Amelioration of mechanism-based inactivation of CYP3A4 by a H-PGDS inhibitor

This work describes the rational amelioration of mechanism-based inactivation (MBI) of Cytochrome P450 (CYP) 3A4 in a human hematopoietic prostaglandin D synthase (hH-PGDS) inhibitor (cpd 1). We utilized metabolism reports in order to check if patterns in the metabolism of 1 and similar compounds by CYP3A4 could be deciphered. Then we used structure based design, first modifying the CYP3A4 crystal structure (pdb code: 4NY4) by adding an oxyferryl moiety to the heme, followed by validating the modified structure to obtain the 1′ and 4 position oxidation products of midazolam and then recapitulating the metabolism patterns deciphered previously for 1 and analogs. We checked if the pattern deciphered could lead to a putative reactive moiety. Finally we used the docking pose of 1 into this model of the modified CYP3A4 crystal structure to guide transformation of 1 into MBI-free H-PGDS inhibitors.     

A behavioral paradigm to study the persistence of reward memory extinction in Drosophila

<正>Drosophila has been proven to be a powerful animal model to study genetic mechanisms underlying different behaviors and diseases (Sokolowski,2001;Bier,2005).Extinction is a process that repeated presentation of a conditioned stimulus without reinforcement results in decreased conditioned responses (Bouton,2004) and receives increasing attention for treating its related diseases such as post-traumatic stress disorder (PTSD) and addiction     

VCSRA: A fast and accurate multiple sequence alignment algorithm with a high degree of parallelism

正Multiple sequence alignment (MSA)is the alignment among more than two molecular biological sequences,which is a fundamental method to analyze evolutionary events such as mutations,insertions,deletions,and re-arrangements.In theory,a dynamic programming algorithm can be employed to produce the optimal     

LncPipe: A Nextflow-based pipeline for identification and analysis of long non-coding RNAs from RNA-Seq data

正Long noncoding RNAs(lncRNAs)have been increasingly implicated in a variety of human diseases,including autoimmune disease(Wu et al.,2015),neurodegenerative diseases(Wapinski and Chang,2011)and cancer(Huarte,2015).Due to recent advances in next-generation sequencing technologies,tens of thousands of lnc RNAs have been identified and annotated,a number of them     

Prosthetic groups for radioiodination and astatination of peptides and proteins: A comparative study of five potential bioorthogonal labeling strategies

¹²⁵I- and ²¹¹At-labeled azide and tetrazine based prosthetic groups for bioorthogonal conjugation were designed and tested in a comparative study of five bioorthogonal systems. All five bioconjugation reactions conducted on a model clickable peptide led to quantitative yields within less than a minute to several hours depending on the system used. Transferability to the labeling of an IgG was demonstrated with one of the bioorthogonal system. This study provides several new alternatives to the conventional and suboptimal approach currently in use for radioiodination and astatination of biomolecules and should accelerate the development of new probes with these radionuclides for applications in nuclear imaging and targeted alpha-therapy.     

Temporary feeding inhibition caused by artificial abdominal distension in the bedbug, Cimex lectularius

Abdominal distension of haematophagous insects caused by ingested blood has been recognised as an important contributor to triggering meal termination, feeding inhibition and further susceptibility to host signals. Factors that regulate feeding behaviour of the common bedbug, Cimex lectularius, are poorly understood. By injecting air directly into the body cavity of virgin female C. lectularius we artificially induced abdominal distension without providing chemical cues of the blood meal and without applying gut distension. Body length increased to 138% after feeding and 147% after inflation. The early decline in body volume is similar in blood-fed bugs but after between 8 and 24h became faster in inflated than fed bedbugs. Artificially inflated individuals remained feeding-inhibited at lower abdominal distensions than those that terminate blood ingestion (to ca. 135% initial body length, or up to about 5h). Feeding activity resumed earlier in inflated than blood-fed bugs. These results suggest that artificial abdominal distension has an inhibitory effect on feeding but is not the sole mechanism in preventing further feeding.     

Presence and distribution of sensory structures on the mouthparts of self-medicating moths

Unique structures often accompany unusual feeding behaviors in erebid moths. We test whether self-medicating (e.g., pharmacophagous) adult tiger moths have specialized structures on their mouthparts. We examined mouthparts of pharmacophagous and non-pharmacophagous adults using scanning electron microscopy (SEM). Self-medicating adults had significantly higher numbers of chemosensory structures when compared with non-self-medicating adults. Putative olfactory sensilla are reported on the proboscis of Nyctemera coleta and pollen grains were found adhered to the proboscis of Nyctemera secundiana. Sensilla on the observed tiger moth proboscides may play a role in the recognition of pyrrolizidine alkaloid plants by pharmacophagous adults.     

