The extracellular matrix: an active or passive player in fibrosis?

Fibrosis is characterized by excessive accumulation of collagen and other extracellular matrix (ECM) components, and this process has been likened to aberrant wound healing. The early phases of wound healing involve the formation of a provisional ECM containing fibrin, fibrinogen, and fibronectin. Fibroblasts occupy this matrix and proliferate in response to activators elaborated by leukocytes that have migrated into the wound and are retained by the ECM. This coincides with the appearance of the myofibroblast, a specialized form of fibroblast whose differentiation is primarily driven by cytokines, such as transforming growth factor-β (TGF-β), and by mechanical tension. When these signals are reduced, as when TGF-β secretion is reduced, or as in scar shrinkage, myofibroblasts undergo apoptosis, resulting in a collagen-rich, cell-poor scar. Retention of myofibroblasts in fibrosis has been described as the result of imbalanced cytokine signaling, especially with respect to levels of activated TGF-β. ECM components can regulate myofibroblast persistence directly, since this phenotype is dependent on extracellular hyaluronan, tenascin-C, and the fibronectin splice variant containing the "extra domain A," and also, indirectly, through retention of TGF-β-secreting cells such as eosinophils. Thus the ECM is actively involved in both cellular and extracellular events that lead to fibrosis. Targeting components of the ECM as cells respond to injury and inflammatory stimuli holds promise as a means to avoid development of fibrosis and direct the wound-healing process toward reestablishment of a healthy equilibrium.     

The role of iNOS in chronic inflammatory processes in vivo: is it damage-promoting, protective, or active at all?

The expression of the inducible nitric oxide synthase (iNOS) is one of the direct consequences of an inflammatory process. Early studies have focused on the potential toxicity of the ensuing high-output NO-synthesis serving as a means to eliminate pathogens or tumor cells but also contributing to local tissue destruction during chronic inflammation. More recently, however, data are accumulating on a protective effect of high-output NO synthesis and - equally important - on a gene-regulatory function that helps to mount a protective stress response and simultaneously aids in down-regulating the proinflammatory response. These findings appear to contrast to the often observed sustained iNOS-expression during chronic inflammatory diseases, as for instance in Psoriasis vulgaris and other conditions with a chronic Th1-like reactivity. We here pose the question as to whether the iNOS is really active in these diseases. We review the data accumulated on iNOS expression in chronic diseases. We also report on the various factors that potentially interfere with proper NO formation by the expressed enzyme. We also highlight the recent findings of how, why and where evidences emerge that impeded NO formation contributes to chronic disease processes and finally present details on our current understanding of such abnormally low NO synthesis and its contribution to the pathophysiological processes of the human proinflammatory skin disease Psoriasis vulgaris.     

The role of corridors in conservation: Solution or bandwagon?

Corridors are currently a major buzzword in conservation biology and landscape ecology. These linear landscape features may perform numerous functions, but it is their role in facilitating movement of fauna that has attracted much recent debate. The database supporting the idea of corridors acting as faunal conduits is remarkably small, and few studies have actually demonstrated that movement along corridors is important for any given species. Such data are very difficult to obtain, and conservation biologists are thus faced with the problem of whether to recommend the allocation of resources to corridors on the assumption that they may be important.     

The role of VDAC in cell death: Friend or foe?

As the voltage-dependent anion channel (VDAC) forms the interface between mitochondria and the cytosol, its importance in metabolism is well understood. However, research on VDAC's role in cell death is a rapidly growing field, unfortunately with much confusing and contradictory results. The fact that VDAC plays a role in outer mitochondrial membrane permeabilization is undeniable, however, the mechanisms behind this remain very poorly understood. In this review, we will summarize the studies that show evidence of VDAC playing a role in cell death. To begin, we will discuss the evidence for and against VDAC's involvement in mitochondrial permeability transition (MPT) and attempt to clarify that VDAC is not an essential component of the MPT pore (MPTP). Next, we will evaluate the remaining literature on VDAC in cell death which can be divided into three models: proapoptotic agents escaping through VDAC, VDAC homo- or hetero-oligomerization, or VDAC closure resulting in outer mitochondrial membrane permeabilization through an unknown pathway. We will then discuss the growing list of modulators of VDAC activity that have been associated with induction/protection against cell death. This article is part of a Special Issue entitled: VDAC structure, function, and regulation of mitochondrial metabolism.     

