A Potential Prognostic Gene Signature Associated with p53-Dependent NTRK1 Activation and Increased Survival of Neuroblastoma Patients.

Neuroblastoma is the most common extracranial solid tumour in children, comprising close to 10% of childhood cancer-related deaths. We have demonstrated that activation of NTRK1 by TP53 repression of PTPN6 expression is significantly associated with favourable survival in neuroblastoma. The molecular mechanisms by which this activation elicits cell molecular changes need to be determined. This is critical to identify dependable biomarkers for the early detection and prognosis of tumours, and for the development of personalised treatment. In this investigation we have identified and validated a gene signature for the prognosis of neuroblastoma using genes differentially expressed upon activation of the NTRK1-PTPN6-TP53 module. A random survival forest model was used to construct a gene signature, which was then assessed across validation datasets using Kaplan-Meier analysis and ROC curves. The analysis demonstrated that high BASP1, CD9, DLG2, FNBP1, FRMD3, IL11RA, ISGF10, IQCE, KCNQ3, and TOX2, and low BSG/CD147, CCDC125, GABRB3, GNB2L1/RACK1 HAPLN4, HEBP2, and HSD17B12 expression was significantly associated with favourable patient event-free survival (EFS). The gene signature was associated with favourable tumour histology and NTRK1-PTPN6-TP53 module activation. Importantly, all genes were significantly associated with favourable EFS in an independent manner. Six of the signature genes, BSG/CD147, GNB2L1/RACK1, TXNDC5, FNPB1, B3GAT1, and IGSF10, play a role in cell differentiation. Our findings strongly suggest that the identified gene signature is a potential prognostic biomarker and therapeutic target for neuroblastoma patients and that it is associated with neuroblastoma cell differentiation through the activation of the NTRK1-PTPN6-TP53 module.

A Novel RNA Virus, Macrobrachium rosenbergii Golda Virus (MrGV), Linked to Mass Mortalities of the Larval Giant Freshwater Prawn in Bangladesh.

Mass mortalities of the larval stage of the giant freshwater prawn, Macrobrachium rosenbergii, have been occurring in Bangladesh since 2011. Mortalities can reach 100% and have resulted in an 80% decline in the number of hatcheries actively producing M. rosenbergii. To investigate a causative agent for the mortalities, a disease challenge was carried out using infected material from a hatchery experiencing mortalities. Moribund larvae from the challenge were prepared for metatranscriptomic sequencing. De novo virus assembly revealed a 29 kb single­stranded positive-sense RNA virus with similarities in key protein motif sequences to yellow head virus (YHV), an RNA virus that causes mass mortalities in marine shrimp aquaculture, and other viruses in the Nidovirales order. Primers were designed against the novel virus and used to screen cDNA from larvae sampled from hatcheries in the South of Bangladesh from two consecutive years. Larvae from all hatcheries screened from both years were positive by PCR for the novel virus, including larvae from a hatchery that at the point of sampling appeared healthy, but later experienced mortalities. These screens suggest that the virus is widespread in M. rosenbergii hatchery culture in southern Bangladesh, and that early detection of the virus can be achieved by PCR. The hypothesised protein motifs of Macrobrachium rosenbergii golda virus (MrGV) suggest that it is likely to be a new species within the Nidovirales order. Biosecurity measures should be taken in order to mitigate global spread through the movement of post-larvae within and between countries, which has previously been linked to other virus outbreaks in crustacean aquaculture.

The extent and predictability of the biodiversity-carbon correlation.

Protecting biomass carbon stocks to mitigate climate change has direct implications for biodiversity conservation. Yet, evidence that a positive association exists between carbon density and species richness is contrasting. Here, we test how this association varies (1) across spatial extents and (2) as a function of how strongly carbon and species richness depend on environmental variables. We found the correlation weakens when moving from larger extents, e.g. realms, to narrower extents, e.g. ecoregions. For ecoregions, a positive correlation emerges when both species richness and carbon density vary as functions of the same environmental variables (climate, soil, elevation). In 20% of tropical ecoregions, there are opportunities to pursue carbon conservation with direct biodiversity co-benefits, while other ecoregions require careful planning for both species and carbon to avoid potentially perverse outcomes. The broad assumption of a linear relationship between carbon and biodiversity can lead to undesired outcomes.

