TNF family members and malaria: Old observations, new insights and future directions

Tumor necrosis factor (TNF) has long been recognized to promote malaria parasite killing, but also to contribute to the development of severe malaria disease. The precise molecular mechanisms that influence these different outcomes in malaria patients are not well understood, but the virulence and drug-resistance phenotype of malaria parasites and the genetic background and age of patients are likely to be important determinants. In the past few years, important roles for other TNF family members in host immune responses to malaria parasites and the induction of disease pathology have been discovered. In this review, we will summarize these more recent findings and highlight major gaps in our current knowledge. We will also discuss future research strategies that may allow us to better understand the sometimes subtle and intricate effects of TNF family molecules during malaria infection.     

Multiple sclerosis: etiological mechanisms and future directions

Multiple sclerosis (MS) is a complex human autoimmune-type disease with a predominantly unknown etiology. Immunologic destruction of myelin basic protein (MBP) throughout the nervous system is the major pathology of multiple sclerosis. This review will attempt to update new information about basic mechanisms and therapeutic management of the disease. The significance of the structure of MBP is discussed with respect to the contribution of such structures to the disease process. A number of MBP peptides that serve as the immunodominant antigens in MS patients have been identified. These peptides have been studied in animal models for their antigenic characteristics and ability to induce disease. Evidence for genetic contributions is reviewed with multigenerational twin studies providing the best evidence for susceptible haplotypes. The role of microorganisms/viruses and environmental agents are discussed as potential etiological factors but are now thought to be of minor importance to the primary causal development of the disease. Of major consideration are immunological mechanisms that contribute to the development of autoimmunity. In particular, antigen expression, cytokine and leukocyte interactions, and regulatory T-cells are discussed. Particular attention is given to regulatory T-cells (Treg), which help balance/modulate other T-cells such as Th1 and Th2 cells, and how such Treg regulate autoimmunity is addressed. The importance of the role of Tregs is exemplified by the demonstration that administration of oral antigens can induce specific Tregs that counteract experimental autoimmune encephalomyelitis in animal models. The significance of animal studies to human multiple sclerosis is discussed. A potential role for natural antibodies and innate immune mechanisms to help provide resistance to disease development is also reviewed. Finally, a variety of therapeutic agents that have been and continue to be utilized for multiple sclerosis is reviewed. Trials with oral antigens, such as glatirmer acetate (copolymer 1) especially in combination with interferon-beta, have shown promise. Antibody therapy and bone marrow transplantation are also briefly discussed.     

Interspecific behavioural interference and range dynamics: current insights and future directions

Novel biotic interactions in shifting communities play a key role in determining the ability of species' ranges to track suitable habitat. To date, the impact of biotic interactions on range dynamics have predominantly been studied in the context of interactions between different trophic levels or, to a lesser extent, exploitative competition between species of the same trophic level. Yet, both theory and a growing number of empirical studies show that interspecific behavioural interference, such as interspecific territorial and mating interactions, can slow down range expansions, preclude coexistence, or drive local extinction, even in the absence of resource competition. We conducted a systematic review of the current empirical research into the consequences of interspecific behavioural interference on range dynamics. Our findings demonstrate there is abundant evidence that behavioural interference by one species can impact the spatial distribution of another. Furthermore, we identify several gaps where more empirical work is needed to test predictions from theory robustly. Finally, we outline several avenues for future research, providing suggestions for how interspecific behavioural interference could be incorporated into existing scientific frameworks for understanding how biotic interactions influence range expansions, such as species distribution models, to build a stronger understanding of the potential consequences of behavioural interference on the outcome of future range dynamics.     

Short sleep duration and obesity: mechanisms and future perspectives

A reduction of sleep time has become common over the last century, and growing evidence from both epidemiological and laboratory-based studies suggests sleep curtailment is a new risk factor for the development of obesity. On this basis, the present review examines the role of sleep curtailment in the metabolic and endocrine alterations, including decreased glucose tolerance and insulin sensitivity, increased evening concentrations of cortisol, increased levels of ghrelin, decreased levels of leptin and increased hunger and appetite. It will be discussed how sleep restriction may lead to increase in food intake and result in greater fatigue, which may favour decreased energy expenditure. Altogether, evidences point to a possible role of decreased sleep duration in the current epidemic of obesity and therefore present literature highlights the importance of getting enough good sleep for metabolic health. Many aspects still need to be clarified and intervention studies also need to be conducted. Copyright ? 2012 John Wiley & Sons, Ltd.     

Paternal contribution: new insights and future challenges

It has been widely held that all that fathers essentially contribute to the next generation is half their genome. However, recent progress towards understanding biological processes such as sperm maturation and fertilization now indicates that the paternal contribution has been underestimated. To tackle some of the misconceptions surrounding the paternal contribution, the factors that are actually delivered by the sperm at fertilization and their potential developmental functions will be discussed using data from humans and animal models. Although still in their infancy, the practical applications of using sperm RNAs have already emerged in reproductive medicine as markers that are indicative of successful vasectomy. They are also beginning to appear in the forensic sciences and, within the next decade, might appear in the environmental sciences.     

ErbB receptors: new insights on mechanisms and biology

The ErbB family of four receptor tyrosine kinases occupies a central role in a wide variety of biological processes from neuronal development to breast cancer. New information continues to expand their biologic significance and to unravel the molecular mechanisms that underlie the signaling capacity of these receptors. Here, we review several aspects of ErbB receptor physiology for which new and significant information is available. These include ligand-dependent receptor dimerization and kinase activation, which is a prerequisite for all subsequent growth factor-dependent cell responses. We also address novel roles of receptor fragments in signaling, trafficking to intracellular sites, such as the nucleus, and ErbB roles in non-cancer disease processes, including schizophrenia, chronic renal disease, hypertension, and the cellular entry of infectious pathogens.     

