Peripheral natural killer cell maturation depends on the transcription factor Aiolos

Natural killer (NK) cells are an innate lymphoid cell lineage characterized by their capacity to provide rapid effector functions, including cytokine production and cytotoxicity. Here, we identify the Ikaros family member, Aiolos, as a regulator of NK-cell maturation. Aiolos expression is initiated at the point of lineage commitment and maintained throughout NK-cell ontogeny. Analysis of cell surface markers representative of distinct stages of peripheral NK-cell maturation revealed that Aiolos was required for the maturation in the spleen of CD11b^highCD27⁻ NK cells. The differentiation block was intrinsic to the NK-cell lineage and resembled that found in mice lacking either T-bet or Blimp1; however, genetic analysis revealed that Aiolos acted independently of all other known regulators of NK-cell differentiation. NK cells lacking Aiolos were strongly hyper-reactive to a variety of NK-cell-mediated tumor models, yet impaired in controlling viral infection, suggesting a regulatory function for CD27⁻ NK cells in balancing these two arms of the immune response. These data place Aiolos in the emerging gene regulatory network controlling NK-cell maturation and function.     

Automatic 4D Reconstruction of Patient-Specific Cardiac Mesh with 1-to-1 Vertex Correspondence from Segmented Contours Lines

We propose an automatic algorithm for the reconstruction of patient-specific cardiac mesh models with 1-to-1 vertex correspondence. In this framework, a series of 3D meshes depicting the endocardial surface of the heart at each time step is constructed, based on a set of border delineated magnetic resonance imaging (MRI) data of the whole cardiac cycle. The key contribution in this work involves a novel reconstruction technique to generate a 4D (i.e., spatial–temporal) model of the heart with 1-to-1 vertex mapping throughout the time frames. The reconstructed 3D model from the first time step is used as a base template model and then deformed to fit the segmented contours from the subsequent time steps. A method to determine a tree-based connectivity relationship is proposed to ensure robust mapping during mesh deformation. The novel feature is the ability to handle intra- and inter-frame 2D topology changes of the contours, which manifests as a series of merging and splitting of contours when the images are viewed either in a spatial or temporal sequence. Our algorithm has been tested on five acquisitions of cardiac MRI and can successfully reconstruct the full 4D heart model in around 30 minutes per subject. The generated 4D heart model conforms very well with the input segmented contours and the mesh element shape is of reasonably good quality. The work is important in the support of downstream computational simulation activities.     

Evaluating temporal factors in combined interventions of workforce shift and school closure for mitigating the spread of influenza

Background

It is believed that combined interventions may be more effective than individual interventions in mitigating epidemic. However there is a lack of quantitative studies on performance of the combination of individual interventions under different temporal settings.

Methodology/Principal Findings

To better understand the problem, we develop an individual-based simulation model running on top of contact networks based on real-life contact data in Singapore. We model and evaluate the spread of influenza epidemic with intervention strategies of workforce shift and its combination with school closure, and examine the impacts of temporal factors, namely the trigger threshold and the duration of an intervention. By comparing simulation results for intervention scenarios with different temporal factors, we find that combined interventions do not always outperform individual interventions and are more effective only when the duration is longer than 6 weeks or school closure is triggered at the 5% threshold; combined interventions may be more effective if school closure starts first when the duration is less than 4 weeks or workforce shift starts first when the duration is longer than 4 weeks.

Conclusions/Significance

We therefore conclude that identifying the appropriate timing configuration is crucial for achieving optimal or near optimal performance in mitigating the spread of influenza epidemic. The results of this study are useful to policy makers in deliberating and planning individual and combined interventions.     

Analysis of a genome-wide association study-linked locus (CCR6) in Asian rheumatoid arthritis

A genome-wide association study in Japan identified the C-C chemokine receptor type 6 gene (CCR6) as associated with rheumatoid arthritis (RA). This finding has not been validated in other Asian populations. A case-control study involving 996 subjects, comprising 440 controls and 556 RA patients, was done to determine their anticyclic citrullinated peptide (anti-CCP) antibody status and CCR6 polymorphism (rs3093024) genotype. Three hundred eighty-seven patients were anti-CCP positive and 153 anti-CCP negative. Logistic regression showed that allele A was likely to increase the risk of developing RA among females via a recessive model (odds ratio [OR]=1.55, 95% confidence interval [CI]=1.01, 2.39), whereas the risk effect appeared to be reduced among males via an additive model (OR=0.60, 95% CI=0.42, 0.85). Considering only subjects who are anti-CCP positive, allele A increased RA risk among females via a recessive model (OR=1.68, 95% CI=1.07, 2.64) but decreased the risk among males via an additive model (OR=0.59, 95% CI=0.39, 0.89). We showed that CCR6 polymorphism was a risk factor among females but a protective factor among males. Functional studies are warranted to unravel the pathophysiological relevance of the gene variant and other linked variants with RA.     