Selfish or selfless? The role of empathy in economics

Empathy is a longstanding issue in economics, especially for welfare economics, but one which has faded from the scene in recent years. However, with the rise of neuroeconomics, there is now a renewed interest in this subject. Some economists have even gone so far as to suggest that neuroscientific experiments reveal heterogeneous empathy levels across individuals. If this were the case, this would be in line with economists'' usual assumption of stable and given preferences and would greatly facilitate the study of prosocial behaviour with which empathy is often associated. After reviewing some neuroscientific psychological and neuroeconomic evidence on empathy, we will, however, criticize the notion of a given empathy distribution in the population by referring to recent experiments on a public goods game that suggest that, on the contrary, the degree of empathy that individuals exhibit is very much dependent on context and social interaction.     

The role of oxidative stress in anxiety disorder: cause or consequence?

Anxiety disorders are the most common mental illness in the USA affecting 18% of the population. The cause(s) of anxiety disorders is/are not completely clear, and research in the neurobiology of anxiety at the molecular level is still rather limited. Although mounting clinical and preclinical evidence now indicates that oxidative stress may be a major component of anxiety pathology, whether oxidative stress is the cause or consequence remains elusive. Studies conducted over the past few years suggest that anxiety disorders may be characterised by lowered antioxidant defences and increased oxidative damage to proteins, lipids, and nucleic acids. In particular, oxidative modifications to proteins have actually been proposed as a potential factor in the onset and progression of several psychiatric disorders, including anxiety and depressive disorders. Oxidised proteins are normally degraded by the proteasome proteolytic complex in the cell cytoplasm, nucleus, and endoplasmic reticulum. The Lon protease performs a similar protective function inside mitochondria. Impairment of the proteasome and/or the Lon protease results in the accumulation of toxic oxidised proteins in the brain, which can cause severe neuronal trauma. Recent evidence points to possible proteolytic dysfunction and accumulation of damaged, oxidised proteins as factors that may determine the appearance and severity of psychotic symptoms in mood disorders. Thus, critical interactions between oxidative stress, proteasome, and the Lon protease may provide keys to the molecular mechanisms involved in emotional regulation, and may also be of great help in designing and screening novel anxiolytics and antidepressants.     

The role of habitat in avian community composition: physiognomy or floristics?

Summary It has been proposed that within rather broad habitat types the distribution and abundance of bird species may be more closely associated with plant taxonomic composition than with the structure and configuration of the vegetation. Birds from a sample of eight representative grassland habitats in middle and western North America are consistent with this hypothesis. Over half (55%) of the variation in bird community composition was associated with floristic variation, but only a third (35%) was associated with physiognomy. Separating the interacting effects of floristics and physiognomy from each other served to accentuate the difference between them with respect to the avifauna. It is postulated that bird species/plant taxa associations, especially within similar habitat types, are mediated by the specific food resources that different plant taxa provide. Summary indices such as diversity measures obscure the taxonomic information content of plant or animal assemblages, and the use of such indices has likely impeded detection of the relationships described here.     

The role of phytic acid in legumes: antinutrient or beneficial function?

This review describes the present state of knowledge about phytic acid (phytate), which is often present in legume seeds. The antinutritional effects of phytic acid primarily relate to the strong chelating associated with its six reactive phosphate groups. Its ability to complex with proteins and particularly with minerals has been a subject of investigation from chemical and nutritional viewpoints. The hydrolysis of phytate into inositol and phosphates or phosphoric acid occurs as a result of phytase or nonenzymatic cleavage. Enzymes capable of hydrolysing phytates are widely distributed in micro-organisms, plants and animals. Phytases act in a stepwise manner to catalyse the hydrolysis of phytic acid. To reduce or eliminate the chelating ability of phytate, dephosphorylation of hexa- and penta-phosphate forms is essential since a high degree of phosphorylation is necessary to bind minerals. There are several methods of decreasing the inhibitory effect of phytic acid on mineral absorption (cooking, germination, fermentation, soaking, autolysis). Nevertheless, inositol hexaphosphate is receiving increased attention owing to its role in cancer prevention and/or therapy and its hypocholesterolaemic effect.     

The physiological role of GLP-1 in human: incretin, ileal brake or more?

