Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death

Mitochondria play a critical role in mediating both apoptotic and necrotic cell death. The mitochondrial permeability transition (mPT) leads to mitochondrial swelling, outer membrane rupture and the release of apoptotic mediators. The mPT pore is thought to consist of the adenine nucleotide translocator, a voltage-dependent anion channel, and cyclophilin D (the Ppif gene product), a prolyl isomerase located within the mitochondrial matrix. Here we generated mice lacking Ppif and mice overexpressing cyclophilin D in the heart. Ppif null mice are protected from ischaemia/reperfusion-induced cell death in vivo, whereas cyclophilin D-overexpressing mice show mitochondrial swelling and spontaneous cell death. Mitochondria isolated from the livers, hearts and brains of Ppif null mice are resistant to mitochondrial swelling and permeability transition in vitro. Moreover, primary hepatocytes and fibroblasts isolated from Ppif null mice are largely protected from Ca2+-overload and oxidative stress-induced cell death. However, Bcl-2 family member-induced cell death does not depend on cyclophilin D, and Ppif null fibroblasts are not protected from staurosporine or tumour-necrosis factor-alpha-induced death. Thus, cyclophilin D and the mitochondrial permeability transition are required for mediating Ca2+- and oxidative damage-induced cell death, but not Bcl-2 family member-regulated death.     

天空巡礼：双筒望远镜和大视场望远镜天文学

本书是一本长篇巨著．作者从春、夏、秋、冬各个季节的星空论述了恒星、恒星群、星云、星系、球状星团、行星、开放星团、银河及其亮星星云。书中生动地描述了这些可见天体，介绍了如何找到它们，讲解了它们在银河系旋臂结构中的位置，论述了用双筒望远镜和大视场望远镜可以观测到的令人惊奇的许多星系的事件，以及这些事件与我们的关系。书中收集了近100幅彩色和黑白照片，读者通过这些照片可以漫步在银河际空间。     

Testing the neutral theory of molecular evolution with genomic data from Drosophila

Although positive selection has been detected in many genes, its overall contribution to protein evolution is debatable. If the bulk of molecular evolution is neutral, then the ratio of amino-acid (A) to synonymous (S) polymorphism should, on average, equal that of divergence. A comparison of the A/S ratio of polymorphism in Drosophila melanogaster with that of divergence from Drosophila simulans shows that the A/S ratio of divergence is twice as high---a difference that is often attributed to positive selection. But an increase in selective constraint owing to an increase in effective population size could also explain this observation, and, if so, all genes should be affected similarly. Here we show that the difference between polymorphism and divergence is limited to only a fraction of the genes, which are also evolving more rapidly, and this implies that positive selection is responsible. A higher A/S ratio of divergence than of polymorphism is also observed in other species, which suggests a rate of adaptive evolution that is far higher than permitted by the neutral theory of molecular evolution.     

TLR signalling augments macrophage bactericidal activity through mitochondrial ROS

Reactive oxygen species (ROS) are essential components of the innate immune response against intracellular bacteria and it is thought that professional phagocytes generate ROS primarily via the phagosomal NADPH oxidase machinery. However, recent studies have suggested that mitochondrial ROS (mROS) also contribute to mouse macrophage bactericidal activity, although the mechanisms linking innate immune signalling to mitochondria for mROS generation remain unclear. Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT- and TRAF6-depleted macrophages have decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS levels by expressing catalase in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. These results reveal a novel pathway linking innate immune signalling to mitochondria, implicate mROS as an important component of antibacterial responses and further establish mitochondria as hubs for innate immune signalling.     

Science as Systemic Intervention: Some Implications of Systems Thinking and Complexity for the Philosophy of Science

This paper sidesteps the usual starting points for debate about complexity and the philosophy of science, which tend to assume that science is primarily about observation. Instead, the starting point is intervention, defined as purposeful action by an agent to create change. While some authors suggest that intervention and observation are opposites, it is argued here that observation (as undertaken in science) should be viewed as just one type of intervention. We should therefore welcome scientific techniques of observation into a pluralistic set of intervention methods, alongside methods for exploring values, reflecting on subjective understandings, planning future activities, etc. However, there is a need to explicitly counter a possible pernicious interpretation of this argument: intervention could (erroneously) be viewed as flawlessly preplanned change based on accurate predictions of the consequences of action. This is the mechanistic worldview that systems thinking and complexity science seek to challenge. Therefore, having redefined scientific observation as intervention, the paper revisits insights from systems thinking and complexity to propose a methodology of systemic intervention. Some brief reflections are then provided on the wider social implications of this methodology.