Spatial Autocorrelation Can Generate Stronger Correlations between Range Size and Climatic Niches Than the Biological Signal - A Demonstration Using Bird and Mammal Range Maps.

Species' geographic ranges could primarily be physiological tolerances drawn in space. Alternatively, geographic ranges could be only broadly constrained by physiological climatic tolerances: there could generally be much more proximate constraints on species' ranges (dispersal limitation, biotic interactions, etc.) such that species often occupy a small and unpredictable subset of tolerable climates. In the literature, species' climatic tolerances are typically estimated from the set of conditions observed within their geographic range. Using this method, studies have concluded that broader climatic niches permit larger ranges. Similarly, other studies have investigated the biological causes of incomplete range filling. But, when climatic constraints are measured directly from species' ranges, are correlations between species' range size and climate necessarily consistent with a causal link? We evaluated the extent to which variation in range size among 3277 bird and 1659 mammal species occurring in the Americas is statistically related to characteristics of species' realized climatic niches. We then compared how these relationships differed from the ones expected in the absence of a causal link. We used a null model that randomizes the predictor variables (climate), while retaining their broad spatial autocorrelation structure, thereby removing any causal relationship between range size and climate. We found that, although range size is strongly positively related to climatic niche breadth, range filling and, to a lesser extent, niche position in nature, the observed relationships are not always stronger than expected from spatial autocorrelation alone. Thus, we conclude that equally strong relationships between range size and climate would result from any processes causing ranges to be highly spatially autocorrelated.

Enhanced purification of plasmid DNA isoforms by exploiting ionic strength effects during ultrafiltration.

The solution structure of plasmid DNA is known to be a strong function of solution conditions due to intramolecular electrostatic interactions between the charged phosphate groups along the DNA backbone. The objective of this work was to determine whether it was possible to enhance the use of ultrafiltration for separation of different plasmid isoforms by proper selection of the solution ionic strength and ion type. Experiments were performed with a 3.0 kbp plasmid using composite regenerated cellulose ultrafiltration membranes. The transmission of the linear isoform was nearly independent of solution ionic strength, but increased significantly with increasing filtrate flux due to the elongation of the highly flexible plasmid in the converging flow field into the membrane pores. In contrast, the transmission of the open-circular and supercoiled plasmids both increased with increasing NaCl or MgCl2 concentration due to the change in plasmid size and conformational flexibility. The effect of ionic strength was greatest for the supercoiled plasmid, providing opportunities for enhanced purification of this therapeutically active isoform. This behavior was confirmed using experiments performed with binary mixtures of the different isoforms. These results clearly demonstrate the potential for enhancing the performance of membrane systems for plasmid DNA separations by proper selection of the ionic conditions.

Macrofaunal Patterns in and around du Couedic and Bonney Submarine Canyons, South Australia.

Two South Australian canyons, one shelf-incising (du Couedic) and one slope-limited (Bonney) were compared for macrofaunal patterns on the shelf and slope that spanned three water masses. It was hypothesized that community structure would (H1) significantly differ by water mass, (H2) show significant regional differences and (H3) differ significantly between interior and exterior of each canyon. Five hundred and thirty-one species of macrofauna ≥ 1 mm were captured at 27 stations situated in depth stratified transects inside and outside the canyons from 100 to 1500 m depth. The macrofauna showed a positive relationship to depth in abundance, biomass, species richness and community composition while taxonomic distinctness and evenness remained high at all depths. Biotic variation on the shelf was best defined by variation in bottom water primary production while sediment characteristics and bottom water oxygen, temperature and nutrients defined biotic variation at greater depth. Community structure differed significantly (p<0.01) among the three water masses (shelf-flowing South Australian current, upper slope Flinders current and lower slope Antarctic Intermediate Water) (H1). Although community differences between the du Couedic and Bonney regions were marginally above significance at p = 0.05 (H2), over half of the species captured were unique to each region. This supports the evidence from fish and megafaunal distributions that the du Couedic and Bonney areas are in different bioregions. Overall, the canyon interiors were not significantly different in community composition from the exterior (H3). However, both canyons had higher abundance and/or biomass, increased species dominance, different species composition and coarser sediments near the canyon heads compared to outside the canyons at the same depth (500 m), suggestive of heightened currents within the canyons that influence community composition there. At 1000-1500 m, the canyon interiors were depauperate, typical of V-shaped canyons elsewhere. The large number of species captured, given the relatively low sampling effort and focus on the larger macrofauna, support previous studies that identify the South Australian coast as a high biodiversity area.

