The 2.7 A crystal structure of the autoinhibited human c-Fms kinase domain

c-Fms, a member of the Platelet-derived Growth Factor (PDGF) receptor family of receptor tyrosine kinases (RTKs), is the receptor for macrophage colony stimulating factor (CSF-1) that regulates proliferation, differentiation and survival of cells of the mononuclear phagocyte lineage. Abnormal expression of c-fms proto-oncogene is associated with a significant number of human pathologies, including a variety of cancers and rheumatoid arthritis. Accordingly, c-Fms represents an attractive therapeutic target. To further understand the regulation of c-Fms, we determined the 2.7 A resolution crystal structure of the cytosolic domain of c-Fms that comprised the kinase domain and the juxtamembrane domain. The structure reveals the crucial inhibitory role of the juxtamembrane domain (JM) that binds to a hydrophobic site immediately adjacent to the ATP binding pocket. This interaction prevents the activation loop from adopting an active conformation thereby locking the c-Fms kinase into an autoinhibited state. As observed for other members of the PDGF receptor family, namely c-Kit and Flt3, three JM-derived tyrosine residues primarily drive the mechanism for autoinhibition in c-Fms, therefore defining a common autoinhibitory mechanism within this family. Moreover the structure provides an understanding of c-Fms inhibition by Gleevec as well as providing a platform for the development of more selective inhibitors that target the inactive conformation of c-Fms kinase.     

Human lactoferrin upregulates expression of KDR/Flk-1 and stimulates VEGF-A-mediated endothelial cell proliferation and migration

Lactoferrin (LF) is a multifunctional iron-binding glycoprotein, which plays a variety of biological processes including immunity. In this study, we demonstrate that human LF upregulates KDR/Flk-1 mRNA and protein levels in HUVECs at an optimal concentration of 5 microg/ml, which subsequently promotes the VEGF-induced proliferation and migration of the endothelial cells. Exposure of HUVECs to LF significantly increased VEGF-induced ERK MAP kinase phosphorylation. The maximal stimulation of KDR/Flk-1 expression by LF was correlated with LF-induced increase in cell proliferation and migration. These findings suggest that LF may stimulate in vivo angiogenesis via upregulation of KDR/Flk-1 expression in endothelial cells.     

Persistence of tree cavities used by cavity-nesting vertebrates declines in harvested forests

An abundant supply of cavity-bearing trees is important for maintaining wildlife communities in harvested forests. During harvesting, suitable trees and cavities are directly removed, and the longevity of cavities in retained trees may be reduced by increased exposure to wind and other disturbance factors. We examined patterns of cavity survival in retained trembling aspen (Populus tremuloides) trees in harvested stands compared with those in unharvested mature stands by monitoring the persistence of individual cavities. We followed 930 cavities in 3 harvest treatments for up to 17 years in pre-cut and uncut forest, and up to 13 years post-harvest (reserve patches and dispersed retention), in temperate-mixed forests of interior British Columbia, Canada. Average annual cavity loss rates were 5.6% in pre-cut and uncut forest, 7.2% for cavities in trees retained in reserves, and 8.1% for cavities in retained trees dispersed throughout cuts. Correspondingly, median cavity longevity was 15 years for cavities in pre-cut and uncut forest, 10 years for cavities retained in reserves, and 9 years for those in dispersed retention. Risk of loss increased most for cavities in living trees (factor of 2.17), but we found no detectable difference for cavities in recently dead trees and trees with advanced decay. We suggest retention of a range of aspen size and decay classes to allow for future cavity-tree recruitment in harvested stands. Inclusion of wildlife reserves as part of an overall forest management plan will also help to mitigate the effects of windthrow and maintain long-lived cavity resources required by a large portion of forest wildlife. © 2013 The Wildlife Society     

Structures composing protein domains

This review summarizes available data concerning intradomain structures (IS) such as functionally important amino acid residues, short linear motifs, conserved or disordered regions, peptide repeats, broadly occurring secondary structures or folds, etc. IS form structural features (units or elements) necessary for interactions with proteins or non-peptidic ligands, enzyme reactions and some structural properties of proteins. These features have often been related to a single structural level (e.g. primary structure) mostly requiring certain structural context of other levels (e.g. secondary structures or supersecondary folds) as follows also from some examples reported or demonstrated here. In addition, we deal with some functionally important dynamic properties of IS (e.g. flexibility and different forms of accessibility), and more special dynamic changes of IS during enzyme reactions and allosteric regulation. Selected notes concern also some experimental methods, still more necessary tools of bioinformatic processing and clinically interesting relationships.     

