Social and competitive demands often differ between the sexes in mammals. These differing demands should be expected to produce variation in the relative sizes of various brain structures. Sexual selection on males can be predicted to influence brain components handling sensory-motor skills that are important for physical competition or neural pathways involving aggression. Conversely, because female fitness is more closely linked to ecological factors and social interactions that enable better acquisition of resources, social selection on females should select for brain components important for navigating social networks. Sexual and social selection acting on one sex could produce sexual dimorphism in brain structures, which would result in larger species averages for those same brain structures. Alternatively, sex-specific selection pressures could produce correlated effects in the other sex, resulting in larger brain structures for both males and females of a species. Data are presently unavailable for the sex-specific sizes of brain structures for anthropoid primates, but under either scenario, the effects of sexual and social selection should leave a detectable signal in average sizes of brain structures for different species.The degree of male intra-sexual selection was positively correlated with several structures involved in autonomic functions and sensory-motor skills, and in pathways relating to aggression and aggression control. The degree of male intra-sexual selection was not correlated with relative neocortex size, which instead was significantly positively correlated with female social group size, but negatively correlated with male group size.Sexual selection on males and social selection on females have exerted different effects on primate brain architecture. Species with a higher degree of male intra-sexual selection carry a neural signature of an evolutionary history centered on physical conflicts, but no traces of increased demands on sociocognitive tasks. Conversely, female sociality is indicated to have driven the evolution of socio-cognitive skills. Primate brain architecture is therefore likely to be a product of ecological and species-specific social factors as well as different sex-specific selection pressures. Our results also highlight the need for acquisition and analysis of sex-specific brain components in mammals. Primate brain architecture has been shown to correlate with both ecological -3 and soSelection in relation to sex occurs whenever any genetically influenced morphological trait or behavior increases the fitness of one sex, but not the other. One well-known instance of this process in mammals is male-male competition for sexual access to females, which has resulted in a diverse array of characters important for males in conflict situations ,13. In pWe used phylogenetic comparative methods to investigate whether two types of selection in relation to sex-intra-sexual selection on males through male-male physical competition and social selection in females-have had predictable effects on species-typical brain structures in primates. To be successful in male-male physical competition, a primate male in a polygynous species not only needs to be large and have imposing canines, but also to display, control and use his weapons and size effectively. No matter what their physical equipment might be, males without such abilities should self-evidently be less able to succeed in competitive situations. A male can potentially be proficient in the use of his assets through quick, agile and skillful movements, thus gaining an edge on his opponent physically, or he can use intelligence to outwit the competition, thus decreasing the amount of direct physical conflict necessary. The former strategy involves physical movements, while the latter involves cognitive processes intended at avoiding such movements.From this reasoning, we derived four, not mutually exclusive, hypotheses involving male intra-sexual selection. (i) If physical combat is important, the effects of sexual selection on brain architecture should mainly act on brain regions with roles in motor skills and the coordination between sensory and motor information , whereasWe investigated four predictions derived from these hypotheses. These are all subject to the caveat that brain functions are often distributed between many separate structures; selection for a specific function will therefore tend to change several functionally connected brain structures simultaneously ,19. (1) We also investigated a hypothesis related to the drivers of female reproductive success. In comparison with males, female reproductive success is more closely linked to ecological factors, including the acquisition and defense of resources and protection from predators -23. ThatIn summary, at least two sex-specific selection factors should leave imprints on how the brain is organized in different primate species, producing five predictions. Predictions 1–4 involve sexual selection on males for increased sensory-motor coordination, increased size of the areas relating to autonomic functions, cognitive abilities in the context of strategic planning and social networks, and changes in the structures that relate to aggression and fear. The fifth and final prediction involves social selection on females, related to increased cognitive abilities in the context of social networks.If social or sexual selection exists, it could have one of two effects on sex-specific brain measurements. On the one hand, it could select for larger brain structures in both sexes; on the other hand, it could lead to sexual dimorphisms. Regarding the first possibility, recent research has shown that in anthropoid primates, the degree of sexual selection on males is correlated with larger canine size and greater body mass not only in males, but also in females ,17. EffeAlternatively, if a selection pressure results in sexual dimorphisms in brain architecture, this would also result in a higher average value for the trait in a species, simply because the values for one sex would be increased relative to the other sex and would therefore increase the mean for that species. We therefore had strong reasons to expect that selection in relation to sex should be clearly detectable regardless of its specific effects on male and female brains. We emphasize these points because the brain volume data examined in our study are from unsexed primate specimens , female group size was positively correlated with relative neocortex volume [To further assess how functional differences between males and females operate on different brain structures, we analyzed specific structures of the telencephalon. The results concerning social selection showed that sociality for both males and females was correlated with different components of the telencephalon. Whereas male group size was significantly negatively correlated with the relative volumes of the septum, schizocortex and perhaps the neocortex , we re-ran all analyses with female body mass forced into the regression models  and amygdala, all involved in governing aggressive behaviors, are positively correlated with the degree of sexual selection, whereas the septum, which has a role in facilitating aggression control, is instead negatively correlated with the degree of sexual selection. Moreover, male group size is positively correlated with the relative volume of the diencephalon  all contain important motor centers. The same is true for the cerebellum and the telencephalon, but the former is not significantly correlated with size dimorphism and the latter even exhibits a negative correlation. Given the distributed nature of the motor centers in the brain, analyses of the main brain structures provides only indirect support for the hypothesis that sexual selection acts on motor centers; more detailed data on specific brain structures are therefore needed.The medulla oblongata and the diencephalon are important for autonomic nervous system activity. Significant correlations involving these structures suggest that larger body size resulting from sexual selection has placed demands on brain structures involved in handling a larger body. Thus, while not providing direct support, our results are in line with two hypotheses that deserve further scrutiny: that sexual selection selects for (i) brain structures important for success in male-male conflict through better body control, and (ii) better handling of a larger body through increased importance of structures involved in autonomic tasks.The effects of social selection are more clear-cut in that they suggest that different strategies used by males and females have left marks on primate brain architecture, with female social group size positively and male group size negatively correlated with telencephalon size. Thus, demands of male and female sociality differ fundamentally in skills governed by the telencephalon, and within this region, especially the neocortex. The neocortex is important for cognitive skills involved in navigating complex webs of social relationships ,45. As sAn important question concerns the epigenetic mechanisms by which species differences in brain architecture arise during ontogeny, in particular the relative roles of early, genetically guided ontogenetic processes versus later processes influenced substantially by environmental input and/or hormones. For example, experimental evidence indicates that perturbations of sensory inputs cause neural reorganization ,47. HoweFrom our study of unsexed specimens, we cannot determine if social and sexual selection have produced sexual dimorphisms in brain size, or whether selection acting on one sex has had correlated effects on the other sex, thus producing larger brains for that species. The results presented here therefore emphasize the value of obtaining sex-specific data on brain structures. Several authors have proposed or tested hypotheses for sexual dimorphism in brain structures ,20,55,56We have no reason to expect that the patterns presented here apply only to anthropoid primates; similar patterns should be detectable in other mammal clades, provided of course that sufficient variation in sociality and/or intra-sexual competition exists. It is even possible that these factors have driven brain evolution in mammals and thus may explain differences in brain architecture among different mammal orders. This especially concerns the relatively large neocortex-a hallmark of primates and a trait indicated by this study to be a consequence of the high degree of female sociality in primates-but should also involve other structures.The results presented here indicate that selection in relation to sex is an underappreciated force in primate brain evolution. Social selection on females and sexual selection on males accounts for significant variation in primate brain architecture. Whereas female sociality is tied to increased cognitive abilities, male sociality and sexual selection on males is not. Instead, sexual selection on males has favored brain structures involved in aggression, sensory motor functions and autonomic functions. This is important because selection pressures acting on the brain have previously almost exclusively been treated as uniform in males and females. Given available data, however, it is impossible to know whether these effects lead to dimorphism or correlated effects in both sexes. Development of new datasets that make use of sexed brains will be needed to address this fundamental question.Data on volumes of different brain structures were gathered from the literature ,58. The We also gathered data on body mass  and grouHaplorhine (Old World) primates are generally larger, more dimorphic and live in larger groups than platyrrhine (New World) primates. That is, the causal factors we use in this study are similar within taxonomic groups, because of their shared evolutionary history. For this reason, we employed phylogenetically independent contrasts that use differences between species and taxonomic groups instead of the species' values themselves . This apBecause we were interested in investigating the effects of multiple independent variables on different brain components, we analyzed the influence of these variables using stepwise multiple regression. To investigate which variables were significantly correlated with the dependent variables, we used a backwards-removal procedure with all variables initially included in the model, and then sequentially removed variables with significance levels > 0.1. Because correlations exist between female body mass and total brain volumes, between female body mass and dimorphism, and between male and female group sizes, we tested whether collinearity rendered our multiple regression models unstable by calculating Variance Inflation Factors (VIFs) . With onp << 0.001; Table To control for allometric effects, we subtracted the volume of the brain component under scrutiny from the total brain volume and used this "remaining brain volume" as a covariate in all regression models. Including total brain volume instead of the "remaining brain volume" as a covariate produced results similar to those presented here, but we feel that the measure we used better corrects for part-whole correlation problems. The volumes of all examined brain parts were closely correlated to our "remaining brain volume" measure p << 0.00; Table 1vice versa) have to be judged carefully  is by far the largest substructure in the haplorhine primate brain  and the largest substructure within the telencephalon is by far the neocortex . Selection pressures affecting the relative size of the neocortex could therefore also affect the relative sizes of all other brain components . For this reason, we checked our results by repeating the analyses while excluding the neocortex from the "remaining brain volume" variable. Results that were statistically significant in the first round of analyses but non-significant when excluding the neocortex volumes (or PL conceived of the hypotheses and carried out the analyses. PL, CN and RB co- wrote the paper.Data on body mass, group size and volumes of major brain components for the primate species analyzed in this study.Click here for fileVolumes of telencephalon structures for the primate species analyzed in this study.Click here for fileStepwise multiple regression models with forced inclusion of female body mass: brain components.Click here for fileStepwise multiple regression models with forced inclusion of female body mass: telencephalon components.Click here for fileStepwise multiple regression models without the neocortex: brain components.Click here for fileStepwise multiple regression models without the neocortex: telencephalon components.Click here for file


