Evolutionarily singular strategies and the adaptive growth and branching of the evolutionary tree

We present a general framework for modelling adaptive trait dynamics in which we integrate various concepts and techniques from modern ESS-theory. The concept of evolutionarily singular strategies is introduced as a generalization of the ESS-concept. We give a full classification of the singular strategies in terms of ESS-stability, convergence stability, the ability of the singular strategy to invade other populations if initially rare itself, and the possibility of protected dimorphisms occurring within the singular strategy's neighbourhood. Of particular interest is a type of singular strategy that is an evolutionary attractor from a great distance, but once in its neighbourhood a population becomes dimorphic and undergoes disruptive selection leading to evolutionary branching. Modelling the adaptive growth and branching of the evolutionary tree can thus be considered as a major application of the framework. A haploid version of Levene's soft selection model is developed as a specific example to demonstrate evolutionary dynamics and branching in monomorphic and polymorphic populations.     

Anthrax lethal toxin enhances cytokine-induced VCAM-1 expression on human endothelial cells

Vascular endothelial dysfunction is thought to play a prominent role in systemic anthrax pathogenesis. We examined the effect of anthrax lethal toxin (LTx), a key virulence factor of Bacillus anthracis, on the expression of vascular cell adhesion molecule-1 (VCAM-1) on normal and cytokine-stimulated human lung microvascular endothelial cells. Confluent endothelial monolayers were treated with lethal factor (LF), protective antigen (PA), or both (LTx) in the presence or absence of tumor necrosis factor-alpha (TNFalpha). LTx enhanced cytokine-induced VCAM-1 expression and monocyte adhesion. LTx alone had no effect on VCAM-1 expression. LF, PA or the combination of a catalytically inactive mutant LF and PA failed to enhance cytokine-induced VCAM-1 expression. Treatment with inhibitors of mitogen-activated protein kinase kinases (MEKs) and mitogen-activated protein kinases did not reproduce the VCAM-1 enhancement effect of LTx, a known MEK metalloprotease, suggesting LTx-mediated MEK cleavage may not be a contributing factor.     

鸡PPARγ基因的表达特性及其对脂肪细胞增殖分化的影响

为分析鸡PPARγ基因的组织表达特性及其在脂肪细胞增殖和分化过程中的功能,文章以东北农业大学高、低腹脂双向选择品系肉鸡为实验材料,利用Western blotting方法,检测PPARγ基因的组织表达特性及其在高、低脂系肉鸡腹部脂肪组织间的表达差异;采用RNAi技术,在鸡原代脂肪细胞中抑制PPARγ基因的表达后,通过MTT和油红O提取比色的方法,研究鸡PPARγ基因对脂肪细胞增殖和分化的调控作用;利用Real-timePCR和Western blotting技术,分析PPARγ基因表达下调后,其他脂肪细胞分化转录因子以及与脂肪细胞分化相关的重要基因的表达变化情况。结果表明,PPARγ基因在7周龄高脂系肉鸡腹部脂肪组织、肌胃、脾脏、肾脏组织中表达量较高,在心脏中表达量较低,在肝脏、胸肌、腿肌、十二指肠中未检测到表达信号;与高脂系相比,PPARγ基因在5和7周龄低脂系肉鸡腹部脂肪组织中的表达量较低(P<0.05);PPARγ基因的表达量下降后,鸡脂肪细胞的增殖能力增强,分化能力减弱;同时,C/EBPα、SREBP1、A-FABP、Perilipin1、LPL、IGFBP-2基因的表达量均下降(P<0.05)。由此可见,PPARγ基因的表达可能与肉鸡腹部脂肪的沉积有一定的关系,该基因可能是调控鸡脂肪细胞增殖与分化的关键因子。     

Multimodal signals in male European treefrog (Hyla arborea) and the influence of population isolation on signal expression

In nocturnal treefrogs, mate choice implies the use of acoustic and visual signals. Multimodality is suspected to have evolved for either information redundancy or information complementariness. It is essential to explore multimodality in a natural context to understand the selection pressures operating on the signals. In the present study, we investigated calling and coloration in relation to male biometry and condition in four populations of European treefrog (Hyla arborea) varying in size and genetic isolation. We compared the signal intensity between core and satellite populations to estimate the impact of genetic diversity on male secondary sexual traits. The results obtained show important regional variations in both traits, likely as a result of local adaptations. Call and coloration are weakly correlated within an individual, implying that these traits likely convey different information about the signaller's identity or quality, thus supporting the hypothesis of complementariness of multiple messages. By contrast to the experimental evidence, we find that call and coloration are not related to male condition (as estimated by the residual of mass over size), suggesting that the condition‐dependence of these traits may be mediated by complex mechanisms not accurately reflected by the chosen estimator. Finally, male call and colour phenotypes present no robust pattern of variation with isolation status, probably because of variation in local selective pressures and in history of population dynamics. © 2011 The Linnean Society of London, Biological Journal of the Linnean Society, 2011, 103 , 633–647.     

