Protein Phosphatase 2A Catalytic Subunit α Plays a MyD88-Dependent,Central Role in the Gene-Specific Regulation of Endotoxin Tolerance

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Highlights? PP2Ac is constitutively activated and targets MyD88 in LPS-tolerized macrophages ? Constitutively active PP2Ac shifts a proinflammatory MyD88 to its prosurvival mode ? Constitutively active PP2Ac reprograms gene-specific chromatin modification landscape ? Constitutively active PP2Ac broadly defines ET at both signaling and epigenetic levels     

A conserved histidine in insulin is required for the foldability of human proinsulin: structure and function of an ALAB5 analog

The insulins of eutherian mammals contain histidines at positions B5 and B10. The role of His(B10) is well defined: although not required in the mature hormone for receptor binding, in the islet beta cell this side chain functions in targeting proinsulin to glucose-regulated secretory granules and provides axial zincbinding sites in storage hexamers. In contrast, the role of His(B5) is less well understood. Here, we demonstrate that its substitution with Ala markedly impairs insulin chain combination in vitro and blocks the folding and secretion of human proinsulin in a transfected mammalian cell line. The structure and stability of an Ala(B5)-insulin analog were investigated in an engineered monomer (DKP-insulin). Despite its impaired foldability, the structure of the Ala(B5) analog retains a native-like T-state conformation. At the site of substitution, interchain nuclear Overhauser effects are observed between the methyl resonance of Ala(B5) and side chains in the A chain; these nuclear Overhauser effects resemble those characteristic of His(B5) in native insulin. Substantial receptor binding activity is retained (80 +/- 10% relative to the parent monomer). Although the thermodynamic stability of the Ala(B5) analog is decreased (DeltaDeltaG(u) = 1.7 +/- 0.1 kcal/mol), consistent with loss of His(B5)-related interchain packing and hydrogen bonds, control studies suggest that this decrement cannot account for its impaired foldability. We propose that nascent long-range interactions by His(B5) facilitate alignment of Cys(A7) and Cys(B7) in protein-folding intermediates; its conservation thus reflects mechanisms of oxidative folding rather than structure-function relationships in the native state.     

A geographically explicit genetic model of worldwide human-settlement history

Currently available genetic and archaeological evidence is generally interpreted as supportive of a recent single origin of modern humans in East Africa. However, this is where the near consensus on human settlement history ends, and considerable uncertainty clouds any more detailed aspect of human colonization history. Here, we present a dynamic genetic model of human settlement history coupled with explicit geographical distances from East Africa, the likely origin of modern humans. We search for the best-supported parameter space by fitting our analytical prediction to genetic data that are based on 52 human populations analyzed at 783 autosomal microsatellite markers. This framework allows us to jointly estimate the key parameters of the expansion of modern humans. Our best estimates suggest an initial expansion of modern humans approximately 56,000 years ago from a small founding population of approximately 1,000 effective individuals. Our model further points to high growth rates in newly colonized habitats. The general fit of the model with the data is excellent. This suggests that coupling analytical genetic models with explicit demography and geography provides a powerful tool for making inferences on human-settlement history.     

Overexpression of miR-26b-5p regulates the cell cycle by targeting CCND2 in GC-2 cells under exposure to extremely low frequency electromagnetic fields

The increasing prevalence of extremely low frequency electromagnetic fields (ELF-EMFs) exposure has raised considerable public concern regarding the potential hazardous effects of ELF-EMFs on male reproductive function. Increasing evidence indicates that miRNAs are necessary for spermatogenesis and male fertility. However, the regulation of miRNA expression and the roles of miRNAs in response to ELF-EMFs remain unclear. In our study, mouse spermatocyte-derived GC-2 cells were intermittently exposed to a 50 Hz ELF-EMF for 72 h (5 min on/10 min off) at magnetic field intensities of 1 mT, 2 mT and 3 mT. MiR-26b-5p was differentially expressed in response to different magnetic field intensities of ELF-EMFs. The host gene CTDSP1 showed an unmethylation status in GC-2 cells at different magnetic field intensities of ELF-EMF exposure. MiR-26b-5p had no significant, obvious influence on the cell viability, apoptosis or cell cycle of GC-2 cells. However, the overexpression of miR-26b-5p significantly decreased the percentage of G0/G1 phase cells and slightly increased the percentage of S phase cells compared to the sham group that was exposed to a 50 Hz ELF-EMF. Computational algorithms identified Cyclin D2 (CCND2) as a direct target of miR-26b-5p. MiR-26b-5p and a 50 Hz ELF-EMF altered the expression of CCND2 at both the mRNA and protein levels. Overexpressed miR-26b-5p in GC-2 cells can change the mRNA expression of CCND2 following 50 Hz ELF-EMF at 3 mT. These findings demonstrate that miR-26b-5p could serve as a potential biomarker following 50 Hz ELF-EMF exposure, and miR-26b-5p-CCND2-mediated cell cycle regulation might play a pivotal role in the biological effects of ELF-EMFs.     

Complete Preoperative Evaluation of Pulmonary Atresia with Ventricular Septal Defect with Multi-Detector Computed Tomography

Objective

To compare multi-detector computed tomography (MDCT) with cardiac catheterization and transthoracic echocardiography (TTE) in comprehensive evaluation of the global cardiovascular anatomy in patients with pulmonary atresia with ventricular septal defect (PA-VSD).

Methods

The clinical and imaging data of 116 patients with PA-VSD confirmed by surgery were reviewed. Using findings at surgery as the reference standard, data from MDCT, TTE and catheterization were reviewed for assessment of native pulmonary vasculature and intracardiac defects.