Presence and distribution of sensory structures on the mouthparts of self-medicating moths

Unique structures often accompany unusual feeding behaviors in erebid moths. We test whether self-medicating (e.g., pharmacophagous) adult tiger moths have specialized structures on their mouthparts. We examined mouthparts of pharmacophagous and non-pharmacophagous adults using scanning electron microscopy (SEM). Self-medicating adults had significantly higher numbers of chemosensory structures when compared with non-self-medicating adults. Putative olfactory sensilla are reported on the proboscis of Nyctemera coleta and pollen grains were found adhered to the proboscis of Nyctemera secundiana. Sensilla on the observed tiger moth proboscides may play a role in the recognition of pyrrolizidine alkaloid plants by pharmacophagous adults.     

渤海真刺唇角水蚤摄食的初步研究

1992年 8月至 1 993年 5～ 6月在渤海调查过程中取得了大量海洋浮游生物样品 ,从中获得 80 0个消化道内含有食物的真刺唇角水蚤标本 ,经分析得出 :真刺唇角水蚤营小型浮游生物食性 ,主要摄食小型桡足类 (占其食物组成的 76.4% ) ,其中小拟哲水蚤是它的主要摄食对象 ( 74.7% ) .此外 ,它也摄食少量硅藻类 ( 2 3.0 % )、甲藻类 ( 1 .1 % )、金藻类 ( <0 .1 % )和纤毛虫类 ( 1 .5% ) ;其食物组成有明显的季节变化 ;其类群更替率各季平均达 30 .7% ,其种类更替率达 40 .3% ,并显示出硅藻类自春至冬逐渐增高而桡足类逐渐降低的规律性 .其摄食强度以春季为最高 ,秋季居第二位 ,夏季居第三位 ,冬季最低 .     

Synthesis and biological activity of structurally diverse phthalazine derivatives: A systematic review

Phthalazine, a structurally and pharmacologically versatile nitrogen-containing heterocycle, has gained more attention from medicinal chemists in the design and synthesis of novel drugs owing to its pharmacological potential. In particular, phthalazine scaffold appeared as a pharmacophoric feature numerous drugs exhibiting pharmacological activities, in particular, antidiabetic, anticancer, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant and antimicrobial activities. This review presents a summary of updated and detailed information on phthalazine as illustrated in both patented and non-patented literature. The reported literature have described the optimal pharmacological characteristics of phthalazine derivatives and highlighted the applicability of phthalazine, as potent scaffold in drug discovery.     

鲥鱼的驯养与生物学研究Ⅰ.O+龄幼鱼的生长与食性

本文主要描述池塘养殖条件下鲥鱼幼鱼的生长与食性。1)1987-1989年8月至11月幼鱼生长迅速,快于同期珠江天然个体的生长速度;2)体长26.6-94.9mm的幼鱼主要摄食浮游动物,轮虫和浮游植物出现率随个体增大而减少。食物共有18个属种,摄食频度为100%;3)幼鱼的平均饱满指数为75.70‰。各类食物重量百分比的顺序为:桡足类>枝角类>无节幼体>虾类溞状幼体>轮虫>藻类。     

鲥鱼的驯养与生物学研究Ⅰ.O~+龄幼鱼的生长与食性

本文主要描述池塘养殖条件下鲥鱼幼鱼的生长与食性。1)1987—1989年8月至11月幼鱼生长迅速,快于同期珠江天然个体的生长速度;2)体长26.6—94.9mm的幼鱼主要摄食浮游动物,轮虫和浮游植物出现率随个体增大而减少。食物共有18个属种,摄食频度为100％;3)幼鱼的平均饱满指数为75.70‰。各类食物重量百分比的顺序为:桡足类>枝角类>无节幼体>虾类溞状幼体>轮虫>藻类。     

Systematics and body size: implications for feeding adaptations in New World monkeys.

