of Scope to All-Carbon Tethers.

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The unusual intramolecular arene/allene cycloaddition described 30 years ago by Himbert permits rapid access to strained polycyclic compounds that offer great potential for the synthesis of complex scaffolds. To more fully understand the mechanism of this cycloaddition reaction, and to guide efforts to extend its scope to new substrates, quantum mechanical computational methods were employed in concert with laboratory experiments. These studies indicated that the cycloadditions likely proceed via concerted processes; a stepwise biradical mechanism was shown to be higher in energy in the cases studied. The original Himbert cycloaddition chemistry is also extended from heterocyclic to carbocyclic systems, with computational guidance used to predict thermodynamically favorable cases. Complex polycyclic scaffolds result from the combination of the cycloaddition and subsequent ring-rearrangement metathesis reactions.

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Reversible Sliding in Networks of Nanowires.

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This work demonstrates that metal nanowires in a percolating network can reversibly slide across one another. Reversible sliding allows networks of metal nanowires to maintain electrical contact while being stretched to strains greater than the fracture strain for individual nanowires. This phenomenon was demonstrated by using networks of nanowires as compliant electrodes for a dielectric elastomer actuator. Reversible nanowire sliding enabled actuation to a maximum area strain of 200%, and repetitive cycling of the actuator to an area strain of 25% over 150 times. During actuation, the transmittance of the network increased 4.5 times, from 13% to 58%. Compared to carbon-based compliant electrodes, networks of metal nanowires can actuate across a broader range of optical transmittance. The widely tunable transmittance of nanowire-based actuators allows for their use as a light valve.

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Piezotronic Effect in Solution-Grown p-Type ZnO Nanowires and Films.

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Investigating the piezotronic effect in p-type piezoelectric semiconductor is critical for developing a complete piezotronic theory and designing/fabricating novel piezotronic applications with more complex functionality. Using a low temperature solution method, we were able to produce ultralong (up to 60 μm in length) Sb doped p-type ZnO nanowires on both rigid and flexible substrates. For the p-type nanowire field effect transistor, the on/off ratio, threshold voltage, mobility, and carrier concentration of 0.2% Sb-doped sample are found to be 10(5), 2.1 V, 0.82 cm(2)·V(-1)·s(-1), and 2.6 × 10(17) cm(-3), respectively, and the corresponding values for 1% Sb doped samples are 10(4), 2.0 V, 1.24 cm(2)·V(-1)·s(-1), and 3.8 × 10(17) cm(-3). We further investigated the universality of piezotronic effect in the as-synthesized Sb-doped p-type ZnO NWs and reported for the first time strain-gated piezotronic transistors as well as piezopotential-driven mechanical energy harvesting based on solution-grown p-type ZnO NWs. The results presented here broaden the scope of piezotronics and extend the framework for its potential applications in electronics, optoelectronics, smart MEMS/NEMS, and human-machine interfacing.

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Topographically-patterned porous membranes in a microfluidic device as an in vitro model of renal reabsorptive barriers.

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Models of reabsorptive barriers require both a means to provide realistic physiologic cues to and quantify transport across a layer of cells forming the barrier. Here we have topographically-patterned porous membranes with several user-defined pattern types. To demonstrate the utility of the patterned membranes, we selected one type of pattern and applied it to a membrane to serve as a cell culture support in a microfluidic model of a renal reabsorptive barrier. The topographic cues in the model resemble physiological cues found in vivo while the porous structure allows quantification of transport across the cell layer. Sub-micron surface topography generated via hot-embossing onto a track-etched polycarbonate membrane, fully replicated topographical features and preserved porous architecture. Pore size and shape were analyzed with SEM and image analysis to determine the effect of hot embossing on pore morphology. The membrane was assembled into a bilayer microfluidic device and a human kidney proximal tubule epithelial cell line (HK-2) and primary renal proximal tubule epithelial cells (RPTEC) were cultured to confluency on the membrane. Immunofluorescent staining of both cell types revealed protein expression indicative of the formation of a reabsorptive barrier responsive to mechanical stimulation: ZO-1 (tight junction), paxillin (focal adhesions) and acetylated α-tubulin (primary cilia). HK-2 and RPTEC aligned in the direction of ridge/groove topography of the membrane in the device, evidence that the device has mechanical control over cell response. This topographically-patterned porous membrane provides an in vitro platform on which to model reabsorptive barriers with meaningful applications for understanding biological transport phenomenon, underlying disease mechanisms, and drug toxicity.