An empirical investigation of why species-area relationships overestimate species losses.

It is generally assumed that, when natural habitat is converted to human-dominated land cover, such habitat is lost to its native species. Most literature assumes that species richness should vary as a function of remaining natural area, following the well-known species-area relationship (i.e., classic SAR). However, classic SARs have consistently overestimated species losses resulting from conversion of natural forested land cover to human-dominated landscapes. Moreover, richness is sometimes a peaked function of remaining natural habitat. Recent studies propose modified SAR models based on species' utilization of multiple habitat types, yet none fully explain a peaked species-area relationship. Here, we evaluate the responses of total avian richness, forest bird richness, and open-habitat bird richness to remaining natural land cover within 991 quadrats, each 100 km2, across southern Ontario, Canada. Total bird species richness peaks at roughly 50% natural land cover. Richness of forest birds varies as a classic power function of forested area. In contrast, richness of birds that prefer open habitats does not increase monotonically with either natural- or human-dominated land cover. Richness of open-habitat species can be predicted when we partition human-dominated land cover into an "available human-dominated" component and "lost" habitat. Disiinguishing three land-cover types (natural, available human-dominated, and lost) can thus permit accurate predictions of species richness in landscapes with differing levels of natural habitat conversion.

Does climate limit species richness by limiting individual species' ranges?

Broad-scale geographical variation in species richness is strongly correlated with climate, yet the mechanisms underlying this correlation are still unclear. We test two broad classes of hypotheses to explain this pattern. Bottom-up hypotheses propose that the environment determines individual species' ranges. Ranges then sum up to yield species richness patterns. Top-down hypotheses propose that the environment limits the number of species that occur in a region, but not which ones. We test these two classes of hypotheses using a natural experiment: seasonal changes in environmental variables and seasonal range shifts of 625 migratory birds in the Americas. We show that richness seasonally tracks the environment. By contrast, individual species' geographical distributions do not. Rather, species occupy different sets of environmental conditions in two seasons. Our results are inconsistent with extant bottom-up hypotheses. Instead, a top-down mechanism appears to constrain the number of species that can occur in a given region.

Big Science vs. Little Science: How Scientific Impact Scales with Funding.

AGENCIES THAT FUND SCIENTIFIC RESEARCH MUST CHOOSE: is it more effective to give large grants to a few elite researchers, or small grants to many researchers? Large grants would be more effective only if scientific impact increases as an accelerating function of grant size. Here, we examine the scientific impact of individual university-based researchers in three disciplines funded by the Natural Sciences and Engineering Research Council of Canada (NSERC). We considered four indices of scientific impact: numbers of articles published, numbers of citations to those articles, the most cited article, and the number of highly cited articles, each measured over a four-year period. We related these to the amount of NSERC funding received. Impact is positively, but only weakly, related to funding. Researchers who received additional funds from a second federal granting council, the Canadian Institutes for Health Research, were not more productive than those who received only NSERC funding. Impact was generally a decelerating function of funding. Impact per dollar was therefore lower for large grant-holders. This is inconsistent with the hypothesis that larger grants lead to larger discoveries. Further, the impact of researchers who received increases in funding did not predictably increase. We conclude that scientific impact (as reflected by publications) is only weakly limited by funding. We suggest that funding strategies that target diversity, rather than "excellence", are likely to prove to be more productive.

Protecting endangered species: do the main legislative tools work?