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. Atrial fibrillation (AF) is the most common serious rhythm disturbance worldwide  and its Traditionally, a rhythm control approach with electrical or pharmacological cardioversion followed by antiarrhythmic drug prophylaxis was preferred by physician even if strong evidence of its superiority have never been available . TheoretGenerally, a rate control approach is considered effective when associated with relief of symptoms and when mean ventricular response ranges between 60 and 80 beats per minute (bpm) at rest and between 90 and 115 bpm during a common moderate exercise test . Beta blThe “ablate and pace” approach consists of the ablation of atrioventricular node followed by implantation of a permanent pacemaker. The ventricular rate is completely controlled by the pace-maker and also a more physiological contraction of the ventricle is restored thus positively affecting the cardiac haemodynamic . As the Current guidelines state which antiarrhythmic drugs have proven efficacy in converting atrial fibrillation into sinus rhythm both for atrial fibrillation with less and more than 7 days of duration . Also whElectrical cardioversion has a very high initial success rate, but only about 23% of patients at 1 year and 15% at 2 years remain in sinus rhythm 32]. Man. Man32].Recently, newer strategies were developed, including catheter ablation by means of radiofrequency. Ectopic foci, localized within the pulmonary vein, were found in the majority of atrial fibrillation  and the Several trials addressing this issue were published in the last years -45 and tThe Strategies of Treatment of Atrial Fibrillation study (STAF)  enrolledThe RACE study  enrolledThe AFFIRM study  enrolledThe HOT CAFÉ  enrolledThe Control of Rate versus Rhythm in Rheumatic Atrial Fibrillation trial (CRRAFT)  trial diIn the evidence-based medicine era the highest level of evidence is that of meta-analytic approach  but the In a post hoc analysis of AFFIRM population the trend toward a lower total mortality in the rate-control versus the rhythm-control group appears entirely explained by non cardiovascular deaths. Independent predictors of non cardiovascular death were rhythm-control strategy, age, male gender, previous smoking history, heart failure, and coronary heart disease . In anotAs previously stated, current guidelines recommend only a short term anticoagulation therapy after restoration of sinus rhythm while those patients treated with rate control approach continue to take Vitamin K antagonists or aspirin potentially for all the life. This issue rises some concerns: oral anticoagulants, but also aspirin, are associated with at least a two fold risk of major haemorrhages compared to placebo , on the As previously reported , there iIn the future, new, safer and more effective antiarrhythmic agents, associated with careful and prolonged anticoagulation, will probably make the rhythm-control strategy superior to the rate control one but, according to current evidence, rate-control strategy represents the gold standard strategy, especially for those patients with echocardiographic and clinical features that make unlikely the maintenance of sinus rhythm with or without antiarrhythmic prophylaxis for recurrences.


Hepatitis B is a serious global public health problem but is preventable with safe and effective vaccines that have been available since 1982. Despite these vaccines, about 2 billion people have been infected with hepatitis B virus (HBV), and more than 350 million have lifelong infections. These chronically infected people are at high risk of death from cirrhosis of the liver and liver cancer, which both kill about 1 million people each year.Suppression of viral replication in chronic carriers of HBV is an effective approach to controlling disease progression. Current antiviral therapies include lamivudine and alpha-interferon, but long-term resolution of the disease is disappointing because of low seroconversion rates and the development of drug-resistant viral mutants.PLoS Medicine, Lisa F. P. Ng and colleagues describe the identification of a host factor that has a significant effect on viral replication efficiency. The team began by examining the serum viral load of a group of carriers of hepatitis B in relation to the HBV genome carried. They found a significant association between high serum viral load and a natural sequence variant within the HBV enhancer II regulatory region at position 1752. Upon testing all four possible 1752 variants, the 1752A variant had the highest transcriptional activity.In this month's Further investigation of this enhanced transcriptional activity revealed evidence of possible interaction with host DNA binding proteins. The team found that a protein present in the human host—hnRNPK—could be isolated by direct binding to a viral fragment derived from the HBV variant of these infected patients.hnRNPK has previously been shown to be involved in several cellular functions—for example, as a regulator of signal transduction and of gene expression. On further examination of the role of hnRNPK in HBV replication, they established that hnRNPK is capable of acting on the full length of HBV, rather than just a partial fragment. They compared four full-length replicative HBV clones, identical except for a single base change at position 1752, that were transfected with two different hnRNPK expression constructs and showed that 1752A was more efficient at promoting replication than the other three variants.To further show the role of hnRNPK in HBV replication, the team tested the effect of over-expression and down-regulation of the cellular protein. Using siRNA, designed to reduce endogenous hnRNPK, they showed suppression of both hnRNPK mRNA and HBV viral load, whereas a control siRNA had no effect on HBV viral load.Despite these findings, the mechanism behind hnRNPK on HBV replication needs further exploration, the authors say, concluding that viral replication efficiency was determined by a combination of viral sequence and interaction with specific host proteins. However, they suggest that these results indicate that although drug development of antivirals is an established research avenue, targeting the host is an untapped opportunity.They describe parallels with anti-EGFR antibody treatment of breast cancer cells, which produced a decrease in cell replication rate and corresponding reduction in hnRNPK expression levels; this result suggested that hnRNPK levels could be modulated by anti-EGFR treatment, thus highlighting new treatment options for altering the HBV viral load in chronic carriers.The authors conclude that the future of long-term viral clearance will require combination therapy of targeting the virus directly, blocking host support proteins, and using immuno-modulating agents.


In their letter, Krieger and Zhang note that our article  is “founKrieger and Zhang also state that there is “substantial … data available related to work tasks of handlers,” and they specifically cite the Pesticide Handlers Exposure Database and the U.S. Environmental Protection Agency (EPA) Transfer Coefficients. The Pesticide Handlers Exposure Database aims to determine how much residue (as a percentage of pesticide applied) ends up as external exposure to workers . These dWe agree that these databases represent important sources of data on both exposure and body burden. However, because formulas used in the calculations of exposure rely on fixed values for protection incurred by personal protective equipment, work hours, absorption rates, and spray patterns, they generate hypothesized risk estimates. Various studies have reported that < 100% of workers routinely use personal protective equipment while applying pesticides, and many may enter recently treated fields , resulting in potentially higher exposures than estimated in these databases.Our data are unique in that they provide real-world data on differences in proportion of detection of dimethyl urinary metabolites of adult workers. Moreover, by documenting differences in proportions of detection of urinary metabolites among children of farm-workers, our analyses begin to answer the question of whether or not pesticide residues are being brought into homes where children may be exposed. Because it is widely believed that pesticide residues accumulate in home environments, that they degrade more slowly than pesticides in fields, and that children have unique susceptibilities to and frequencies of exposure (given their propensity for hand-to-mouth behaviors and their frequent contact with floors), such a question merits investigation. Moreover, the relationship between workers’ job task and pesticide residues in collected house dust and vehicle dust samples provide compelling evidence that the take-home pathway is an important source of exposure.p-value = 0.003; vehicle dust p-value = 0.001). Although in our analyses we did not assess the associations between dust levels and urinary metabolite concentrations, our results do suggest that contamination of the home environment varies by occupational characteristics (Krieger and Zhang argue that urinary OP metabolite levels of children are more likely linked to dietary exposure than to environmental sources. The findings of eristics .In the next 5 years we will explore the take-home pathways as well as other pathways of pesticide exposure among children, including the dietary pathway. It is our hope that continued research will help clarify the important pathways involved in children’s exposure to pesticides. We believe that the most meaningful and relevant scientific discoveries result from hypotheses that are controversial. We look forward to further research and discovery on this topic.


