Why is it that some parasites cause high levels of host damage (i.e. virulence) whereas others are relatively benign? There are now numerous reviews of virulence evolution in the literature but it is nevertheless still difficult to find a comprehensive treatment of the theory and data on the subject that is easily accessible to non-specialists. Here we attempt to do so by distilling the vast theoretical literature on the topic into a set of relatively few robust predictions. We then provide a comprehensive assessment of the available empirical literature that tests these predictions. Our results show that there have been some notable successes in integrating theory and data but also that theory and empiricism in this field do not ‘speak’ to each other very well. We offer a few suggestions for how the connection between the two might be improved. The virulence of parasites is shaped by evolutionary trade-offs at different biological scales. At the host population scale, parasites that are able to best monopolize susceptible individuals tend to be most successful. However, the ability of a parasite to monopolize susceptible hosts is intimately tied to its ability to persist within hosts and to spread effectively between them. Therefore success at the host population scale is also tied to success at the scale of physiological interactions within a host  and the duration of infection (μ + ν + γ)−1  and/or by prolonging the infection . Trade-off theory assumes that a parasite cannot simultaneously increase transmission and prolong infection, and so parasites are attempting to maximize R0 subject to these constraints. Although within-host processes may not be explicitly represented in the models, epidemiological trade-offs are thought to emerge from the dynamics of the within-host interactions between the immune system and parasite.Here, parasite fitness is the product of the rate at which new infections are caused by an infected host  with better water sanitation have lower virulence, perhaps because improving water sanitation reduces the opportunity for environmental transmission, thereby increasing the importance of direct transmission  had reduced environmental persistence (higher rates of inactivation), in apparent contradiction to the general theoretical expectation that more virulent parasites would persist longer in the environment .Note that all theoretical work summarized here assumes parasites are obligate rather than opportunistic. When parasites can grow in both the environment and the host (i.e. opportunistic parasites), none of these conclusions would necessarily hold. The addition of growth in the environment effectively creates another selective arena; thus how virulence should evolve will critically depend upon whether or not there is any linkage between virulence within-host and survival or growth in the environment. For example, empirical work on opportunistic parasites shows that selection for anti-predator adaptations in the environment can lead to decreased within-host virulence  to influence virulence expression in the other (e.g. the host). Thus, on the basis of both theory and data, it is unclear that any simple predictions will hold for vector-borne diseases.Empirical evidence for these predictions is equivocal. Correlational evidence for the hypotheses has been found for some human diseases Ewald, , 1994. AThe simple prediction for parasites that can be transmitted from parent to offspring is that vertical transmission should select for reduced virulence: because the parasite depends on host survival and reproduction for its transmission, virulence that increases mortality or reduces fecundity will be under strong negative selection Ebert, . In realet al.et al. . Mixed . et al.. This isvs horizontal transmission have shown that increasing vertical transmission reduces virulence, whereas increasing horizontal transmission increases virulence  and horizontal transmission Herre, . Studieset al.et al.et al.et al.et al.Classic life history theory predicts that reducing lifespan will increase reproductive effort at earlier ages  than parasites under selection imposed by late host mortality  high mutation rates, this assumption is likely overly restrictive. Moreover, this framework necessarily ignores potential evolutionary changes in virulence that might occur when epidemiology and evolution happen at similar rates. However, a number of authors have studied how virulence evolves during the epidemic, rather than endemic, phase of epidemiological dynamics  phage dominated early in an epidemic, but as prevalence increased, the less virulent  strain won out. One of the strengths of this study was that it was paired with a mathematical model for the system that predicted, a priori, both the qualitative and quantitative dynamics of virulence evolution.Experimental or observational evidence for this prediction is challenging to find, as it requires both that virulence is measured over the course of an epidemic and the ability to rule out alternative explanations for changes in virulence, such as host evolution or parasite evolution in response to other factors, like medical intervention. The classic reference for rapid evolution of virulence is of course the rabbit-et al.et al.et al.et al.et al.The overall consensus from the theoretical literature is that lower virulence will evolve in populations with restricted spatial movement, and higher virulence will evolve in populations with greater connectivity  . VaccinMultiple infection can arise because a host is infected with multiple strains of the same parasite or with multiple species of parasite. Infection with multiple strains of the same parasite can result from separate infection events of co-circulating strains, or because the parasite has a rapid mutation rate and generates strain diversity through mutation within the host. Biologically, distinctions between ‘types’ of multiple infection matter because they affect the relatedness of the co-infecting parasites and relatedness can influence the optimal virulence strategy for the parasite. For clarity and simplicity, we will use the term ‘strains’ to refer to the different parasites infecting a host, acknowledging that different ‘strains’ may actually represent different species of parasite.et al.There have been three primary theoretical frameworks used to study multiple infection. Under a superinfection framework, each host is infected by a single strain at a time, but strains can displace one another based on strain traits, like virulence  strains dominated transmission, and virulence experienced by the host was approximately equal to the virulence induced by the most virulent strain  was positively associated with both within-host competitive ability and transmission success, such that the most virulent strain dominated in mixed-strain infections  Cox, . This tyAlizon and van Baalen  study viet al.et al.et al.How immune-mediated apparent competition should affect virulence evolution is also unclear from an empirical perspective. Some early experiments with rodent malaria suggested that apparent competition might explain why avirulent strains suffer more in competition with virulent strains in immunocompetent mice than in immunocompromised mice  than single-strain infections , whereas low relatedness leads to the persistence of cheater strains and lower virulence  Spatiaet al.Outside of identifying broad and robust theoretical predictions, the purpose of this review was to evaluate the empirical evidence for these predictions. Previous authors have noted that the theoretical and empirical literatures are not easy to reconcile  or integrating into the cell's genome  and the potential for integration to prevent superinfection. They then used these models to predict key features of the evolutionary process and tested those predictions directly, a key advantage of working in bacteria-phage host-parasite systems. However, this approach has been successful in other systems as well: Gandon et al.  to be determined by the dynamics of the within-host model, which captures interactions between parasite strains, the immune system and parasite resources (Mideo et al.et al.et al.et al.et al.et al.et al. (Nested models (.et al.  illustraet al.Another interesting potential avenue for future theory development and theory/data integration is motivated by a consideration of the relative sensitivity of parasite fitness (Frank and Schmid-Hempel, et al.Despite the considerable theoretical literature surrounding virulence evolution, there is still a clear need for general theory in some areas. At the most basic level, almost all of the work summarized here assumed the existence of a trade-off between virulence and transmission. Other potential trade-offs, such as between virulence and recovery (Anderson and May, However, given the challenge of experimentally measuring the quantities implicated by current theory as crucial in shaping virulence evolution, we feel that the onus is on theoreticians to better connect mathematical models with empirical data. This connection could come through developing models of specific systems or by developing general theory that better captures common empirical measures of virulence, such as host morbidity or physiological condition.