The proglucagon-derived peptide glucagon-like peptide-1 (GLP-1) is an intestinal signal peptide postprandially released from the L cells of the lower gut. Exogenously administered the synthetic hormone exerts a glucose-dependent insulinotropic effect at the pancreatic beta-cells and lowers plasma glucagon by an inhibitory effect against the alpha-cells. It delays gastric emptying by relaxation of the gastric fundus, inhibition of antral contractility, and stimulation of both the tonic and phasic motility of the pyloric sphincter. Enhancement of insulin, suppression of glucagon, and inhibition of gastric emptying are the main determinants controlling glucose homeostasis with GLP-1. Human studies employing the specific GLP-1 receptor antagonist exendin(9-39) show that endogenously released GLP-1 likewise controls fasting plasma glucagon, stimulates insulin, and influences all the motoric mechanisms known to control gastric emptying. Therefore, GLP-1 is discussed as an incretin hormone and as an enterogastrone in man. Synthetic GLP-1 also suppresses gastric acid and pancreatic enzyme secretion. The inhibitory effects on upper gastrointestinal functions are at least partly mediated by vagal-cholinergic inhibition and may involve interactions with vagal afferent pathways and/or circumventricular regions within the CNS. GLP-1 is a candidate humoral mediator of the 'ileal brake' exerting inhibition of upper gastrointestinal function preventing malabsorption and postprandial metabolic disturbances. As human studies indicate a central action of GLP-1 in reduction of food intake, it is uncertain if this is a consequence of induction of satiety or of transduction of visceral aversive stress signals.     

The role of ecotourism in conservation: panacea or Pandora’s box?

Does ecotourism contribute towards conservation of threatened species and habitats or is it just a marketing ploy of the tourism industry? Using 251 case studies on ecotourism from the literature, I looked at the distribution of case studies over continents, habitats and flagship species types and what factors influenced whether an ecotourism regime was perceived as ecologically sustainable by authors. Over 50% of ecotourism case studies were reported from Africa and Central America. The overall distribution of ecotourism case studies did not reflect vertebrate endemism, nor overall tourism distribution in terms of tourist numbers and receipts. There were significant differences between continents and habitats with regard to the proportion of sustainable case studies: ecotourism is perceived to be less sustainable in South America and Asia, and in island and mountain habitats. The type of flagship species also influenced whether ecotourism was classified as sustainable or not: ecotourism with no flagship species was rarely classified as sustainable while charismatic bird and mammal species were associated with a higher probability of sustainability. In a multivariate analysis, flagship species type and local community involvement were important predictors of sustainability in ecotourism. Detailed a priori planning, local involvement and control measures were perceived by authors of case studies to increase the success of ecotourism in conservation. They also perceived that ecotourism can only be an effective conservation tool under certain conditions. If these are met, the evidence indicates that ecotourism can make a contribution to conservation.     

The role of sphingosine kinase 1 in cancer: oncogene or non-oncogene addiction?

Sphingosine kinase 1 (SphK1) is a lipid kinase that catalyses the phosphorylation of sphingosine to sphingosine-1-phosphate. There is strong evidence from cellular or animal systems that SphK1 is involved in the major mechanisms underpinning oncogenesis, namely, the promotion of cellular survival, proliferation and transformation, the prevention of apoptosis and the stimulation of angiogenesis. Furthermore there is also good evidence from clinical samples that SphK1 is overexpressed in many, if not most tumor types examined and that many inhibitors of SphK1 render tumors sensitive to chemotherapeutic agents. A major question that remains concerns the exact mechanism of action of SphK1 in cancer. The tools available to probe SphK1 function perturb a set of cellular functions, and it is possible that several of these are involved in driving its oncogenic role. Furthermore, the importance of SphK1 functions in normal physiology and the lack of mutations of SphK1 in cancer, suggest that the mechanism in cancer might be an over reliance on this system of cellular signaling; an example of non-oncogene addiction.     

Iron in infectious diseases friend or foe?: The role of gut microbiota

Iron is a trace element involved in metabolic functions for all organisms, from microorganisms to mammalians. Iron deficiency is a prevalent health problem that affects billions of people worldwide, and iron overload could have some hazardous effect. The complex microbial community in the human body, also called microbiota, influences the host immune defence against infections. An imbalance in gut microbiota, dysbiosis, changes the host's susceptibility to infections by regulating the immune system. In recent years, the number of studies on the relationship between infectious diseases and microbiota has increased. Gut microbiota is affected by different parameters, including mode of delivery, hygiene habits, diet, drugs, and plasma iron levels during the lifetime. Gut microbiota may influence iron levels in the body, and iron overload and deficiency can also affect gut microbiota composition. Novel researches on microbiota shed light on the fact that the bidirectional interactions between gut microbiota and iron play a role in the pathogenesis of many diseases, especially infections. A better understanding of these interactions may help us to comprehend the pathogenesis of many infectious and metabolic diseases affecting people worldwide and following the development of more effective preventive and/or therapeutic strategies. In this review, we aimed to present the iron-mediated host-gut microbiota interactions, susceptibility to bacterial infections, and iron-targeted therapy approaches for infections.     

