Mitochondrial disappearance from cells: a clue to the role of autophagy in programmed cell death and disease?

When cells are induced to undergo apoptosis in the presence of general caspase inhibitors and then returned to their normal growth environment, there follows an extended period of life during which the entire cohort of mitochondria (including mitochondrial DNA) disappears from the cells. This phenomenon is widespread; it occurs in NGF-deprived sympathetic neurons, in NGF-maintained neurons treated with cytosine arabinoside, and in diverse cell lines treated with staurosporine, including HeLa, CHO, 3T3 and Rat 1 cells. Mitochondrial removal is highly selective since the structure of all other organelles remains unperturbed. Since Bcl2 overexpression blocks the removal of mitochondria without preventing death-inducing signals, it appears that the mitochondria are responsible for initiating their own demise. Degradation of mitochondria is not in itself a rare event. It occurs in large part by autophagy during normal cell house-keeping, during ecdysis in insects, as well as after induction of apoptosis. However, the complete and selective removal of an entire cohort of mitochondria in otherwise living mammalian cells has not been described previously. These findings raise several questions. What are the mechanisms which remove mitochondria in such a 'clean' fashion? What are the signals that target mitochondria for such selective degradation? How are cells that have lost their mitochondria different from rho0 cells (which retain mitochondria but lack mitochondrial DNA, and cannot carry out oxidative phosphorylation)? Are the cells which have lost mitochondria absolutely committed to die or might they be repaired by mitochondrial therapy? The answers will be especially relevant when considering treatment of diseases affecting long-lived and non-renewable organs such as the nervous system.     

Cardiovascular risk and attitudes to lifestyle: what do patients think?

OBJECTIVE--To examine the relation between subjects'' level of cardiovascular risk and their beliefs about the harmfulness of their smoking habit, current diet, and level of exercise, together with their stated desire to modify such behaviour. DESIGN--Self administered postal health and life-style questionnaire followed by a structured health check conducted by a nurse. SETTING--Five general practices in Luton and Dunstable, Bedfordshire. SUBJECTS--5803 people aged 35-64 years enrolled in the OXCHECK trial who attended for a health check before 1 March 1992. MAIN OUTCOME MEASURES--Perceived risk to health of lifestyle behaviours, desire to modify behaviour, and a reported serious attempt to modify behaviour in the preceding year. RESULTS--A high proportion of smokers and those who were physically inactive perceived their behaviour to be harmful (1020; (76%; 95% confidence interval 74% to 79%) and 350 (74%; 70% to 78%) respectively) and wished to modify it (1212 (79%; 77% to 81%) and 375 (74%; 71% to 78%) respectively). In contrast, only 289 (45%; 41% to 48%) of obese people and 188 (14%; 12% to 16%) of people with a high dietary fat intake perceived their current diet to be harmful. The more cardiovascular risk factors present, the more likely subjects were to perceive a health risk attached to their diet and lack of exercise (p < 0.01 in both cases) and to want to improve their diet. CONCLUSION--Awareness of the health risk from smoking and motivation to stop is high. Further efforts are required, however, to educate the public about the risks associated with a high dietary fat intake. Although the health risks of inactivity were widely recognised, motivation to take more exercise needs to be increased.     

Exploring the difficulties of studying futures in ecology: what do ecological scientists think?

In a mainly experimental science based traditionally on hypothesis testing such as ecology, studying futures may be difficult. However, in the last few decades, predicting the consequences of global changes on the dynamics and function of ecological systems has become a major challenge in ecological research. To study how ecological scientists deal with potential difficulties in studying futures, we adopted a reflexive viewpoint on how scientists address the study of ecological futures. To do so we questioned a panel of ecological scientists on their practical involvement and point of view. Quantitative and qualitative analyses of their responses showed that predictions or predictive models were the dominant theme. Many quantitative models, based on statistical correlations, empirical rules or processes have been developed and their methodological limitations explored by the researchers we interviewed. In a small proportion of studies, qualitative scenarios have been elaborated to explore the range of possible futures. Interviewees emphasized the problem of dealing with ecological complexity and multiple future possibilities. Specificities of futures compared to past or present events were not fully identified. In fact, researchers studying futures mainly adopted a reductionist approach, trying to simplify complex ecological systems. But methods and tools promoted by such an approach to science may not always be appropriate to deal with future ecological complexity. Indeed, an emphasis on prediction prevents ecologists from acknowledging the multiplicity and undetermined nature of futures.     

The high sex ratio in China: what do the Chinese think?

High sex ratios are well documented in many Asian countries, including China. This study was conducted in three Chinese provinces to explore awareness of the high sex ratios and its effects. Questionnaires were completed by 7435 respondents; 46% were urban and 53% were female. Sixty-four per cent were aware of the high sex ratio, and the majority were able to identify a range of consequences both for society and for unmarried men. These high levels of awareness of the negative impacts of high sex ratios should ultimately help to reduce the sex ratio at birth.     

What do children think happens to the food they eat?

