Ablation of PRC1 by small interfering RNA demonstrates that cytokinetic abscission requires a central spindle bundle in mammalian cells, whereas completion of furrowing does not

The temporal and spatial regulation of cytokinesis requires an interaction between the anaphase mitotic spindle and the cell cortex. However, the relative roles of the spindle asters or the central spindle bundle are not clear in mammalian cells. The central spindle normally serves as a platform to localize key regulators of cell cleavage, including passenger proteins. Using time-lapse and immunofluorescence analysis, we have addressed the consequences of eliminating the central spindle by ablation of PRC1, a microtubule bundling protein that is critical to the formation of the central spindle. Without a central spindle, the asters guide the equatorial cortical accumulation of anillin and actin, and of the passenger proteins, which organize into a subcortical ring in anaphase. Furrowing goes to completion, but abscission to create two daughter cells fails. We conclude the central spindle bundle is required for abscission but not for furrowing in mammalian cells.     

Role of Abca7 in Mouse Behaviours Relevant to Neurodegenerative Diseases

ATP-binding cassette transporters of the subfamily A (ABCA) are responsible for the translocation of lipids including cholesterol, which is crucial for neurological function. Recent studies suggest that the ABC transporter ABCA7 may play a role in the development of brain disorders such as schizophrenia and Alzheimer’s disease. However, Abca7’s role in cognition and other behaviours has not been investigated. Therefore, we characterised homozygous Abca7 knockout mice in a battery of tests for baseline behaviours (i.e. physical exam, baseline locomotion and anxiety) and behaviours relevant to schizophrenia (i.e. prepulse inhibition and locomotor response to psychotropic drugs) and Alzheimer’s disease (i.e. cognitive domains). Knockout mice had normal motor functions and sensory abilities and performed the same as wild type-like animals in anxiety tasks. Short-term spatial memory and fear-associated learning was also intact in Abca7 knockout mice. However, male knockout mice exhibited significantly impaired novel object recognition memory. Task acquisition was unaffected in the cheeseboard task. Female mice exhibited impaired spatial reference memory. This phenomenon was more pronounced in female Abca7 null mice. Acoustic startle response, sensorimotor gating and baseline locomotion was unaltered in Abca7 knockout mice. Female knockouts showed a moderately increased motor response to MK-801 than control mice. In conclusion, Abca7 appears to play only a minor role in behavioural domains with a subtle sex-specific impact on particular cognitive domains.     

FoxP3+ Regulatory T Cells Determine Disease Severity in Rodent Models of Inflammatory Neuropathies

Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies.     

Inositol 1,4,5-trisphosphate receptor-isoform diversity in cell death and survival

Cell-death and -survival decisions are critically controlled by intracellular Ca^2 + homeostasis and dynamics at the level of the endoplasmic reticulum (ER). Inositol 1,4,5-trisphosphate (IP₃) receptors (IP₃Rs) play a pivotal role in these processes by mediating Ca^2 + flux from the ER into the cytosol and mitochondria. Hence, it is clear that many pro-survival and pro-death signaling pathways and proteins affect Ca^2 + signaling by directly targeting IP₃R channels, which can happen in an IP₃R-isoform-dependent manner. In this review, we will focus on how the different IP₃R isoforms (IP₃R1, IP₃R2 and IP₃R3) control cell death and survival. First, we will present an overview of the isoform-specific regulation of IP₃Rs by cellular factors like IP₃, Ca^2 +, Ca^2 +-binding proteins, adenosine triphosphate (ATP), thiol modification, phosphorylation and interacting proteins, and of IP₃R-isoform specific expression patterns. Second, we will discuss the role of the ER as a Ca^2 + store in cell death and survival and how IP₃Rs and pro-survival/pro-death proteins can modulate the basal ER Ca^2 + leak. Third, we will review the regulation of the Ca^2 +-flux properties of the IP₃R isoforms by the ER-resident and by the cytoplasmic proteins involved in cell death and survival as well as by redox regulation. Hence, we aim to highlight the specific roles of the various IP₃R isoforms in cell-death and -survival signaling. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.     

记河北省后城组新发现之小型兽脚类足迹(英文)

几十年前人们就已经开始研究中国东北侏罗纪—白垩纪界线附近地层中的小型兽脚类恐龙足迹,虽然这些遗迹化石比辽宁省义县组带羽毛的恐龙及其他实体化石逊色了许多。本文记述了河北省承德南双庙后城组(土城子组)最下部河流相沉积中发现的一组兽脚类恐龙足迹。南双庙足迹具有三趾,趾粗大,其形态与美国下侏罗统经典的"brontozoid"足迹(Gral- lator,Anchisauripus和Eubrontes)相符。虽然许多产自辽宁土城子组中基本同时的brontozoid足迹被鉴定为小型的跷脚龙足迹属(Grallator),但南双庙足迹更大一些(全长可达28.8 cm),可能应该归入安琪龙足迹属(Anchisauripus)。南双庙足迹很可能是一群小型兽脚类行走而产生。在辽宁义县组的兽脚类恐龙中,最可能留下这类足迹的是小型的窃蛋龙类——尾羽龙(Caudipteryx)。不过这个解释还很勉强,因为这些足迹缺乏鉴定性特征,而且河北的后城组与辽宁的义县组之间还有一定的时间及地理间隔。     