The fly immune response is actively turned down, and if it is not, pathology results. Drosophila, provides crucial insights into the evolution and conservation of fundamental immune mechanisms. The best example of molecules discovered in the fly that are shared in human immunity operate in the Toll signaling pathway, one of first lines of defense against pathogens. Drosophila can also benefit human health by providing a model for immune systems of arthropod vectors of infectious disease. Additionally, from a comparative immunological perspective, it is useful to know how different organisms have evolved solutions for fighting infections, because this information can lead to new ways of thinking about disease.With its powerful genetics and rapid generation time, the fruit fly, At a simple level, it is clear that many immune responses are designed to turn on when needed, presumably because their constitutive expression would be deleterious. After induction, immune responses must also be turned off, for the same reason they are not left on from birth. The resolution of inflammation in humans occurs through a complex active signaling program . This neDrosophila genital tract in a Toll- and imd-dependent manner [In the fly, two well-described signaling pathways (Toll and imd) respond to microbial elicitors and induce the transcription of antimicrobial peptide (AMP) genes . Experimt manner .Signaling through the Toll and imd pathways leads to the activation and translocation of NF- B–like proteins into the nuclei of activated cells . In the Two important questions remained unanswered by this early work: “How and (perhaps more importantly) why does the immune system turn off this activated response?” A simple answer to “how?” might be that the immune response turns off when the elicitors are cleared. However, work in the last 3 years suggests that the story is more complicated and that several layers of negative regulation actively turn down immune signaling. The answer to “why?” appears to be that the immune response causes pathology when it is hyper-activated.At a very basic level, one might view the clearance of microbes as a negative regulator of the immune response—if the microbes are gone, there will be no more inducers and the immune response is no longer activated. Physical clearance of microbes occurs rapidly in flies through the action of phagocytic cells called hemocytes. This story is complicated because, after phagocytosis (the ingestion of particulates), hemocytes release unknown signals that activate a systemic immune response . PhagocyClearance of subcellular microbial elicitors follows a similar pattern. The bacterial cell wall component peptidoglycan is the chief bacterial elicitor known to activate Toll and imd signaling; amidases that degrade peptidoglycan likely help clear this material from the circulation. Mutant flies lacking these enzymes induce more AMP transcription ,6; againListeria monocytogenes. This is surprising because an increased immune response might be expected to lead to increased survival during an infection. In most cases, we don't understand why flies die when they are infected. It is possible that the increased production of AMPs uses energy that might otherwise be important for survival or that the immune response itself could be pathogenic.Besides this clearing activity, both cell-autonomous and cell–non-autonomous timing mechanisms exist to turn down immune responses. Toll signaling can be repressed by a Toll-regulated secreted inhibitor. Toll activation results in the transcription of wntD, a member of the wnt family of signaling ligands ,9, formigene defense repressor 1 (dnr1) [The imd pathway is also controlled by a simple negative-feedback loop. Activation of the imd pathway induces transcription of the conserved 1 (dnr1) . Dnr1 isActivation of the imd pathway leads to signaling through both the imd and JNK signaling pathways, and both pathways negatively regulate each other. Imd regulates JNK signaling by inducing genes downstream of relish that cause the degradation of the kinase dTAK1 . ActivatThis inhibition of imd signaling through the JNK pathway suggests that there might be communication between cells leading to immune inhibition. The JNK pathway can be activated by Eiger, the sole tumor necrosis factor (TNF) homolog in the fly . In vertPLoS Biology [domeless, which expresses the receptor in the fly JAK/STAT pathway. The requirement for JAK/STAT signaling in addition to Stat93E concentration suggests that this negative regulatory switch is sensitive to extracellular signals. The Domeless-JAK/STAT signaling pathway is the fly homolog of vertebrate cytokine signaling pathways, which are involved in both the positive and negative regulation of human immune responses [New research by Kim and colleagues published in this issue of  Biology  builds oesponses .By moving from a mechanistic description of this signaling circuit in cultured cells to a phenotypic description in whole flies, the authors demonstrated that reduced Jra or Stat93E levels resulted in increased AMP production in whole flies during an immune response. As was seen in wntD mutant flies, these mutants transcribed more AMP transcripts but were more sensitive to infections; thus there are now several examples demonstrating that appropriate down-regulation of the immune response is important for the survival of flies during an infection.We can now start to put this information together and imagine the progress of an infection in the fly. Cells at the initial site of infection likely respond by producing AMPs, nitric oxide, releasing bacterial elicitors of innate immunity, and synthesizing other signaling molecules. Multiple factors  will produce both positive and negative immune regulators that will color the systemic response of the rest of the fly. Thus a fly does not receive a single signal (“fungus here!”) nor does it robotically respond (“turn on AMP expression”); rather, a mixture of signals, in combination, allow more nuanced alarms  permits more complex, spatially, and temporally regulated responses.


To the untrained observer, the collective feats of social insects appear downright mysterious. How could insects with decidedly less-complex neural circuits than humans evolve the highly sophisticated communication strategies needed to build 3- to 4-meter-tall mound nests (termites), haul vegetation back to the home colony to cultivate fungi for food (leafcutter ants), or launch mass predatory attacks on other social insects like bees or wasps (giant hornets)? Though the past quarter century has yielded critical insights into the molecular and physiological underpinnings of insect sociality, scientists have yet to elucidate key aspects of social behavior and its regulation.The honeybee and its waggle dance emerged as a model of animal communication and social behavior in 1947, when Karl von Frisch discovered that waggling tells other bees where to find bountiful forage away from the hive. Biologists have been trying to figure out how wagglers convey this information and attract recruits in the darkness of the hive ever since. Sounds, comb vibrations, tactile cues (from touching antennae), and odors all play some role in this elaborate transfer of information, but none of these signals can fully explain how foragers are recruited.Now in a new study, Corinna Thom et al. report yet another component of the waggling honeybee’s lexicon. Waggle-dancing bees, the researchers found, produce four distinctive odors that induce foraging activity in other honeybees. Previous studies have shown that odors picked up while foraging may help recruits pinpoint a rich food source, but this is the first evidence that wagglers emit olfactory compounds  that influence the behavior of other foragers. Based on evidence that honeybees  use pheromones to organize colony mates for hive tasks, the researchers reasoned that olfactory cues may also play an important role in coordinating foraging activity.They tested this hypothesis by sampling the airspace around waggle dancers and nondancing bees with filters designed to extract volatile compounds from the air. Waggle dancers, they discovered, emitted four compounds that were absent from the airspace of nondancing bees. Compared with nondancing foragers and nonforaging bees, wagglers also had significantly higher amounts of these compounds, called cuticular hydrocarbons, on their abdomens. Cuticular hydrocarbons, produced beneath the insects’ outer covering , act as recognition cues in social insects, signaling nest mates and castes, for example. Interestingly, the most energetic waggle dancers produced the most copious quantities of these compounds.To find out whether the isolated chemicals influenced behavior, the researchers injected one of two mixtures onto the honeybee “dance floor” and then counted the number of bees exiting the hive. The first mixture contained three of the isolated compounds  dissolved in a solvent (hexane). The second mixture contained only the solvent.  Bees exposed to the treatment mixture of the three hydrocarbons left the hive in far greater numbers than bees exposed only to the hexane injections.Altogether, these observations indicate that pheromones unique to waggle-dancing bees activate foraging behavior in the hive, revealing an unappreciated role for semiochemicals in waggle-dance communication. The researchers propose that synthesis of the compounds increases in dancing bees and that the waggle-dance scent may be released as dancing raises their body temperature.Vespula wasps use them to establish and follow trails, and flies use them as sex attractants—the compounds had not been linked to specific honeybee behavior before. These new results suggest that the waggle scent serves as an attractant for honeybees, too. The scent of wagglers may serve to identify them as successful provisioners and attract the attention of recruits, who home in on the dancing foragers for details on the food site. It could then induce the hive to quickly organize a profitable foraging effort. The waggle scent may even convey trip-related details to recruits who are temporarily jostled away from the dancer. With evidence for a new role for olfactory cues in symbolic animal communication, researchers can explore just how the waggle scent elicits a behavioral response—and continue to decode the myriad communication mechanisms underlying the cooperative exploits of social insects.Though waggle-dance scent compounds have been associated with specific behaviors in other insects—for example,