Common Polymorphism in the Phosphatase PHLPP2 Results in Reduced Regulation of Akt and Protein Kinase C

PHLPP2 (PH domain leucine-rich repeat protein phosphatase 2) terminates Akt and protein kinase C (PKC) activity by specifically dephosphorylating these kinases at a key regulatory site, the hydrophobic motif (Ser-473 in Akt1). Here we identify a polymorphism that results in an amino acid change from a Leu to Ser at codon 1016 in the phosphatase domain of PHLPP2, which reduces phosphatase activity toward Akt both in vitro and in cells, in turn resulting in reduced apoptosis. Depletion of endogenous PHLPP2 variants in breast cancer cells revealed the Ser-1016 variant is less functional toward both Akt and PKC. In pair-matched high grade breast cancer samples we observed retention of only the Ser allele from heterozygous patients (identical results were observed in a pair-matched normal and tumor cell line). Thus, we have identified a functional polymorphism that impairs the activity of PHLPP2 and correlates with elevated Akt phosphorylation and increased PKC levels.Breast cancer is diagnosed in ∼180,000 women and is the cause of 40,000 deaths each year in the U.S.² A prevalent underlying mechanism driving tumorigenesis is aberrant signal transduction pathways that result in constitutive activation of cell growth, proliferation, and survival pathways (2). A well characterized signal transduction pathway in breast cancer that promotes cellular survival, growth, and proliferation is the phosphatidylinositol 3-kinase/Akt pathway (3). This pathway is activated by a number of mechanisms, including gene amplification or gain of function mutations in upstream receptor protein-tyrosine kinases (4, 5), constitutive activation of hormone receptors (6), activating mutations in phosphatidylinositol 3-kinase and Akt (7, 8), and loss of function mutations in the regulatory phosphatase PTEN³ (phosphatase and tensin homolog on chromosome ten) (9). Thus, Akt is a major regulator of breast tumorigenesis.There are three isoforms of Akt present in humans. All three isoforms contain activating phosphorylation sites in the activation loop (Thr-308 in Akt1) and in the C-terminal hydrophobic motif (Ser-473 in Akt1) (10). Upon growth factor receptor stimulation, phosphatidylinositol 3-kinase becomes activated and phosphorylates the D3 position of, typically, phosphatidylinositol (4, 5) bisphosphate to generate phosphatidylinositol (3,4,5)-trisphosphate (11). This 3′-phosphorylated lipid recruits Akt to the plasma membrane by binding to its PH domain, resulting in conformational changes that allow access to the activation loop phosphorylation site (11). Constitutively bound phosphatidylinositol-dependent kinase-1 then phosphorylates Akt at Thr-308, accompanied by phosphorylation at Ser-473 resulting in a catalytically active kinase (12). Phosphorylation of Ser-473 depends on the mTORC2 complex (13-16). Signaling through this pathway is terminated by removal of the lipid second messenger phosphatidylinositol (3,4,5)-trisphosphate catalyzed by the phosphatase PTEN and by direct dephosphorylation of Akt by the recently-identified PHLPP family of phosphatases and protein phosphatase 2A-type phosphatases (17-20).The PHLPP family of phosphatases comprise three variants, the alternatively spliced PHLPP1α and PHLPP1β, and PHLPP2 (21). PHLPP1 and PHLPP2 specifically dephosphorylate the hydrophobic motif of specific Akt isozymes, thus decreasing Akt activity and promoting apoptosis (18, 19). PHLPP2 binds and dephosphorylates Akt1 and Akt3, whereas PHLPP1 binds and dephosphorylates Akt2 and Akt3 (18, 22). Their role in inactivating Akt suggests that both PHLPP1 and PHLPP2 could be potential tumor suppressors. Consistent with such a role, these phosphatases also dephosphorylate the hydrophobic motif of PKC, resulting in degradation of PKC. For this kinase, phosphorylation stabilizes the enzyme, so that the effect of depletion of the PHLPP phosphatases is to increase PKC protein levels (23). PKC is a well characterized oncogene, and loss of function of the PHLPP phosphatases could increase PKC protein levels and promote tumorigenesis (24). Providing further rationale that PHLPP2 could be a potential tumor suppressor, the phosphatase is located on chromosome 16q22.3, a region that encounters frequent loss of heterozygosity (LOH) in many primary and malignant breast tumors (25).Here we identify a non-synonymous polymorphism that results in an amino acid change from a Leu to a Ser at codon 1016 in the PP2C phosphatase domain of PHLPP2. Overexpression studies reveal the Ser-1016 variant has impaired phosphatase activity and is less effective at inducing apoptosis than the Leu-1016 variant. When comparing a pair-matched normal and breast cancer cell line or pair-matched normal and high grade tumor patient samples that are heterozygous, we observe preferential loss of the Leu allele in the tumor tissue or breast cancer cell line. This observation provides evidence that PHLPP2 could be one of the elusive tumor suppressor genes on chromosome 16q, and for heterozygous patients, loss of the more catalytically active Leu-1016 may promote breast tumorigenesis.     

Male preponderance in early diagnosed type 2 diabetes is associated with the ARE insertion/deletion polymorphism in the <Emphasis Type="Italic">PPP1R3A</Emphasis> locus

Background  

The ARE insertion/deletion polymorphism of PPP1R3A has been associated with variation in glycaemic parameters and prevalence of diabetes. We have investigated its role in age of diagnosis, body weight and glycaemic control in 1,950 individuals with type 2 diabetes in Tayside, Scotland, and compared the ARE2 allele frequencies with 1,014 local schoolchildren.