We argued this finding is consistent with lexical selection by competition accounts, and might entail additional spread of activation to related concepts that share the non-distinctive feature via the appropriate category node . In their commentary, Montefinese and Vinson . Surprisingly, Montefinese and Vinson chose to cite Nieuwenhuis et al.  and by items (p = 0.003), of moderate to large effect size . It is worth emphasizing planned contrasts are typically conducted whether or not the overall F-test is significant; at least this is the convention according to introductory experimental design and statistics textbooks  were not listed in the McRae et al.'s . We concur with Montefinese et al.  vs. low production frequencies  according to McRae et al.'s  norms. WMini) produced interference when related objects were named at the basic level . Montefinese and Vinson (knee) might “permit further activation of its name as a potentially plausible alternative to the basic-level target name” .Aside from dominance, another theoretical issue introduced by Montefinese and Vinson  in theird Vinson  speculatwheel). We note the similarity of this proposal with Mahon et al.'s (Montefinese and Vinson do not provide an adequate explanation of the mechanism by which merely raising the lexical activation level of a feature-level distractor representation would make it a plausible response when the instruction is to name the entire target object (e.g., in Hantsch et al.'s level-of-specificity manipulation above, Mini and CAR are appropriate names for a picture of a Mini as they both denote the entire object, unlike et al.'s  responseet al.'s , the reset al.'s  assumptinot significant at both of these SOAs within the same experiment (e.g., La Heij et al., Montefinese and Vinson's  more empAccording to the lexical selection by competition account, semantic interference is the result of a tradeoff between the priming of the target representation by the distractor and the priming of the distractor's lexical representation by the target (e.g., Roelofs, In conclusion, we find none of the theoretical, empirical, or statistical objections raised by Montefinese and Vinson  to be paThis work was supported by Australian Research Council Discovery Project Grants DP1092619 and DP150103997.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This paper seeks to contribute to the characterization of the relation between osteogenesis and neurogenesis by approaching it from the field of the neurobiology of language and cognition; specifically, from an evolutionary perspective. It is difficult to ascertain how the hominin brain changed to support modern language and cognitive abilities because we can only rely on skull remains. But insights can be gained from fossils because the brain and the skull exhibit a tight relationship. Skull shape and brain shape and connectivity influence one another  to CBL, in turn linked to Noonan syndrome-like disorder, a condition involving facial dysmorphism, a reduced growth, and several cognitive deficits  with RUNX2 and FOXP2 has recently been experimentally demonstrated    and the BMP suite : most of them also interact with RUNX2. Consider, e.g., DLX2. It is involved in craniofacial development (Jeong et al., BMP2 promotes the differentiation of mesenchymal cells into bone cells (Dwivedi et al., Dlx1, Dlx2, Dlx5, and Runx2 (Bustos-Valenzuela et al., BMP2, BMP7 is involved in osteogenesis (Cheng et al., Other bone morphogenetic factors may well play a key role in the emergence of our language-readiness and our globular brain. Among them we wish highlight the DLX suite (particularly, Gli1+ cells within the suture mesenchyme as the main mesenchymal stem cell population for craniofacial bones. Ablation of these Gli1+ cells leads to craniosynostosis, known to be associated with cognitive deficits (Starr et al., Runx2 (Kim et al., Gli1 expression (Schreck et al., Gli1 is the direct response gene of Shh (Liu et al., FoxP2 lies downstream of Shh, as suggested by Scharff and Haesler (We further believe that the genetic aspects highlighted here may contribute not only to gain a better understanding of the way in which both aspects of our modernity emerged and interact, but specifically to tune the crosstalk between the osteogenic and neurogenic stem cell niches. Zhao et al.  have rec Haesler , who obs Haesler . Dysregu Haesler . As a ma Haesler . Most in Haesler  have sho Haesler . The latThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We make three recommendations to inform the ongoing process of consolidating a key biodiversity areas standard: (i) thresholds for the threatened species criterion currently consider a site's share of a threatened species' population; expand these to include the proportion of the species' genetic diversity unique to a site; (ii) expand criterion for ‘threatened species' to consider ‘threatened taxa’ and (iii) expand the centre of endemism criterion to identify as key biodiversity areas those sites holding a threshold proportion of the compositional or phylogenetic diversity of species (within a taxonomic group) whose restricted ranges collectively define a centre of endemism. We also recommend consideration of occurrence of EDGE species (i.e. threatened phylogenetic diversity) in key biodiversity areas to prioritize species-specific conservation actions among sites.‘Key biodiversity areas' are defined as sites contributing significantly to the global persistence of biodiversity. The identification of these sites builds from existing approaches based on measures of species and ecosystem diversity and process. Here, we therefore build from the work of Sgró  Given tIn response to this demand, numerous systems have been developed for identifying important sites for biodiversity for different taxonomic groups, different ecosystems, and different countries and regions. The earliest such efforts were initiated by what is now the BirdLife International partnership, which developed standards for the identification of Important Bird Areas in the late 1970s , and hasHowever, while these taxon-, ecosystem- and theme-specific approaches to the identification of important sites have delivered substantial benefits by providing information on where site safeguard can make the greatest contributions towards reducing the rate of biodiversity loss , the proOver the last decade, the IUCN Species Survival Commission and World Commission on Protected Areas have been jointly leading this process. Building from an initial scientific paper , construOne implication of this definition is that it considers biodiversity comprehensively, in contrast to the focus of existing approaches on specific taxa or ecosystems. Thus, a challenge for the process of consolidating a global standard for the identification of key biodiversity areas has been to ensure that the criteria for site identification span scales and components of ecological organization. Noss  derived Here, we develop a general framework and three specific recommendations on how the process of consolidating a global standard for the identification of key biodiversity areas might address components of biodiversity below the species level, for consideration in the review of the draft standard. These include genetic diversity within species, phylogenetic diversity among species and the evolutionary processes which drive and maintain both of these . This pa2.et al. [The many ways in which biodiversity below the species level could be addressed in the key biodiversity area criteria can be organized through the framework presented by Sgrò et al. , originaet al.  and Gastet al.  definitiet al. [per se. To ‘increase connectedness and gene flow across environmental gradients' generally requires planning and action at the levels of entire landscapes or seascapes—beyond individual sites. This is the case even where environmental gradients are very sharp , and certainly where they are represented by broad ecotones. For example, Smith et al. [Andropadus virens populations in tropical forest and those in forest-savannah, compared with low divergence (for the same level of gene flow) between tropical forest sites and between forest-savannah sites. There is some counter-evidence against this: Henry et al. [Ochotona princeps in British Colombia. In any case, the location of given key biodiversity areas along environmental gradients will be relevant in prioritizing their conservation and connectedness, where these are important for the persistence of the biodiversity feature triggering the site's identification [The relevance of the last two elements of the Sgrò et al.  frameworh et al.  found hiy et al.  found lofication .a priori to the identification of key biodiversity areas. However, translocation (or reintroduction or restoration) could trigger the identification of new key biodiversity areas, if, as, and when such actions are successful enough to trigger the criteria for a new site in their own right [Meanwhile, given that key biodiversity areas are sites contributing significantly to the persistence of biodiversity features which they currently hold, to ‘increase adaptability to future environments by translocation’  is not relevant wn right .et al.'s [We also considered whether there might be any aims for incorporation of biodiversity below the species level in informing decision-making more broadly which were not proposed in Sgrò et al.'s  frameworWe discuss each of the elements in turn, seeking to develop practical recommendations of how consolidating a global standard for the identification of key biodiversity areas might address components of biodiversity below the species level. In each case, we strive to strike a balance in how demanding we are of genetic and phylogenetic data availability. Thus, on the one hand, our proposals should be robust enough to be applied today in conditions of relatively sparse data availability, while on the other hand, they should be unlikely to destabilize site identification (e.g. through identification of orders of magnitude more sites), if, as, and when data volumes increase into the future.3.et al.'s [The first component of Sgrò et al.'s  frameworet al.'s –27 and tet al.'s . This iset al.'s , assessiet al.'s –32.Given this, an argument can be constructed for ensuring that the criterion for presence of threshold populations of a threatened species triggering key biodiversity area identification be extended to also consider ‘threatened genetic diversity’. Thus, for criteria structured in the form of ‘at least X% of the global population of a threatened species occur at a site’, this population metric could be supplemented by one of ‘X% genetic diversity of a threatened species being unique to the site’. This would ensure that sites holding a disproportionately high genetic diversity of a threatened species triggered key biodiversity area identification, even if the population of the species at the site was relatively small and insufficient to trigger site identification in its own right. The use of a subcriterion requiring the presence of a threshold population of ‘functional reproductive units' at the site would ensure that this extension does not trigger identification of sites holding tiny, unviable populations.Recommendation no. 1. Thresholds for the threatened species criterion currently consider a site's share of a threatened species' population; expand these to include the proportion of the species' genetic diversity unique to a site.et al. [et al. [et al. [While this recommendation would ensure that key biodiversity areas are indeed sites contributing significantly to the persistence of genetic diversity overall, these sites may be very different from those where genetic diversity contributes significantly to the evolution or persistence of the species in question. Thus, Petit et al. , for exa [et al.  found si [et al.  to human [et al. , is neut [et al. . Althoug [et al. , we cann [et al. . Sgrò et [et al.  recognizThe general approach to addressing adaptive variation in practice has been to incorporate it into the definition of evolutionary significant units –42. The In the meantime, a rule of thumb for incorporating adaptive genetic diversity into the identification of key biodiversity areas could be simply to broaden the scope of the threatened species criterion to consider ‘threatened taxa’, as long as these are globally relevant. The IUCN Red List of Threatened Species , which pRecommendation no. 2. Expand criterion for ‘threatened species' to consider ‘threatened taxa’.Lupinus in the Andes [Laupala crickets in Hawaii [While such a recommendation would in effect allow this criterion to support the conditions for future diversification, it is not framed as such given the very slow rate of macro-evolution relative to anthropogenic land-use impacts. The fastest documented rates of speciation are for he Andes , Laupalan Hawaii , and forn Hawaii . However4.et al.'s [The fourth component of Sgrò et al.'s  frameworet al.'s –57.The last two decades have seen substantial advances in the compilation of phylogenies from molecular and other types of data, and their calibration to derive trees that incorporate time into their branch lengths using molecular clock approaches . These het al. [2, corresponding to the 25th percentile of the range-size distribution in the class Aves, and a minimum of two species to define an Endemic Bird Area; and (iii) the definition of the proportion of these restricted-range species necessary to confirm the site's identification as a key biodiversity area.The general form for key biodiversity area criteria for centres of endemism can be expressed as requiring that a site holds ‘at least X% of the species within a taxonomic group whose restricted ranges collectively define a centre of endemism’. This criterion encompasses three operational components: (i) the definition of the taxonomic group for consideration ; (ii) the definition of a maximum range size for species whose overlapping ranges can define a ‘centre of endemism’—Stattersfield et al.  used 50 The second and third of these components could be extended to consider evolutionary refugia based on a site's complement of the phylogenetic diversity restricted to the centre of endemism . Such anRecommendation no. 3. Expand the centre of endemism criterion to identify as key biodiversity areas those sites holding a threshold proportion of the compositional or phylogenetic diversity of species (within a taxonomic group) whose restricted ranges collectively define a centre of endemism.5.While the definition of key biodiversity areas recommended by the framing workshop establishes them as important sites for biodiversity, this does not imply any particular kind of conservation management action upon them . This said, knowledge of where key biodiversity areas are and what biodiversity features trigger them is used by many different sectors of society for many different kinds of applications. These include conservation actions; the science of optimal allocation of resources for such conservation actions is known as systematic conservation planning ,71. MostBearing this in mind, one aspect of evolutionary history notable by its absence from the four recommendations above is the incorporation of the phylogenetic diversity unique to a species  into thet al. [et al. [Safi et al.  combinedet al.  proposes [et al.  and comb [et al.  and thre [et al. .Recommendation no. 4. Consider occurrence of species making the greatest contributions to maintaining phylogenetic diversity (i.e. EDGE species) in key biodiversity areas to inform prioritization of species-specific conservation actions among sites.6.The initial discussions of the IUCN Species Survival Commission and World Commission on Protected Areas process considered establishment of a new subcriterion for triggering key biodiversity area identification for sites contributing significantly to the global persistence of biodiversity through their importance in maintaining outstanding evolutionary process, possibly to sit alongside the criteria for outstanding ecological process (e.g. species congregations and aggregations). However, in subsequent deliberations, it proved impossible to establish a mechanism by which such a criterion could be put into operation. One possible final recommendation would therefore be to establish a non-operational criterion for sites of global significance for evolutionary process and leave the operationalization of this as a priority for future research.et al. [On reflection, the development of such a criterion appears to be unnecessary in any case. Our three recommendations for incorporation of components of biodiversity below the species level into existing key biodiversity area criteria appear to span aspects of composition, structure and function of genetic diversity, and also the breadth of mechanisms for putting this into practice proposed by Sgrò et al. . Much wo


