Virtual screening,docking, and dynamics of potential new inhibitors of dihydrofolate reductase from Yersinia pestis

In the present work, we propose to design drugs that target the enzyme dihydrofolate redutase (DHFR) as a means of a novel drug therapy against plague. Potential inhibitors of DHFR from Yersinia pestis (YpDHFR) were selected by virtual screening and subjected to docking, molecular dynamics (MD) simulations, and Poisson–Boltzmann surface area method, in order to evaluate their interactions in the active sites of YpDHFR and human DHFR (HssDHFR). The results suggested selectivity for three compounds that were further used to propose the structures of six new potential selective inhibitors for YpDHFR.     

The nociceptin pharmacophore site for opioid receptor binding derived from the NMR structure and bioactivity relationships

Nociceptin, a 17 amino acid opioid-like peptide that has an inhibitory effect on synaptic transmission in the nervous system, is involved in learning, memory, attention, and emotion and is also implicated in the perception of pain and visual, auditory, and olfactory functions. In this study, we investigated the NMR solution structure of nociceptin in membrane-like environments (trifluoroethanol and SDS micelles) and found it to have a relatively stable helix conformation from residues 4-17 with functionally important N-terminal residues being folded aperidoically on top of the helix. In functional assays for receptor binding and calcium flux, alanine-scanning variants of nociceptin indicated that functionally important residues generally followed helix periodicity, consistent with the NMR structural model. Structure-activity relationships allowed identification of pharmacophore sites that were used in small molecule data base searches, affording hits with demonstrated nociceptin receptor binding affinities.     

Kin selection may contribute to lek evolution and trait introgression across an avian hybrid zone

Understanding the mechanism(s) that favour cooperation among individuals competing for the same resources provides direct insights into the evolution of grouping behaviour. In a hybrid zone between golden-/yellow-collared (Manacus vitellinus) and white-collared (Manacus candei) manakins, males form aggregations composed of white and yellow males solely to attract females ('mixed leks'). Previous work shows that yellow males in these mixed leks experience a clear mating advantage over white males, resulting in the preferential introgression of yellow plumage allele(s) into the white species. However, the yellow male mating advantage only occurs in mixed leks with high frequencies of yellow males, and only a few of these males probably mate. Hence, it remains unclear why unsuccessful males join leks. Here, we used microsatellite markers to estimate pairwise relatedness among males within and between leks to test whether indirect genetic benefits of helping kin ('kin selection') can promote grouping. We found that yellow males are significantly more related to each other within than between leks, while relatedness among white males did not differ within and between leks. This suggests that yellow males may indirectly enhance their own reproductive success by preferentially lekking with relatives because yellow plumage is under positive frequency-dependent selection (positive FDS). Our results are consistent with the hypothesis that kin selection may promote grouping and facilitate positive FDS for yellow males, mediating the movement of yellow plumage across this hybrid zone.     

Normal human colon cells suppress malignancy when fused with colon cancer cells

Summary Normal human colon mucosa cells and cells obtained from histologically normal tissues near that cancer were fused with human colon cancer cells. Resultant hybrid populations of normal and malignant cell fusions behaved as nonmalignant cells in culture, were unable to grow in soft agar, did not express tumor-associated antigens, and were nontumorigenic in nude mice. Autofusion of the cancer cell population led to a phenotype intermediate between normal and malignant cells. That is, the cultures had a much lower plating efficiency in soft agar, and the tumors had a longer latency and slower growth rate in nude mice. This is the first cell culture system to demonstrate that normal epithelial cells can suppress malignancy of their autologous cancer cells, and is a prelude to more extensive studies of genetic events involved in malignant conversion of human colonic epithelium. This study was supported by The University of Texas Health Science Center at San Antonio Center for Human Cell Biotechnology and a graduate student stipend (T. J.) from the Department of Cellular and Structural Biology.     

Local competition sparks concerns for fairness in the ultimatum game

Humans reject uneven divisions of resources, even at personal cost. This is observed in countless experiments using the ultimatum game, where a proposer offers to divide a resource with a responder who either accepts the division or rejects it (whereupon both earn zero). Researchers debate why humans evolved a psychology that is so averse to inequity within partnerships. We suggest that the scale of competition is crucial: under local competition with few competitors, individuals reject low offers, because they cannot afford to be disadvantaged relative to competitors. If one competes against the broader population (i.e. global competition), then it pays to accept low offers to increase one''s absolute pay-off. We support this intuition with an illustrative game-theoretical model. We also conducted ultimatum games where participants received prizes based on pay-offs relative to immediate partners (local competition) versus a larger group (global competition). Participants demanded higher offers under local competition, suggesting that local competition increases people''s demands for fairness and aversion to inequality.     

