Sinteza i anthelmintičko djelovanje novih 2-supstituiranih-4,5-difenil imidazola

A series of 2-substituted-4,5-diphenyl imidazoles 1a-j were synthesized by refluxing benzil with different substituted aldehydes in the presence of ammonium acetate and glacial acetic acid. Structures of the synthesized compounds were confirmed on the basis of IR, 1H NMR and mass spectral data. Compounds 1a-j were screened for anthelmintic activity. Test results revealed that compounds showed paralysis time of 0.24 to 1.54 s and death time of 0.39 to 4.40 s while the standard drugs albendazole and piperazine citrate showed paralysis time of 0.54 and 0.58 s and death time of 2.16 and 2.47 s, respectively, at the same concentration of 1 % (m/V). Five compounds, 2-[2-hydroxyphenyl]-4,5-diphenyl imidazole (1b), 2-[3-methoxyphenyl]-4,5-diphenyl imidazole (1c), 2-[2-phenylethenyl]-4,5-diphenyl imidazole (1e), 2-[4-fluorophenyl]-4,5-diphenyl imidazole (1g) and 2-[3-nitrophenyl]-4,5-diphenyl imidazole (1h) showed significant anthelmintic activity compared to the standard drugs.Refluksiranjem benzila s različitim supstituiranim aldehidima u prisutnosti amonijeva acetata i ledene octene kiseline sintetizirana je serija 2-supstituiranih-4,5-difenil imidazola (1a-j). Strukture sintetiziranih spojeva potvrđene su IR, 1H NMR i masenom spektroskopijom. U testovima na anthelmintičko djelovanje određeno je vrijeme paralize 0,24 do 1,54 min i vrijeme smrti 0,39 do 4,40 min, dok standarni lijekovi albendazol i piperazin citrat imaju vrijeme paralize 0,54 i 0,58 min, a vrijeme smrti 2,16, odnosno 2,47 min pri istim koncentracijama (1 % m/V). Pet spojeva, 2-[2-hidroksifenil]-4,5-difenil imidazol (1b), 2-[3-metoksifenil]-4,5-difenil imidazol (1c), 2-[2-feniletenil]-4,5-difenil imidazol (1e), 2-[4-fluorofenil]-4,5-difenil imidazol (1g) i 2-[3-nitrofenil]-4,5-difenil imidazol (1h) pokazuju značajno anthelmintičko djelovanje u odnosnu na standardne lijekove

Set Theory and its Place in the Foundations of Mathematics:a new look at an old question

This paper reviews the claims of several main-stream candidates to be the foundations of mathematics, including set theory. The review concludes that at this level of mathematical knowledge it would be very unreasonable to settle with any one of these foundations and that the only reasonable choice is a pluralist one

Tetraspanin (TSP-17) Protects Dopaminergic Neurons against 6-OHDA-Induced Neurodegeneration in <i>C. elegans</i>

Parkinson's disease (PD), the second most prevalent neurodegenerative disease after Alzheimer's disease, is linked to the gradual loss of dopaminergic neurons in the substantia nigra. Disease loci causing hereditary forms of PD are known, but most cases are attributable to a combination of genetic and environmental risk factors. Increased incidence of PD is associated with rural living and pesticide exposure, and dopaminergic neurodegeneration can be triggered by neurotoxins such as 6-hydroxydopamine (6-OHDA). In C. elegans, this drug is taken up by the presynaptic dopamine reuptake transporter (DAT-1) and causes selective death of the eight dopaminergic neurons of the adult hermaphrodite. Using a forward genetic approach to find genes that protect against 6-OHDA-mediated neurodegeneration, we identified tsp-17, which encodes a member of the tetraspanin family of membrane proteins. We show that TSP-17 is expressed in dopaminergic neurons and provide genetic, pharmacological and biochemical evidence that it inhibits DAT-1, thus leading to increased 6-OHDA uptake in tsp-17 loss-of-function mutants. TSP-17 also protects against toxicity conferred by excessive intracellular dopamine. We provide genetic and biochemical evidence that TSP-17 acts partly via the DOP-2 dopamine receptor to negatively regulate DAT-1. tsp-17 mutants also have subtle behavioral phenotypes, some of which are conferred by aberrant dopamine signaling. Incubating mutant worms in liquid medium leads to swimming-induced paralysis. In the L1 larval stage, this phenotype is linked to lethality and cannot be rescued by a dop-3 null mutant. In contrast, mild paralysis occurring in the L4 larval stage is suppressed by dop-3, suggesting defects in dopaminergic signaling. In summary, we show that TSP-17 protects against neurodegeneration and has a role in modulating behaviors linked to dopamine signaling