For example, action potential duration  are circumferentially arranged (Streeter et al., The importance of the findings reported by Kindo et al.  reinforcThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To the Editor: We read with interest the discussion between de Steenwinkel et al. and Werngren  generation and selection of resistant mutants. Thus, the frequency of 10–3 resistant CFUs selected on rifampin may represent not the frequency of preexisting mutants but rather frequency of mutants generated by a population of persisting (stressed) cells during exposure to low levels of antimicrobial drugs. We investigated the effect of transient exposure to rifampin on colony growth rate and post–antimicrobial drug outgrowth on a panel of Beijing and non-Beijing M. tuberculosis strains, including some studied in the work of Steenwinkel et al.  and in-house software  was almost completely inhibited during the first 24 hours after rifampin exposure. In contrast, all the Beijing genotype strains studied showed residual growth in most colonies in the first 24 hours after rifampin exposure. At 1–5 days postexposure, the pattern remained the same; the Beijing strain colonies were more capable of persisting and exhibited slow but sustained growth after exposure to low concentrations of rifampin. To confirm that this effect was a result of persistence rather than generation of resistant mutants, we transferred the colonies growing after transient rifampin exposure of Beijing strain 1585 to a medium containing 8 mg/L rifampin. Their growth was completely inhibited, and molecular analysis did not detect any of the most prevalent rifampin resistance–associated mutants (data not shown).rpoB gene mutants have shown to exhibit a stringent-like response  mutation frequency reported by de Steenwinkel et al. (M. tuberculosis strain mutation frequency reported by de Steenwinkel et al. (In summary, our data show that the high apparent


Harmful Algal Blooms (HABs) affect the quality of fresh and marine waters and adversely affect both animals and humans. Public health risks include exposure to toxins through consumption of contaminated drinking water and fish and shellfish, and by recreating on or in contaminated waters. Federal and State professionals and researchers contributed to this Special Issue on HABs and Public Health with research papers and reviews on various aspects of public health including the occurrence and fate of toxins in the environment, monitoring efforts in freshwater and marine water systems, human health risk assessment, effectiveness of treatment techniques, and guideline development. et al. [et al. [et al. [et al. [et al. [et al. [Understanding the processes cyanobacteria and their toxins undergo in the environment is considered in the papers by Schmidt et al. , Fadel e [et al. , and Son [et al. . Schmidt [et al.  discusse [et al. . The aut [et al. . MicrocyHABs have an adverse impact in recreational waters by fouling beaches and shoreline, affecting the quality of the water, and limiting recreational activities such as fishing, swimming, and boating. The adverse effect of the occurrence of both marine and freshwater toxic algal blooms in recreational waters in Washington State was discussed by Trainer and Hardy , with a et al. [HABs also could be present in drinking water and could potentially affect drinking water treatment. Taste-and-odor problems have led some utilities to change processes during the drinking-water treatment to decrease tastes and odors in finished drinking water caused by algal blooms in the supply reservoir. Another problem is the presence of cyanobacterial cells and toxins in finished drinking water. In the paper by Szlag et al. , the autet al. [et al. [Human health risks from exposure to HABs is another topic discussed in this special issue. The paper by Hilborn and Beasley  used haret al. , with a  [et al. . In thiset al. [et al. [et al. [et al., and proved to be ineffective at low levels. However, although a reduction of toxins was observed, still a significant release of the toxins into the water was detected. Ultrasound treatment only caused minimal growth inhibition and some release of toxins into the water, showing the treatment to be ineffective at controlling cyanobacteria. In these proposals, toxin reducing bacterial strains are used in water reservoirs as another option that may help in the reduction of microcystins occurrence. The use of bioreactors to eliminate microcystins is suggested by Dziga et al. [Numerous techniques already exist for managing blooms in reservoirs. However, the effectiveness of these techniques is relative. For example, Bauza et al.  exposed  [et al. , the pap [et al.  also evaa et al.  as an alet al. [This special issue also includes a paper describing the development of guideline values for cyanotoxins in the state of Oregon. In the United States, drinking water contaminants are regulated under the Safe Drinking Water Act (SDWA). Currently, there are no regulations for cyanotoxins in drinking water under the SDWA, but EPA developed in June 2015, Health Advisories (HAs) for the cyanotoxins microcystins and cylindrospermopsin, to assist federal, state and local officials in protecting public health from exposure to these two toxins in drinking water systems. Regulations or guidelines have not been developed either for aquatic life, aesthetics, or recreation in any body of water under the Clean Water Act (CWA). In the absence of these guidelines, many US States, including Oregon  have dePublic health professionals have taken measures to protect public health by assessing and monitoring HABs occurrence and health effects, developing guidelines and HAB-related public health programs, and implementing remediation and treatment technologies. Despite these efforts, it is reasonable to say that the factors that promote HABs and their toxin production, the health impacts, and the fate of these blooms and their toxins in the environment is not totally understood. The different studies published in this special issue recognized these knowledge gaps including the spatial variability among cyanobacteria and their toxins in water and sediments, the complexity of monitoring and inconsistency in treatment techniques, and the importance of the development of guidelines for the protection of public health.


Brunner et al.  showed aIn contrast with the study of Brunner et al., HMA is most often exogenously induced by too liberal infusion of chloride-containing intravenous fluids for hydration and resuscitation purposes . HMA ind


Pulmonary hypertension (PH) is a progressive and devastating disease of various causes that is associated with structural and functional disorder and inappropriately increased pressure of pulmonary small- to medium-sized vasculature. Extensive pulmonary vascular remodeling with narrowing lumen is well characterized in all forms of PH, which is hemodynamically defined by a mean pulmonary artery pressure exceeding 25 mmHg at rest  and mesenchymal α-SMA markers. Combined with this analysis result, the protein and mRNA expression patterns consolidate the notion of a key role of EndMT in PH pathology (Ranchoux et al., in vivo EndMT characteristics in these mouse models are comparable to those in human PH tissues. Excitingly, partial rescue of EndMT-related gene expression and phenotypes has been achieved by rapamycin (Ranchoux et al., Writing in The headline finding of these two studies is that the concept of EndMT in PH has been initially proposed on the basis of compelling experimental proofs (Good et al.,


The understanding of the neural basis of limb apraxia (deficits in performing previously learned skilled movements) has benefited greatly from cognitive research on gesture processing and recognition, but the influence of this research on the treatment of apraxia is limited (Cantagallo et al., Apraxia typically results from left-brain lesions but impairs movements in both upper limbs equally. This is because disturbances affect the conceptual formulation of the movement rather than their executive ability Frey, . ResearcThis converges with results from the recent literature on the cognitive rehabilitation of limb apraxia (for reviews, see Buxbaum et al., Priming refers to a change in the nervous system triggered by prior exposure to a stimulus, which guides the order of activation in a given neural network according to previous experience (Pachalska et al., At a basic level, the common effects of RVF priming for both gestures, consistent with recent findings with fMRI (Króliczak and Frey, What do these results suggest for rehabilitation? First, more attention should be paid to the interdependence between motor and language functions when dealing with apraxic patients. “Intersystemic gestural reorganization” Luria, , a methoAdditionally, the deficits that apraxic patients often exhibit in gestural communication (Borod et al., Second, the differential effects found by Helon and Kroliczak  for tranThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Escherichia coli together with the use of non-optimal cloning vectors for the construction of metagenomic libraries generally results in an extremely low success rate for enzyme identification. The bottleneck arising from inefficient screening of enzymatic activities has been addressed from several perspectives; however, the limitations related to biased expression in heterologous hosts cannot be overcome by using a single approach, but rather requires the synergetic implementation of multiple methodologies. Here, we review some of the principal constraints regarding the discovery of new enzymes in metagenomic libraries and discuss how these might be resolved by using synthetic biology methods.There is a growing demand for enzymes with improved catalytic performance or tolerance to process-specific parameters, and biotechnology plays a crucial role in the development of biocatalysts for use in industry, agriculture, medicine and energy generation. Metagenomics takes advantage of the wealth of genetic and biochemical diversity present in the genomes of microorganisms found in environmental samples, and provides a set of new technologies directed towards screening for new catalytic activities from environmental samples with potential biotechnology applications. However, biased and low level of expression of heterologous proteins in  In the industrial context, many manufacturing processes that previously depended strictly on complex (and frequently harmful) chemical reactions have been superseded by much simpler and safer enzyme-based catalysis , then 4 × 108 potential proteins might be expected in just 1 g of soil. Supposing that 40% of these proteins display catalytic activity  while still allowing growth of this organism. Alternatively, screening could be performed without subjecting the host to any selective pressure, for example in cases where the host organism is used to clone total metagenomic DNA and the screening is performed under regular growth conditions. In both cases, after the initial identification of the enzymes, characterization of the desired catalytic properties of the source clones can be made with crude culture extracts and selected enzymes may then be purified for a more detailed characterization. For instance, a novel alkaliphilic esterase active at 7°C was identified by screening a metagenomic library from Antarctic desert soil , which was probably a consequence of the expression of the correctly folded enzymes in E. coli. No cellobiohydrolases active against crystalline cellulose substrates have as yet been isolated from metagenomic libraries  (Cambray E. coli, several attempts have been focused on the use of alternative hosts to increase the rate of enzyme identification in metagenomic screening (Craig et al., et al., et al., et al., et al., et al., et al., In addition to genetic engineering of the more common hosts such as et al., et al., et al., et al., et al., in vivo strategy that has been used to identify specific enzymatic activities using engineered regulatory circuits coupled to a reporter gene, such as lacZ, green fluorescent protein or luciferase (Mohn et al., et al., et al., et al., et al., et al., et al., et al., Currently available methods that are used to screen for new catalytic activities in metagenomic libraries frequently rely either on the use of chromogenic enzyme substrates (Hu in vitro evolution and rational design techniques for the improvement of their catalytic properties. However, the diversity of proteins identified using this strategy is restricted, the methods are time-consuming, costly and in the case of in vitro evolution, it is impossible to test all variants (Sommer et al., Classic approaches for isolating industrial enzymes involve their identification from cultured microorganisms, and more recently, this strategy has been expanded to include None declared.


