Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer's disease?

: The amyloid cascade hypothesis of Alzheimer's disease envisages that the initial elevation of amyloid β-peptide (Aβ) levels, especially of Aβ(1-42) , is the primary trigger for the neuronal cell death specific to onset of Alzheimer's disease. There is now substantial evidence that brain amyloid levels are manipulable because of a dynamic equilibrium between their synthesis from the amyloid precursor protein and their removal by amyloid-degrading enzymes (ADEs) providing a potential therapeutic strategy. Since the initial reports over a decade ago that two zinc metallopeptidases, insulin-degrading enzyme and neprilysin (NEP), contributed to amyloid degradation in the brain, there is now an embarras de richesses in relation to this category of enzymes, which currently number almost 20. These now include serine and cysteine proteinases, as well as numerous zinc peptidases. The experimental validation for each of these enzymes, and which to target, varies enormously but up-regulation of several of them individually in mouse models of Alzheimer's disease has proved effective in amyloid and plaque clearance, as well as cognitive enhancement. The relative status of each of these enzymes will be critically evaluated. NEP and its homologues, as well as insulin-degrading enzyme, remain as principal ADEs and recently discovered mechanisms of epigenetic regulation of NEP expression potentially open new avenues in manipulation of AD-related genes, including ADEs.     

Are lactoferrin receptors in Gram-negative bacteria viable vaccine targets?

A number of important Gram-negative pathogens that reside exclusively in the upper respiratory or genitourinary tract of their mammalian host rely on surface receptors that specifically bind host transferrin and lactoferrin as a source of iron for growth. The transferrin receptors have been targeted for vaccine development due to their critical role in acquiring iron during invasive infection and for survival on the mucosal surface. In this study, we focus on the lactoferrin receptors, determining their prevalence in pathogenic bacteria and comparing their prevalence in commensal Neisseria to other surface antigens targeted for vaccines; addressing the issue of a reservoir for vaccine escape and impact of vaccination on the microbiome. Since the selective release of the surface lipoprotein lactoferrin binding protein B by the NalP protease in Neisseria meningitidis argues against its utility as a vaccine target, we evaluated the release of outer membrane vesicles, and transferrin and lactoferrin binding in N. meningitidis and Moraxella catarrhalis. The results indicate that the presence of NalP reduces the binding of transferrin and lactoferrin by cells and native outer membrane vesicles, suggesting that NalP may impact all lipoprotein targets, thus this should not exclude lactoferrin binding protein B as a target.     

Cereal phytochromes: targets of selection, targets for manipulation?

Plants respond to shading through an adaptive syndrome termed shade avoidance. In high-density crop plantings, shade avoidance generally increases extension growth at the expense of yield and can be at odds with the agronomic performance of the crop as a whole. Studies in Arabidopsis are beginning to reveal the essential role phytochromes play in regulating this process and to identify genes underlying the response. In this article, we focus on how phytochrome signaling networks have been targeted in cereal breeding programs in the past and discuss the potential to alter these pathways through breeding and transgenic manipulation to develop crops that perform better under typical high density conditions.     

Are phylogenies resolved at the genus level appropriate for studies on phylogenetic structure of species assemblages?

Phylogenies are essential to studies investigating the effect of evolutionary history on assembly of species in ecological communities and geographical and ecological patterns of phylogenetic structure of species assemblages. Because phylogenies well resolved at the species level are lacking for many major groups of organisms such as vascular plants, researchers often generate a species-level phylogenies using a phylogeny well resolved at the genus level as a backbone and attaching species to their respective genera in the phylogeny as polytomies or by using a megaphylogeny well resolved at the genus level as a backbone and adding additional species to the megaphylogeny as polytomies of their respective genera. However, whether the result of a study using species-level phylogenies generated in these ways is robust, compared to that based on phylogenies fully resolved at the species level, has not been assessed. Here, we use 1093 angiosperm tree assemblages (each in a 110 × 110 km quadrat) in North America as a model system to address this question, by examining six commonly used metrics of phylogenetic structure (phylogenetic diversity and phylogenetic relatedness) and six climate variables commonly used in ecology. Our results showed that (1) the scores of phylogenetic metrics derived from species-level phylogenies resolved at the genus level with species being attached to their respective genera as polytomies are very strongly or perfectly correlated to those derived from a phylogeny fully resolved at the species level (the mean of correlation coefficients is 0.973), and (2) the relationships between the scores of phylogenetic metrics and climate variables are consistent between the two sets of analyses based on the two types of phylogeny. Our study suggests that using species-level phylogenies resolved at the genus level with species being attached to their genera as polytomies is appropriate in studies exploring patterns of phylogenetic structure of species in ecological communities across geographical and ecological gradients.     

Are Private Reserves Effective for Jaguar Conservation?