Markers of enhanced cholesterol absorption are a strong predictor for cardiovascular diseases in patients without diabetes mellitus

Objective

Hypercholesterolemia is a major risk factor for cardiovascular disease (CVD), and diabetes mellitus and statin treatment affect cholesterol metabolism. The aim of the present study was to evaluate markers of cholesterol metabolism and determine their relationship with CVD in patients without diabetes mellitus who were not receiving statin treatment.

Methods

In addition to conventional CVD risk factors, plasma levels of campesterol and sitosterol (indicators of cholesterol absorption) and lathosterol (an indicator of cholesterol synthesis) were determined in 835 consecutive patients referred for coronary angiography. Coronary artery disease was evaluated by coronary angiograms, carotid atherosclerosis and peripheral vascular disease were assessed by Doppler ultrasound, and cerebrovascular accidents and transient ischemic attacks were identified by medical history.

Results

After excluding patients with known diabetes mellitus and those receiving statin treatment, 177 patients were included in the analysis. Compared to patients without CVDs (n = 111), patients with concomitant CVDs (n = 66) had a reduced lathosterol-to-cholesterol ratio (1.25 ± 0.61 vs. 1.38 ± 0.63, P < 0.05) and an increased campesterol-to-cholesterol ratio (1.81 ± 1.04 vs. 1.50 ± 0.69, P < 0.05), indicating that enhanced absorption and reduced synthesis of cholesterol is associated with CVD development. Logistic regression analysis including all established cardiovascular risk factors (age, sex, total cholesterol, arterial hypertension, body mass index and smoking) revealed that campesterol and the campesterol-to-cholesterol ratio were significant predictors of concomitant CVD in this patient population.

Conclusion

In patients without diabetes mellitus, markers of enhanced cholesterol absorption were a strong predictor for concomitant CVD.     

Hormonal and metabolic responses to nesting activities in the green turtle, Chelonia mydas

We examined the association between green turtle nesting activities and plasma profiles of hormones that are widely implicated in aspects of heightened metabolism and energy regulation; epinephrine (EPI), norepinephrine (NE) and corticosterone. In conjunction, we examined plasma profiles of glucose and lactate to infer metabolic processes associated with green turtle nesting behaviour. Finally, because these hormones are also involved in mediating behaviour and physiology associated with stressful situations, we examined the effect of a stressor encountered during nesting, physical disturbance, on hormone levels. Plasma profiles of epinephrine, norepinephrine and corticosterone were not significantly altered across different stages of nesting. Plasma glucose and lactate both exhibited significant increases related to nesting activity; glucose increased dramatically during the emergence stage of nesting before stabilizing, and lactate levels continued to increase throughout the nesting process. There was no significant association between plasma hormones and glucose. For female turtles that abandoned nesting activities due to competition for nest space, there was no significant difference in plasma levels of epinephrine, norepinephrine and corticosterone compared to females that persisted with nesting activities. Overall, while distinct metabolic changes took place in nesting females, there was little association in profiles of hormones typically considered important for regulating heightened metabolism and nesting activity. This disassociation could arise because hormonal action may be altered in breeding female green turtles to facilitate reproductive processes.     

The contribution of the mitochondrial genome to sex‐specific fitness variance

Maternal inheritance of mitochondrial DNA (mtDNA) facilitates the evolutionary accumulation of mutations with sex‐biased fitness effects. Whereas maternal inheritance closely aligns mtDNA evolution with natural selection in females, it makes it indifferent to evolutionary changes that exclusively benefit males. The constrained response of mtDNA to selection in males can lead to asymmetries in the relative contributions of mitochondrial genes to female versus male fitness variation. Here, we examine the impact of genetic drift and the distribution of fitness effects (DFE) among mutations—including the correlation of mutant fitness effects between the sexes—on mitochondrial genetic variation for fitness. We show how drift, genetic correlations, and skewness of the DFE determine the relative contributions of mitochondrial genes to male versus female fitness variance. When mutant fitness effects are weakly correlated between the sexes, and the effective population size is large, mitochondrial genes should contribute much more to male than to female fitness variance. In contrast, high fitness correlations and small population sizes tend to equalize the contributions of mitochondrial genes to female versus male variance. We discuss implications of these results for the evolution of mitochondrial genome diversity and the genetic architecture of female and male fitness.