It is critical to assess the effectiveness of the tools used to protect endangered species. The main tools enabled under the U.S. Endangered Species Act (ESA) to promote species recovery are funding, recovery plan development and critical habitat designation. Earlier studies sometimes found that statistically significant effects of these tools could be detected, but they have not answered the question of whether the effects were large enough to be biologically meaningful. Here, we ask: how much does the recovery status of ESA-listed species improve with the application of these tools? We used species' staus reports to Congress from 1988 to 2006 to quantify two measures of recovery for 1179 species. We related these to the amount of federal funding, years with a recovery plan, years with critical habitat designation, the amount of peer-reviewed scientific information, and time listed. We found that change in recovery status of listed species was, at best, only very weakly related to any of these tools. Recovery was positively related to the number of years listed, years with a recovery plan, and funding, however, these tools combined explain <13% of the variation in recovery status among species. Earlier studies that reported significant effects of these tools did not focus on effect sizes; however, they are in fact similarly small. One must conclude either that these tools are not very effective in promoting species' recovery, or (as we suspect) that species recovery data are so poor that it is impossible to tell whether the tools are effective or not. It is critically important to assess the effectiveness of tools used to promote species recovery; it is therefore also critically important to obtain population status data that are adequate to that task.

Biophysical factors affecting the distribution of demersal fish around the head of a Submarine Canyon off the Bonney Coast, South Australia.

We sampled the demersal fish community of the Bonney Canyon, South Australia at depths (100-1,500 m) and locations that are poorly known. Seventy-eight species of demersal fish were obtained from 12 depth-stratified trawls along, and to either side, of the central canyon axis. Distributional patterns in species richness and biomass were highly correlated. Three fish assemblage groupings, characterised by small suites of species with narrow depth distributions, were identified on the shelf, upper slope and mid slope. The assemblage groupings were largely explained by depth (ρw = 0.78). Compared to the depth gradient, canyon-related effects are weak or occur at spatial or temporal scales not sampled in this study. A conceptual physical model displayed features consistent with the depth zonational patterns in fish, and also indicated that canyon upwelling can occur. The depth zonation of the fish assemblage was associated with the depth distribution of water masses in the area. Notably, the mid-slope community (1,000 m) coincided with a layer of Antarctic Intermediate Water, the upper slope community (500 m) resided within the core of the Flinders Current, and the shelf community was located in a well-mixed layer of surface water (<450 m depth).

Quantifying the importance of regional and local filters for community trait structure in tropical and temperate zones.

The influence of regional and local processes on community structure is a major focus of ecology. Classically, ecologists have used local-regional richness regressions to evaluate the role of local and regional processes in determining community structure, an approach that has numerous flaws. Here, we implemented a novel trait-based approach that treats local and regional influences as a continuum, rather than a dichotomy. Using hylid frogs (Hylidae), we compared trait dispersion among members of local species assemblages to the trait dispersion in the regional assemblage from which they were drawn. Similarly, we compared trait dispersion in the regional assemblages to dispersion in the continental species pool. We estimated the contributions of local and regional filters, and we compared their strength in temperate and tropical zones. We found that regional and local filters explained 80% of the total variation among local assemblages in community body size dispersion. Overall, regional filters reduced trait dispersion, and local filters increased it, a pattern driven by particularly strong antagonistic effects in temperate zones that reduced the realized total variation by more than 40%. In contrast, local and regional filters acted in concert in tropical regions. Patterns within the tropics did not differ from the random expectation based on a null model, but within the temperate zone, local community filtering was stronger than expected by chance. Furthermore, in temperate regions, antagonistic regional and local filtering masked from 76% to 90% of the total variation in trait dispersion. Together, these results suggest that there are fundamental differences in the scale and identity of the processes determining community structure in temperate and tropical regions.

Patterns and causes of species richness: a general simulation model for macroecology.