We present the first study of density and apparent survival for a jaguar (Panthera onca) population in northern Mexico using 13 years of camera trap data from 2000 to 2012. We used the Barker robust design model which combines data from closed sampling periods and resight data between these periods to estimate apparent survival and abundance. We identified 467 jaguar pictures that corresponded to 48 jaguar individuals. We included camera type and field technician as covariates for detection probabilities. We used three covariates to evaluate the effect of reserve on jaguar apparent survival: i) private reserve creation ii) later reserve expansions, and iii) cattle ranches’ conservation activities. We found that the use of digital cameras in addition to film cameras increased detection probability by a factor of 6x compared with the use of only film cameras (p = 0.34 ± 0.05 and p = 0.05 ± 0.02 respectively) in the closed period and more than three times in the open period (R = 0.91 ± 0.08 and R = 0.30 ± 0.13 mixed and film cameras respectively). Our availability estimates showed no temporary emigration and a fidelity probability of 1. Despite an increase of apparent survival probability from 0.47 ± 0.15 to 0.56 ± 0.11 after 2007, no single covariate explained the change in these point estimates. Mean jaguar density was 1.87 ± 0.47 jaguars/100 km². We found that 13 years of jaguar population monitoring with our sampling size were not enough for detecting changes in survival or density. Our results provide a baseline for studies evaluating the effectiveness of protected areas and the inclusion of ranch owners in jaguar conservation programs and long-term population viability.     

Is There Enough Science for Conservation Action?

We argue that there is not enough science to appropriately support many of the conservation measures currently being proposed, and hence, we cannot be sure of the objectivity of the conservation actions being implemented. The objectivity claimed to be underlying conservation actions is more assumed than real. We also suggest that the approach to conservation is driven more by moral commitments than by tested concepts, and it is further biased by our anthropocentric evaluation of ecological processes and their outcomes. Conservation science is a young subject, which needs to be nourished while it continues to feed on its roots-ecology and evolutionary biology.     

VGLUTs--potential targets for the treatment of seizures?

Vesicular glutamate transporters (VGLUTs) load glutamate into synaptic vesicles. In this issue of Neuron, Juge et?al. report that ketone bodies compete with chloride-dependent activation of VGLUTs, leading to suppression of glutamate release and seizures. These findings provide a surprising explanation for the efficacy of the ketogenic diet in controlling epilepsy.     

Mechanisms structuring stream fish assemblages: Are there lessons from introduced species?

Synopsis Stream fish faunas are being increasingly subjected to non-native fishes. Successful establishment of non-native forms varies widely between geographic regions (38–77%), but is generally greater in areas that are either altered by man or initially depauperate in fish species. While such introductions have generally had undesirable effects on native fish species, they show no signs of decreasing. Thus, this essay is an attempt to determine if the introduction of non-native fishes may provide insights into processes structuring stream fish assemblages. There are, unfortunately, few detailed ecological studies documenting the response of stream fish assemblages to introduced fishes. Of the 31 studies included in my analysis, the majority (77%) documents a decline in native fishes following the introduction of exotic or transplanted forms. Only 10 studies examined shifts in resource use, of which 5 documented or suggested shifts in habitat. Overall, the responses of native stream fish assemblages to non-native fishes suggest that biotic interactions are important in structuring the impacted assemblages, being implicated in 62% of the studies. Proposed or demonstrated mechanisms are divided equally between competition and predation. Unfortunately, pre-disturbance data are generally lacking so that processes important in structuring native fish assemblages cannot be determined.     

Is the Genetic Code Optimized for Resource Conservation?

The causes and consequences of the nonrandom structure of the standard genetic code (SGC) have been of long-standing interest. A recent study reported that mutations in present-day protein-coding sequences are less likely to increase proteomic nitrogen and carbon uses under the SGC than under random genetic codes, concluding that the SGC has been selectively optimized for resource conservation. If true, this finding might offer important information on the environment in which the SGC and some of the earliest life forms evolved. However, we here show that the hypothesis of optimization of a genetic code for resource conservation is theoretically untenable. We discover that the aforementioned study estimated the expected mutational effect by inappropriately excluding mutations lowering resource consumptions and including mutations involving stop codons. After remedying these problems, we find no evidence that the SGC is optimized for nitrogen or carbon conservation.     

Influenza-virus-induced signaling cascades: targets for antiviral therapy?

Influenza viruses continue to pose a severe threat worldwide, causing thousands of deaths and an enormous economic loss every year. The major problem in fighting influenza is the high genetic variability of the virus, resulting in the rapid formation of variants that escape the acquired immunity against previous virus strains, or have resistance to antiviral agents. Every virus depends on its host cell and, hence, cellular functions that are essential for viral replication might be suitable targets for antiviral therapy. As a result, intracellular signaling cascades induced by the virus, in particular mitogen-activated protein kinase pathways, have recently come into focus.     

Is parasitism of numerically dominant species in macrolepidopteran assemblages independent of their abundance?