The relationship between body size and feeding ecology is well established for primates. It is argued that the evolutionary history of modern New World monkeys and, in particular, the path to attainment of current body size is significant in understanding the similarities and differences between dietary strategies and other ecological parameters of similar-sized monkeys. Current interpretations of New World monkey evolutionary relationships are reviewed. Based on a synthesis of available body weights and the assumption that the earliest New World monkeys weighed close to 1 kg, similar to modern Aotus and Callicebus, predicted patterns of body size change in each lineage are given. Restrictions on directions of body size change in primates are discussed, and it is shown that "Stanley's Rule" offers a good explanation for differing body size ranges in New and Old World anthropoids. Predicted ecological correlates to body size drawn from the mammalian literature are offered and tested using data on New World monkeys, which show some concurrence and several interesting departures from predicted patterns. Sexual dimorphism in body weight of New World monkey species is reviewed, based on the new summary of body weight data given.     

The effects of prior weight reduction on the running wheel-induced feeding suppression in rats

Adult male rats given ad lib access to food and a running wheel show an initial feeding and weight suppression. Over 6-10 days feeding recovers, but body weight remains low. It is not clear which effect is primary, the wheel-induced feeding or weight change. To test this, rats were first restricted to 15 g of food a day for 8 or 16 days to reduce their weight relative to control non-restricted rats. They were then returned to ad lib feeding and half the restricted and non-restricted control rats were introduced to the wheel either immediately (Experiment 1) or 4 days later (Experiment 2). Food intake, body weight, and wheel running were monitored throughout the experiments. At the return to ad lib feeding, prior food restriction elevated feeding. Both immediate and delayed wheel access suppressed feeding in both groups of wheel access rats compared to the appropriate control rats. Feeding history did not have a significant effect on wheel running. The wheel-induced reductions in feeding from baseline were similar in the weight reduced and normal weight animals suggesting that prior weight restriction did not prevent the onset of the wheel-induced feeding suppression. It is therefore suggested that the feeding suppression is not driven by a reduced weight set point.     

Synthesis and in vitro evaluation of diverse heterocyclic diphenolic compounds as inhibitors of DYRK1A

Dual-specificity tyrosine phosphorylation-related kinase 1A (DYRK1A) is a dual-specificity protein kinase that catalyses phosphorylation and autophosphorylation. Higher DYRK1A expression correlates with cancer, in particular glioblastoma present within the brain. We report here the synthesis and biological evaluation of new heterocyclic diphenolic derivatives designed as novel DYRK1A inhibitors. The generation of these heterocycles such as benzimidazole, imidazole, naphthyridine, pyrazole-pyridines, bipyridine, and triazolopyrazines was made based on the structural modification of the lead DANDY and tested for their ability to inhibit DYRK1A. None of these derivatives showed significant DYRK1A inhibition but provide valuable knowledge around the importance of the 7-azaindole moiety. These data will be of use for developing further structure-activity relationship studies to improve the selective inhibition of DYRK1A.     

Growth and body composition changes in mice selected for high post-weaning weight gain on two levels of feeding

Summary Two lines of mice were selected for high post-weaning weight gain (3 to 6 weeks) adjusted for 3 week weight. One line (F) was grown on freely available food and the other (S) on a feeding scale set at the same level for all mice. Food intake of the S line averaged 80% of the F line. The realised heritabilities after 6 generations of selection were 0.38±0.06 and 0.33±0.07 for the F and S lines, respectively. In generation 7, mice from the F and S lines and from an unselected control line (C) were compared on both free and set levels of feeding from 3 weeks to 9 weeks of age. Measurements taken were growth rate, appetite, food conversion efficiency (weight gain/food intake) and body composition (fat, protein, ash, water). The F and S lines grew more rapidly and efficiently than the C line on both levels of feeding, each line performing best on the level of feeding on which it was selected. The average genetic correlation between growth rates of the same line on the two feeding levels was 0.54±0.10. The F line grew 19% faster and was 9% more efficient than the S line on free feeding but the S line grew 15% faster and was 15% more efficient than the F line on set feeding. Relative to the C line, food intake per day on free feeding was 4% higher in the F line and 6% lower in the S line. There was no difference between the lines in food intake/g body weight. The rate of deposition of all body components increased in both selection lines. In the F, S and C lines respectively, efficiencies of gains in body components (10²x gain/food) were 1.79, 1.31 and 1.06 for fat, 1.53, 1.63 and 1.22 for protein and 5.88, 6.45 and 4.98 for protein + water. Apparently energy lost as heat was reduced in both the F and S lines. The partitioning of energy retained was altered in favour of more fat in the F line and more protein in the S line.     

