Synthesis and anthelmintic activity of some hybrid Benzimidazolyl-chalcone derivatives

Purpose: To synthesize hybrid benzimidazolyl-chalcone derivatives, evaluate their anthelmintic activity, and establish some structural elements which could lead to induction and enhancement of this activity.Methods: A series of 1-(1H-benzimidazol-2-yl)-3-aryl-2-propen-1-one compounds (6a-z) was synthesized by condensation reaction of 2-acetylbenzimidazole with aryl and heteroaryl aldehyde derivatives. The physicochemical characterization of these benzimidazolyl-chalcones was carried out by nuclear magnetic resonance spectroscopy (1H and 13C NMR) and mass spectroscopy (MS). All compounds were screened in vitro for their nematicidal activity against Haemonchus contortus in larval development assay. The anthelmintic activities obtained were compared with those of anthelmintic reference drugs (fenbendazole and ivermectin); 1,3-diphenyl-2-propen-1-one also used as reference for chalcone.Results: Compounds 6a, 6g, 6w and 6y showed good nematicidal activity (LC100) at 0.002 and 0.0092 μg/ml. The activity of these four benzimidazolyl-chalcones is nearly equal to that of fenbendazole. It is also interesting to know that these compounds have anti-haemonchus activity which is equal or more efficient than ivermectin. Four other compounds (6d, 6h, 6o and 6t) possess interesting anthelmintic activities at 0.68 and 0.16 μg/ml.Conclusion: Preliminary structure-activity relationship studies revealed that arylpropenone group in position 2 of the benzimidazole ring can be considered as new pharmacophore for nematicidal activity.Keywords: Benzimidazole, Chalcone, Anthelmintic activity, Haemonchus contortu

An Assessment Of Traditional Uighur Medicine In Current Xinjiang Region (China)

Background: The main objectives of this study were to assess the current research and development of traditional Uighur medicine in Xinjiang (China), and to evaluate the promising pharmacological products of traditional Uighur medicine for further studies.Materials and Methods: Traditional Uighur medicine data of medicine registry, patent, and academic publications was collected and analyzed.Results: Data showed that, among the registered and studied traditional Uighur medicine, the main therapeutic areas of traditional Uighur medicine focused on skin disease, urogenital disease, rheumatism and digestive system disease. The representative traditional Uighur patent medicine included the following: BaixuanXiatare Tablets, Kaliziran Tincture and Vernoniaanthelmintica Injection (Psoriasis and vitiligo); Xi-payimazibiziLiquid (prostatitis); KursiKaknaq (urinary tract infection); Tongzhisurunjiang Capsules (anti-rheumatism medicine); HuganBuzure Granules (digestive system disease). Moreover, ten Uighur herbs were widely used, including: ResinaScammoniae, Folium FumicisDentati, HerbaDracocephali, Semen AmygdaliDulcis, HerbaChamomillae, FructusPimpinellaeanisi, Cortex Foeniculi, FructusVernoniae, FructusApii, and Radix AnacycliPyrethri.Conclusion: This study concluded by indicating that traditional Uighur medicine with excellent curative effect should be screened in details for their phytochemical properties and pharmacological activity to discover new bioactive constituents.Key words: Traditional Uighur medicine, Traditional Uighur patent medicine, Uighur her

Synthesis and DFT investigation of new bismuth-containing MAX phases

The M(n + 1)AX(n) phases (M = early transition metal; A = group A element and X = C and N) are materials exhibiting many important metallic and ceramic properties. In the present study powder processing experiments and density functional theory calculations are employed in parallel to examine formation of Zr(2)(Al(1−x)Bi(x))C (0 ≤ x ≤ 1). Here we show that Zr(2)(Al(1−x)Bi(x))C, and particularly with x ≈ 0.58, can be formed from powders even though the end members Zr(2)BiC and Zr(2)AlC seemingly cannot. This represents a significant extension of the MAX phase family, as this is the first report of a bismuth-based MAX phase