Saccharomyces cerevisiae, which couples a wide array of technical advantages with a high degree of genetic, proteomic and mechanistic conservation. Indeed, this unicellular organism harbours regulatory pathways, such as those related to programmed cell death or nutrient signalling, that are crucial for ageing control and are reminiscent of other eukaryotes, including mammals. Here, we summarize and discuss three different paradigms of yeast ageing: replicative, chronological and colony ageing. We address their physiological relevance as well as the specific and common characteristics and regulators involved, providing an overview of the network underlying ageing in one of the most important eukaryotic model organisms.The identification and characterization of the molecular determinants governing ageing represents the key to counteracting age-related diseases and eventually prolonging our health span. A large number of fundamental insights into the ageing process have been provided by research into the budding yeast  Saccharomyces cerevisiae undergoes programmed cell death (PCD) with characteristic apoptotic changes initiated a new and exciting research field  or mating (haploid cells) guarantees genetic variation and consequently provides an adaptive advantage to the population. Upon failure of either one of these processes, triggering PCD cleans the population from infertile or damaged cells, thus ensuring fitness and survival. In this line, haploid cells undergo PCD upon long-term exposure to pheromones without subsequent mating  and an unusual form of autophagy that resembles PCD-associated mega-autophagy in plants. Besides these roles during sexual and asexual reproduction, additional physiological scenarios associated with PCD in yeast have been described, among which ageing has drawn most attention in the course of the last decade. Mostly, ageing is defined as the progressive loss of function in all constituents of living cells, leading to a decrease in both survival rate and reproductive capability. Several theories have been developed to explain the complex process of ageing, all of which are partly interrelated and mainly cluster into two categories, namely (a) the damage or error theories and (b) the programmed theories. The first group of theories, such as the ‘free radical theory’ or the ‘somatic DNA damage theory’, assumes environmental insults and subsequent accumulating damage as causative for ageing. In contrast, programmed theories, such as the ‘programmed longevity theory’, assume that ageing follows a biological clock and that lifespan and death are genetically programmed. To date, no consensus exists on the issue why organisms age.However, while multicellularity clearly benefits from, and even requires, controlled cellular demise to ensure normal development, tissue homeostasis and regulation and function of the immune system, the reason for the existence of PCD in unicellular organisms seems paradoxal at first, since death provides no advantage for an individual cell. If so, though, natural selection should have worked against the capability of unicellular organisms to undergo programmed suicide. Nevertheless, this trait was sustained throughout evolution, indicating an integral benefit even for single-celled species. In this case, it appears to serve the survival of a clonal population and raises the concept of ‘altruistic’ unicellular behaviour. As microbial life in natural habitats mainly occurs in clustered, social communities such as colonies and biofilms, which enable the cells to cope with ecological stresses and to efficiently adapt to a constantly changing environment, the death of an individual cell might be subsidiary to the survival of the ‘multicellular’ community. For et al., Yeast has become the leading model organism for the study of genetic and mechanistic factors that affect human ageing and disease. The pathways and downstream factors identified to govern yeast senescence seem to be conserved to a large degree in higher eukaryotes and have been instrumental in deciphering ageing modulators in major model organisms up to the mouse , phosphatidylserine externalization and DNA fragmentation , which are retained by the mother cell upon division. Whether the resulting shortened lifespan is due to ERCs themselves or rather to rDNA instability in general remains a matter of discussion. At least two players seem to be involved: the sirtuin Sir2p that suppresses, and the nucleolar protein Fob1p that promotes, homologous recombination in the rDNA. Accordingly, deletion of et al., et al., et al., et al., et al., et al., et al., The modulation of growth, metabolism and stress resistance through the nutrient-responsive Ras–PKA and TOR–Sch9 pathways is intimately connected to the regulation of replicative ageing: mutations or regimens  that compromise Ras–PKA or TOR–Sch9 signalling extend replicative lifespan  but has no effect on chronological lifespan under standard conditions, or even extends it under caloric restriction  stimulates the protein kinase Rim15p, which in turn promotes the activation of the stress-response transcription factors Msn2/4p and Gis1p, finally resulting in extended chronological lifespan (Pedruzzi et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The complex nature of chronological ageing is mirrored by its manifold downstream effects, among them mutagenesis and replication stress (Fabrizio S. cerevisiae in its natural habitat mainly happens in the form of colony formation on solid surfaces, such as fruits and vegetables, a life style that hardly resembles the growth in liquid medium common in laboratory conditions. The growth of a single yeast colony can be divided into a phase of rapid growth, in which the cells genetically and biochemically largely resemble cells dividing in liquid culture, and a subsequent phase of slower growth, in which the colony starts to diversify. Cells at the colony periphery proliferate, while the cells in the colony centre enter stationary phase (Meunier and Choder, et al., et al., et al., et al., et al., The proliferation and ageing of et al., WHI2 (Leadsham et al., In the colony centre, the metabolism remains mostly unaltered. Cells exhibit accumulating oxidative stress and undergo PCD with typical apoptotic markers (Váchová and Palková, et al., tor1, Δsch9 and Δras2 during chronological ageing in liquid culture, suggesting that these might represent typical traits for longevity. Highlighting the impact of mitochondrial respiration on colony development, respiratory deficiency has been shown to suppress the accumulation of ROS and apoptosis in yeast colonies (Ruckenstuhl et al., et al., Besides the differentiation into central and outer cellular sectors, the aged cells in the centre form two distinct subpopulations, starting after about 7 days. Within the upper region, cells exhibit high stress resistance and an extended lifespan, while cells in the lower layers are sensitive to stress and die fast (Cáp et al., et al., et al., Yeast ageing is a complex process involving multiple pathways that are engaged as a response to the manifold physiological situations encountered in nature. As a general phenomenon on which all ageing subtypes converge, PCD seems to be the physiological event that, by regulating cellular lifespan, controls population dynamics. By this altruistic death of single cells that eliminates damaged individuals, the clonal community ensures the possibility of adapting to the changing environment, thus promoting its long-term survival. This suggests that ageing might, at least to some extent, hold programmatic features as an adaptive response to cope with ever rearranging and challenging conditions. Necessarily, this idea leads to controversial group selection theories (Blagosklonny, Importantly, the environmental conditions dictate whether either proliferation, stationary behaviour or colony formation and differentiation is sustained, thus defining the distinct ageing paradigms. Thus, some regulatory and executing elements do not overlap while others do Figure . For exaet al., Besides the ageing subtypes observed under laboratory conditions, there might be more and/or their relevance might be relative in the wild. For instance, the apoptotic death of replicatively old mother cells, which do only represent a very minor percentage of the population, can hardly contribute to the fitness of a clone. As old mothers are very scarce, their death neither spares nor releases notable nutrients. Thus, the apoptotic death of replicatively old mother cells most probably does not represent an adaptive trait, but might solely represent the consequence of accumulating cellular damage. Under natural conditions, the portion of cells achieving a replicatively old status is probably even lower. In stationary phase, the biggest fraction will rather be composed of virgin cells, or cells that have undergone several divisions only. However, physiological changes related to replicative ageing that affect, for example, certain cellular stress resistances already occur after only four or five divisions (Sorokin