We have examined the effectiveness of photodynamic therapy against R3230AC rat mammary adenocarcinoma and human mesothelioma as xenografts in the same host. The results demonstrate that the xenografted human tumour is significantly more responsive to photodynamic treatment than the rodent mammary tumour. Studies also showed that the mesothelioma xenograft was fluence rate- and fluence-dependent while the rat tumour exposed to the same conditions demonstrated neither of these dependencies. This disparity in response was not attributable to a difference in either whole-tumour uptake or subcellular distribution of the porphyrin photosensitiser. Analysis of the effects of visible irradiation on cytochrome c oxidase activity, measured in mitochondria prepared from tumours borne on hosts injected with photosensitiser, demonstrated that photoradiation-induced enzyme inhibition was significantly greater in mesothelioma than in R3230AC mammary tumour preparations. However, in parallel studies conducted in vitro, when photosensitiser and light were delivered to previously unperturbed mitochondria, rates of enzyme inhibition were not significantly different. Both tumours were established in long-term cell culture. While the uptake of porphyrin photosensitiser was equivalent in both cell lines, the R3230AC cells displayed a significantly greater photosensitivity than the mesothelioma cells. The data presented here demonstrate that the mechanisms that govern response to photodynamic therapy are complex, but in the case of these two xenografted tumours host response to therapy is not likely to play a significant role.


The specific objectives are threefold: to describe the biologically plausible mechanistic pathways by which exposure to particulate matter (PM) may lead to the adverse perinatal outcomes of low birth weight (LBW), intrauterine growth retardation (IUGR), and preterm delivery (PTD); review the evidence showing that nutrition affects the biologic pathways; and explain the mechanisms by which nutrition may modify the impact of PM exposure on perinatal outcomes.We propose an interdisciplinary conceptual framework that brings together maternal and infant nutrition, air pollution exposure assessment, and cardiopulmonary and perinatal epidemiology. Five possible albeit not exclusive biologic mechanisms have been put forth in the emerging environmental sciences literature and provide corollaries for the proposed framework.Protecting the environmental health of mothers and infants remains a top global priority. The existing literature indicates that the effects of PM on LBW, PTD, and IUGR may manifest through the cardiovascular mechanisms of oxidative stress, inflammation, coagulation, endothelial function, and hemodynamic responses. PM exposure studies relating mechanistic pathways to perinatal outcomes should consider the likelihood that biologic responses and adverse birth outcomes may be derived from both PM and non-PM sources . In the concluding section, we present strategies for empirically testing the proposed model and developing future research efforts. Low birth weight (LBW) affects 20 million infants worldwide . LBW is Perinatal outcomes are influenced by a multitude of factors including nutrition and health, genetics, physiologic stressors, and environmental toxicants such as ambient air pollution . In termCurrent epidemiologic evidence suggests that maternal PM exposure is correlated with several adverse perinatal outcomes . AlthougThe specific objectives of this review are threefold: to describe the biologically plausible mechanistic pathways by which PM exposure may lead to adverse perinatal outcomes ; review the evidence showing that nutrition affects the biologic pathways; and describe biologic markers that mediate the impact of nutrition and thereby explain the mechanisms by which nutrition may serve as effect modifiers of the association between PM exposure and perinatal outcomes.The specific biologic mechanisms whereby PM influences perinatal outcomes remain to be fully elucidated. However, epidemiologic, clinical, and experimental evidence correlates current levels of PM with both respiratory and cardiovascular effects , and pro2α (8-iso-PGF2α) isoprostane is one of the most promising biomarkers for assessing oxidative injury -1, IL-6, and tumor necrosis factor-α, serum amyloid A , the acuin utero due to interference with some process or processes such as affecting nutrition of the fetus, reduced oxygenation of maternal blood, or both. For example, a rapid decline in the placental delivery of essential fatty acids arachidonic acid and docosahexanoic acid is expected  and plasma fibrinogen—this association was significant only for the warm season. Other measurable biomarkers include factors VII–IX, fibrin d-dimer, and von Willebrand factor ] causes rapid vasoconstriction  and diastolic blood pressure (DBP). Panel studies conducted of adults with preexisting CVD found an increase in SBP associated with elevated particulate exposures  Figure . In contIf PM exposure is also associated with BP elevations in pregnant women, this could increase the risk of adverse perinatal outcomes as a consequence of preexisting hypertension or pregnancy-induced hypertension. Elevation of BP to levels that is defined as pregnancy-induced hypertension has been associated with IUGR  and PTD Although the specific underlying mechanisms that contribute to normal or adverse birth outcomes are not yet fully understood, an adequate periconceptional nutrition status is considered a key determinant . Given tThe nutrition aspects of the framework shown in In the past two decades, understanding of cardioprotective nutrients and foods has grown substantially owing to studies of the molecular mechanisms and the metabolic effects. Investigators typically estimate nutrient intakes using food frequency questionnaires , food re6), cyanocobalamin (B12), and folate. Carotenoids may protect against oxidant damage   indicateThere is a growing list of foods and food groups consumption of which is associated with the various biologic pathways depicted in the present framework . Fruits Dietary pattern analysis serves as a complementary approach to the nutrient-focused and food-group analysis described above. Dietary patterns are food intake patterns over a referent period and consider the overall dietary matrix  indices based on intakes of nutrients (or at least of certain nutrients); b) indices based on the consumption of foods or of groups of foods; and c) indices that combine both approaches resulting in dietary patterns. In the following section, we present examples of these measurement indices that add quantitative elements to qualitative aspects, and some are based on thresholds or recommendations. In a few cases, the indices were studied to link to the biologic parameters in the present framework.Individual dietary constituents may have small biologic effects that emerge only when the components are integrated into a simple unidimensional score. Oxidative stress has been described as a disturbance in the balance between free radical production and antioxidant capacity . ReflectDietary variety determined by Recommended Foods score (simple count of consumed food items) and diversity measured as Dietary Diversity Score (count of represented food groups)  are bothThe possibility that dietary patterns may exert an effect on biologic measures was first suggested through the findings of the DASH clinical trial  Appendi. As showIn The current framework may be advanced by biomonitoring women with unique circumstances . Further research will help identify susceptible population subgroups, such as for the potential for genetic variation in metabolic pathways  that could underlie differences in susceptibility to toxicities related to PM exposures . AlteredThe available data are consistent with the occurrence of PM-related systemic oxidative, inflammatory, and hemodynamic responses, but evidence on endothelial dysfunction and procoagulatory states is limited. In addition to these pathways, other alternate mechanisms   should bSeveral ongoing U.S. population-based research projects funded through the National Institute of Environmental Health Sciences  provide unique opportunities to apply and evaluate the current framework. The resulting findings would be relevant for PM regulation and primary prevention of CVD and other diseases influenced by the pathways proposed in the current framework and reducing the risks for adverse birth effects. If exposure interactions are found for PM with nutrition, they may also offer geographically relevant nutrition–environment interactions-based intervention opportunities through various federal food and nutrition assistance venues including the Special Supplemental Nutrition Program for Women, Infants, and Children.


