Heterosubtypic immunity to influenza A virus: where do we stand?

Influenza A virus (IAV) strains are denoted by the subtype of their hemagglutinin (HA) and neuraminidase (NA) virion surface proteins. Major changes in HA subtype among strains circulating in humans are referred to as "antigenic shift". Antigenic shift can occur by two means: direct transmission of a zoonotic strain to humans or through reshuffling of the segmented genome in cells co-infected with animal and human strains. The lack of circulating anti-HA antibodies in human populations to a novel IAV results in extremely high frequency of illness and the potential for severe morbidity and mortality on a world-wide basis; the dreaded pandemic. Such pandemics could be partially controlled by developing a vaccine that generates effective heterosubtypic immunity (HSI) based on immune recognition of IAV antigens conserved across all viral strains. While it has long been known that T cells exhibit such broad cross-reactive specificity that could provide effective HSI, recent animal studies suggest a potential role for antibodies as well. Here we review current knowledge of the mechanisms contributing to HSI to influenza and speculate on the potential for this approach to contribute to public health.     

Do hookworms elicit protective immunity in man?

The two main species of human hookworm, Ancylostoma duodenale and Necator americanus (Table 1), are together believed to infect about 900 million people - mainly in tropical countries where adequate sanitary facilities may be lacking. But interactions between the two species, and their relative contributions to observed age-related infection patterns and seasonal cycles of transmission, continue to engender controversy. People tend to remain susceptible to infection through-out life, even with constant exposure to the infective stages. So what role does human immunity or resistance play in the epidemiology and control of infection? In this article, Jerzy Behnke reviews the epidemiology of hookworm infection in the light of current understanding of mechanisms involved in host responses to infection and hookworm evasion of those responses. As he stresses, much further work is required.     

The role of fMRI in cognitive neuroscience: where do we stand?

Functional magnetic resonance imaging (fMRI) has quickly become the most prominent tool in cognitive neuroscience. In this article, I outline some of the limits on the kinds of inferences that can be supported by fMRI, focusing particularly on reverse inference, in which the engagement of specific mental processes is inferred from patterns of brain activation. Although this form of inference is weak, newly developed methods from the field of machine learning offer the potential to formalize and strengthen reverse inferences. I conclude by discussing the increasing presence of fMRI results in the popular media and the ethical implications of the increasing predictive power of fMRI.     

Laparoscopic prostatectomy: where do we stand?

Laparoscopic radical prostatectomy is an effective treatment for localized prostate cancer. This cost-intensive and technically demanding operation currently takes longer than the standard open procedures, but with increasing experience, it is eventually associated with lower costs and is nearly as fast. As more urologists gain such experience, the laparoscopic approach may challenge the standard approaches.     

Specialized and generalized dispersal systems: where does ‘the paradigm’ stand?

I explore the specialization versus generalization paradigm in frugivory and seed dispersal. This view predicts that some tropical trees produce nutritious fruits adapted for use by a small coterie of specialized frugivores that provide reliable seed dissemination. Other tree species are expected to offer superabundant fruits of lower nutritional reward, relying instead on common opportunistic frugivores that are individually less reliable, but collectively disperse seeds effectively. Though widely referenced, many aspects of the paradigm are untested with tropical trees and avian frugivores, primarily because plant ecologists rarely determine whether specialist or generalist foragers are responsible for different patterns of seed distribution, while students of foraging behavior rarely determine the effects seed dispersal by different animals for survival of seeds or seedlings of specialist or generalist trees.Ecological paradigms provide alternative hypotheses, without evolutionary arguments. Keystone species have ecological effects disproportionate to their abundance; it is important for management considerations to know whether fruiting trees or frugivores serve as keystone mutualists in tropical forests. Alternatively, the extent to which vertebrate seed dispersers influence density-dependent seed, seedling, sapling, or adult mortality may have important consequences for spatial dispersion and population dynamics of tree species in tropical forests.     

Face transplantation: where do we stand?