In search of relevant predictors for marine species distribution modelling using the MarineSPEED benchmark dataset

Aim

Ideally, datasets for species distribution modelling (SDM) contain evenly sampled records covering the entire distribution of the species, confirmed absences and auxiliary ecophysiological data allowing informed decisions on relevant predictors. Unfortunately, these criteria are rarely met for marine organisms for which distributions are too often only scantly characterized and absences generally not recorded. Here, we investigate predictor relevance as a function of modelling algorithms and settings for a global dataset of marine species.

Location

Global marine.

Methods

We selected well‐studied and identifiable species from all major marine taxonomic groups. Distribution records were compiled from public sources (e.g., OBIS, GBIF, Reef Life Survey) and linked to environmental data from Bio‐ORACLE and MARSPEC. Using this dataset, predictor relevance was analysed under different variations of modelling algorithms, numbers of predictor variables, cross‐validation strategies, sampling bias mitigation methods, evaluation methods and ranking methods. SDMs for all combinations of predictors from eight correlation groups were fitted and ranked, from which the top five predictors were selected as the most relevant.

Results

We collected two million distribution records from 514 species across 18 phyla. Mean sea surface temperature and calcite are, respectively, the most relevant and irrelevant predictors. A less clear pattern was derived from the other predictors. The biggest differences in predictor relevance were induced by varying the number of predictors, the modelling algorithm and the sample selection bias correction. The distribution data and associated environmental data are made available through the R package marinespeed and at http://marinespeed.org .

Main conclusions

While temperature is a relevant predictor of global marine species distributions, considerable variation in predictor relevance is linked to the SDM set‐up. We promote the usage of a standardized benchmark dataset (MarineSPEED) for methodological SDM studies.

     

Effects Ala54Thr polymorphism of FABP2 on obesity index and biochemical variable in response to a aerobic exercise training

The purpose of the current study was to investigate whether or not the FABP2 gene polymorphism modulated obesity indices, hemodynamic factor, blood lipid factor, and insulin resistance markers through 12-week aerobic exercise training in abdominal obesity group of Korean mid-life women. A total of 243 abdominally obese subjects of Korean mid-life women voluntarily participated in aerobic exercise training program for 12 weeks. Polymerase Chain Reaction with Restriction Fragment Length Polymorphism (PCR-RFLP) assay was used to assess the FABP2 genotype of the participants (117 of AA homozygotes, 100 of AT heterozygotes, 26 of TT homozygotes). Prior to the participation of the exercise training program, baseline obesity indices, hemodynamic factor, blood lipid factor, and insulin resistance markers were measured. All the measurements were replicated following the 12-week aerobic exercise training program, and then the following results were found. After 12-week aerobic exercise training program, wild type (Ala54Ala) and mutant type (Ala54Thr+Thr54Thr) significantly decreased weight (P > .001), BMI (P > .001), %bf (P > .001), waist circumference (P > .001), WHR (P > .001), muscle mass (wild type p < .022; mutant type P > .001), RHR (P > .001), viseceral adipose area (wild type p < .005; mutant type P > .001), subcutaneous area (P > .001), insulin (wild type p < .005; mutant type P > .001) and significantly increased VO2max (P > .001). And wild type significantly decresed NEFA (P > .05), glucose (P > .05), OGTT 120min glucose (P > .05) and significantly increased HDLC (p > .005). Mutant type significantly decreased SBP (P > .001), DBP (P > .01), TC (P > .01), LPL (P > .05), LDL (P > .001), HOMA index (P > .01). The result of the present study represents that regular aerobic exercise training may beneficially prevent obesity index, blood pressure, blood lipids and insulin resistance markers independent of FABP Ala54Thr wild type and mutant type.     