Spruce budworm feeding and oviposition are stimulated by monoterpenes in white spruce epicuticular waxes

Monoterpenes, source of the distinctive odor of conifers, are generally considered plant defensive compounds. However, they are also known to act as long‐range insect attractants, as they are volatile and permeate forest airspaces. Moreover, they are lipid soluble and can be absorbed into plant epicuticular waxes. We test their role in short‐range host plant choice by both adult females and larvae of a folivorous forest pest (Choristoneura fumiferana). We conducted laboratory assays testing the responses of Eastern spruce budworm to an artificial monoterpene mix (α‐pinene, β‐pinene, limonene, myrcene) and to white spruce (Picea glauca) epicuticular waxes in closed arenas. Ovipositing females preferred filter paper discs treated with P. glauca waxes to controls, and preferred the waxes + monoterpenes treatment to waxes alone. However, females showed no preference between the monoterpene‐treated disc and the control when presented without waxes. Feeding larvae prefered wax discs to control discs. They also consumed discs treated with realistic monoterpene concentrations and wax preferentially over wax‐only discs, but showed no preference between extremely high monoterpene concentrations and wax‐only controls. In an insect‐free assay, P. glauca epicuticular wax decreased monoterpene volatilization. These results suggest that P. glauca waxes and realistic concentrations of monoterpenes are stimulatory to both egg‐laying females and feeding larvae, and that their effects are synergistic.     

Birth Prevalence of Neural Tube Defects and Orofacial Clefts in India: A Systematic Review and Meta-Analysis

Background

In the last two decades, India has witnessed a substantial decrease in infant mortality attributed to infectious disease and malnutrition. However, the mortality attributed to birth defects remains constant. Studies on the prevalence of birth defects such as neural tube defects and orofacial clefts in India have reported inconsistent results. Therefore, we conducted a systematic review of observational studies to document the birth prevalence of neural tube defects and orofacial clefts.

Methods

A comprehensive literature search for observational studies was conducted in MEDLINE and EMBASE databases using key MeSH terms (neural tube defects OR cleft lip OR cleft palate AND Prevalence AND India). Two reviewers independently reviewed the retrieved studies, and studies satisfying the eligibility were included. The quality of included studies was assessed using selected criteria from STROBE statement.

Results

The overall pooled birth prevalence (random effect) of neural tube defects in India is 4.5 per 1000 total births (95% CI 4.2 to 4.9). The overall pooled birth prevalence (random effect) of orofacial clefts is 1.3 per 1000 total births (95% CI 1.1 to 1.5). Subgroup analyses were performed by region, time period, consanguinity, and gender of newborn.

Conclusion

The overall prevalence of neural tube defects from India is high compared to other regions of the world, while that of orofacial clefts is similar to other countries. The majority of studies included in the review were hospital based. The quality of these studies ranged from low to moderate. Further well-designed, high quality community-based observational studies are needed to accurately estimate the burden of neural tube defects and orofacial clefts in India.     

Analysis of lipocyte viability after liposuction

Free fat grafts from liposuction aspirate can be used as donor material for soft-tissue augmentation. The purpose of this study was to attempt to identify a subpopulation of adipose cells within liposuction aspirate with the greatest viability and, it is hoped, a greater chance for increased survival after transplantation. Liposuction samples were obtained from 20 individuals (16 women, four men; age range, 27 to 49 years). These samples were then centrifuged at 50 g. At 2-minute intervals, specimens from three different areas (superficial, middle, deep) were obtained from each specimen. After collagenase degradation, the specimens were stained with trypan blue, and the number of viable cells were counted. The bottom (deepest) layer consistently contained the highest number of viable cells after centrifugation: 250 percent more viable cells when compared with the top layer (p < 0.0001) and 140 percent more viable cells when compared with the middle layer (p < 0.0002). Centrifugation beyond 2 minutes did not increase the number or proportion of viable adipocytes. When using aspirated fat from liposuction for soft-tissue augmentation, centrifugation for 2 minutes at 50 g will stratify the adipocytes, with more viable cells being found at the deepest layer. Using only this bottom portion of the fat layer for transplantation will yield a fat graft with a greater number of viable adipocytes, potentially improving fat graft survival and decreased fat graft resorption.     

The use of AFLPs to examine genetic relatedness in barley

The generation of AFLPs in spring barley cultivars provided genetic information relating to the development of the crop in the UK since 1953. Principal co-ordinate (PCO) analysis of genetic similarities (gs) confirmed the marked contrast in the cultivars used in the 1970s and 1980s. The earliest cultivars, many derived from Proctor, were succeeded by tall-strawed, disease-resistant types with high yield but poor malting potential. In the 1980s they were in turn replaced by short-strawed cultivars with excellent yield and good malting quality, which originated from Triumph. A PCO plot of gs provided insight into the effects of selection for disease resistance and the antagonism between malting quality and particular resistance genes. The analysis of gs was more useful than pedigrees and estimates of kinship in revealing the genetic relationship between cultivars. Theoretical considerations for maximising the efficiency of an AFLP genotyping programme are discussed in the context of the number of primer pairs required to distinguish genotypes at varying levels of similarity.