Endothelial progenitor cells in cardiovascular diseases

Endothelial dysfunction has been associated with the development of atherosclerosis and cardiovascular diseases. Adult endothelial progenitor cells(EPCs) are derived from hematopoietic stem cells and are capable of forming new blood vessels through a process of vas-culogenesis. There are studies which report correlations between circulating EPCs and cardiovascular risk fac-tors. There are also studies on how pharmacotherapies may influence levels of circulating EPCs. In this review, we discuss the potential role of endothelial progenitor cells as both diagnostic and prognostic biomarkers. In addition, we look at the interaction between cardio-vascular pharmacotherapies and endothelial progenitor cells. We also discuss how EPCs can be used directly and indirectly as a therapeutic agent. Finally, we evalu-ate the challenges facing EPC research and how these may be overcome.     

原代培养过程中壳聚糖衍生物对CTCF/YB-1/C-myc和p53蛋白表达的影响

成功建立了人增生性瘢痕细胞和正常皮肤成纤维细胞的原代培养, 并利用热休克蛋白(HSP47)和成纤维细胞特异蛋白(FSP)标记物进行了鉴定。研究发现, 经过壳聚糖衍生物处理, 人增生性瘢痕成纤维细胞和正常皮肤成纤维细胞在培养中均出现了不同类型的蛋白表达。多功能转录因子蛋白(CTCF)在壳聚糖衍生物处理的增生性瘢痕成纤维细胞中出现表达上调; 在聚糖衍生物处理的正常皮肤成纤维细胞中数量无变化。YB-1结合蛋白在经壳聚糖处理的正常皮肤成纤维细胞与人增生性瘢痕细胞中的表达几乎无异, 但在未经壳聚糖处理的细胞中表达不同。C-MYC和P53蛋白在壳聚糖衍生物处理的增生性瘢痕纤维细胞中表达上调, 但在正常皮肤成纤维细胞中, 无论是否经过壳聚糖衍生物处理, 这两种蛋白都没有表达。上述4种蛋白在人增生性瘢痕细胞和正常皮肤成纤维细胞中表现出不同的表达方式, 这种新型壳聚糖衍生物可能在控制人增生性瘢痕细胞和正常皮肤成纤维细胞生长和增殖过程中起着重要作用。这些蛋白因子的表达机制目前还不是完全清楚, 有待于进一步研究。     

Sequence variants in the PLEKHH2 region are associated with diabetic nephropathy in the GoKinD study population

Nephropathy is a common microvascular complication of diabetes with a genetic component for disease development. Genetic analyses have implicated multiple chromosomal regions for disease susceptibility but no single locus can account for the majority of the genetic component. Here, we report a genetic analysis of the PLEKHH2 gene that was identified through a single nucleotide polymorphism (SNP) genome-wide association study (GWAS) for association with the development of diabetic nephropathy (DN) in the Genetics of Kidneys in Diabetes (GoKinD) study population. We initially examined the GWAS results from a subset of the GoKinD singleton population based on the two most common HLA diplotypes consisting of 112 cases and 148 controls. We observed two-adjacent markers mapping to the PLEKHH2 locus, rs1368086 and rs725238, each associated at P < 0.001. Additional SNPs were selected for linkage disequilibrium mapping and transmission disequilibrium testing (TdT) in 246 case trio families. A single marker, rs11886047, located upstream of the PLEKHH2 promoter was associated with DN by TdT in the case trios (P = 0.0307), and there was a increase of heterozygous genotypes in cases, relative to controls, from the 601 case and 577 control GoKinD singleton case/control population (P = 0.00256). These findings suggest that PLEKHH2, which has mRNA and protein expression exclusively in the glomerulus, may be a genetic risk factor for susceptibility to DN in the GoKinD population. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Prior exercise increases basal and insulin-induced p38 mitogen-activated protein kinase phosphorylation in human skeletal muscle.

We have examined the effects of insulin on p38 mitogen-activated protein kinase (MAPK) phosphorylation in human skeletal muscle and the effects of prior exercise hereon. Seven men performed 1-h one-legged knee extensor exercise 3 h before the initiation of a 100-min euglycemic-hyperinsulinemic (600 pmol/l) clamp. Glucose uptake across the legs was measured with the leg balance technique, and muscle biopsies were obtained from the rested and exercised vastus lateralis before and during insulin infusion. Net glucose uptake during the clamp was approximately 50% higher (P < 0.05) in the exercised leg than in the rested leg. Insulin induced a modest sustained 1.2- and 1.3-fold increase (P < 0.05) in p38 MAPK phosphorylation in the rested and exercised legs, respectively. However, p38 phosphorylation was approximately 50% higher (P < 0.05) in the exercised compared with the rested leg before and during insulin infusion. We conclude that a physiological concentration of insulin causes modest but sustained activation of the p38 MAPK pathway in human skeletal muscle. Furthermore, the stimulatory effect of exercise on p38 phosphorylation is persistent for at least 3 h after exercise and remains evident during subsequent insulin stimulation. Because p38 MAPK has been suggested to play a necessary role in activation of GLUT-4 at the cell surface, the present data may suggest a putative role of p38 MAPK in the increased insulin sensitivity of skeletal muscle after exercise.