Determination of the Fermion Pair Size in a Resonantly Interacting Superfluid

Fermionic superfluidity requires the formation of pairs. The actual size of these fermion pairs varies by orders of magnitude from the femtometer scale in neutron stars and nuclei to the micrometer range in conventional superconductors. Many properties of the superfluid depend on the pair size relative to the interparticle spacing. This is expressed in BCS-BEC crossover theories, describing the crossover from a Bardeen-Cooper-Schrieffer (BCS) type superfluid of loosely bound and large Cooper pairs to Bose-Einstein condensation (BEC) of tightly bound molecules. Such a crossover superfluid has been realized in ultracold atomic gases where high temperature superfluidity has been observed. The microscopic properties of the fermion pairs can be probed with radio-frequency (rf) spectroscopy. Previous work was difficult to interpret due to strong and not well understood final state interactions. Here we realize a new superfluid spin mixture where such interactions have negligible influence and present fermion-pair dissociation spectra that reveal the underlying pairing correlations. This allows us to determine the spectroscopic pair size in the resonantly interacting gas to be 2.6(2)/kF (kF is the Fermi wave number). The pairs are therefore smaller than the interparticle spacing and the smallest pairs observed in fermionic superfluids. This finding highlights the importance of small fermion pairs for superfluidity at high critical temperatures. We have also identified transitions from fermion pairs into bound molecular states and into many-body bound states in the case of strong final state interactions.Comment: 8 pages, 7 figures; Figures updated; New Figures added; Updated discussion of fit function

Synergistic melanoma cell death mediated by inhibition of both MCL1 and BCL2 in high-risk tumors driven by NF1/PTEN loss

Melanomas driven by loss of the NF1 tumor suppressor have a high risk of treatment failure and effective therapies have not been developed. Here we show that loss-of-function mutations of nf1 and pten result in aggressive melanomas in zebrafish, representing the first animal model of NF1-mutant melanomas harboring PTEN loss. MEK or PI3K inhibitors show little activity when given alone due to cross-talk between the pathways, and high toxicity when given together. The mTOR inhibitors, sirolimus, everolimus, and temsirolimus, were the most active single agents tested, potently induced tumor-suppressive autophagy, but not apoptosis. Because addition of the BCL2 inhibitor venetoclax resulted in compensatory upregulation of MCL1, we established a three-drug combination composed of sirolimus, venetoclax, and the MCL1 inhibitor S63845. This well-tolerated drug combination potently and synergistically induces apoptosis in both zebrafish and human NF1/PTEN-deficient melanoma cells, providing preclinical evidence justifying an early-stage clinical trial in patients with NF1/PTEN-deficient melanoma

Editorial: Improving reliability of brain stimulation: What works and what doesn't?

Editorial on the Research Topic: Improving reliability of brain stimulation: What works and what doesn't

Calibration of myocardial T2 and T1 against iron concentration.

BACKGROUND: The assessment of myocardial iron using T2* cardiovascular magnetic resonance (CMR) has been validated and calibrated, and is in clinical use. However, there is very limited data assessing the relaxation parameters T1 and T2 for measurement of human myocardial iron. METHODS: Twelve hearts were examined from transfusion-dependent patients: 11 with end-stage heart failure, either following death (n=7) or cardiac transplantation (n=4), and 1 heart from a patient who died from a stroke with no cardiac iron loading. Ex-vivo R1 and R2 measurements (R1=1/T1 and R2=1/T2) at 1.5 Tesla were compared with myocardial iron concentration measured using inductively coupled plasma atomic emission spectroscopy. RESULTS: From a single myocardial slice in formalin which was repeatedly examined, a modest decrease in T2 was observed with time, from mean (± SD) 23.7 ± 0.93 ms at baseline (13 days after death and formalin fixation) to 18.5 ± 1.41 ms at day 566 (p<0.001). Raw T2 values were therefore adjusted to correct for this fall over time. Myocardial R2 was correlated with iron concentration [Fe] (R2 0.566, p<0.001), but the correlation was stronger between LnR2 and Ln[Fe] (R2 0.790, p<0.001). The relation was [Fe] = 5081•(T2)-2.22 between T2 (ms) and myocardial iron (mg/g dry weight). Analysis of T1 proved challenging with a dichotomous distribution of T1, with very short T1 (mean 72.3 ± 25.8 ms) that was independent of iron concentration in all hearts stored in formalin for greater than 12 months. In the remaining hearts stored for <10 weeks prior to scanning, LnR1 and iron concentration were correlated but with marked scatter (R2 0.517, p<0.001). A linear relationship was present between T1 and T2 in the hearts stored for a short period (R2 0.657, p<0.001). CONCLUSION: Myocardial T2 correlates well with myocardial iron concentration, which raises the possibility that T2 may provide additive information to T2* for patients with myocardial siderosis. However, ex-vivo T1 measurements are less reliable due to the severe chemical effects of formalin on T1 shortening, and therefore T1 calibration may only be practical from in-vivo human studies