NTR), that is required for hippocampal long-term depression  is a neurotrophic protein that is strongly expressed in the Central Nervous System (CNS) and supports neuronal growth and survival , might be an optimal tool to investigate the role of BDNF polymorphism in activity-dependent plasticity , unbalanced analysis might have affected statistical sensitivity (Hector et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A critical issue in the field of time perception is whether or not explicit judgments about time are processed by some internal clock mechanism. A subsequent issue is whether or not this clock, if any, is central . There are several ways of marking time, including the use of signals delivered from different sensory modalities. In other words, do we have sensory specific representations of time, or is there an amodal—central—mechanism Bueti, ? This fuThe interest for the effect of modalities on perceived duration and sensitivity to time has grown recently. Researchers have reported that intervals marked by auditory signals are perceived as longer than time intervals marked by visual signals  reached with intermodal conditions. The recent data reported by Mayer et al.  are alsoThe stability of the Weber fraction over time reported by Mayer et al.  is a bitper se, but in the comparison of intra- and intermodal intervals. It is well-established that the discrimination of time intervals is much easier with auditory than with visual markers  over the primary auditory cortex, Kanai et al.  observedNote however that for intervals lasting 1.6 s, the large difference between the threshold value in AA and AV conditions is washed out when an explicit count of numbers is used for completing the task (Grondin et al., Recent EEG data, and more specifically the amplitude of the contingent negative variations recorded at fronto-central electrodes, revealed a basic difference between the AA condition and other modality conditions (Gontier et al., In brief, the different perceived durations and discrimination levels observed in the different intra- and intermodal conditions is a challenge for the single-clock hypothesis. An interpretation based only on sensory latencies (Mayer et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


C. elegans  which has been utilized to block exclusively gliotransmission -CA1 pyramidal neuron (excitatory) synapses. During repetitive or tetanic stimulation of SC, astrocytes showed short-term depression of cytosolic Ca2+ signals associated with a simultaneous short-term potentiation at SC-CA1 synapses. Moreover, chelation of Ca2+ in astrocytes resulted in enhanced synaptic transmission and short-term plasticity at SC-CA1 synapses. This finding adds to a growing body of evidence that astrocytes are critical for certain types of synaptic plasticity  conditional knockout mouse line that a battery of behavioral assessments  failed to reveal any behavioral deficits. The above studies are reviewed by Xie et al. (in vivo.Following up on work that proposed that Gq protein-coupled receptor Cae et al. , who als2+ increases that could bypass downstream signaling cascades, and which result in non-specific modulation of astrocyte function (Wang et al., Although optogenetics has proven to be clearly advantageous for studying neuronal correlates of behavior and functional connectivity in the brain (Friedman et al., What are the current obstacles that need to be overcome to advance the field? Jahn et al. , Xie et The goal of this Research Topic has been to summarize our most recent understanding of glial cells in the regulation of plasticity of neural circuits. It is abundantly clear that genetic approaches have been instrumental in elucidating the role of glia in plasticity and behavior and that outstanding issues are likely to be resolved in the near future with novel genetic tools. Thus, exciting times lie ahead for the study of astrocytes in the dish and the behaving brain.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


First, some dicotyledonous species  and other commelinid families consist of high silica accumulators in which silicification patterns and roles are highly consistent. The effects of water availability  is a dicotyledonous family of high silica accumulators, but given there are dissimilarities in silicification mechanisms, patterns and roles between the two families it is likely that high levels of silicon accumulation evolved independently in this family (e.g., Mitani and Ma, It is clear that some groups, such as the grasses, commelinids and some aquatic macrophytes (Schoelynck et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In August 23 , The LanWe would like to thank all contributors for their valuable work helping us to present wide-ranged aspects in the field. Currently we know that a physical barrier due to the formation of tight junctions in cerebrovascular endothelial cells is the main component of the BBB. In this Research Topic, the implication of astrocyte functions in the protection of the BBB was reviewed (Cabezas et al., in vitro stroke model of the BBB was used to investigate how oxygen/glucose deprivation can affect tight junction proteins, as well as the expression of ABC-transporters (Neuhaus et al., Currently we know that the BBB is more than a physical barrier. Several drug- and xenobiotic-metabolizing enzymes are expressed in endothelial and glial cells, constituting a metabolic barrier. The expression of xenobiotic metabolizing enzymes in the BBB was discussed (Agúndez et al., It seems that there is also an antioxidant barrier, which protects the central nervous system against the oxidative stress. The endogenous protection against reactive oxygen species can occur through the increased expression of mitochondrial enzymes in astrocytes (Cabezas et al., N. caninum was evaluated (Jesus et al., Cells involved in the BBB can establish immune communications. Interactions between the microglia and the vascular system (Fonseca et al., The connection between the BBB and pain was reviewed, focusing on cellular and molecular mechanisms of BBB permeability induced by inflammatory or neuropathic pain and migraine (DosSantos et al., A century after the work of Goldmann, who contributed to the discovery of the BBB, several questions remains without answers. However, it is already known that BBB is far more than a physical barrier. Endothelial and glial cells also exert metabolic, antioxidant and immunological activities. It seems of great importance to understand the role of BBB in neurodegenerative diseases. Compounds that could show an ability to repair BBB injury, to suppress neuroinflammation and to provide neuroprotection remain to be discovered. The role of microglia and macrophages in the BBB needs to be better understood, if we want to design effective therapies against neuroinflammation. Efforts to discover strategies that could protect neurons in ischemic events continue to defy neuroscientists. Advances in biochemistry, molecular biology, and genetics will improve our knowledge about the BBB in the next 100 years.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dear Editor,We read with great interest the recent article by Farzanegan et al. regarding the effect of lumbar discectomy on disability and depression in patients with chronic low back pain . Pain an