The recent clinical cases of hand and composite tissue allotransplantation opened a new era in the practice of reconstructive surgery. Some have suggested that face (allo)transplantation could be the next step to benefit patients whose conditions cannot be addressed by conventional techniques of reconstructive surgery using autologous tissues. This article reviews the current status of science regarding the prospect of human face transplantation. The main issues fall into three categories: (1) the surgical challenge of the procedure, specifically regarding vascular viability and functional recovery of the graft; (2) the risks of side effects from life-long immunosuppression necessary to prevent graft rejection; and (3) the ethical debate and the effects of the procedure on the population. Although face transplantation could one day be performed and extend the boundaries of reconstructive surgery, there are currently many obstacles that need to be overcome first.     

Regulatory T cells: friend or foe in immunity to infection?

Homeostasis in the immune system depends on a balance between the responses that control infection and tumour growth and the reciprocal responses that prevent inflammation and autoimmune diseases. It is now recognized that regulatory T cells have a crucial role in suppressing immune responses to self-antigens and in preventing autoimmune diseases. Evidence is also emerging that regulatory T cells control immune responses to bacteria, viruses, parasites and fungi. This article explores the possibility that regulatory T cells can be both beneficial to the host, through limiting the immunopathology associated with anti-pathogen immune responses, and beneficial to the pathogen, through subversion of the protective immune responses of the host.     

Joint analysis of demography and selection in population genetics: where do we stand and where could we go?

Teasing apart the effects of selection and demography on genetic polymorphism remains one of the major challenges in the analysis of population genomic data. The traditional approach has been to assume that demography would leave a genome-wide signature, whereas the effect of selection would be local. In the light of recent genomic surveys of sequence polymorphism, several authors have argued that this approach is questionable based on the evidence of the pervasive role of positive selection and that new approaches are needed. In the first part of this review, we give a few empirical and theoretical examples illustrating the difficulty in teasing apart the effects of selection and demography on genomic polymorphism patterns. In the second part, we review recent efforts to detect recent positive selection. Most available methods still rely on an a priori classification of sites in the genome but there are many promising new approaches. These new methods make use of the latest developments in statistics, explore aspects of the data that had been neglected hitherto or take advantage of the emerging population genomic data. A current and promising approach is based on first estimating demographic and genetic parameters, using, e.g., a likelihood or approximate Bayesian computation framework, focusing on extreme outlier regions, and then using an independent method to confirm these. Finally, especially for species where evidence of natural selection has been limited, more experimental and versatile approaches that contrast populations under varied environmental constraints might be more successful compared with species-wide genome scans in search of specific signatures.     

Phagocytosis of microorganisms by means of overshooting pseudopods: where do we stand?

During the endocytic uptake of particulate material such as microorganisms, the transition from the engulfment step to the internalization step of phagocytosis may be disturbed. Thus, the pseudopods flanking the particles do not close to a phagosome, but lie on top of each other. This uncoupling of pseudopod extension and phagosome formation provides useful information about the regular course of phagocytosis. Experimental models on the phenomena of coiling and overlapping phagocytosis have so far been established with legionellas, spirochetes, trypanosomatids, fungal cells, and zymosan.     

Rate-control or rhythm-control: where do we stand?

Atrial fibrillation is the most common sustained rhythm disturbance and its prevalence is increasing worldwide due to the progressive aging of the population. Current guidelines clearly depict the gold standard management of acute symptomatic atrial fibrillation but the best-long term approach for first or recurrent atrial fibrillation is still debated with regard to quality of life, risk of new hospitalizations, and possible disabling complications, such as thromboembolic stroke, major bleeds and death. Some authors propose that regaining sinus rhythm in all cases, thus re-establishing a physiologic cardiac function not requiring a prolonged antithrombotic therapy, avoids the threat of intracranial or extracranial haemorrhages due to Vitamin K antagonists or aspirin. On the contrary, advocates of a rate control approach with an accurate antithrombotic prophylaxis propose that such a strategy may avoid the risk of cardiovascular and non cardiovascular side effects related to antiarrhythmic drugs. This review aims to explore the state of our knowledge in order to summarize evidences and issues that need to be furthermore clarified.     