Molecular and genetic mechanisms of obesity: implications for future management

Obesity has become a worldwide public health problem affecting millions of people. A disruption of the balance between energy intake and energy expenditure is believed to be the major cause of obesity. Substantial progress has been made in deciphering the pathogenesis of energy homeostasis over the past few years. The fact that obesity is under strong genetic control has been well established. Human monogenic obesity is rare in large populations, the most common form of obesity is considered to be a polygenic disorder arising from the interaction of multiple genetic and environmental factors. Here, we attempt to briefly review the most recent understanding of molecular mechanisms involved in energy homeostasis and adipogenesis. We discuss the advantages and disadvantages of various approaches commonly used in search for susceptibility genes for obesity. The main results from these genetic studies are summarized, with comments made on the most striking or representative findings. Finally, the implications of the recent advances in the understanding of molecular genetic mechanisms of body weight regulation on prevention and therapeutic intervention of obesity will be discussed.     

Periodontitis and mechanisms of cardiometabolic risk: Novel insights and future perspectives

Periodontitis is an infectious and inflammatory disease of the tooth-supporting tissues caused by the accumulation of subgingival plaque and the action of specific periodontopathogenic bacteria. Periodontitis has been associated with cardiovascular diseases and considered a cardiovascular risk factor. Several mechanisms have been proposed to explain this association, such as the infection of atherosclerotic plaques by periodontal pathogens, the pro-atherogenic effect on the lipid profile, the systemic dissemination of pro-inflammatory mediators or the contribution to type 2 diabetes mellitus. Periodontal treatment has also been related to improvement in cardiometabolic risk variables, and oral hygiene techniques may be useful in reducing cardiometabolic risk. The aim of this review is to provide new and recent insights on the relationship between periodontitis and cardiometabolic risk, focusing on recent evidence. Comments on shared potential therapeutic targets, such as the role of glucagon-like peptide 1, are also highlighted.     

BMP signaling in congenital heart disease: new developments and future directions

Congenital heart malformations are the most common of all congenital human birth anomalies. During the past decade, research with zebrafish, chick, and mouse models have elucidated many fundamental genetic pathways that govern early cardiac patterning and differentiation. This review highlights the roles of the bone morphogenetic protein (BMP) signaling pathway in cardiogenesis and how defective BMP signals can disrupt the intricate steps of cardiac formation and cause congenital heart defects.     

How aging impacts vaccine efficacy: known molecular and cellular mechanisms and future directions

Aging leads to a gradual dysregulation of immune functions, one consequence of which is reduced vaccine efficacy. In this review, we discuss several key contributing factors to the age-related decline in vaccine efficacy, such as alterations within the lymph nodes where germinal center (GC) reactions take place, alterations in the B cell compartment, alterations in the T cell compartment, and dysregulation of innate immune pathways. Additionally, we discuss several methods currently used in vaccine development to bolster vaccine efficacy in older adults. This review highlights the multifactorial defects that impair vaccine responses with aging.     

Neurotransmission by ATP: new insights, novel mechanisms

Purines have long been known for their roles in extracellular signaling. One of the most interesting functions to come to light recently has been the involvement, particularly of adenosine 5'-triphosphate (ATP), as a neurotransmitter in the central and the sympathetic nervous system. ATP is stored in and released from synaptic nerve terminals, like other neurotransmitters, and is known to act post-synaptically via specific rapidly-conducting, ligand-gated ion channels, the P2x receptors. Another interesting feature is the discovery that ATP is widely found to be a "co-transmitter" at the same synapses in combination with other neurotransmitters such as noradrenaline, acetylcholine, and GABA, altering our picture of the biophysics and biochemistry of neurotransmission at these synapses. We describe here these and other aspects of neurotransmission by ATP being investigated vigorously today, including recent findings on P2x receptors and those on the synaptic inactivation of ATP by ecto-ATPase. We conclude by pointing out possible pharmacological and clinical implications of neurotransmission by ATP.     

Fibrocytes: Bringing new insights into mechanisms of inflammation and fibrosis

Regeneration and fibrosis are integral parts of the recovery process following tissue injury, and impaired regulation of these mechanisms is a hallmark of many chronic diseases. A population of bone marrow-derived mesenchymal progenitor cells known as fibrocytes, play an important role in tissue remodeling and fibrosis in both physiologic and pathologic settings. In this review we summarize the key concepts regarding the pathophysiology of wound healing and fibrosis, and present data to support the contention that circulating fibrocytes are important in both normal repair process and aberrant healing and fibrotic damage associated with a diverse set of disease states.     

Alcoholic liver disease: new insights into mechanisms and preventative strategies

Alcoholic liver disease has a known aetiology but a complex pathogenesis. It is an extremely common disease with a high mortality, but the reason why only a relatively small proportion of heavy drinkers progress to advanced disease remains elusive. Accumulating evidence points towards an elaborate interplay between metabolism, inflammation and immunity in the development of steatosis, hepatitis and fibrosis. These complex pathways leading to liver injury offer many potential susceptibility loci, as well as sites for potential therapeutic intervention.     

Human aneuploidy: mechanisms and new insights into an age-old problem

Trisomic and monosomic (aneuploid) embryos account for at least 10% of human pregnancies and, for women nearing the end of their reproductive lifespan, the incidence may exceed 50%. The errors that lead to aneuploidy almost always occur in the oocyte but, despite intensive investigation, the underlying molecular basis has remained elusive. Recent studies of humans and model organisms have shed new light on the complexity of meiotic defects, providing evidence that the age-related increase in errors in the human female is not attributable to a single factor but to an interplay between unique features of oogenesis and a host of endogenous and exogenous factors.