Here, we review studies supporting the concept that telomeres are important cellular structures whose function not only is to count cell divisions, but also to act as molecular switches that can rapidly stop cell cycle progression permanently in response to a variety of stresses, including oncogenic signals.Telomeres, the ends of our linear chromosomes, can function as ‘replicometers’, capable of counting cell division cycles as they progressively erode with every round of DNA replication. Once they are critically short, telomeres become dysfunctional and consequently activate a proliferative arrest called replicative senescence. For many years, telomeres were thought to be autonomous structures, largely isolated from cell intrinsic and extrinsic signals, whose function is to prevent limitless cellular proliferation, a characteristic of most cancer cells. It is becoming increasingly evident, however, that telomeres not only count cell divisions, but also function as sensors of genotoxic stresses to stop cell cycle progression prematurely and long before cells would have entered replicative senescence. This stable growth arrest, triggered by dysfunctional telomeres that are not necessarily critically short, likely evolved as a tumor-suppressing mechanism as it prevents proliferation of cells that are at risk for acquiring potentially hazardous and transforming mutations both  The most common and deadly of these diseases is cancer. To counteract the development of cancer, these organisms developed a number of cell extrinsic and intrinsic tumor-suppressing mechanisms one of which is cellular senescence, a proliferative arrest that forces cells to exit the cell division cycle permanently. In cultured mammalian cells, senescence is activated in response to a number of signals including critical telomere erosion, oncogene activation, loss of tumor-suppressing pathways, as well as numerous cell extrinsic stresses  can be detected in cells of inactive and benign human neoplasms, suggesting a role for DNA damage checkpoints in initiating and stabilizing this proliferative arrest. Recent data suggest that the DDR primarily initiates at telomeres, revealing a potentially critical role for dysfunctional telomeres in suppressing cancer growth in humans. In the following sections, we will review our current understanding of cellular senescence induced by a variety of stimuli and stresses that affect telomere length and structure, as well as summarize studies that shed light into the likely causes for telomere dysfunction and cellular senescence in cells of inactive and benign human tumors.Cellular senescence was first described in the early 1960’s by L. Hayflick, who observed that somatic human cells do not have the ability to divide indefinitely , cellular senescence can certainly be activated in the absence of any apparent telomere damage. Some cultured cell strains, for example, undergo cellular senescence without critical telomere erosion, visible DNA damage, or p53 activation. Instead, they initiate cellular senescence by upregulation of the Cdk inhibitor p16et al., et al., Activating mutations in certain proto-oncogenes can also lead to a permanent proliferative arrest called oncogene-induced senescence (OIS). Depending on the cell type, strength, and duration of the oncogenic signal, oncogenes induce cellular senescence through multiple and distinct pathways (Courtois-Cox et al., in vivo biological response of human cells encountering oncogenic signaling imbalances (Croce, First direct evidence that OIS can function as a tumor-suppressing mechanism in mouse model systems was published almost a decade ago and has since been verified in numerous other studies (Collado & Serrano, s Croce, . With fes Croce, .et al., et al., et al., et al., et al., et al., et al., et al., Precisely, how oncogenes cause DNA replication stress and DSBs is still not entirely clear. Cells expressing oncogenic H-Ras show signs of DNA hyper-replication, such as increased numbers of active replication origins as well as origins that appear to have initiated replication more than once per cell cycle (Di Micco Common fragile sites are chromosomal loci that exhibit discontinuities, such as gaps and breaks, when viewed on metaphase chromosomes. Cells cultured under conditions that cause DNA replication stress, such as incubation with the DNA polymerase inhibitor aphidicolin, display an increased number of these chromosomal abnormalities, revealing that CFS are generated while cells replicate DNA. Functional disruption of kinases ATR and Chk1, which function to signal a stalled replication fork, as well as deficiency in recombination factors Rad51, BRCA1, and BLM, that act during the recovery of a stalled replication fork, enhances CFS expression, which is consistent with the model that CFS are generated as a result of DNA replication fork stalling. Significantly, CFS are not randomly distributed on chromosomes. Rather, they appear at a limited number of discrete loci indicating that specific features inherent to CFS sequences present a challenge to the replication machinery. Indeed, CFS often contain sequences that are prone to forming secondary structures and therefore act as a natural barrier to replication fork progression (Durkin & Glover, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., In recent years, it has become evident that CFS are much more abundant than previously thought. With the discovery that telomeres share many features of CFS, including the appearance of telomeric discontinuities on metaphase chromosomes following exposure to replication stresses (Martinez et al., et al., et al., et al., et al., et al., et al., Why telomeres impede replication fork progression is still subject to investigation. Repetitive DNA sequences, in general, are known to challenge efficient and accurate DNA replication. This is primarily due to an increased abundance of hairpin secondary structures, due to polymerase slippage, or primer template misalignments (Voineagu et al., et al., in vitro and in vivo (Fumagalli et al., et al., et al., Failure to restart DNA synthesis at stalled replication forks, telomeric or nontelomeric, generates DSBs, and consequently DDR foci, near the stalled fork and causes cells to arrest the cell division cycle (Jossen & Bermejo, Why should telomeres be resistant to DNA repair activities? Linear DNA molecules are inherently unstable and either rapidly become degraded or fused to other exposed DNA ends by cellular DNA repair mechanisms to suppress DDR signaling. One critical function of our chromosome ends, therefore, is to suppress chromosome degradation and prevent end fusions with telomeres of sister chromatids, or with telomeres of other chromosomes. One mechanism that this could be accomplished is if telomeres, or associated proteins, somehow inhibit the DNA damage repair machinery. Indeed, components of shelterin, including TRF2, inhibit the functions of essential DSB checkpoint kinases as well as DSB repair factors and thereby suppress telomere end-to-end fusions Sfeir, . As a coet al., et al., et al., et al., et al., et al., et al., At first thought, it might seem disadvantageous for the organism to prevent DSB repair in telomeric repeats. As our cells are frequently exposed to genotoxic stresses, occasional DSBs in telomeric sequences would force these cells to senesce prematurely, accumulate in our tissues, and potentially negatively impact tissue function as we age. Indeed, cells with persistent telomeric breaks, or dysfunctional telomeres, have been reported to increase in abundance in an aging-associated manner in tissue of mice (Hewitt et al., et al., et al., et al., et al., et al., de novo telomeric repeats to the exposed 3′ overhang of a telomeric DSB or single-stranded nick close to a stalled telomeric replication fork, thereby preventing telomere dysfunction. This mechanism, which resembles chromosome healing, has been described previously in cells that display telomerase activity (Murnane, While telomerase cannot prevent formation of telomeric DDR foci in response to ionizing radiation, or even resolve these foci with high efficiency once generated (Fumagalli Murnane, .et al., et al., et al., Because telomerase suppresses the formation of a telomeric DDR in response to DNA replication stress, cells expressing hTERT are significantly less sensitive to hyperproliferative signals and stresses that impede replication fork progression. While somatic human cells undergo TDIS prematurely and rapidly in response to DNA replication stress induced by drugs, oncogenes, or impairment of DNA replication factors, cells that over express hTERT, or cancer cells that have reactivated telomerase expression, are generally insensitive to these treatments (Suram et al., et al., It is becoming increasingly evident that telomeres are far from being replicometers that simply count cell division cycles. Mounting evidence supports the model that telomeres also function as sensors of genotoxic events, capable of shutting down cell cycle progression prematurely before telomeres had eroded to critically short lengths. Furthermore, while telomere dysfunction can promote cancer progression by seeding the events that lead to genomic instability in cells with compromised DNA damage responses, it is also clearly beneficial for the organism as it promotes cell death and stabilizes cellular senescence as demonstrated both in animal model systems (Cosme-Blanco Cells with features of TDIS have been detected in inactive and benign lesions in the skin, as well as in colonic and breast epithelium. TDIS therefore can be activated in distinct cell types and throughout our tissues. While we don’t yet have a thorough knowledge of what other tissues are protected from developing neoplasms due to activation of TDIS, future studies should reveal the entire extent to which this tumor-suppressing mechanism protects us from developing malignant cancers. Also still unresolved is how telomerase suppresses formation of dysfunctional telomeres and induction of TDIS in response to DNA replication stress. As this function requires its catalytic activity, it is also targetable using existing antitelomerase drugs which were designed to inhibit the telomere extending abilities of telomerase. The vulnerability of telomeres to oncogenic and hyperproliferative signals in the absence of telomerase activity could therefore be exploited by using drug combination cancer therapies, targeting both telomerase while inducing DNA replication stress. While much still remains to be learned about the role of dysfunctional telomeres during aging and cancer development, it is becoming increasingly evident that the beneficial and tumor-suppressing properties of telomere dysfunction are vital for human health.


Journal of Venomous Animals and Toxins including Tropical Diseases in 1995, special attention has been given to the publication of results from research studies on products developed from animal toxins [Since the foundation of the l toxins . For yeal toxins .Crotalus durissus terrificus associated with a fibrinogen-rich cryoprecipitate and coagulation factors extracted from buffalos [About 20 years ago the researchers of the Center for the Study of Venoms and Venomous Animals (CEVAP) at UNESP proposed to engage in prospecting for a new sealant from a serine protease extracted from the venom of buffalos ,3,4. Forbuffalos . In humabuffalos -10.Recently, we have investigated the effects of the fibrin sealant as a scaffold for mesenchymal stem cells in order to demonstrate the ability of cells to interact with the biological microenvironment . We obseet al.[Similarly, de la Puente et al.-14 develet al.-14.et al.[et al.[The results of de la Puente et al.-14 are il.[et al., since tThe author declares that there are no competing interests.


In his valuable commentary on our recent publication Ashley Craig pointed out that the observed “strong connection between mental distress and a disorder like cerebral visual injury is highly important for directing future research in the area.” Within this context we wish to emphasize another significant factor: patients' quality of life that may be relevant as a potential mediator variable.cope with daily visual tasks. For brain-damaged patients the NEI-VFQ may be ideally conducted together with a neuroophthalmological supplement which is available in English and German (Raphael et al., Besides generic health-related quality of life, vision-related quality of life as assessed with questionnaires such as the National Eye Institute—Visual Functioning Questionnaire (NEI-VFQ, Mangione et al., Recently, we have observed that a higher extent of vision-related quality of life in patients with cerebral visual injury was related to lower levels of mental distress (Gall et al., Dr. Craig also highlighted the other side of the hypothesis, i.e., that “quality of life will improve should mental health problems be addressed” (Gall et al., Brief Symptom Inventory (BSI, Franke, As pointed out in the commentary, very similar phenomena of elevated mental distress have been observed in patients with physical disorders after damage to the central nervous system Craig, . A next The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Moths (Lepidoptera) are the major nocturnal pollinators of flowers. However, their importance and contribution to the provision of pollination ecosystem services may have been under-appreciated. Evidence was identified that moths are important pollinators of a diverse range of plant species in diverse ecosystems across the world.2. Moth populations are known to be undergoing significant declines in several European countries. Among the potential drivers of this decline is increasing light pollution. The known and possible effects of artificial night lighting upon moths were reviewed, and suggest how artificial night lighting might in turn affect the provision of pollination by moths. The need for studies of the effects of artificial night lighting upon whole communities of moths was highlighted.3. An ecological network approach is one valuable method to consider the effects of artificial night lighting upon the provision of pollination by moths, as it provides useful insights into ecosystem functioning and stability, and may help elucidate the indirect effects of artificial light upon communities of moths and the plants they pollinate.4. It was concluded that nocturnal pollination is an ecosystem process that may potentially be disrupted by increasing light pollution, although the nature of this disruption remains to be tested. Any paper demonstrating the existence of a moth–plant pollination interaction or providing evidence for such an interaction was considered relevant and included in the review. Levels of evidence supporting pollination interactions varied from observed flower visitation alone to proven dependence of the flower on moths for pollination , reportedly pollinated by moths of Geometridae and Pyralidae , visited by large numbers of moths in the genus Pyroderces  and diurnal pollinators; for example, The literature, therefore, contains numerous examples of moths serving as pollinators which, in many cases, are of considerable importance to individual species and to communities. A diverse selection of plant taxa in an equally wide range of ecosystems benefit from pollination by moths. It is important to consider how environmental change may threaten this ecosystem service.et al.,et al.,et al.,et al.,There are many drivers of environmental change, but artificial night lighting is one which is uniquely important for nocturnal organisms, through direct interaction with a light source such as a streetlamp, increased background illumination at night, and altered perception of photoperiod . Even at a low intensity, light caused reductions in age and mass at pupation in males and inhibited diapause in both sexes of a Noctuidae species in the laboratory  have simple eyes  that are sensitive to changes in light intensity  radiation (10–400 nm), predominantly at longer wavelengths close to visible light  of interactions between species, such as plants and pollinators  Skeels  tend to interact with generalists (with many connections) more frequently than with other specialists (Dicks et al. (Most studies of plant–pollinator networks to date have focused on diurnal interactions. Two exceptions considering nocturnal plant–pollinator networks are Devoto et al.  and Banzet al. ; these aet al.,et al.,et al.,A variety of changes in moth abundance, composition of moth assemblages, and moth behaviour are all possible results of artificial lighting at night, but the overall effect on the whole community via disruption of pollination remains to be tested . Moths mWe believe that our findings in this review highlight a number of key priorities for future research . While wet al.,The effects of artificial night lighting on moths, too, should be investigated further. Many of the individual-level effects summarised above have not been empirically demonstrated to occur under natural conditions. Moreover, there are no published studies into the community-level effects of artificial night lighting on moths; this is a major research gap (Fox, In this review, we show the importance of moths as pollinators for a diverse range of plant species in ecosystems worldwide and, hence, their role in ecosystem functioning. We discuss the many ways in which moths are known to be affected by artificial night lighting, and suggest how these effects may, in turn, impact pollination interactions between moths and plants.The effects of artificial night lighting may go beyond simple declines in moth populations, with potential changes in the composition of moth assemblages and in the nature and frequency of interspecies interactions between moths and other taxa; this justifies an ecological network approach to the problem .Artificial night lighting may negatively affect a range of ecosystem services (Lyytimäki,