T cell immunity to herpes simplex viruses in seronegative subjects: silent infection or acquired immunity?

During the course of investigating T cell responses to HSV among volunteers entering trials of investigational genital herpes vaccines, 6 of the 24 immunocompetent subjects with no prior history of oral/labial or genital herpes possessed HSV-specific T cell immunity but, by multiple determinants of even the most sensitive serological assays, remained seronegative to HSV-1 and -2. Of these six immune seronegative (IS; HSV-seronegative with HSV-specific T cell responses) subjects, two had transient HSV-specific T cell responses, while four had CD4(+) and CD8(+) T cell responses directed at HSV that persisted for up to 4 years. CD4(+) T cell clones were isolated that recognized and had high binding affinities to epitopes in HSV-2 tegument proteins. All six IS subjects had potential sexual exposure to an HSV-2-infected sexual partner. Oral and genital mucosal secretions were sampled and tested for the presence of infectious HSV and HSV DNA. No evidence of HSV was detected in >1500 samples obtained from these IS subjects. The identification of persistent T cell responses to HSV in seronegative subjects is a novel finding in the herpesvirus field and suggests either undetected infection or acquired immunity in the absence of infection. Understanding the basis of these acquired immune responses may be critical in developing effective vaccines for genital herpes.     

Abscisic acid in the xylem: where does it come from, where does it go to?

Abscisic acid is a hormonal stress signal that moves in the xylem from the root to the different parts of the shoot where it regulates transpirational water loss and leaf growth. The factors that modify the intensity of the ABA signal in the xylem are of particular interest because target cells recognize concentrations. ABA(xyl), will be decreased as radial water flow through the roots is increased, assuming that radial ABA transport occurs in the symplast only. Such dilutions of the plant hormone concentration can be compensated in different ways, which help to keep the ABA-concentrations in the xylem constant: (i) apoplastic bypass flows of ABA, (ii) ABA flows between the stem parenchyma and the xylem during transport and (iii) the action of beta-D-glucosidases that release free ABA from its conjugates to the root cortex and the leaf apoplast. The significance of reflection coefficients (sigma(ABA)), permeability coefficients of membranes (P(S)(ABA)) and apoplastic barriers for ABA is discussed.     

Immune-mediated pathology of nematode infection in sheep--is immunity beneficial to the animal?

Nematode parasitism is a severe impediment to sustainable and profitable sheep production in many countries in the world. Parasite resistance to anthelmintic treatment and consumer demand for organic agricultural products has led to much research into harnessing natural immunity as a long-term control measure. However, there is evidence that many of the clinical signs of nematode infection in sheep are due to immune-mediated pathology rather than direct effects of the parasite. Therefore, the desirability of promoting a strong natural immunity in sheep has been questioned. This review attempts to clarify some of the arguments for and against promoting strong natural immunity, particularly through selective breeding of parasite-resistant animals. It is concluded that the detrimental effects of immune-mediated pathology are outweighed by epidemiological and welfare benefits. Thus, control of nematode parasites through selection of naturally resistant sheep is a sustainable and desirable objective.     

The human HSP70 family of chaperones: where do we stand?

The 70-kDa heat shock protein (HSP70) family of molecular chaperones represents one of the most ubiquitous classes of chaperones and is highly conserved in all organisms. Members of the HSP70 family control all aspects of cellular proteostasis such as nascent protein chain folding, protein import into organelles, recovering of proteins from aggregation, and assembly of multi-protein complexes. These chaperones augment organismal survival and longevity in the face of proteotoxic stress by enhancing cell viability and facilitating protein damage repair. Extracellular HSP70s have a number of cytoprotective and immunomodulatory functions, the latter either in the context of facilitating the cross-presentation of immunogenic peptides via major histocompatibility complex (MHC) antigens or in the context of acting as “chaperokines” or stimulators of innate immune responses. Studies have linked the expression of HSP70s to several types of carcinoma, with Hsp70 expression being associated with therapeutic resistance, metastasis, and poor clinical outcome. In malignantly transformed cells, HSP70s protect cells from the proteotoxic stress associated with abnormally rapid proliferation, suppress cellular senescence, and confer resistance to stress-induced apoptosis including protection against cytostatic drugs and radiation therapy. All of the cellular activities of HSP70s depend on their adenosine-5′-triphosphate (ATP)-regulated ability to interact with exposed hydrophobic surfaces of proteins. ATP hydrolysis and adenosine diphosphate (ADP)/ATP exchange are key events for substrate binding and Hsp70 release during folding of nascent polypeptides. Several proteins that bind to distinct subdomains of Hsp70 and consequently modulate the activity of the chaperone have been identified as HSP70 co-chaperones. This review focuses on the regulation, function, and relevance of the molecular Hsp70 chaperone machinery to disease and its potential as a therapeutic target.     