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Rapeseed oil-rich diet alters hepatic mitochondrial membrane lipid composition and disrupts bioenergetics.

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Diet is directly related with physiological alterations occurring at a cell and subcellular level. However, the role of diet manipulation on mitochondrial physiology is still largely unexplored. Aiming at correlating diet with alterations of mitochondrial membrane composition and bioenergetics, Wistar-Han male rats were fed for 11, 22 and 33 days with a rapeseed oil-based diet and mitochondrial bioenergetics, and membrane composition were compared at each time point with a standard diet group. Considerable differences were noticed in mitochondrial membrane lipid composition, namely in terms of fatty acyl chains and relative proportions of phospholipid classes, the modified diet inducing a decrease in the saturated to unsaturated molar ratio and an increase in the phosphatidylcholine to phosphatidylethanolamine molar ratio. Mass spectrometry lipid analysis showed significant differences in the major species of cardiolipin, with an apparent increased incorporation of oleic acid as a result of exposure to the modified diet. Rats fed the modified diet during 22 days showed decreased hepatic mitochondrial state 3 respiration and were more susceptible to Ca(2+)-induced transition pore opening. Rapeseed oil-enriched diet also appeared to promote a decrease in hydroperoxide production by the respiratory chain, although a simultaneous decrease in vitamin E content was detected. In conclusion, our data indicate that the rapeseed oil diet causes negative alterations on hepatic mitochondrial bioenergetics, which may result from membrane remodeling. Such alterations may have an impact not only on energy supply to the cell, but also on drug-induced hepatic mitochondrial liabilities.

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Individual multi-locus heterozygosity is associated with lower morning plasma cortisol concentration.

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OBJECTIVE. STRESS IS IMPLICATED AS A RISK FACTOR FOR NUMEROUS ILLNESSES IN HUMANS, PUTATIVELY IN PART MEDIATED BY BIOLOGICAL RESPONSES TO STRESS, SUCH AS ELEVATED CORTISOL. THE THEORY OF GENETIC HOMEOSTASIS SUGGESTS THAT INDIVIDUAL HETEROZYGOSITY FACILITATES COMPENSATION FOR ENVIRONMENTAL STRESSES. WE HYPOTHESIZED THAT HETEROZYGOSITY AMELIORATES THE BIOLOGICAL RESPONSE TO A GIVEN LEVEL OF PERCEIVED STRESS, REFLECTED IN LOWER PLASMA CORTISOL CONCENTRATIONS.DESIGN. WE EXAMINE THE ROLE OF HETEROZYGOSITY ON THE ASSOCIATION BETWEEN PERCEIVED PSYCHOLOGICAL STRESS AND MORNING CORTISOL CONCENTRATIONS IN 854 INDIVIDUALS FROM THE ISOLATED ISLAND OF VIS, CROATIA.METHODS. CORTISOL WAS MEASURED IN MORNING PLASMA SAMPLES. 1184 AUTOSOMAL MICROSATELLITE MARKERS WERE GENOTYPED AND INDIVIDUAL MULTI-LOCUS HETEROZYGOSITY WAS CALCULATED AS THE PROPORTION OF HETEROZYGOUS MARKERS. GENERAL HEALTH QUESTIONNAIRE (GHQ-30) WAS USED TO ASSESS THE DEGREE OF PSYCHOLOGICAL DISTRESS.RESULTS. MEAN MULTI-LOCUS HETEROZYGOSITY WAS 34.850.45% (RANGE: 31.97-36.22%). Psychological distress (GHQ Likert score >31) was more prevalent in women (37% versus 18% in men, p<0.0001), in less educated people (β=-0.35 per year in school, p<0.001) and in lower socio-economic classes (β=-3.59, p<0.0001). Cortisol was positively associated with psychological distress (β=2.20, p=0.01). In a regression model adjusting for age, BMI, education and GHQ-30 score, multi-locus heterozygosity was independently and inversely associated with morning plasma cortisol (p=0.005).Conclusion. More heterozygous individuals, as measured by microsatellite markers, had lower morning plasma cortisol concentrations for a given level of perceived psychological stress. This may be important, as higher cortisol concentrations may increase allostatic load and be associated with higher risk of stress-related illness.

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