Understanding the causes of spatial variation in species richness is a major research focus of biogeography and macroecology. Gridded environmental data and species richness maps have been used in increasingly sophisticated curve-fitting analyses, but these methods have not brought us much closer to a mechanistic understanding of the patterns. During the past two decades, macroecologists have successfully addressed technical problems posed by spatial autocorrelation, intercorrelation of predictor variables and non-linearity. However, curve-fitting approaches are problematic because most theoretical models in macroecology do not make quantitative predictions, and they do not incorporate interactions among multiple forces. As an alternative, we propose a mechanistic modelling approach. We describe computer simulation models of the stochastic origin, spread, and extinction of species' geographical ranges in an environmentally heterogeneous, gridded domain and describe progress to date regarding their implementation. The output from such a general simulation model (GSM) would, at a minimum, consist of the simulated distribution of species ranges on a map, yielding the predicted number of species in each grid cell of the domain. In contrast to curve-fitting analysis, simulation modelling explicitly incorporates the processes believed to be affecting the geographical ranges of species and generates a number of quantitative predictions that can be compared to empirical patterns. We describe three of the 'control knobs' for a GSM that specify simple rules for dispersal, evolutionary origins and environmental gradients. Binary combinations of different knob settings correspond to eight distinct simulation models, five of which are already represented in the literature of macroecology. The output from such a GSM will include the predicted species richness per grid cell, the range size frequency distribution, the simulated phylogeny and simulated geographical ranges of the component species, all of which can be compared to empirical patterns. Challenges to the development of the GSM include the measurement of goodness of fit (GOF) between observed data and model predictions, as well as the estimation, optimization and interpretation of the model parameters. The simulation approach offers new insights into the origin and maintenance of species richness patterns, and may provide a common framework for investigating the effects of contemporary climate, evolutionary history and geometric constraints on global biodiversity gradients. With further development, the GSM has the potential to provide a conceptual bridge between macroecology and historical biogeography.

Cole-Cole, linear and multivariate modeling of capacitance data for on-line monitoring of biomass.

This work evaluates three techniques of calibrating capacitance (dielectric) spectrometers used for on-line monitoring of biomass: modeling of cell properties using the theoretical Cole-Cole equation, linear regression of dual-frequency capacitance measurements on biomass concentration, and multivariate (PLS) modeling of scanning dielectric spectra. The performance and robustness of each technique is assessed during a sequence of validation batches in two experimental settings of differing signal noise. In more noisy conditions, the Cole-Cole model had significantly higher biomass concentration prediction errors than the linear and multivariate models. The PLS model was the most robust in handling signal noise. In less noisy conditions, the three models performed similarly. Estimates of the mean cell size were done additionally using the Cole-Cole and PLS models, the latter technique giving more satisfactory results.

Evolutionary constraints on regional faunas: whom, but not how many.

The latitudinal diversity gradient has been hypothesized to reflect past evolutionary dynamics driven by climatic niche conservation during cladogenesis, i.e. the tropical conservatism hypothesis. Here we show that the species diversity of treefrogs (Hylidae) across the western hemisphere is actually independent of evolutionary niche dynamics. We evaluated three key predictions of the tropical conservatism hypothesis that relate to the relationships between climate, species richness and the phylogenetic structure of regional treefrog faunas across the continental Americas. Species composition was dependent on the inability of some lineages to evolve cold tolerance, but the actual number of species in a region was strongly predicted by precipitation, not temperature. Moreover, phylogenetic structure was independent of precipitation. Thus, species in low-richness areas were no more closely related than species in highly diverse regions. These results provide no support for the tropical conservatism hypothesis. Instead, they show that regional species composition and richness are constrained by different climatic components, demonstrating that global biodiversity gradients can be independent of niche stasis during cladogenesis.

Tracing the colonization history of the Indian Ocean scops-owls (Strigiformes: Otus) with further insight into the spatio-temporal origin of the Malagasy avifauna.