Hypertrophic cardiomyopathy (HCM) is an important cardiovascular disease with sudden cardiac death as the most devastating presentation. Implantable cardioverter defibrillators (ICD) are the optimal therapy for prevention of sudden death from ventricular tachycardia or fibrillation of any cause. While there is no controversy with implanting ICDs in patients who have already survived a cardiac arrest, identifying high-risk patients for primary prevention in this disease remains a challenge. Implanting ICDs in patients with HCM is an important clinical consideration since many individuals could achieve normal or near-normal lifespans with this protection. Hypertrophic cardiomyopathy (HCM) is the most common genetically inherited cardiac disorder with an estimated prevalence of 1 in 500 in the general population ,3.The causes of sudden death in HCM remain controversial. While earlier theories outflow-tract obstruction, addressedthe current consensus favors primary ventricular arrhythmias, while recognising that the pathogenesis of such arrhythmias is multifactorial and involve complex interactions between a combination of factors. Given the high liklihood of prevention of sudden death from ventricular tachycardia or ventricular fibrillation by implantable cardioverter-defibrillators (ICD) in multiple primary and secondary prevention trials of ischemic and non-ischemic dilated cardiomyopathy, it is a reasonable expectation that such results can be replicated in patients with HCM. The difference between HCM and coronary artery disease is that risk-stratification in HCM with such variable natural history is exceedingly difficult and there exists no definitive consensus on precisely which patients should receive an ICD for primary prevention. On the other hand the ICD is strongly indicated for any patient, including those with HCM, who has survived a documented cardiac arrest i.e., secondary prevention , 5.It is important to remember that unlike other patients with ischemic or non-ischemic cardiomyopathy and ICD implants who have a limited life-span owing to advanced congestive heart failure and age, high risk HCM patients are usually younger and asymptomatic. Consequently, the potential of the ICD to prolong life is much greater in the HCM population, and therefore it is vitally important that patients be identified correctly for this therapy. In order to create a high risk profile, all HCM patients should undergo an initial comprehensive ambulatory risk stratification assessment, including detailed personal and family history and physical examination, 12-lead ECG, echocardiogram, ambulatory Holter monitoring and exercise testing. The currently recognised major risk factors for SCD in HCM include: unexplained syncope, , family history of HCM-related sudden death, identification of high-risk mutant genes, frequent, multiple or prolonged  episodes of non-sustained ventricular tachycardia on Holter monitoring, abnormal blood pressure response to exercise and extreme degrees of left ventricular hypertrophy , particularly in adolescents and young adults . InvasivControversy exists as to how many major risk factors are required in a particular patient to be considered deserving of an ICD, and some of this is uncertainty is due to the fact that the magnitude of risk conferred by each risk marker may not be the same. While the presence of multiple risk factors may convey an increased risk, a single risk factor may be adequate in a given patient to justify an ICD implant. ICD trials in HCM have documented their efficacy for sensing and terminating arrhythmias. A recent study by Maron, et al. showed appropriate discharges triggered by VT in 23% of patients when followed over 3 years, with an average discharge rate of 5% per year for primary prevention and 11% per year for secondary prevention. About 60% of the patients with appropriate interventions received multiple discharges .There are certain technical considerations for the electrophysiologist implanting ICD's in this population that deserve mention. The first relates to whether a single- or dual-chamber system should be employed. Dual chamber devices have the benefit of AV synchrony with pacing, although for the most part pacing as a treatment modality in HCM to reduce symptoms and outflow gradient was largely abandoned after the M-PATHY trial . More imLead fractures and device recalls are particularly relevant events that affect young HCM patients who will likely spend their whole lives with the ICD system. Unfortunately, these are impossible to predict in advance, and lead removal, in particular for older leads, is fraught with difficulties . WheneveThe number of HCM patients who meet criteria for an ICD implant is increasing. It behoves the cardiovascular community to offer these patients all major advances in treatment so that they can continue to lead productive lives, given their preserved systolic function and often minimum symptoms. Many of the current uncertainties about patient selection will be resolved soon with further clinical trials, and in the future more HCM patients will live longer lives with the aid of more technologically advanced ICD systems.


Each day, the bone marrow of an adult makes upwards of 200 billion new red blood cells, along with lesser numbers of white blood cells and platelets. This process, called hematopoiesis, depends on hematopoietic stem cells (HSCs), which divide to make both more stem cells and progenitor cells that differentiate into all the cell types of the blood. The genetic controls on this process are poorly understood. In this issue, Catherine Verfaillie and colleagues show how a two-stage analysis, generation of transcript microarrays followed by functional validation in zebrafish, can identify key regulators of the hematopoietic process.The study of human hematopoiesis has been hampered in part because it's not possible to use surface markers to identify and isolate HSCs, a technique used to purify other cell types. The authors used a strategy they had previously developed to isolate HSCs from bone marrow and umbilical cord blood that produces a yield up to 10-fold greater than standard protocols for purifying human HSC. Gene expression in this HSC-enriched cell population was then compared with that in an HSC-depleted population using transcript microarrays (“RNA chips”) to identify those genes whose expression was most different between the two groups of cells. They identified 277 genes whose expression in both marrow and cord blood significantly different between the HSC-enriched and -depleted populations. Of these 277 genes, Verfaillie and colleagues identified 61 whose functions were not already known and which had close matches in the zebrafish, a small fish in which hematopoiesis follows essentially the same path as in humans. To prevent expression of these 61genes, they designed complementary antisense molecules against them, and injected them into zebrafish embryos. In 14 of the 61 genes, knocking down expression led to observable defects in hematopoiesis.The authors note that three of these 14 genes are involved in signaling of fibroblast growth factor, a powerful regulator of development, suggesting that fibroblast growth factor may play a central role in hematopoiesis. More generally, they believe that the combination of using gene transcript microarrays to identify candidates and producing antisense molecules in zebrafish for functional screening of these candidates offers a way to quickly identify genes with central roles in vertebrate development.


Mendelian models for predicting who may carry an inherited deleterious mutation of known disease genes based on family history are used in a variety of clinical and research activities. People presenting for genetic counseling are increasingly reporting risk-reducing medical interventions in their family histories because, recently, a slew of prophylactic interventions have become available for certain diseases. For example, oophorectomy reduces risk of breast and ovarian cancers, and is now increasingly being offered to women with family histories of breast and ovarian cancer. Mendelian models should account for medical interventions because interventions modify mutation penetrances and thus affect the carrier probability estimate.BRCA1 and BRCA2 based on her family history of breast and ovarian cancer. This new BRCAPRO is available for clinical use.We extend Mendelian models to account for medical interventions by accounting for post-intervention disease history through an extra factor that can be estimated from published studies of the effects of interventions. We apply our methods to incorporate oophorectomy into the BRCAPRO model, which predicts a woman's risk of carrying mutations in We show that accounting for interventions undergone by family members can seriously affect the mutation carrier probability estimate, especially if the family member has lived many years post-intervention. We show that interventions have more impact on the carrier probability as the benefits of intervention differ more between carriers and non-carriers.These findings imply that carrier probability estimates that do not account for medical interventions may be seriously misleading and could affect a clinician's recommendation about offering genetic testing. The BayesMendel software, which allows one to implement any Mendelian carrier probability model, has been extended to allow medical interventions, so future Mendelian models can easily account for interventions. People who are concerned that their family has a high prevalence of disease may seek counseling to assess their probability of carrying inherited genetic mutations that cause disease . The carTo aid such people ("consultands"), genetic counselors use statistical models that predict whether the consultand carries deleterious mutations by using the consultand's reported family history of disease. Mendelian models use Mendel's laws and Bayes's rule to combine family history information with each mutation's known prevalence and penetrance to determine the probability that the consultand is a mutation carrier . For synBRCA1 [MIM 113705] and BRCA2 [MIM 600185] genes, based on family history of breast and ovarian cancer, while MMRPRO computes the probability of carrying a mutation in the DNA mismatch repair genes MLH1 [MIM 120436], MSH2 [MIM 609309], and MSH6 [MIM 600678] given family history of colorectal and endometrial cancer. Genetic counselors use BRCAPRO and MMRPRO via CancerGene  andanalysis  to averaBRCA non-carriers, only studies that mix carriers with non-carriers. A population-based study found a hazard ratio of 0.50 [Unfortunately, there are no comparable studies of oophorectomy in  of 0.50  and anot of 0.50 . Since t of 0.50 . Althoug of 0.50  doesn't This section computes the post-intervention contributions to the BRCAPRO Bayes Factor (as in equation (11)) from a woman who underwent oophorectomy at age 35, for all three possibilities of developing breast or peritoneal cancer, or current age without either cancer .BRCA1 Bayes Factor, by accounting for her oophorectomy at age 35 (solid lines), ignoring her oophorectomy (dashed lines), or censoring her at the age of oophorectomy (dotted lines). A woman can get breast or peritoneal cancer, or no cancer, at the age indicated on the x-axis. Since the effect of oophorectomy in non-carriers has not been well-studied, each panel of figure Figure The top left panel of figure In the top right panel of figure The bottom right panel of figure BRCA carriers undergo oophorectomy [People with a family history of disease may undergo prophylactic interventions to prevent future disease. Interventions are informative about the carrier probability not only because interventions reduce the penetrance of mutations, but also because only those with high disease risk  will opt for it. Furthermore, as interventions become more commonly undergone (most studies show that about 50% of orectomy ) and conorectomy .Incorporating interventions into Mendelian mutation prediction models requires only a post-intervention factor multiplying the likelihood contribution from family members with the intervention. The only new quantities required are the post-intervention disease hazards which can be estimated by multiplying the pre-intervention hazards by hazard ratios for the effect of intervention that can be found in published studies of intervention effects. We extended the BayesMendel software to handle interventions, and the new BRCAPRO that accounts for oophorectomy is available for clinical use. Other interventions that BayesMendel could incorporate are prophylactic tamoxifen therapy into BRCAPRO, and colectomy and hysterectomy with oophorectomy into MMRPRO.BRCA mutation carriers found in previous studies [BRCA mutation carriers benefit less from oophorectomy because they have earlier age of onset of breast cancer. Since our incorporation sets equal benefits to prevent breast cancer, this may underestimate the impact of oophorectomy, but further studies of oophorectomy in non-carriers are needed to clarify this situation. Fortunately, forthcoming prospective studies of the benefit of oophorectomy in women at high risk of ovarian cancer, such as GOG-0199 [BRCA mutation non-carriers, allowing estimation of the intervention hazard ratio in non-carriers.To incorporate oophorectomy into BRCAPRO, we relied on hazard ratios for the effect of oophorectomy in  studies ,16,28, a studies . Althoug studies ,31 show GOG-0199 , could pFigure Our incorporation of interventions shows that there is no information about carrier status in whether a relative chooses intervention or not, as long as the full family history and genetic test results are known. This is reflected in the fact that the first factor of equation (7) is ignorable. This factor will not be ignorable if the relative based her intervention decision on factors predictive of carrier status that are not available to the consultand. For example, if a consultand is unaware of genetic test results on a relative who opted for or against intervention based on those test results, then the first factor is not ignorable. However, the first factor can be estimated from a survival analysis of age at intervention given pre-intervention disease history and carrier status. Prospective studies such as GOG-0199 could provide the required data.Although this paper has emphasized using Mendelian models in genetic counseling, other applications exist. Mendelian models can help gene characterization research by helping to select high-risk individuals for studies (such as in GOG-0199) and also to help build statistical models that estimate individualized disease risks . Both apThese results show that not accounting for medical interventions can lead to seriously misleading carrier probability estimates that could affect a clinician's recommendation about offering genetic testing. This is especially true if an intervention was undergone long ago by a family member or if the intervention has different effects on carriers versus non-carriers. The new BayesMendel software has been extended to allow medical interventions, so any carrier probability model can easily account for interventions.The author(s) declare that they have no competing interests.The pre-publication history for this paper can be accessed here:


