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.     

Two populations of X-ray pulsars produced by two types of supernova

Two types of supernova are thought to produce the overwhelming majority of neutron stars in the Universe. The first type, iron-core-collapse supernovae, occurs when a high-mass star develops a degenerate iron core that exceeds the Chandrasekhar limit. The second type, electron-capture supernovae, is associated with the collapse of a lower-mass oxygen-neon-magnesium core as it loses pressure support owing to the sudden capture of electrons by neon and/or magnesium nuclei. It has hitherto been impossible to identify the two distinct families of neutron stars produced in these formation channels. Here we report that a large, well-known class of neutron-star-hosting X-ray pulsars is actually composed of two distinct subpopulations with different characteristic spin periods, orbital periods and orbital eccentricities. This class, the Be/X-ray binaries, contains neutron stars that accrete material from a more massive companion star. The two subpopulations are most probably associated with the two distinct types of neutron-star-forming supernova, with electron-capture supernovae preferentially producing systems with short spin periods, short orbital periods and low eccentricities. Intriguingly, the split between the two subpopulations is clearest in the distribution of the logarithm of spin period, a result that had not been predicted and which still remains to be explained.     

Activin- and Nodal-related factors control antero-posterior patterning of the zebrafish embryo

Definition of cell fates along the dorso-ventral axis depends on an antagonistic relationship between ventralizing transforming growth factor-beta superfamily members, the bone morphogenetic proteins and factors secreted from the dorsal organizer, such as Noggin and Chordin. The extracellular binding of the last group to the bone morphogenetic proteins prevents them from activating their receptors, and the relative ventralizer:antagonist ratio is thought to specify different dorso-ventral cell fates. Here, by taking advantage of a non-genetic interference method using a specific competitive inhibitor, the Lefty-related gene product Antivin, we provide evidence that cell fate along the antero-posterior axis of the zebrafish embryo is controlled by the morphogenetic activity of another transforming growth factor-beta superfamily subgroup--the Activin and Nodal-related factors. Increasing antivin doses progressively deleted posterior fates within the ectoderm, eventually resulting in the removal of all fates except forebrain and eyes. In contrast, overexpression of activin or nodal-related factors converted ectoderm that was fated to be forebrain into more posterior ectodermal or mesendodermal fates. We propose that modulation of intercellular signalling by Antivin/Activin and Nodal-related factors provides a mechanism for the graded establishment of cell fates along the antero-posterior axis of the zebrafish embryo.     

A novel <Emphasis Type=Italic>in vitro</Emphasis> angiogenesis model based on a microfluidic device

Angiogenesis is very important for many physiological and pathological processes. However, the molecular mechanisms of angiogenesis are unclear. To elucidate the molecular mechanisms of angiogenesis and to develop treatments for angiogenesis-dependent diseases, it is essential to establish a suitable in vitro angiogenesis model. In this study, we created a novel in vitro angiogenesis model based on a microfluidic device. Our model provides an in vivo-like microenvironment for endothelial cells (ECs) cultures and monitors the response of ECs to changes in their microenvironment in real time. To evaluate the potential of this microfluidic device for researching angiogenesis, the effects of pro-angiogenic factors on ECs proliferation, migration and tube-like structure formation were investigated. Our results showed the proliferation rate of ECs in 3D matrix was significantly promoted by the pro-angiogenic factors (with an increase of 59.12%). With the stimulation of pro-angiogenic factors gradients, ECs directionally migrated into the Matrigel from low concentrations to high concentrations and consequently formed multi-cell chords and tube-like structures. These results suggest that the device can provide a suitable platform for elucidating the mechanisms of angiogenesis and for screening pro-angiogenic or anti-angiogenic drugs for angiogenesis-dependent diseases.     

First episode psychosis with extrapyramidal signs prior to antipsychotic drug treatment

Extrapyramidal movement disorders are common in chronic schizophrenia, and may be an intrinsic feature of the illness as well as related to antipsychotic drug treatment. Similar dysfunctions at illness onset may have implications for outcome, and for under- standing the mechanisms of illness. The objectives were to examine the clinical correlates of pre-treatment movement disorders at first episode of psychosis, and determine associations with neuropsychological function and striatal structure. Never medicated subjects were recruited from consecutive admissions to Early Psychosis Programs with defined catchment areas in Hong Kong, China, and Halifax, Canada. Standardized clinical, neuropsychological and brain imaging assessments were carried out at baseline and following acute and long term treatment with typical or atypical antipsychotic drugs. At the Hong Kong site, we studied 84 subjects with first episode psychosis (n = 10 with EPS). At the Halifax site, we studied 40 subjects with first episode psychosis (n = 17 with EPS), and 23 healthy comparison subjects. Subjects with movement disorders prior to treatment (EPS+) had higher total PANSS scores at baseline (mean elevation 19.9% Hong Kong, P = 0.016; 14.7% Halifax, P = 0.049). In subjects treated with atypical antipsychotics (all Halifax), EPS+ status at baseline predicted more movement disorders at long term follow up (P = 0.0005). In both cohorts, EPS+ subjects had poorer acute symptomatic treatment response assessed with the PANSS (Hong Kong P = 0.005; Halifax P = 0.017). Neuropsychological impairment related to executive dysfunction appeared greater in a small sam- ple of EPS+ subjects (Hong Kong, effect size 0.26-0.27, P < 0.05). Caudate volumes were 4.5% larger in EPS+ compared with EPS-subjects (Halifax P = 0.042), and correlations between striatal volumes and age were different in the EPS+ group. In conclu- sion, pre-treatment EPS is present in a substantial minority of subjects with first episode psychosis, appears to persist at long term follow up, and is associated with poorer response of symptoms to treatment. Selective impairment of executive function and stria- tal enlargement provides evidence of abnormalities of brain function and structure associated with this aspect of early psychosis.     

曲梁桥地震分析的有限单元法

本文采用曲线座标系来计算曲梁桥的地震反应。为了计入约束扭转的影响,演引了每节点八个自由度的曲梁单元及墩单元的刚度矩阵及三个方向地震质量矩阵,经过数例的计算比较,效果良好。