Dunaliella but also for the halophilic Archaea in blooms that occasionally develop in the lake when conditions become favorable (Oren, Halobacteriaceae have developed mechanisms to use not only phosphate ions but other phosphorus sources as well. Thus, the square archaeon Haloquadratum walsbyi possesses a gene cluster that allows uptake of phosphonates and cleavage of the stable carbon-phosphorus bond (Bolhuis et al., Phosphorus is a key element for life, and in many ecosystems phosphate is the limiting nutrient. This is also true for many hypersaline ecosystems. A well-known example is the Dead Sea, where the possibility of massive development of microbial blooms is determined by the excessively high concentrations of magnesium and calcium and phosphate is the limiting inorganic nutrient, not only for the alga le Oren, . It is tHalobacterium salinarum, Haloferax mediterranei, and Haloferax volcanii. Cell sorting of prokaryotes from saltern brines provided further evidence for polyploidy (Zhaxybayeva et al., Hfx. volcanii cells are starved for phosphorus, the number of genome copies is reduced from ~30 to ~2, allowing for about three additional cell division cycles. The degree of ploidy is thus determined by the level of available nutrients. The number of ribosomes is not decreased, showing that rRNA does not serve as a phosphorus reserve. In non-starved cells the amount of DNA-bound phosphorus is about twice that found in the ribosomes, making DNA more suitable as phosphorus storage material (Zerulla et al., DNA contains 10% phosphorus by weight. Many halophilic Archaea have discovered the advantage of DNA as a phosphorus storage polymer: they are commonly polyploid: some species may contain up to 30 genome copies (Breuert et al., Halobacteriales (Oren et al., Halorubrum spp. (Makhdoumi Kakhki et al., Halorubrum and a Halobacterium showed the activity (Birbir et al., Halogeometricum-affiliated isolates from salterns of Tamil Nadu, India (Manikandan et al., Halobacteriaceae was never ascertained. An ISI Web of Science search did not yield any papers dedicated to the properties of haloarchaeal DNases.Another way to obtain phosphorus is by degrading DNA outside the cells. Extracellular DNA is found in all environments, including hypersaline ones (Chimileski et al., Haloferax mating systems are based on direct contact between cells of the same species (Rosenshine et al., Halorubrum (Papke et al., Halobacteriaceae came from a metagenomic study in Deep Lake, an Antactic hypersaline lake. The four organisms dominating the community and belonging to different genera share contiguous up to 35-kb long regions of ~100% identity (DeMaere et al., Mechanisms of degradation of DNA to be used as a nutrient and to be taken up as a source of new genes may be related (Finkel and Kolter, Hfx. volcanii. They showed that exogenous double-stranded DNA can be used as a nutrient to supply essential phosphorus. Not all sources of DNA are equally suitable, and there is a large degree of specificity involved. DNA of the same species supports growth, but herring sperm DNA or Escherichia coli DNA were not effective. However, unmethylated E. coli DNA was metabolized. Thus, there is a bias against highly divergent methylated DNA.In a recent “Frontiers in Microbiology” paper, Chimileski et al.  studied Hvo_1477 was identified as a factor likely involved in DNA processing at the cell surface. It is the first identified archaeal extracellular DNA processing / uptake-related gene. Its deletion created a strain unable to grow on extracellular DNA. Hvo_1477 homologs are commonly found in genomes of Halobacteriaceae and other Archaea. Hvo_1477 codes for a 327 amino acid lipoprotein attached to the membrane, homologous with known Bacillus and Staphylococcus nucleases.The gene Use of DNA as a nutrient may be considered a form of natural DNA uptake or natural competence. However, natural competence requires internalization of intact DNA fragments and the presence of a complex molecular machine for binding and intracellular processing of DNA. Import of high-molecular-weight DNA through membranes of halophilic Archaea is yet to be conclusively demonstrated.The data presented have important implications for different disciplines including microbial ecology, nutrition, and evolution. They raise some intriguing questions:Halobacteriaceae?- To what extent is extracellular DNA exploited as a phosphorus source in natural communities of Hfx. volcanii were the sequestering of phosphorus to avoid starvation, why are not all types of DNA taken up with equal efficiency?- If the sole purpose of DNA uptake by - If DNA can be internalized, how does the cell decide whether to degrade it as a source of nutrient or explore the possibility that it may encode useful genetic material?The study by Chimileski et al. may thus lead to basic new insights in more than one field of microbiology.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Structural magnetic resonance imaging (MRI) techniques are a representative example of the current progress in neuroimaging and enable imaging neuroanatomy to be directly applied to clinical practice. Particularly the field of stereotactic and functional neurosurgery has begun to gain remarkable benefits from this revolutionary evolution. Such techniques are ideal for studying clinical populations considered for functional neurosurgery, especially when crucial structures of complicated neuronal networks are targeted. Another benefit is the possibility for a personalized treatment, as was well illustrated in the recent article by Lujan et al.  regardinLujan et al.  presenteThe findings of Lujan et al.  suggestein vivo  and obsessive-compulsive disorder  has yielded promising results (Schlaepfer et al., Thinking of cautions that unavoidably come with new technologies, we should keep in mind that DTI tracts are complex mathematical objects and the validity of tractography-derived information in clinical settings has yet to be fully established (Pujol et al., In conclusion, tractography appears as an imaging tool of great value in functional neurosurgery. It can reveal the spectrum of network changes associated with DBS and also the differences in the activated pathways which result from small differences in electrode location. Thanks to such modern structural MRI modalities, as tractography, we nowadays know that activation of a critical mass of unique anatomic connectivity may be necessary for achieving the desired DBS-induced therapeutic benefit. Finally, tractography enables personalized treatment, which appears to be crucial for a successful neuromodulation procedure, especially a DBS application.Dr. IM is the sole contributor of this article.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Our planet is experiencing rates of environmental change unprecedented in modern times, and an understanding of how microbes both mediate and respond to these shifts is an important research challenge (De Vries and Shade, Trait-based approaches can provide mechanistic links between community structure and function, and are gaining popularity in microbial ecology (Krause et al., As well, species-species interactions can affect the relationship between communities and processes. In the model presented by Folse and Allison , the impnirK genes, which are thought to be subject to HGT, is not related to N2O accumulation rates. Furthermore, for nirS and 16S rRNA genes, Salles et al. (Evolutionary dynamics can also alter relationships between structure and function. In a Perspectives Article, Choudoir et al.  advocates et al.  showed ts et al.  used mets et al.  used a mCommunity assembly processes may also alter the relationship between “who's there” and “what they do” (Nemergut et al., Physical dynamics may also be key in regulating the relationship between structure and function. Schimel and Schaeffer  propose Together, the studies in this special issue highlight the role of a variety of ecological, evolutionary and physical dynamics in microbial community structure and function Figure . This boThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Nomura et al. show that the positive cAMP/PKA response is moderated by the co-activation of Gi-coupled receptors coexpressed in the same neuron (Nomura et al., 1 receptors that are tonically activated by the endogenous production of endocannabinoids (Ladarre et al., The articles in this Frontiers Research Topic describe how neurons integrate the signals carried by cyclic nucleotide. Three articles present original research, two papers provide provocative opinions about aspects of cyclic nucleotides signaling and four reviews provide timely summary and analysis of the state of the field. The three original articles illustrate how biosensors can reveal the details of signaling cascades in “native” neurons, a major advance compared to the use of heterologous expression systems. Nomura et al.  quantifyIn an opinion piece, Iyengar proposes that spatially restricted elevation of cAMP levels and their action on downstream effectors may function as a scaling agent for computations by signaling networks Iyengar, . Goto, KPV was supported by Labex Bio-Psy. NS was supported by NIH, the Ellison Medical Foundation and the W. M. Keck Foundation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In the past decade, human cortical activity has been shown to be modulated by applying direct low electrical current. The current flowing through the skull and brain between two surface electrodes increases excitability of the cortical tissue under the anode and decreases it under the cathode. This transcranial direct current stimulation (tDCS) improves motor adaptation to environmental change  on motor skill learning (Cantarero et al., Recently, the cerebellum has shown multimodal arrangements, providing an anatomical basis for this sensory-motor integration. Proville et al.  demonstrResults of Cantarero et al.  showed tThe effect of ctDCS on motor accuracy is unlikely related to the visual system which can hardly be improved. This effect may rather result from improved proprioception. Specifically, in the sequential visual isometric pinch task, improving proprioception would improve the ability to accurately match visual and muscle-force information. Based on studies testing cerebellar patients (e.g., Bhanpuri et al., M1 tDCS also immediately improves performance in a motor skill task, as demonstrated by Prichard et al. , and visIn conclusion, Cantarero et al.  study shThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


There is an error in the last sentence of the penultimate paragraph of the Discussion. The sentence should read:Our data indicated that the C allele  was related to higher MI values, thus corroborating the propositions of Norton et al. [6], Spichenok et al. [17], and Walsh et al., [18].