Results

MDCT was more accurate than catheterization and TTE in identification of native pulmonary arteries. MDCT is also the most accurate test for delineation of the major aortopulmonary collateral arteries. The inter-modality agreement for evaluation of overriding aorta and VSD were both excellent. In the subgroup with surgical correlation, excellent agreement was found between TTE and surgery, and substantial agreement was also found at MDCT.

Conclusion

MDCT can correctly delineate the native pulmonary vasculatures and intracardiac defects and may be a reliable method for noninvasive assessment of global cardiovascular abnormalities in patients with PA-VSD.     

黄顶菊凋落物分解对节肢动物群落结构的影响

选择黄顶菊(Flaveria bidentis)入侵的林地、农田、荒地、沟渠等4种生境作为调查样地, 比较黄顶菊与本地植物凋落物的分解速率及凋落物分解对节肢动物群落结构的影响。于2014年10月凋落物高峰期在各样地内分别搜集黄顶菊与本地植物的凋落物, 每种凋落物称取20 g装入尼龙网分解袋中, 放入各生境。2015年的每个月将不同生境不同处理凋落袋各取回10袋, 用Tullgren法分离节肢动物。 4种生境共捕获17,466头, 隶属8纲18目, 4种生境的优势类群皆为蜱螨目和啮目。其中, 林地、农田、荒地、沟渠4种生境处理组中节肢动物数量分别为1,698头, 1,838头, 2,631头, 3,413头, 分别比对照组高18%, 53%, 22%, 11%。多数月份黄顶菊凋落物中的节肢动物丰富度及多样性指数高于同生境对照组, 并且在黄顶菊生长盛期差异显著; 黄顶菊凋落物的分解速率高于对照植物分解速率, 且各月份凋落物分解速率动态与节肢动物数量变化动态呈显著相关。黄顶菊凋落物对节肢动物的影响与人为干扰程度有关, 这种影响在人为干扰较小的荒地与沟渠生境中更为明显。综上所述, 黄顶菊凋落物的分解改变了节肢动物群落结构, 并引起节肢动物多样性的升高。     

Expression of an Acid Urease with Urethanase Activity in <Emphasis Type="Italic">E. coli</Emphasis> and Analysis of Urease Gene

Urea in alcoholic beverage is a precursor of ethyl carbamate (EC), which is carcinogenic. Enzymatic elimination of urea has attracted much research interest. Acid urease with good tolerance toward ethanol and acid is ideal enzyme for such applications. In the present work, the structural genes of urease from Providencia rettgeri JN-B815, ureABC were efficiently expressed in E. coli BL21(DE3) in an active form (apourease) exhibiting both urease and urethanase (hydrolyze EC) activities. The specific activities of the purified apourease were comparatively low, which were 2.1 U/mg for urease and 0.6 U/mg for urethanase, respectively. However, apourease exhibited good resistance toward ethanol and acidic conditions. The relative activities of urease and urethanase remained over 80% in the buffers within pH 4–7. And the recoveries of both urease and urethanase activities were more than 50% in 5–25% ethanol solution. Apourease was utilized to eliminate urea in wine, and the residual urea in model wine was less than 50% after treatment with apourease for 30 h. Then 3D structure of UreC was predicted, and it was docked with urea and EC, respectively. The docking result revealed that three hydrogen bonds were formed between urea and amino acid residues in the active site of urease, whereas only one hydrogen bond can be formed between EC and the active center. Moreover, EC exhibited greater steric hindrance than urea when combined with the active site. Due to the low specific activities of apourease, both structural genes and accessory genes of urease were co-expressed in E. coli BL21(DE3). The holoenzyme was expressed as inclusion body. After renaturation and purification, the specific activities of urease and urethanase reached 10.7 and 3.8 U/mg, which were 5.62-fold and 6.33-fold of those of apourease, respectively. Therefore, accessory subunits of urease play an important role in enhancing urease and urethanase activities.     

CT Permeability Imaging Predicts Clinical Outcomes in Acute Ischemic Stroke Patients Treated with Intra-arterial Thrombolytic Therapy

In this study, we determined whether a prediction of final infarct volume (FIV) and clinical outcomes in patients with an acute stroke is improved by using a contrast transfer coefficient (K ^trans) as a biomarker for blood–brain barrier (BBB) dysfunction. Here, consecutive patients admitted with signs and symptoms suggesting acute hemispheric stroke were included in this study. Ninety-eight participants with intra-arterial therapy were assessed (46 female). Definition of predicted FIV was performed using conventional perfusion CT (PCT-PIV) parameters alone and in combination with K ^trans (K ^trans-PIV). Multiple logistic regression analyses and linear regression modeling were conducted to determine independent predictors of the 90-day modified Rankin score (mRS) and FIV, respectively. We found that patients with favorable outcomes were younger and had lower National Institutes of Health Stroke Scale (NIHSS) score, smaller PCT-PIV, K ^trans-PIV, and smaller FIV (P?<?0.001). K ^trans-PIV showed good correlation with FIV (P?<?00.001, R ²?=?0.6997). In the regression analyses, K ^trans-PIV was the best predictor of clinical outcomes (P?=?0.009, odds ratio (OR)?=?1.960) and also the best predictor for FIV (F?=?75.590, P?<?0.0001). In conclusion, combining PCT and K ^trans maps derived from first-pass PCT can identify at-risk cerebral ischemic tissue more precisely than perfusion parameters alone. This provides improved accuracy in predicting FIV and clinical outcomes.