Refuge theory proposes that a determinant of species richness (and percent parasitism) is the presence of host refuges. Plant structural refuges are good predictors of species richness for endophytic herbivores, but not for exophytic herbivores. For exophytic herbivores other traits such as relative abundance may provide refuge from parasitism. Using unbiased data on both relative abundance and larval parasitism of species in macrolepidopteran assemblages we tested the null hypothesis that percent parasitism was independent of abundance. Numerically subdominant species do not gain refuge from parasitism by persisting at low abundance. Parasitism was not different from what would be expected based on their numbers. Among numerically dominant species there was, nevertheless, a significant positive association between abundance and parasitism rate. However, dominant herbivores displayed high levels of parasitism even in the years when their abundance was low relative to other years. This suggests that dominant species may possess other traits that enhance their susceptibility to parasitoids.     

Plant targets for Pseudomonas syringae type III effectors: virulence targets or guarded decoys?

The phytopathogenic bacterium Pseudomonas syringae can suppress both pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI) by the injection of type III effector (T3E) proteins into host cells. T3Es achieve immune suppression using a variety of strategies including interference with immune receptor signaling, blocking RNA pathways and vesicle trafficking, and altering organelle function. T3Es can be recognized indirectly by resistance proteins monitoring specific T3E targets resulting in ETI. It is presently unclear whether the monitored targets represent bona fide virulence targets or guarded decoys. Extensive overlap between PTI and ETI signaling suggests that T3Es may suppress both pathways through common targets and by possessing multiple activities.     

Are streamside buffers edge-affected habitat for ground-dwelling forest beetle assemblages?

Reservation of forest in riparian buffers is common practice in commercial forestry areas worldwide, potentially providing valuable habitat for biodiversity dependent on mature forest. However, the habitat value of narrow reserve corridors can be compromised by edge effects. We investigated the habitat value of streamside buffers in wet eucalypt forest for ground-dwelling beetles in Tasmania, Australia. Beetles were collected with pitfall traps in five replicates of four habitats: unlogged corridors of mature forest in streamside reserves (buffers) with clearfelling-derived logging regeneration either side; continuous mature upslope forest; continuous mature riparian forest; and <20-year-old upslope clearfelling-derived logging regeneration. Streamside reserve widths on each side of the stream were on average 40 ± 6 m (±95% CI) from reserve edge to stream. Beetle assemblages in logging regeneration differed substantially from those in the unlogged habitats, including the streamside reserves. Streamside reserve assemblages nevertheless differed from those of the continuous unlogged areas. Assemblage composition in streamside reserves was most similar to that in continuous mature riparian forest, although beetle diversity was higher in the reserves. Our results suggest that although streamside reserves provide habitat for the majority of commonly collected beetle species occurring in continuous mature forest, wider reserve corridors in the wet eucalypt forests of Tasmania may be required to provide habitat that is not edge-affected.     

A consistent terminology for quantifying species diversity?

There is a genuine need for consensus on a clear terminology in the study of species diversity given that the nature of the components of diversity is the subject of an ongoing debate and may be the key to understanding changes in ecosystem processes. A recent and thought-provoking paper (Jurasinski et al. Oecologia 159:15–26, 2009) draws attention to the lack of precision with which the terms alpha, beta, and gamma diversity are used and proposes three new terms in their place. While this valuable effort may improve our understanding of the different facets of species diversity, it still leaves us far from achieving a consistent terminology. As such, the conceptual contribution of these authors is limited and does little to elucidate the facets of species diversity. It is, however, a good starting point for an in-depth review of the available concepts and methods.     

Do larvae of species in macrolepidopteran assemblages share traits that influence susceptibility to parasitism?

Research on how morphology, behavior, and life histories of insects determine their susceptibility to parasitism has primarily focused on the traits of single host species. Very little research has been conducted attempting to determine if similarities or differences in the traits of co-occurring species, on a single plant or in a habitat, influence levels of parasitism imposed on any member of an assemblage. In this study, we use categorical and regression tree analyses to determine which traits of the larvae of macrolepidopteran species are associated with highest levels of parasitism. Of a variety of morphological, behavioral, and ecological traits of 72 species (representing eight families), caterpillar color was the trait that had the greatest influence on susceptibility to parasitism. The highest levels of parasitism were associated primarily with green larvae. These results suggest that the herbivore species composition and, specifically, the traits possessed by the species may influence community or assemblagewide patterns of parasitism. That is, sharing of traits that enhance host finding and successful parasitism may result in associational susceptibility to parasitism, whereas co-occurrence with species that differ morphologically, behaviorally, or ecologically may reduce the likelihood of parasitism and thus result in associational resistance. The concepts of associational resistance and susceptibility have historically been restricted to plant-plant interactions. The extension of these concepts to herbivores is novel. If found to be widespread, these interactions can have significant impacts on our expectations of the effectiveness of biological control agents.