While young fathers have been neglected in social research in the UK, over the past fifteen years a small but growing body of empirical evidence has emerged across a range of studies. This review article draws selectively on this literature to document the characteristics of young fathers in the UK and their lived experiences. It presents compelling evidence for the desire of young fathers to be engaged as parents, despite the sometimes multiple challenges that they face. The article begins with a demographic profile of young fathers and documents what is known of young fathers’ relationships with their children, the child's mother and wider kin. It goes on to consider a range of practical issues facing young fathers. The article concludes with a consideration of young fathers’ support needs and experiences of professional support, drawing out the implications for policy and professional practice. Concerns about youthful fertility are not new. In popular discourse young parents are often portrayed as being irresponsible, ignorant and as a threat to the social order Duncan, . Motherset al., et al., et al., et al., et al., et al., et al., Although young fathers are an under-represented research group, academic interest in fatherhood can be traced back to the 1970s in both the US and the UK. A rich and diverse body of work has emerged from the 1990s onwards, in line with changing patterns of partnering and parenting  in the time leading up to the birth and afterwards (Ayoola et al., et al., et al., The challenge, then, is one of changing the culture of professional practice so that young fathers are no longer discounted as ‘hard to reach’, ‘disinterested’, or ‘risky’ but sought out and welcomed as clients with a valuable contribution to make.If a young father refrains from seeking out professional support due to negative responses from practitioners or discriminatory attitudes, they risk being labelled as irresponsible or absent (Featherstone et al., When appropriate formal support is provided, this is linked to better psychological, emotional and economic wellbeing of young parents, better quality of parenting and may prevent serious case reviews from occurring Hadley, . ExampleOverall, this article indicates that young men's abilities to engage and sustain a fathering role are dependent on a number of complex and often interlinking factors such as education, training and employment opportunities, relationship status with the baby's mother, support levels from maternal and paternal grandparents, residence arrangements and access to formal service provision – many of which can become barriers for them to overcome.With regards to formal service provision, timely access to appropriate support can help a young man's positive transition into parenthood, promote fatherhood engagement and is shown to be beneficial, regardless of the father's relationship status with the baby's mother. However, commentators argue that provision for young fathers is still lacking. While young mothers encounter universal provision, such as midwifery and health visiting, such systematic contact with young fathers continues to be limited. Much more needs to be done to support and promote a father inclusive culture within policy and professional practice. Listening to the voices of young fathers and understanding their lived experiences can help overturn negative perceptions of them as parents and thereby contribute to better service provision. As Lammy : 11 obse


Dear Friends,Warm GreetingsThe editorial team at Journal of Current Glaucoma Practice (JOCGP), the official Journal of International Society of Glaucoma Surgery, hopes to chronicle new developments in the field of glaucoma for you, ensuring a critical evaluation of existing and new techniques for better patient care. We are indeed grateful to the dynamic and illustrious editorial board for agreeing to join us in this endeavor.In this issue, Coote et al review the techniques of bleb revision for failing blebs. Stirbu et al review various materials and modalities for drainage tube repair.The role of selective laser trabeculoplasty and prostaglandin analogs in the current glaucoma treatment paradigm is discussed by Clement, in the perspectives section. Louati et al draw attention to the implications of long-term BAK use in patients of a chronic disease like glaucoma.Nuyen et al introduce the technique of imaging the lamina cribrosa using the swept-source optical coherence tomography in the diagnostics section. Maheshwari et al review the methods and implications of tonometry in glaucoma while assessment of diurnal fluctuations in intraocular pressure is dealt with, by Bhartiya et al.Ichhpujani et al discuss the extremely important assessment of knowledge, attitudes and self-care practices associated with glaucoma in hospital personnel.We hope you enjoy reading this issue of the JOCGP and will always welcome any comments, criticisms or suggestions that you may have.Looking forward to seeing you all at Glasgow in September.Best wishesShibal BhartiyaTarek ShaarawyTanuj Dada


The global pandemic of non-vector borne environmental diseases may, in large part, be attributed to chronic exposures to ever increasing levels of exogenous lipophilic chemicals. These chemicals include persistent organic pollutants, semi-volatile compounds and low molecular weight hydrocarbons. Such chemicals facilitate the sequential absorption of otherwise not absorbed more toxic hydrophilic species that attack numerous body organs and systems, leading to environmental disease. Co-morbidities of non-communicable environmental diseases are alarmingly high, with as many as half of all individuals chronically ill with two or more diseases. Co-morbidity is to be anticipated, since all of the causative chemicals identified have independently been shown to trigger the individual diseases. All are triggered by a combination of genetic susceptibility and environmental exposure . Hypertension is about twice as common in diabetics as in those without diabetes and either disease can precede the other , semi-volatile exogenous chemicals (SVOCs) and low molecular weight hydrocarbons (LMWHCs). Examples of POPs are polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCs). Examples of semi-volatile compounds are bisphenol A, phthalates and polynuclear aromatic hydrocarbons. Examples of volatile organic compounds are 8 carbon or less aliphatic and single-chain aromatic hydrocarbons. POPs are slowly metabolized and eliminated and are stored in white adipose tissue, from where they are slowly released into the blood stream. SVOCs are more rapidly metabolized and eliminated andLMWHCs are very rapidly metabolized and eliminated, but continued exposure to SVOCs and LMWHCs leads to continuous levels in the blood as well. A steady state of lipophilic load is in effect in the body, and since lipophiles facilitate the absorption of hydrophiles, a body containing high levels of lipophiles is more likely to absorb toxic levels of hydrophiles when exposure to these occurs than one with low levels of lipophiles. This is shown by the dose-response relationships for the onset of T2D, cardiovascular disease and neurological disease .et al., et al., et al., One in four individuals with one of these diseases is likely to be stricken with at lease one more of these diseases (Bauer Eleven (11) types of environmental diseases are listed in et al., All the diseases in Further credence to the theory just proposed is provided by the following considerations:et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., A consideration of obesity is in order here. Body Mass Index (BMI) of 30 or greater is considered obese  are known trigger environmental diseases, including type 2 diabetes, cardovascular diseases and neurological diseases (Carocci et al., In conclusion, it has been previously shown that chemically sensitive individuals had numerous co-morbidities when exposed to LMWHCs (Zeliger


These need antioxidant mechanisms, such as the local production of antioxidant molecules (such as glutathione and ascorbate) and antioxidant enzymes, for protection of the neuron and its component chemicals , glutathione (the major lipophilic antioxidant), carnosine, and the antioxidant enzyme superoxide dismutase (SOD) (Smythies, — In the retina, Neal et al.  showed t— Using slow-scan voltammetry following the injection of ascorbate oxidase into the rat striatum, Rebec and Wang  reported— Using microdialysis, Morales et al.  showed tHowever, less data is available about the antioxidant protection of catecholamines in and around the synapse. In this regard it is important to note that the major mode of interneuronal communication by dopamine is by volume transmission—dopamine is released directly into the extracellular space modulated by the hydrophilic environment of the extracellular matrix (Rice and Cragg, Other than this, there is scant information of other antioxidant mechanisms in this system. However, a clue is offered from an obscure clinical source.Blake et al.  reportedIn a previous communication, Smythies  suggesteIron is a highly reactive molecule, and the only place within a neuron that free iron is known to exist is in endosomes, where, however, free dopamine is not to be found. With that said, there may be an alternate location worthy of consideration, that being the extracellular space between neurons. Here, as we have noted above, dopamine is present and functioning in its volume transmission role, as well as superoxide derived from NADPH-oxidase on the extracellular side of cell membranes (Oakley et al., 2O2 and toxic aldehydes (Kaludercic et al., per se lie outside the scope of this paper.It is well established that dopamine oxidation products, such as dopamine quinone and dopaminochrome, that play a role in the O'Brien cycle, can be highly neurotoxic (Smythies, Another aspect of redox mechanisms at the dopamine synapse may be related to its co-transmission with glutamate. Most if not all dopaminergic neurons in the midbrain utilize glutamate as a co-transmitter (Descarries et al., Our hypothesis for the cause of the desferrioxamine-prochlorperazine coma is predicated on the fact that the brain has two powerful antioxidant-protective mechanisms in play that both involve dopamine. The first mechanism is the activation of a series of antioxidant enzymes by the dopamine D2-receptor, which is blocked by prochlorperazine. The second is the O'Brien cycle that would collapse if deprived of iron by desferrioxamine. The brain may be able to operate in the absence of either of these mechanisms, but not both. A series of experiments are indicated to test this hypothesis. These would include repeating the rat experiment by Blake et al.  using a — Modulation of both GABAergic and glutamatergic functions (Frantseva et al., — Blockade of catecholamine and glutamate uptake by synaptic vesicles (Wang and Floor, — Inhibition of synaptic dopamine release (Chen et al., — Inhibition of an adenosine-mediated synaptic transmission in hippocampal slices (Masino et al., — Maintenance of essential cell populations in the brain (Dickinson et al., — Modulation of membrane and cytoskeletal properties in astrocytes and increasing their intercellular connections (Zhu et al., The implications of confirming that the O'Brien cycle is present and active in the brain are broad, and would extend well beyond a simple redox function or control of superoxide toxicity. The main product of the O'Brien cycle is hydrogen peroxide. This molecule is involved in a wide range of signaling pathways in the brain. For example:A general review of this topic is provided by Rice . ConceivThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.