Mapping localized surface plasmons within silver nanocubes using cathodoluminescence hyperspectral imaging

Localized surface plasmons within silver nanocubes less than 50 nm in size are investigated using high resolution cathodoluminescence hyperspectral imaging. Multivariate statistical analysis of the multidimensional luminescence dataset allows both the identification of distinct spectral features in the emission and the mapping of their spatial distribution. These results show a 490 nm peak emitted from the cube faces, with shorter wavelength luminescence coming from the vertices and edges; this provides direct experimental confirmation of theoretical predictions

Shared midgut binding sites for Cry1A.105, Cry1Aa, Cry1Ab, Cry1Ac and Cry1Fa proteins from Bacillus thuringiensis in two important corn pests, Ostrinia nubilalis and Spodoptera frugiperda

First generation of insect-protected transgenic corn (Bt-corn) was based on the expression of Cry1Ab or Cry1Fa proteins. Currently, the trend is the combination of two or more genes expressing proteins that bind to different targets. In addition to broadening the spectrum of action, this strategy helps to delay the evolution of resistance in exposed insect populations. One of such examples is the combination of Cry1A.105 with Cry1Fa and Cry2Ab to control O. nubilalis and S. frugiperda. Cry1A.105 is a chimeric protein with domains I and II and the C-terminal half of the protein from Cry1Ac, and domain III almost identical to Cry1Fa. The aim of the present study was to determine whether the chimeric Cry1A.105 has shared binding sites either with Cry1A proteins, with Cry1Fa, or with both, in O. nubilalis and in S. frugiperda. Brush-border membrane vesicles (BBMV) from last instar larval midguts were used in competition binding assays with 125I-labeled Cry1A.105, Cry1Ab, and Cry1Fa, and unlabeled Cry1A.105, Cry1Aa, Cry1Ab, Cry1Ac, Cry1Fa, Cry2Ab and Cry2Ae. The results showed that Cry1A.105, Cry1Ab, Cry1Ac and Cry1Fa competed with high affinity for the same binding sites in both insect species. However, Cry2Ab and Cry2Ae did not compete for the binding sites of Cry1 proteins. Therefore, according to our results, the development of cross-resistance among Cry1Ab/Ac, Cry1A.105, and Cry1Fa proteins is possible in these two insect species if the alteration of shared binding sites occurs. Conversely, cross-resistance between these proteins and Cry2A proteins is very unlikely in such case

Dose-Specific Adverse Drug Reaction Identification in Electronic Patient Records: Temporal Data Mining in an Inpatient Psychiatric Population

BACKGROUND: Data collected for medical, filing and administrative purposes in electronic patient records (EPRs) represent a rich source of individualised clinical data, which has great potential for improved detection of patients experiencing adverse drug reactions (ADRs), across all approved drugs and across all indication areas. OBJECTIVES: The aim of this study was to take advantage of techniques for temporal data mining of EPRs in order to detect ADRs in a patient- and dose-specific manner. METHODS: We used a psychiatric hospital’s EPR system to investigate undesired drug effects. Within one workflow the method identified patient-specific adverse events (AEs) and links these to specific drugs and dosages in a temporal manner, based on integration of text mining results and structured data. The structured data contained precise information on drug identity, dosage and strength. RESULTS: When applying the method to the 3,394 patients in the cohort, we identified AEs linked with a drug in 2,402 patients (70.8 %). Of the 43,528 patient-specific drug substances prescribed, 14,736 (33.9 %) were linked with AEs. From these links we identified multiple ADRs (p < 0.05) and found them to occur at similar frequencies, as stated by the manufacturer and in the literature. We showed that drugs displaying similar ADR profiles share targets, and we compared submitted spontaneous AE reports with our findings. For nine of the ten most prescribed antipsychotics in the patient population, larger doses were prescribed to sedated patients than non-sedated patients; five patients exhibited a significant difference (p < 0.05). Finally, we present two cases (p < 0.05) identified by the workflow. The method identified the potentially fatal AE QT prolongation caused by methadone, and a non-described likely ADR between levomepromazine and nightmares found among the hundreds of identified novel links between drugs and AEs (p < 0.05). CONCLUSIONS: The developed method can be used to extract dose-dependent ADR information from already collected EPR data. Large-scale AE extraction from EPRs may complement or even replace current drug safety monitoring methods in the future, reducing or eliminating manual reporting and enabling much faster ADR detection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40264-014-0145-z) contains supplementary material, which is available to authorised users