Maternal inheritance and rapid evolution of sexual size dimorphism: passive effects or active strategies?

Adaptive evolution is often strongly influenced by maternal inheritance that transfers the parental strategies across generations. The consequences of maternal effects for the offspring generation depend on the between-generation similarity in environments and on the evolved sensitivity of the offspring's ontogeny to maternal effects. When these factors differ between sons and daughters, maternal effects can influence the evolution of sexual dimorphism. The establishment of house finch populations across western Montana during the last 30 years was accompanied by rapid evolutionary change in sexual size dimorphism. Here I show that traits that changed the most across generations were most influenced by maternal effects in males but not females. Maternal effects differentially affected sons' and daughters' survival; greater maternal effects were commonly associated with higher survival of sons, especially when maternal and offspring environments were similar. Stronger maternal effects extended preselection phenotypic variance in morphological traits of males, thereby producing some locally adaptive phenotypes and lessening juvenile mortality. Thus, the observed sex-specific maternal effects and their contribution to the evolution of sexual size dimorphism are likely a passive consequence of the distinct sensitivity of sons and daughters to maternal adaptations to breeding in ecologically distinct parts of the house finch's expanding range.     

The role of floods in the lives of fish-eating birds: predator loss or benefit?

Floods accompanied by high flow and high water turbidity are usually believed to cause problems to fish-eating birds and mammals searching visually for their prey. In the present study the diets of breeding kingfishers were studied during the normal river situation and during a long-lasting flood event with respect to diet composition, size of fish prey and food diversity index. During the normal situation (flow 1.75 m³ s^?1, Secchi disc depth 0.5–1 m), the diet of a kingfisher was dominated by benthic fish species (52.9% by numbers, 63.9% by weight), the average size of fish taken was 6.5 cm L _T and 3.0 g and the food diversity index reached its lowest value (1.57). In contrast, during the long-lasting flood event (flow 5–28 m³ s^?1, Secchi disc depth 0.03–0.4 m) the diet of the kingfisher was dominated by sub-surface fish species (72.4% by numbers, 76.1% by weight) and both the average size of fish taken (7.4 cm L _T and 3.7 g) and the food diversity index (1.83) increased significantly. The birds provided their nestlings with lower numbers of fish of larger sizes, which resulted in very similar weights of the young birds prior to fledging when the flood and normal situations were compared. This study provides evidence that in different foraging conditions the kingfishers adopt different foraging strategies to maintain their high breeding success.     

Cellular kinases incorporated into HIV-1 particles: passive or active passengers?

Phosphorylation is one of the major mechanisms by which the activities of protein factors can be regulated. Such regulation impacts multiple key-functions of mammalian cells, including signal transduction, nucleo-cytoplasmic shuttling, macromolecular complexes assembly, DNA binding and regulation of enzymatic activities to name a few. To ensure their capacities to replicate and propagate efficiently in their hosts, viruses may rely on the phosphorylation of viral proteins to assist diverse steps of their life cycle. It has been known for several decades that particles from diverse virus families contain some protein kinase activity. While large DNA viruses generally encode for viral kinases, RNA viruses and more precisely retroviruses have acquired the capacity to hijack the signaling machinery of the host cell and to embark cellular kinases when budding. Such property was demonstrated for HIV-1 more than a decade ago. This review summarizes the knowledge acquired in the field of HIV-1-associated kinases and discusses their possible function in the retroviral life cycle.     

Putative partners in Bax mediated cytochrome-c release: ANT,CypD, VDAC or none of them?

Release of cytochrome-c from mitochondria is a key regulatory event in the intrinsic pathway of apoptosis, and its mechanism has been the subject of extensive debate with investigators proposing different and contrasting models. While some models suggest that cytochrome-c release can occur in absence of permeability transition and is mediated by the pro-apoptotic protein Bax, some suggest involvement of various components of permeability transition pore with or without cooperative action of Bax. Various models of PTP-dependent or -independent cytochrome-c release are discussed in this review with special emphasis on all the independent/cooperative roles of Bax evidenced so far.