In this study, the explanations of two classes of 10-year old children about what happens to the food that they eat were explored, particularly in the context of theories about the development of children's concepts of the human body. These ideas were investigated in a number of ways: obtaining children's own writing and drawings; semi-structured individual interviews; and examining choices made between alternative explanations. The results suggested that children applied their knowledge of everyday materials to understand the initial stages of what happens to food, but their ideas about later stages were more tentative and within the group there was a range of different kinds of explanation preferred. The limitations and achievements of the children's thinking are considered in the context of the school curriculum.     

Sex and death: what is the connection?

A cost of reproduction, where lifespan and fecundity are negatively correlated, is of widespread occurrence. Mutations in insulin/IGF signaling (IIS) pathways and dietary restriction (DR) can extend lifespan in model organisms but do not always reduce fecundity, suggesting that the link between lifespan and fecundity is not inevitable. Understanding the molecular basis of the cost of reproduction will be informed by elucidation of the mechanisms by which DR and IIS affect these two traits.     

POPP the question: what do LEA proteins do?

Late embryogenesis abundant (LEA) proteins are produced in maturing seeds and anhydrobiotic plants, animals and microorganisms, in which their expression correlates with desiccation tolerance. However, their function has remained obscure for 20 years. We argue that novel computational tools devised for non-globular proteins might now overcome this problem. Predictions arising from bioinformatics fit well with recent data on Group 3 proteins, which potentially form cytoskeletal filaments, and suggest experimentally testable functions for these and other LEA protein groups.     

Ecological signature of the end-Triassic biotic crisis: what do bivalves have to say?

In order to understand the causes underlying the Triassic–Jurassic (T/J) mass extinction, we tested different bivalve features for extinction selectivity, i.e. shell mineralogy, age at the Rhaetian and three main autoecologic traits (feeding mechanism, tiering and motility/attachment). Also, diversity and turnover rates throughout the Triassic and the Early Jurassic were analysed in detail. The dataset employed for this analysis was a precise database at genus level including data from Induan to Sinemurian times. Results point to a true mass extinction for bivalves around the T/J boundary. This extinction was not age-selective at the boundary. Certain analyses suggested that shell mineralogy was a character significantly increasing survival odds, but this relationship seems to reflect selectivity on autoecologic traits. There was no difference in extinction proportions between both feeding types (i.e. deposit feeders and filter feeders); among the other traits, deep burrowers, epifaunal-motile and endobyssate forms seem to have been favoured, while shallow burrowers (and probably reclined forms) were more heavily affected. This pattern suggests an environmental stress at the boundary with some particular issues affecting the different life modes. Models linking magmatism in the Central Atlantic Magmatic Province with the end-Triassic mass extinction are a plausible scenario for this kind of perturbation.     

Mechanisms of tolerance to herbivore damage:what do we know?

Identifying mechanisms of tolerance to herbivore damage will facilitate attempts to understand the role of tolerance in the evolutionary and ecological dynamics of plants and herbivores. Investigations of the physiological and morphological changes that occur in plants in response to herbivore damage have identified several potential mechanisms of tolerance. However, it is unlikely that all physiological changes that occur following damage are tolerance mechanisms. Few studies have made direct comparisons between the expression of tolerance and the relative expression of putative mechanisms. I briefly review empirical evidence for some of the better-studied potential mechanisms, including increased photosynthetic activity, compensatory growth, utilization of stored reserves, and phenological delays. For each of these mechanisms I discuss reasons why the relationship between tolerance and these characters may be more complicated than it first appears. I conclude by discussing several empirical approaches, including herbivore manipulations, quantitative trait loci (QTL) analysis, and selection experiments, that will further our understanding of tolerance mechanisms. This revised version was published online in July 2006 with corrections to the Cover Date.     

The regulation of autophagy in eukaryotic cells: do all roads pass through Atg1?

The induction of autophagy appears to be tightly controlled in all eukaryotic cells. This highly conserved, degradative process is induced by a variety of signals, including nutrient deprivation, and is generally thought to be incompatible with rapid cell growth. Recent work in the budding yeast, Saccharomyces cerevisiae, has suggested that the Atg1 protein kinase is at the center of this control. Atg1, and its associated proteins, appear to be directly targeted by multiple signaling pathways important for the control of both autophagy and cell growth. These pathways involve the small GTP-binding Ras proteins, the Tor protein kinases and the AMP-activated protein kinase, Snf1, respectively. A key question that remains is whether this regulatory paradigm has been evolutionarily conserved. In other words, is Atg1 the primary target of those signaling pathways responsible for coordinating growth with environmental influences in other eukaryotes? Here, we suggest that Atg1 is very likely to fulfill this role but that a truly definitive answer will require that we develop a better understanding of this protein kinase and its targets in all eukaryotes.     

Neuroendocrine control of life histories: what do we need to know to understand the evolution of phenotypic plasticity?