Despite increasing attention to the human dimension of conservation projects, a rigorous, systematic methodology for planning for ecosystem services has not been developed. This is in part because flows of ecosystem services remain poorly characterized at local-to-regional scales, and their protection has not generally been made a priority. We used a spatially explicit conservation planning framework to explore the trade-offs and opportunities for aligning conservation goals for biodiversity with six ecosystem services  in the Central Coast ecoregion of California, United States. We found weak positive and some weak negative associations between the priority areas for biodiversity conservation and the flows of the six ecosystem services across the ecoregion. Excluding the two agriculture-focused services—crop pollination and forage production—eliminates all negative correlations. We compared the degree to which four contrasting conservation network designs protect biodiversity and the flow of the six services. We found that biodiversity conservation protects substantial collateral flows of services. Targeting ecosystem services directly can meet the multiple ecosystem services and biodiversity goals more efficiently but cannot substitute for targeted biodiversity protection . Strategically targeting only biodiversity plus the four positively associated services offers much promise (relative biodiversity losses of 7%). Here we present an initial analytical framework for integrating biodiversity and ecosystem services in conservation planning and illustrate its application. We found that although there are important potential trade-offs between conservation for biodiversity and for ecosystem services, a systematic planning framework offers scope for identifying valuable synergies. A spatially explicit framework reveals whether areas important for the provision of ecosystem services align with areas important for biodiversity conservation and indicates the need to broaden current conservation goals. Despite the vital importance of ecosystem services—the supply of benefits from ecosystems to society—leaders in both the private and public sectors have been slow to incorporate these benefits into decision making. This slow incorporation traces to a complex of factors well beyond science, but at the core is the poor characterization of the flow of services in the necessary biophysical and economic terms at the local and regional scales most useful to decision makers –3. In reThese advances have come on numerous fronts, including the following: (i) the maturation of conservation planning –7; (ii) Replicating and scaling up these small-scale efforts is a challenge requiring formal strategic planning for ecosystem services and biodiversity. To begin to address this challenge, we applied spatially explicit biodiversity-planning methodologies to a suite of six ecosystem services, yielding ecosystem-service conservation blueprints. We compared these to existing biodiversity blueprints to gain a preliminary understanding of trade-offs and side benefits between biodiversity and ecosystem services.In developing a blueprint for biodiversity conservation, species, communities, and ecosystems are “features” for which “targets” are expressed . The bluPlanning for services is inherently more complex. The Millennium Ecosystem Assessment  distinguThis paper has two parts. First, we demonstrate how a formal, quantitative planning framework can integrate ecosystem-service values into biodiversity conservation planning. Second, we provide a preliminary assessment of the possibilities for aligning goals of conserving biodiversity and ecosystem services. We adapted and applied methodologies for conservation planning to six ecosystem services of the Central Coast ecoregion in California, United States. We chose an area and services for which we had sufficient spatial data and an empirical understanding for an illustrative integrated analysis, rather than a definitive study of each service. The six ecosystem services—which are important locally, regionally, or globally—are described as follows.2 emissions has resulted from land conversion , which determines practical significance as the proportion of the networks affected by these associations between services.We assessed network overlap in two ways: “best” network overlap and irreplaceability similarity. For the best network overlap, we calculated the number of cells for each pair-wise combination of services that occur in each best network and the number that co-occur. We calculated the expected number of overlapping cells based on an assumption of independence between the two networks asr) between the “summed-solution” networks .Because our interest is primarily in practical significance, and even associations with little practical importance will be statistically significant with such large sample sizes, we do not calculate statistical significance with sophistication and ignore the issues of spatial autocorrelation and multiple tests. For irreplaceability similarity, we calculated the correlation . For trade-offs, we analyzed four different combined networks of services: Biodiversity (only biodiversity); Non-biodiversity ; All; and Strategic .Our “Strategic” network is intended to be strategic only in the context of this analysis to avoid trying to optimize across too many poorly correlated ends, because we recognize that many other factors must be considered in determining the course of conservation action. For “All” and “Strategic,” we used the same suitability layer as for “Biodiversity” and set MARXAN's cost threshold value to the same as that of the best “Biodiversity” run to ensure that these networks would be comparable. For “Non-biodiversity,” we used a flat cost value of 500 for each planning unit. Otherwise, the same MARXAN parameters were used as those described in the For each combined network, we assessed the proportion of ecosystem-service targets achieved for each stratification unit . We capped these target-achievement proportions at 1, because exceeding one stratification unit's target does not easily compensate for failing to meet another stratification unit's target. We calculated the ecoregion-wide target achievements for each ecosystem service by averaging across stratification units weighted by the size of the target. In some cases, it will be advantageous to exceed targets, however; accordingly, we separately calculated surpluses /target) for each stratification unit and for the ecoregion (again through weighted averages).For side-benefit analyses, we performed MARXAN runs to meet individual ecosystem-service targets assuming prior protection of the biodiversity network. We calculated the additional land needed (as a percentage of the biodiversity network), the additional “cost” of this land (using the service's suitability layer), and the benefit of these added lands for biodiversity (using RWRI).The seven benefit functions—for biodiversity, carbon storage, flood control, forage production, pollination, recreation, and water provision—have distinctly different spatial distributions, although some areas are of high value to multiple services and other areas are of low value to many . For exaThe spatial correlations between the ecosystems services are low A, with nThe pair-wise overlap between the seven networks derived by MARXAN for individual benefit functions  is displayed in The seven individual networks are summed over space in Other areas, such as San Luis Obispo County, are selected for only a few benefits (in light blue). Although much of San Luis Obispo County is agricultural, there are few high-value crops that benefit from animal pollination. Furthermore, because of the sparse forest cover, this county has relatively low values for carbon storage. Although livestock values are relatively high in San Luis Obispo County, neighboring Kern County has far higher values likely because of nearby feedlots, slaughterhouses, and transportation routes. Accordingly, Kern dominates the network for forage production E. A portThe extent to which individual benefit-function targets are met by the four comprehensive networks is depicted in Because target achievement was assessed at the stratification-unit level and then aggregated to the ecoregion level, there are services for which there are considerable surpluses despite unmet targets  and targets  natural habitat within a human-dominated landscape . Not surprisingly, the two features are negatively associated spatially , and eacSecond, independent scales of supply and demand can affect relationships between target achievement and the total size of benefit demand and supply. Targets may be poorly met despite relatively high overall availability or they may be well met despite barely adequate availability. Targets are more easily met if demand occurs at broad scales and supply varies considerably at local to regional scales. For example, carbon storage demand is global, but supply varies greatly based on vegetation cover and climatic conditions; consequently, it was possible to meet the target of 50% of the ecoregion's carbon storage in all networks . AlthougFor some ecosystem services, demand scales positively with the number of people in close proximity, whereas developed and agricultural lands are less productive or less suitable for management. These two factors result in a tension in planning, even for an individual service. For example, the demand and therefore the value of recreation opportunities is much greater close to cities  will be incompatible with management for another purpose . Fifth, a tool must account for the flow from particular ecosystems to particular beneficiaries. Site-selection software like MARXAN assigns value to a planning unit in the context of the larger stratification unit, without more specific accounting of spatial context or ecological processes . For exaFinally, a tool should allow flexibility between the ends of benefit maximization (used by Naidoo and Ricketts ) and suiEcosystem-service planning must involve multidisciplinary and transdisciplinary teams. Interdisciplinarity (research between disciplines) is not sufficient, because ecosystem-service research and planning requires deep knowledge within—and across—multiple disciplines. Planning for ecosystem services requires expertise in biology, chemistry, physics, economics, finance, geosciences, geography, and particular analytical tools. The integration of theoretical understanding and empirical expertise from these diverse fields therefore requires a multidisciplinary team of experts working in close communication, spearheaded by transdisciplinary scholars and practitioners.Only by analyzing both the trade-offs and the side benefits for biodiversity of conserving ecosystem services and vice versa can we guide conservation efforts more effectively. Trade-off analyses will be applied most successfully when management for an ecosystem service cannot help to meet the targets of biodiversity conservation.Analyses of the ancillary benefits of an ecosystem-service project to biodiversity conservation and vice versa have two purposes. Such analyses can reveal when an ecosystem-service project offers promise for attracting new conservation partners and funds for biodiversity projects, and when such projects are especially important for their biodiversity benefits.By combining trade-off and side-benefit analyses with a thorough scoping of potential partnerships and new markets, we may achieve substantial increases in biodiversity conservation while conserving the ecosystem services critical for human well-being. For example, case studies of water regulation and delivery and flood control reveal that conservation of forests and wetlands are sometimes worthwhile from an ecosystem-service perspective alone Click here for additional data file.