Thermodynamics of phase transition in higher dimensional AdS black holes

We investigate the thermodynamics of phase transition for $(n+1)$ dimensional Reissner Nordstrom (RN)-AdS black holes using a grand canonical ensemble. This phase transition is characterized by a discontinuity in specific heat. The phase transition occurs from a lower mass black hole with negative specific heat to a higher mass black hole with positive specific heat. By exploring Ehrenfest's scheme we show that this is a second order phase transition. Explicit expressions for the critical temperature and critical mass are derived. In appropriate limits the results for $(n+1)$ dimensional Schwarzschild AdS black holes are obtained.Comment: LaTex, 11 pages, 5 figures, To appear in JHE

Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain

Earlier reports showed that hyperplasia of sympathoadrenal cell precursors during embryogenesis in Nf1-deficient mice is independent of Nf1’s role in down-modulating RAS-MAPK signaling. We demonstrate in zebrafish that nf1 loss leads to aberrant activation of RAS signaling in MYCN-induced neuroblastomas that arise in these precursors, and that the GTPase-activating protein (GAP)-related domain (GRD) is sufficient to suppress the acceleration of neuroblastoma in nf1-deficient fish, but not the hypertrophy of sympathoadrenal cells in nf1 mutant embryos. Thus, even though neuroblastoma is a classical “developmental tumor”, NF1 relies on a very different mechanism to suppress malignant transformation than it does to modulate normal neural crest cell growth. We also show marked synergy in tumor cell killing between MEK inhibitors (trametinib) and retinoids (isotretinoin) in primary nf1a-/- zebrafish neuroblastomas. Thus, our model system has considerable translational potential for investigating new strategies to improve the treatment of very high-risk neuroblastomas with aberrant RAS-MAPK activation

The MC1R gene in the guppy (Poecilia reticulata): Genotypic and phenotypic polymorphisms

<p>Abstract</p> <p>Background</p> <p>The guppy (<it>Poecilia reticulata</it>) is an important model organism for studying sexual selection; male guppies have complex and conspicuous pigmentation, and female guppies exhibit preferences for males with specific color spots. Understanding the genetic basis underlying pigmentation variation in the guppy is important for exploring the factors causing the maintenance of color polymorphism in wild populations.</p> <p>Findings</p> <p>We focused on the melanic black pigmentation of guppies, and examined genetic variations in the <it>melanocortin 1 receptor </it>(<it>MC1R</it>) gene because variation in this gene is known to contribute to polymorphism of melanin pigmentation in several animal species. The complete coding sequence of the guppy <it>MC1R </it>gene was determined, and two different <it>MC1R </it>alleles (963 and 969 bp) were found in wild populations. Ornamental strain guppies with a 963-bp <it>MC1R </it>tended to show less black pigmentation than those with a 969-bp <it>MC1R</it>, although the association between <it>MC1R </it>genotype and black pigmentation disappeared in the F₂offspring.</p> <p>Conclusions</p> <p>The guppy <it>MC1R </it>gene showed variation in the five wild Trinidadian populations we examined, and these populations also differed in terms of allele frequencies. We identified a significant association between black pigmentation and <it>MC1R </it>genotype in fish obtained from aquarium shops. However, the results from F₂families suggest that there are other genes that modify the effects of the <it>MC1R </it>gene.</p