Influence of aphid honeydew on the foraging behaviour of Hippodamia convergens larvae

1. Environmental cues associated with prey are known to increase predator foraging efficiency. Ladybird larvae are major predators of aphids. The sugary excretion of aphids (honeydew) has been proposed to serve as a prey‐associated cue for ladybird larvae. 2. Ladybird larvae are regularly found on the ground moving between plants or after falling off plants. The use of prey‐associated cues would be particularly beneficial for ladybird larvae on the ground in that such cues would help them to decide which plants to climb because aphids are patchily distributed within as well as amongst plants and, as a result, many plants are either not infested with aphids or do not host an aphid species of high nutritional value for ladybird larvae. 3. Laboratory experiments with larvae of Hippodamia convergens Guérin‐Méneville (Coleoptera: Coccinellidae) were carried out to explore whether honeydew accumulated on the ground is used as a foraging cue. The study also investigated whether, if honeydew is a foraging cue, larvae show differential responses to honeydew of high‐quality prey Acyrthosiphon pisum Harris compared with that of low‐quality prey Aphis fabae Scopoli (both: Homoptera: Aphididae). 4. Hippodamia convergens larvae stayed longer in areas containing honeydew but did not engage in longer bouts of searching. Furthermore, larvae did not distinguish between honeydew from high‐ and low‐quality aphid prey.     

Overlapping territory of the benthophagous cichlid fish, Lobochilotes labiatus, in Lake Tanganyika

Synopsis Feeding territories do not usually overlap in the same fish species. We studied overlapping territories and feeding behaviours of a benthophagous cichlid fish Lobochilotes labiatus Boulenger in a coastal area of Lake Tanganyika. Forty-four individuals of both sexes, 6–31 cm in total length, maintained territories in a 21 m × 25 m area. These could be regarded as feeding territories. The territories of similar-sized owners (usually different by less than 5 cm) did not overlap each other, but those of different-sized owners overlapped widely. Aggressive interactions were rarely observed between fish distinctly different in body size. Both large and small fish took benthic animals of the same kinds and of similar size. In contrast, the size of foraging sites (crevices) was different between them: the large fish foraged at large crevices and small fish at small crevices. This partitioning of foraging sites may enable the overlap of territories in this benthivore.     

Rapid photogrammetry of morphological traits of free-ranging moths

1. Photogrammetric studies of free-ranging animals are limited to mammals and birds. Recent advances in insect photogrammetry, including 3D imaging, are entirely associated with museum specimens.
2. We present a rapid, simple, accurate, and inexpensive morphometric method targeting thousands of free-ranging insects attracted to light screens using images taken without collecting a specimen or even constraining the individual in any manner. A reference grid printed on the screen is used to calibrate the images for shape and size without prior knowledge of the camera-subject configuration. The method requires only inexpensive, off-the-shelf, consumer equipment, and freely available programming (R statistical language) and image processing (ImageMagick) tools.
3. We demonstrate the efficacy of the method using a dataset of 3675 images of free-ranging hawkmoths (Lepidoptera:Sphingidae) imaged in natural repose on a screen. We show that this method introduces no bias and has a high degree of correspondence with traditional morphometry using collected specimens. We also propose error metrics, which quantify the calibration quality and identify images with poor data.
4. Although this method is particularly suited for the hyperdiverse moth community, which dominates the dynamics of many terrestrial ecosystems, it can be used for other phototropic taxa identifiable on an image to (morpho)-species. It will help in accumulating reliable trait data from hundreds of thousands of individual insects without any expenditure on specimen collection. It is particularly suited for studies which require multi-epoch, multi-locate sampling like investigations into ecosystem stability, climate change, and community assembly.

     

A reusable magnetic nickel nanoparticle based catalyst for the aqueous synthesis of diverse heterocycles and their evaluation as potential anti-bacterial agent

A library of biologically important heterocycles, viz. pyrazolyl pyrimidine-triones, bis(heterocyclyl)methanes were successfully synthesised by the condensation of barbituric acid, pyrazolone with an aldehyde and dimedone/4-hydoxy coumarin with various substituted aldehydes in aqueous medium at room temperature catalysed by nickel nanoparticles which proved to be an efficient magnetically recyclable catalyst. The method is simple, eco-friendly and gave excellent yields of the products without taking recourse to column chromatographic separation procedures. Computational method was employed to elucidate the selective formation of uncyclised product in reaction course. The biological activity of the synthesized compounds were investigated and the results demonstrated profound antibacterial activity.