BACKGROUND: The island of Madagascar and surrounding volcanic and coralline islands are considered to form a biodiversity hotspot with large numbers of unique taxa. The origin of this endemic fauna can be explained by two different factors: vicariance or over-water-dispersal. Deciphering which factor explains the current distributional pattern of a given taxonomic group requires robust phylogenies as well as estimates of divergence times. The lineage of Indian Ocean scops-owls (Otus: Strigidae) includes six or seven species that are endemic to Madagascar and portions of the Comoros and Seychelles archipelagos; little is known about the species limits, biogeographic affinities and relationships to each other. In the present study, using DNA sequence data gathered from six loci, we examine the biogeographic history of the Indian Ocean scops-owls. We also compare the pattern and timing of colonization of the Indian Ocean islands by scops-owls with divergence times already proposed for other bird taxa. RESULTS: Our analyses revealed that Indian Ocean islands scops-owls do not form a monophyletic assemblage: the Seychelles Otus insularis is genetically closer to the South-East Asian endemic O. sunia than to species from the Comoros and Madagascar. The Pemba Scops-owls O. pembaensis, often considered closely related to, if not conspecific with O. rutilus of Madagascar, is instead closely related to the African mainland O. senegalensis. Relationships among the Indian Ocean taxa from the Comoros and Madagascar are unresolved, despite the analysis of over 4000 bp, suggesting a diversification burst after the initial colonization event. We also highlight one case of putative back-colonization to the Asian mainland from an island ancestor (O. sunia). Our divergence date estimates, using a Bayesian relaxed clock method, suggest that all these events occurred during the last 3.6 myr; albeit colonization of the Indian Ocean islands were not synchronous, O. pembaensis diverged from O. senegalensis about 1.7 mya while species from Madagascar and the Comoro diverged from their continental sister-group about 3.6 mya. We highlight that our estimates coincide with estimates of diversification from other bird lineages. CONCLUSION: Our analyses revealed the occurrence of multiple synchronous colonization events of the Indian Ocean islands by scops-owls, at a time when faunistic exchanges involving Madagascar was common as a result of lowered sea-level that would have allowed the formation of stepping-stone islands. Patterns of diversification that emerged from the scops-owls data are: 1) a star-like pattern concerning the order of colonization of the Indian Ocean islands and 2) the high genetic distinctiveness among all Indian Ocean taxa, reinforcing their recognition as distinct species.

Social behavior following traumatic brain injury and its association with emotion recognition, understanding of intentions, and cognitive flexibility.

Although the adverse consequences of changes in social behavior following traumatic brain injury (TBI) are well documented, relatively little is known about possible underlying neuropsychological deficits. Following a model originally developed for social behavior deficits in schizophrenia, we investigated whether impairments in emotion recognition, understanding of other people's intentions ("theory of mind"), and cognitive flexibility soon after first TBI or 1 year later were associated with self and proxy ratings of behavior following TBI. Each of the three functions was assessed with two separate tests, and ratings of behavior were collected on three questionnaires. Patients with TBI (n = 33) were impaired in emotion recognition, "theory of mind," and cognitive flexibility compared with matched orthopedic controls (n = 34). Proxy ratings showed increases in behavioral problems 1 year following injury in the TBI group but not in the control group. However, test performance was not associated with questionnaire data. Severity of the impairments in emotion recognition, understanding intention, and flexibility were unrelated to the severity of behavioral problems following TBI. These findings failed to confirm the used model for social behavior deficits and may cast doubt on the alleged link between deficits in emotion recognition or theory of mind and social functioning.

Longitudinal aspects of emotion recognition in patients with traumatic brain injury.

Changes in emotional and social behaviour are relatively common following traumatic brain injury (TBI). Impairments in recognising the emotional state of others may underlie some of the problems in social relationships that these patients experience. The few previous studies examining emotion recognition in TBI typically assessed patients once, long after the onset of brain injury, making it difficult to distinguish the direct effect of brain injury from the effects of environmental changes. This study examined 30 patients with TBI shortly after brain injury and 32 orthopaedic control patients on their recognition of emotions expressed in the face and the voice using discrimination and labelling tasks. These patients were followed up 1 year later to examine the longitudinal development of emotion recognition deficits. TBI patients were found to be impaired on emotion recognition compared to the control patients both early after injury and 1 year later. The fact that impairments in emotion recognition were evident early after TBI and no evidence of recovery over time was found, suggests a direct effect of brain injury.