Affymetrix microarrays have become a standard experimental platform for studies of mRNA expression profiling. Their success is due, in part, to the multiple oligonucleotide features (probes) against each transcript (probe set). This multiple testing allows for more robust background assessments and gene expression measures, and has permitted the development of many computational methods to translate image data into a single normalized "signal" for mRNA transcript abundance. There are now many probe set algorithms that have been developed, with a gradual movement away from chip-by-chip methods (MAS5), to project-based model-fitting methods . Data interpretation is often profoundly changed by choice of algorithm, with disoriented biologists questioning what the "accurate" interpretation of their experiment is. Here, we summarize the debate concerning probe set algorithms. We provide examples of how changes in mismatch weight, normalizations, and construction of expression ratios each dramatically change data interpretation. All interpretations can be considered as computationally appropriate, but with varying biological credibility. We also illustrate the performance of two new hybrid algorithms  relative to more traditional algorithms  using an interactive power analysis tool. PLIER appears superior to other algorithms in avoiding false positives with poorly performing probe sets. Based on our interpretation of the literature, and examples presented here, we suggest that the variability in performance of probe set algorithms is more dependent upon assumptions regarding "background", than on calculations of "signal". We argue that "background" is an enormously complex variable that can only be vaguely quantified, and thus the "best" probe set algorithm will vary from project to project. The impressive density of oligonucleotides provides adequate space on the chip  for use of multiple probes per mRNA transcript. Thus, each transcript is queried by a probe set . The assessment of the amount of a specific mRNA in a solution from a tissue or cell is determined by the amount of hybridization to the different oligo features for that mRNA. While "hybridization" is a highly sensitive and specific assay, it is not perfectly sensitive or perfectly specific. Thus, it is critical to provide measures of non-specific hybridization and probe binding (background), and one method is to print mismatch probes, where a single base mutation in the center of each 25 mer probe should disrupt most "specific" hybridization. Current expression profiling microarrays use 11 perfect match and mismatch probe pairs for each probe set, although there may be many probe sets per transcript unit.Current Affymetrix microarrays  use chemThe multiple measurements of hybridization for each mRNA allow a more robust measure of expression, as "signal" is derived from many assessments. However, the multiple measures has led to considerable debate with regards to the best method of integrating the 11 perfect match and 11 paired mismatch hybridization intensities into an ensembled "signal" for each gene. There are many calculations intrinsic to the probe set algorithms that derive gene expression signal, including varied penalties for the mismatch signal, different intra-probe set normalizations, and normalizations between microarrays. Recent publications have reviewed the specific calculations used by different probe set algorithms ,3. To ilWhen the same data set is then normalized to time 0, the Y axis becomes a measure of "fold-change" between baseline (time 0), and peak expression (day 3) Figure . As the There has been growing interest on the effect of probe set algorithms on data interpretation, with development of new probe set algorithms, and also comparisons between probe set algorithms   has beenWe recently took a different approach, where three different large data sets with different biological variance intrinsic to each organism and experimental system  were studied. We built an interactive analysis tool to query the statistical power of each probe set on the arrays in the project, with dynamic user-definition of sample size, effect size (fold-change), and statistical significance . We founOne could envision that the ideal probe set algorithm would optimize background correction and normalization for each project and each probe set in that project. While such approaches are doomed to be "data starved", recently, new "hybrid" probe set algorithms have emerged that attempt to better combine the precision of model based approaches, with more judicious use of background correction . These include the Affymetrix PLIER algorithm  and GC-Ronly those probe sets that showed 100% absent calls by MAS5.0 algorithms would enrich for poor quality signals with considerable noise components, due to poorly performing probe sets, low level or absent target mRNAs, or cross-hybridization. By limiting our statistical power analysis to these 100% absent call probe sets, we hypothesized that this would lead to a sensitive test for performance of probe set algorithms with regards to balance of precision and accuracy, and further, an assessment of the potential for false positives.We reasoned that use of We used our public domain power analysis tool (HCE-power)  to study2 = 0.244803) was considerably less accurate than PLIER (R2 = 0.324908).Another method of illustrating this point is to analyze sample mixing data sets. We used a publicly available dataset of two different human tissues (PBMC and placenta) mixed in defined ratios  . To enriLog transformation of microarray data is another method that is frequently used to reduce variance, and hence improve precision -24. We hEfforts to use a single "best" probe set algorithm for all probe sets and projects may be an unattainable goal. Instead, selection of analysis methods for any particular project should be viewed as striving towards an appropriate balance of precision and accuracy. Emerging hybrid probe set algorithms, such as PLIER, may prove particularly powerful in reducing false positives. New tools such as Affycomp and HCE-power can be used to assess this balance.EPH conceived of the study. EPH and JS designed the study together. JS designed and implemented the power analysis tool (HCE-Power), and performed the statistical analysis. All authors read and approved the final manuscript.


Shift work exerts major influences on the physiological functions of the human body. These are primarily mediated by the disruption of circadian rhythms since most body functions are circadian rhythmic. Next to the disturbances caused by changes in the circadian system, shift work has also been suggested to be related to a number of other health disorders. The present study summarizes recently published data on the potential relationship between disorders and shift working. Occupational and environmental medicine cover a broad field of areas including respiratory disorders -6, haemaA PubMed research was performed using the terms "shift", "work", and "shift work" and publication types (date: 2006-01-04). Articles were screened for their contents and relevant data was analysed.For the term „shift" 93718 entries were registrated. To analyse specific articles related to shift work, the search was narrowed and for the terms „shift" AND „work" 5557 entries were found. To further delineate the research the term "Shift work" was entered and 931 entries were registered which were analysed for their contents fig. . Also, rSince shift work has been related to an increased risk of cardiovascular diseases metabolic risk factors like obesity, elevated lipid levels, or disturbed glucose tolerance and not least the sum the metabolic syndrom between shift workers were focused in recent studies ,25. SincAn association between shift work and myocardial infarction has been postulated since many years ,28. In tAntioxidant capacity has been related to numerous diseases and antioxidant enzymes exert major effect on various cellular functions -32. It mAs suggested by a lack in the antioxidative capacity, shift work may also have influence on the prevalence of infections . To analMegdal et al. examined the association between night shift work and breast cancer risk by performing a meta-analysis of observational studies to assess the effects of night work on breast cancer risk. They screened the PubMed from January 1960 to January 2005 using search terms such as night work terms, flight personnel terms, cancer terms, and risk terms and performed independent data extraction by two authors using standardised forms . Based oSeveral studies were performed in Seattle to investigate the effects of factors that can disrupt circadian rhythm and alter normal nocturnal production of melatonin and reproductive hormones of relevance to breast cancer etiology . StudiesThere is a large amount of data pointing to an association between shift work and the prevalence of many medical conditions. However, as these disorders are often based on a variety of non-occupational factors, a distinct separation into either occupational (shift-work-related) or non-occupational can be difficult fig. . For exaThe author(s) declare that they have no competing interests.AvM, LBC, RK, and EB have all been involved in drafting the article or revising it critically for important intellectual content and have given final approval of the version to be published.