Almost all life histories are phenotypically plastic: that is, life-history traits such as timing of breeding, family size or the investment in individual offspring vary with some aspect of the environment, such as temperature or food availability. One approach to understanding this phenotypic plasticity from an evolutionary point of view is to extend the optimality approach to the range of environments experienced by the organism. This approach attempts to understand the value of particular traits in terms of the selection pressures that act on them either directly or owing to trade-offs due to resource allocation and other factors such as predation risk. Because these selection pressures will between environments, the predicted optimal phenotype will too. The relationship expressing the optimal phenotype for different environments is the optimal reaction norm and describes the optimal phenotypic plasticity. However, this view of phenotypic plasticity ignores the fact that the reaction norm must be underlain by some sort of control system: cues about the environment must be collected by sense organs, integrated into a decision about the appropriate life history, and a message sent to the relevant organs to implement that decision. In multicellular animals, this control mechanism is the neuroendocrine system. The central question that this paper addresses is whether the control system affects the reaction norm that evolves. This might happen in two different ways: first, the control system will create constraints on the evolution of reaction norms if it cannot be configured to produce the optimal reaction norm and second, the control system will create additional selection pressures on reaction norms if the neuroendocrine system is costly. If either of these happens, a full understanding of the way in which selection shapes reaction norms must include details of the neuroendocrine control system. This paper presents the conceptual framework needed to explain what is meant by a constraint or cost being created by the neuroendocrine system and discusses the extent to which this occurs and some possible examples. The purpose of doing this is to encourage endocrinologists to take a fresh look at neuroendocrine mechanisms and help identify the properties of the system and situations in which these generate constraints and costs that impinge on the evolution of phenotypic plasticity.     

TRAM flap versus nonautologous breast reconstruction: what do patients really think?

Although there have been many reports of aesthetic outcomes after breast reconstruction, there have been comparatively few studies examining patient satisfaction and related subjective issues. The variables affecting satisfaction are only beginning to be understood, and patient satisfaction issues were explored in a more homogeneous patient population. A questionnaire surveying overall and aesthetic satisfaction, postoperative recuperation time, and symptoms was used to elicit candid patient responses. Fifty-seven patients replied (86 percent response rate), of whom 38 had undergone transverse rectus abdominis musculocutaneous (TRAM) flap (pedicled, n = 29; free, n = 9) reconstruction and 19 had undergone nonautologous reconstruction. Although the median patient satisfaction score was higher for the TRAM flap group, this was not statistically significant (p = 0.92). Recuperation was significantly longer for the TRAM flap group, with only 47 percent of patients being able to resume full activities within 2 months after the surgical procedure, compared with 95 percent of the implant group (p = 0.002). Of the TRAM flap-treated patients, 50 percent described some postoperative abdominal weakness, but only 5 percent of all TRAM flap-treated patients said that abdominal weakness was actually a functional problem. Our results suggest that patients may derive equal satisfaction with the two methods of reconstruction. The postoperative recuperation time after TRAM flap reconstruction is significantly longer than that after nonautologous procedures, although the postoperative abdominal weakness after TRAM flap reconstruction is not as significant a clinical problem as previously thought. The patient-derived information on satisfaction should assist both surgeons and patients in matching reconstructive options with patients' expectations and lifestyle.     

The binary switch that controls the life and death decisions of ER stressed β cells

Diabetes mellitus is a group of common metabolic disorders defined by hyperglycemia. One of the most important factors contributing to hyperglycemia is dysfunction and death of β cells. Increasing experimental, clinical, and genetic evidence indicates that endoplasmic reticulum (ER) stress plays an important role in β cell dysfunction and death during the progression of type 1 and type 2 diabetes as well as genetic forms of diabetes such as Wolfram syndrome. The mechanisms of ER stress-mediated β cell dysfunction and death are complex and not homogenous. Here we review the recent key findings on the role of ER stress and the unfolded protein response (UPR) in β cells and the mechanisms of ER stress-mediated β cell dysfunction and death. Complete understanding of these mechanisms will lead to novel therapeutic modalities for diabetes.     

Adhesion of cells to protein carpets: do cells' feet have to be black?

In most physiological situations, cell contact with a substratum is mediated by proteins of extracellular matrix. Therefore, an increasing number of cell-substratum adhesion studies employ substrata covered with one or more proteins of extracellular matrix. To visualize the most adhesive cell structures, focal contacts and focal adhesions, the interference reflection microscopy has been widely used. It has been generally accepted that these strongly adhesive structures can be seen as black streaks in interference reflection microscopy. Calculations are presented herein, which although simplified, suggest that when cells are plated on protein-covered substrata, their focal contacts may not always appear black in interference reflection microscopy.     

Heat-shock proteins maintain the viability of ATP-deprived cells: what is the mechanism?

ATP depletion causes necrosis in mammalian cells. However, a previous heat shock can protect cells from the effects of energy deprivation, probably as a result of the synthesis and accumulation of heat-shock proteins (hsps). We propose that hsps protect ATP-depleted cells from rapid necrotic death by inhibiting the aggregation of cytoskeletal proteins that occurs when ATP synthesis is blocked.