Estrogens in vascular biology and disease: where do we stand today?

PURPOSE OF REVIEW: Whereas hormone therapy may increase the risk of coronary heart disease and stroke in menopausal women, epidemiological studies (protection in premenopausal women) suggest and experimental studies (prevention of fatty streak development in animals) demonstrate a major atheroprotective action of estradiol. There is also evidence for a thrombogenic effect of oral estrogens. An understanding of the deleterious and beneficial effects of estrogens is thus required. RECENT FINDINGS: The immuno-inflammatory system plays a key role in the development of fatty streak deposit as well as in the rupture of the atherosclerotic plaque. Whereas estradiol favors an anti-inflammatory effect in vitro (cultured cells), it rather elicits a pro-inflammatory response in vivo involving several subpopulations of the immuno-inflammatory system, which could contribute to plaque destabilization. Endothelium is another important target for estrogens, since estradiol potentiates endothelial nitric oxide and prostacyclin production. The respective actions of estrogens on these cell populations may be influenced by the timing of hormonal therapy initiation, hormone regimens, status of the vessel wall and expression of isoforms of estrogen receptors alpha and beta. SUMMARY: A better understanding of the balance between the deleterious and beneficial effects of estrogens is required and should help to improve hormonal therapy safety and to optimize the prevention of cardiovascular disease after menopause.     

Immunostimulation in crustaceans: does it really protect against infection?

There is a growing need to control, prevent or minimise the devastating effects of disease in crustacean culture without recourse to toxic chemicals or antibiotics. In keeping with approaches to disease control in fish and higher mammals, interest is developing in compounds that confer protection and/or enhance immune reactivity to likely pathogens in shellfish (sometimes, erroneously, referred to as as "shellfish vaccines"). The agents currently under scrutiny for crustaceans include glucans, lipopolysaccharides and killed bacterial cells. They are thought to act as "immuno-stimulants" because of their known effects on the crustacean immune system in vitro. A number of papers are now appearing in the literature claiming to demonstrate their positive impact on immunity and immunity and disease resistance. This review article considers the problem of disease and its control in crustacean farming, describing the types of capability in cultured species. Analysis of the validity of the results of many of the published studies raises questions about the value of these compounds for cost-effective control of infection in aquaculture, especially for long lasting protection in both adults and juveniles. This review further discusses the potential risks to the wellbeing of the stock animals from repeated use of these agents and makes the case for rigorous testing of putative stimulants, at the gene, protein and functional levels, as well as for the need to consider alternative strategies and approaches to disease control.     

Curative and protective activity in rabbits after reinfection with Schistosoma mansoni: a new model of immunity?

New Zealand rabbits were infected on day 1 and challenged on days 15, 30, and 60 with 1,000 Schistosoma mansoni cercariae/animal/infection. Challenged and control rabbits were perfused 60 days after each infection, corresponding to days 75, 90, and 120 after the first exposure. No decrease in number of adult schistosomes occurred in animals reinfected 15 days after primary infection, but, when the rabbits were challenged 30 and 60 days after the first infection, worm burden reduction of 61.4% and 92.6%, respectively, was observed as compared to infection controls. These data indicate that rabbits submitted to reinfection are able to kill the worms from their primary infection, besides being protected against challenge parasites.