Mosquito-borne flaviviruses such as Japanese encephalitis virus (JEV) and West Nile virus (WNV) are two of the most important examples of emerging and resurging pathogens. Currently, there are no effective drugs available to treat these infections. Moreover, infections by diverse neurotropic flaviviruses are clinically indistinguishable, which makes it important to develop broad-based therapies effective against multiple flaviviruses.In a new study, Priti Kumar and colleagues examined whether RNA interference (RNAi)–based intervention could suppress lethal JEV and WNV encephalitis in mice. RNAi is a process in which short double-stranded RNA (dsRNA) called short interfering RNA (siRNA) inhibits gene expression in a sequence-specific manner. This process was first discovered in plant cells, and there is still speculation concerning its implications for human physiology. However, RNAi has emerged as a powerful technique for posttranscriptional gene silencing, useful in both research and, potentially, the development of new therapies.Studies of RNAi in plants, invertebrates, and, more recently, mammalian cells have all hinted at the potential of this method. RNAi-mediated posttranscriptional gene silencing appears to have evolved to protect against invading genetic elements such as transposons and viruses. In mammals, although exposure to dsRNAs greater than 30 base pairs in length induces an antiviral interferon response that represses mRNA translation globally, shorter siRNA introduced into mammalian cells leads to specific mRNA degradation without activating the interferon response. Previous work has shown that infection by respiratory syncytial virus (RSV) and parainfluenza virus (PIV) could be specifically prevented and inhibited by siRNAs. In an RSV mouse model, researchers used siRNA to target the P protein, a key subunit of the viral RNA–dependent RNA polymerase, and found that it strongly inhibited RSV gene expression and RSV growth in culture. They also showed that single and concurrent infections in mice could be prevented and treated by specific siRNA applied exclusively intranasally. Their findings suggested that inhaled siRNA could be a promising strategy for anti-RSV and anti-PIV therapy in humans.Studies have also demonstrated that siRNAs expressed by a lentivirus vector could prevent and treat influenza A virus (IAV) pneumonia in mice. When siRNAs specific for conserved regions of the IAV genes  were administered prior or subsequent to the virus challenge, there were reductions in lung virus titers, lethality, or both. Based on these results, in a recent review of siRNAs for treating influenza, Jack Bennink and Tara Palmore have suggested that siRNAs could lead to a therapeutic solution against the variability of the IAV hemagglutinin. Kumar and colleagues from Harvard University describe promising results for the therapeutic potential of RNAi in treating viral encephalitis, both virus-specific and across species. They induced RNAi in mice, with either a lentivirally expressed short hairpin RNA or a synthetic siRNA. By targeting a species-specific sequence in cd loop coding region in domain II of the viral envelope protein for JEV or WNV, the team achieved specific protection in mice against the corresponding virus. And in addition, by targeting a sequence within the cd loop that is conserved across both viral species, they were able to protect mice against encephalitis induced by both viruses.These results suggested that a single treatment with siRNA may be sufficient for protection against fatal encephalitis, which is encouraging from a therapeutic angle. In one set of experiments, they showed that single administration of siRNA could provide more than 60% protection even when administered 18 hours after infection. This time frame is relevant because the burst phase for JEV and WNV replication is around 18 hours—when many virus progeny are released.However, although a single lipid–based siRNA delivery in the brain parenchyma caused some degree of lateral spread and offered protection even in an established infection, this approach is unlikely to work when the infection has spread across the brain. This observation is important for potential clinical applications since usually treatments are not given until after the appearance of clinical symptoms.To address this limitation, the authors suggest, further studies will have to focus on developing improved methods for siRNA delivery to brain cells. And much work will need to be done to establish the safety of this approach in humans. But RNAi technology may be shifting from a laboratory tool to a realistic treatment for viral infection.


A number of biological factors have been identified which correlate with prognosis in neuroblastoma. Among these are genetic aberrations, including ploidy, deletions of chromosome 1p and N-myc amplification. Conventional methods of detecting these changes, such as tissue culture for karyotyping and Southern blotting, are time-consuming and yield interpretable results in only a small proportion of cases. We have developed interphase fluorescence in situ hybridisation for use on tumour imprints and bone marrow smears, allowing rapid visualisation of the relevant genetic changes. Valuable prognostic information is therefore available in a few days: the results in our cases were later confirmed by conventional methods. In the foreseeable future it will be possible to define distinct prognostic categories on the basis both of this genetic information and other parameters, and separate therapeutic strategies may then be employed for the different patient groups.


ABCA4 , CRX and GUCY2D , and RPGR . It is likely that highly deleterious mutations in genes that otherwise cause RP or macular dystrophy may also lead to CRDs. The diagnosis of CRDs is based on clinical history, fundus examination and electroretinogram. Molecular diagnosis can be made for some genes, genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, and the visual prognosis is poor. Management aims at slowing down the degenerative process, treating the complications and helping patients to cope with the social and psychological impact of blindness.Cone rod dystrophies (CRDs)  are inherited retinal dystrophies that belong to the group of pigmentary retinopathies. CRDs are characterized by retinal pigment deposits visible on fundus examination, predominantly localized to the macular region. In contrast to typical retinitis pigmentosa (RP), also called the rod cone dystrophies (RCDs) resulting from the primary loss in rod photoreceptors and later followed by the secondary loss in cone photoreceptors, CRDs reflect the opposite sequence of events. CRD is characterized by primary cone involvement, or, sometimes, by concomitant loss of both cones and rods that explains the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The clinical course of CRDs is generally more severe and rapid than that of RCDs, leading to earlier legal blindness and disability. At end stage, however, CRDs do not differ from RCDs. CRDs are most frequently non syndromic, but they may also be part of several syndromes, such as Bardet Biedl syndrome and Spinocerebellar Ataxia Type 7 (SCA7). Non syndromic CRDs are genetically heterogeneous (ten cloned genes and three loci have been identified so far). The four major causative genes involved in the pathogenesis of CRDs are  Cone rod dystrophies (CRDs)CRDs are inherited retinal dystrophies that belong to the pigmentary retinopathies group.• Decrease in the visual acuity is the earliest symptom• Photophobia also occurs early• Frequent dyschromatopsia• Night blindness occurs later• Central scotoma appears first, preventing fluent reading• Patchy losses of peripheral vision follow• Severe loss of vision occurs earlier than in retinitis pigmentosa (RP)• Normal looking macula or fine macular lesions and pallor of the optic disc may be the only signs at early stage• Pigmentary deposits resembling bone spicules, frequently in macular area• Attenuation of the retinal vessels• Waxy pallor of the optic disc• Various degrees of retinal atrophy• Implicit time (between a- and b-wave peaks) shift at the 30-Hz flicker responses, along with delayed a- and b-wave single flash photopic response are early signs before amplitude reduction• Dramatic decrease of amplitudes of both a- and b-waves• Predominant involvement of photopic (cones) over scotopic (rods) responsesPrevalence of CRDs is estimated at 1/40,000  . For certain genes or severe mutations, this probability will be high, while for others it will be lower. The results of experimental and clinical studies clearly indicate that the mechanisms of photoreceptor degeneration are multiple. In all genetic forms of CRDs studied until now, data are incomplete. In addition, it is likely that several apoptotic pathways are involved in the photoreceptor loss, sometimes concurrently, and this also needs to be carefully investigated. This knowledge is crucial to design therapies. The efficacy of various potential treatments has to be proven in animal models and in humans. For example, gene replacement therapy for RDS in mouse improves photoreceptor ultrastructure, but there is no significant effect on photoreceptor cell loss [42].