Performance of several variable-selection methods applied to real ecological data

I evaluated the predictive ability of statistical models obtained by applying seven methods of variable selection to 12 ecological and environmental data sets. Cross-validation, involving repeated splits of each data set into training and validation subsets, was used to obtain honest estimates of predictive ability that could be fairly compared among methods. There was surprisingly little difference in predictive ability among five methods based on multiple linear regression. Stepwise methods performed similarly to exhaustive algorithms for subset selection, and the choice of criterion for comparing models (Akaike's information criterion, Schwarz's Bayesian information criterion or F statistics) had little effect on predictive ability. For most of the data sets, two methods based on regression trees yielded models with substantially lower predictive ability. I argue that there is no 'best' method of variable selection and that any of the regression-based approaches discussed here is capable of yielding useful predictive models.     

Dermatan sulfate domains defined by the novel antibody GD3A12, in normal tissues and ovarian adenocarcinomas

Dermatan sulfate (DS) expression in normal tissue and ovarian cancer was investigated using the novel, phage display-derived antibody GD3A12 that was selected against embryonic glycosaminoglycans (GAGs). Antibody GD3A12 was especially reactive with DS rich in IdoA-GalNAc4S disaccharide units. IdoA residues are important for antibody recognition as DS polymers with low numbers of IdoA residues were less reactive, and expression of the DS epimerase in ovarian carcinoma cells was associated with expression of the GD3A12 epitope. Moreover, staining of antibody GD3A12 was abolished by chondroitinase-B lyase digestion. Expression of DS domains defined by antibody GD3A12 was confined to connective tissue of most organs examined and presented as a typical fibrillar-type of staining. Differential expression of the DS epitopes recognized by antibodies GD3A12 and LKN1 (4/2,4 di-O-sulfated DS) was best seen in thymus and spleen, indicating differential expression of various DS domains in these organs. In ovarian carcinomas strong DS expression was found in the stromal parts, and occasionally on tumor cells. Partial co-localization in ovarian carcinomas was observed with decorin, versican and type I collagen suggesting a uniform distribution of this specific DS epitope. This unique anti-DS antibody may be instrumental to investigate the function, expression, and localization of specific DS domains in health and disease. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

从噬菌体展示抗体文库筛选对虾白斑综合征病毒的单链抗体

对虾白斑综合征是一种严重危害对虾养殖业的病毒性疾病.由于目前对其病原体对虾白斑综合征病毒（WSSV）的研究不够深入,所以对WSSV的有效防治仍然是一大难题.为此,用完整的对虾白斑综合征病毒粒子作为靶抗原固相包被,淘选噬菌体展示单链抗体文库,得到两个能够与WSSV结合的单链抗体：E2和H4.单链抗体H4能够结合病毒并抑制病毒对原代培养的对虾淋巴细胞的感染,这些结果表明此单链抗体具有开发为诊断试剂盒和抗病毒药物的潜力.     

基于可变模糊评价模型的东山湾生态系统健康评价

根据东山湾海域环境污染现状和生态系统的特点,从水质环境、沉积物环境、生物残毒以及海洋生物方面构建了东山湾生态系统健康评价指标体系,提出了基于可变模糊评价模型的海湾生态系统健康评价方法,并利用该方法对东山湾生态系统健康状况进行了评价。结果表明:东山湾春季生态系统健康指数为2.36,秋季为2.44,均处于"良与中之间,偏良"水平,春季略优于秋季。影响东山湾生态系统健康状况的主要负面指标因子为鱼卵及仔鱼密度(春秋季健康指数均值为4.95)、营养水平(秋季健康指数为4.47)和底栖生物生物量(春季健康指数为3.59)。实例研究表明该方法通过准则参数α和距离参数p的不同组合变化,以线性与非线性相结合,能够较客观系统、标准量化地评价海湾生态系统健康状况的优劣,。