Maternal hemodynamics in screen‐positive and screen‐negative women of the ASPRE trial

Objective To compare maternal hemodynamics and perinatal outcome, in pregnancies that do not develop pre‐eclampsia (PE) or deliver a small‐for‐gestational‐age (SGA) neonate, between those identified at 11–13 weeks' gestation as being screen positive or negative for preterm PE, by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, serum placental growth factor and pregnancy associated plasma protein‐A. Methods This was a prospective longitudinal cohort study of maternal cardiovascular function, assessed using a bioreactance method, in women undergoing first‐trimester screening for PE. Maternal hemodynamics and perinatal outcome were compared between screen‐positive and screen‐negative women who did not have a medical comorbidity, did not develop PE or pregnancy‐induced hypertension and delivered at term a live neonate with birth weight between the 5th and 95th percentiles. A multilevel linear mixed‐effects model was used to compare the repeated measures of cardiac variables, controlling for maternal characteristics. Results The screen‐negative group (n = 926) had normal cardiac function changes across gestation, whereas the screen‐positive group (n = 170) demonstrated static or reduced cardiac output and stroke volume and higher mean arterial pressure and peripheral vascular resistance with advancing gestation. In the screen‐positive group, compared with screen‐negative women, birth‐weight Z‐score was shifted toward lower values, with prevalence of delivery of a neonate below the 35th, 30th or 25th percentile being about 70% higher, and the rate of operative delivery for fetal distress in labor also being higher. Conclusion Women who were screen positive for impaired placentation, even though they did not develop PE or deliver a SGA neonate, had pathological cardiac adaptation in pregnancy and increased risk of adverse perinatal outcome

Effect of high temperature and water stress on pollen germination and spikelet fertility in rice

In future climates, rice could more frequently be subjected to simultaneous high temperature and water stress during sensitive developmental stages such as flowering. In this study, five rice genotypes were exposed to high temperature, water stress and combined high temperature and water stress during flowering to quantify their response through spikelet fertility. Microscopic analyses revealed significant differences in anther dehiscence between treatments and genotypes, with a moderately high association with the number of germinated pollen grains on the stigma. There was a strong relationship between spikelet fertility and the number of germinated pollen on stigmas. Although, all three stress treatments resulted in spikelet sterility, high-temperature stress caused the highest sterility in all five genotypes. A cumulative linear decline in spikelet fertility with increasing duration of independent high-temperature stress and in combination with water stress was quantified. Better anther dehiscence, higher in vivo pollen germination, and higher spikelet fertility were observed in both the N22 accessions compared with IR64, Apo and Moroberekan under high temperature, water stress and combined stress, indicating its ability to tolerate multiple abiotic stresses

Spikelet Proteomic Response to Combined Water Deficit and Heat Stress in Rice (Oryza sativa cv. N22)

In future climates, rice crops will be frequently exposed to water deficit and heat stress at the most sensitive flowering stage, causing spikelet sterility and yield losses. Water deficit alone and in combination with heat stress significantly reduced peduncle elongation, trapping 32% and 55% of spikelets within the leaf sheath, respectively. Trapped spikelets had lower spikelet fertility (66% in control) than those exserted normally (>93%). Average weighted fertility of exserted spikelets was lowest with heat stress (35%) but higher with combined stress (44%), suggesting acquired thermo-tolerance when preceded by water-deficit stress. Proteins favoring pollen germination, i.e., pollen allergens and beta expansin, were highly upregulated with water deficit but were at normal levels under combined stress. The chaperonic heat shock transcripts and proteins were significantly up-regulated under combined stress compared with either heat or water deficit. The importance of spikelet proteins responsive to water deficit and heat stress to critical physiological processes during flowering is discussed