Self-accumulation
of amyloid-β protein (Aβ) into insoluble
fibrils is the major hallmark of Alzheimer’s disease. Real-time
monitoring of fibril growth is essential for clarifying the mechanism
underlying aggregation and discovering therapeutic targets. A variety
of approaches including NMR, electron microscopy (EM), atomic force
microscopy (AFM), and total internal reflection fluorescence microscopy
(TIRFM) have been explored to monitor the fibril growth or reveal
morphology of Aβ aggregates. However, none of the methods allow
real-time observation under physiological conditions while without
any perturbations. Here, we present a fluorescent probe [Ru(phen)2(fipc)]2+ (Ru-fipc) (phen = 1,10-phenanthroline,
fipc = 5-fluoro-N-(1,10-phenanthrolin-5-yl)-1H-indole-2-carboxamide)
that can bind to all the Aβ forms, i.e., monomers, oligomers,
and fibrils, while not perturbing aggregation. Using this probe in
combination with laser confocal microscopy, the entire aggregation
process could be clearly and exactly imaged at the single fibril level.
The reliability of Ru-fipc was confirmed based on colocalization
with thioflavin T (ThT). Importantly, Ru-fipc can be
used to monitor the very early nucleation and oligomerization process,
which is thought to be a critical step in the development of neurotoxicity
while it cannot be visualized with ThT. To our knowledge, this is
the first fluorescent probe developed for real-time monitoring of
Aβ aggregation, especially for the very early assembly stage,
in solution with minimal perturbation. This method is suitable for in vitro and in vivo studies. We believe
this would provide a valuable complementary tool for the study of
pathogenesis and discovery of therapeutic targets of neurodegenerative
diseases.
Litter size is one of the important economic traits of livestock. Seasonal oestrus, ovulation and lambing of sheep have severely restricted the development of sheep farming in Xinjiang, China. The purpose of this study was to investigate the polymorphisms and genetic correlation between GRM1, GNAQ and HCRTR1 genes and the seasonal reproduction and litter size in three sheep breeds. The DNA mixed pool sequencing and PCR-SSCP methods were used to detect single nucleotide polymorphisms (SNPs) of GRM1, GNAQ and HCRTR1 genes in seasonal oestrous (Kazakh and Chinese Merino [Xinjiang Junken type]) and perennial oestrous (Hu) sheep breeds. The association between genetic polymorphism and litter size was also analysed. The results showed that T945C in exon 2 of GRM1 gene, C589T in exon 2 of HCRTR1 gene and A191G in exon 2 of GNAQ gene were identified by Sanger sequencing, and three genotypes were existed in each SNP site, which all belonged to the synonymous mutation. GRM1 (CC), GNAQ (GA) and HCRTR1 (TC) were the dominant genotypes of seasonal reproduction and litter size in Kazakh sheep and Chinese Merino sheep, respectively, while, in perennial oestrous Hu sheep populations, the dominant genotypes were GRM1 (TC), GNAQ (GA) and HCRTR1 (TC), respectively, and association analysis also confirmed the results. The above results implied that GRM1, GNAQ and HCRTR1 genes are significantly associated with lambing traits in Kazakh, Chinese Merino and Hu sheep.Among them, the locus of GRM1 (T945C), GNAQ (A191G) and HCRTR1 (C589T) might be considered as a potential molecular marker, which controls seasonal reproduction and litter size in sheep.
A novel multiresidue analytical method has been developed and validated for the determination of five classes of veterinary drugs including 18 β-lactams, 15 quinolones, 21 sulfonamides, 3 sulfonamide potentiators and 6 antiparasitics in meat using dispersive solid-phase extraction (dispersive-SPE) and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The analytes were extracted with a vortex mixer by 0.1 mol/L Na2 EDTA solution and acetonitrile containing 1% (v/v) acetic acid, and then the extracts were purified using dispersive-SPE with C18 sorbent. Electrospray ionization mass spectrometry was operated in positive mode using dynamic multiple reaction monitoring (DMRM) for the qualitative and quantitative analysis of the 63 analytes after the separation on a Poroshell EC-C18 column (100 mm x 2.1 mm, 2.4 µm). The correlation coefficients of linear calibration curves were over 0.99 in the corresponding concentration ranges. The average recoveries of the 63 analytes ranged from 62.2% to 112.0%, and the relative standard deviations (RSDs) were 3.1%-16.3% in spiked meat (pork, beef and chicken muscle) at three levels. The limits of detection (LODs, S/N ≥ 3) and the limits of quantification (LOQs, S/N ≥ 10) were 0.1-3.0 µg/kg and 0.5-10.0 µg/kg, respectively. The method is simple, rapid, sensitive, reliable and suitable for the determination of residues in animal products.
Purpose
The purpose of this paper is to provide an integrated semantic information retrieval (IR) solution based on an ontology-improved vector space model for situations where a digital collection is established or curated. It aims to create a retrieval approach which could return the results by meanings rather than by keywords.
Design/methodology/approach
In this paper, the authors propose a semantic term frequency algorithm to create a semantic vector space model (SeVSM) based on ontology. To support the calculation, a multi-branches tree model is created to represent the ontology and a set of algorithms is developed to operate it. Then, a semantic ontology-based IR system based on the SeVSM model is designed and developed to verify the effectiveness of the proposed model.
Findings
The experimental study using 30 queries from 15 different domains confirms the effectiveness of the SeVSM and the usability of the proposed system. The results demonstrate that the proposed model and system can be a significant exploration to enhance IR in specific domains, such as a digital library and e-commerce.
Originality/value
This research not only creates a semantic retrieval model, but also provides the application approach via designing and developing a semantic retrieval system based on the model. Comparing with most of the current related research, the proposed research studies the whole process of realizing a semantic retrieval.
Comprehensive Summary
The binding of Sphingosine‐1‐phosphate (S1P) with the S1PR1‐5 plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration and distribution. S1P‐S1PR1 signal axis established roles in immune cell trafficking thus playing a therapeutic role in multiple sclerosis and inflammatory bowel disease. In this study, a series of oxadiazole derivatives were designed and synthesized as S1PR1 agonists based on rational drug design. Among them, compound 9i was identified as a potent and selective S1PR1 agonist with activities on β‐arrestin recruitment (EC50 = 0.36 nmol/L) and receptor internalization (EC50 = 8.09 nmol/L). Meanwhile, compound 9i displayed an oral bioavailability up to 93.6%. Based on its excellent activity to S1PR1 and pharmacokinetic properties, compound 9i effectively alleviated dextran sulfate sodium (DSS)‐induced ulcerative colitis in mice at a dose of 0.1 mg/kg.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.