PRAK is essential for ras-induced senescence and tumor suppression

Like apoptosis, oncogene-induced senescence is a barrier to tumor development. However, relatively little is known about the signaling pathways mediating the senescence response. p38-regulated/activated protein kinase (PRAK) is a p38 MAPK substrate whose physiological functions are poorly understood. Here we describe a role for PRAK in tumor suppression by demonstrating that PRAK mediates senescence upon activation by p38 in response to oncogenic ras. PRAK deficiency in mice enhances DMBA-induced skin carcinogenesis, coinciding with compromised senescence induction. In primary cells, inactivation of PRAK prevents senescence and promotes oncogenic transformation. Furthermore, we show that PRAK activates p53 by direct phosphorylation. We propose that phosphorylation of p53 by PRAK following activation of p38 MAPK by ras plays an important role in ras-induced senescence and tumor suppression.     

Ensemble forecasting of species distributions

Concern over implications of climate change for biodiversity has led to the use of bioclimatic models to forecast the range shifts of species under future climate-change scenarios. Recent studies have demonstrated that projections by alternative models can be so variable as to compromise their usefulness for guiding policy decisions. Here, we advocate the use of multiple models within an ensemble forecasting framework and describe alternative approaches to the analysis of bioclimatic ensembles, including bounding box, consensus and probabilistic techniques. We argue that, although improved accuracy can be delivered through the traditional tasks of trying to build better models with improved data, more robust forecasts can also be achieved if ensemble forecasts are produced and analysed appropriately.     

Spatial adaptations for plant foraging: women excel and calories count

We present evidence for an evolved sexually dimorphic adaptation that activates spatial memory and navigation skills in response to fruits, vegetables and other traditionally gatherable sessile food resources. In spite of extensive evidence for a male advantage on a wide variety of navigational tasks, we demonstrate that a simple but ecologically important shift in content can reverse this sex difference. This effect is predicted by and consistent with the theory that a sexual division in ancestral foraging labour selected for gathering-specific spatial mechanisms, some of which are sexually differentiated. The hypothesis that gathering-specific spatial adaptations exist in the human mind is further supported by our finding that spatial memory is preferentially engaged for resources with higher nutritional quality (e.g. caloric density). This result strongly suggests that the underlying mechanisms evolved in part as adaptations for efficient foraging. Together, these results demonstrate that human spatial cognition is content sensitive, domain specific and designed by natural selection to mesh with important regularities of the ancestral world.     

Anthropogenic disturbance in a changing environment: modelling lifetime reproductive success to predict the consequences of multiple stressors on a migratory population

Animals make behavioural and reproductive decisions that maximise their lifetime reproductive success, and thus their fitness, in light of periodic and stochastic variability of the environment. Modelling the variation of an individual's energy levels formalises this tradeoff and helps to quantify the population‐level consequences of stressors (e.g. disturbance from human activities and environmental change) that can affect behaviour or physiology. In this study, we develop a dynamic state variable model for the spatially explicit behaviour, physiology and reproduction of a female, long‐lived, migratory marine vertebrate. The model can be used to investigate the spatio‐temporal patterns of behaviour and reproduction that allow an individual to maximise its overall reproductive output. We parametrised the model for eastern North Pacific blue whales Balaenoptera musculus, and used it to predict the effects of changing environmental conditions and increasing human disturbance on the population's vital rates. In baseline conditions, the model output had high fidelity to observed energy dynamics, movement patterns and reproductive strategies. Simulated scenarios suggested that environmental changes could have severe consequences on the population's vital rates, but that individuals could tolerate high levels of anthropogenic disturbance. However, this ability depended on where, when and how often disturbance occurred. In scenarios with both environmental change and anthropogenic disturbance, synergistic interactions caused stronger effects than in isolation. In general, larger body size offered a buffer against stochasticity and disturbance, and, consequently, we predicted juveniles to be more susceptible to disturbance. We also predicted that females prioritise their own survival at the expense of the current reproductive attempt, presumably the result of their long lifespan. Our approach provides a general framework to make predictions of the cumulative and synergistic effects of human disturbance and climate change on migratory populations, which can inform effective management and conservation efforts.     

Synchronous fire activity in the tropical high Andes: an indication of regional climate forcing

Global climate models suggest enhanced warming of the tropical mid and upper troposphere, with larger temperature rise rates at higher elevations. Changes in fire activity are amongst the most significant ecological consequences of rising temperatures and changing hydrological properties in mountainous ecosystems, and there is a global evidence of increased fire activity with elevation. Whilst fire research has become popular in the tropical lowlands, much less is known of the tropical high Andean region (>2000masl, from Colombia to Bolivia). This study examines fire trends in the high Andes for three ecosystems, the Puna, the Paramo and the Yungas, for the period 1982–2006. We pose three questions: (i) is there an increased fire response with elevation? (ii) does the El Niño‐ Southern Oscillation control fire activity in this region? (iii) are the observed fire trends human driven (e.g., human practices and their effects on fuel build‐up) or climate driven? We did not find evidence of increased fire activity with elevation but, instead, a quasicyclic and synchronous fire response in Ecuador, Peru and Bolivia, suggesting the influence of high‐frequency climate forcing on fire responses on a subcontinental scale, in the high Andes. ENSO variability did not show a significant relation to fire activity for these three countries, partly because ENSO variability did not significantly relate to precipitation extremes, although it strongly did to temperature extremes. Whilst ENSO did not individually lead the observed regional fire trends, our results suggest a climate influence on fire activity, mainly through a sawtooth pattern of precipitation (increased rainfall before fire‐peak seasons (t‐1) followed by drought spells and unusual low temperatures (t0), which is particularly common where fire is carried by low fuel loads (e.g., grasslands and fine fuel). This climatic sawtooth appeared as the main driver of fire trends, above local human influences and fuel build‐up cyclicity.     

Child Mortality Estimation 2013: An Overview of Updates in Estimation Methods by the United Nations Inter-Agency Group for Child Mortality Estimation

Background

In September 2013, the United Nations Inter-agency Group for Child Mortality Estimation (UN IGME) published an update of the estimates of the under-five mortality rate (U5MR) and under-five deaths for all countries. Compared to the UN IGME estimates published in 2012, updated data inputs and a new method for estimating the U5MR were used.

Methods

We summarize the new U5MR estimation method, which is a Bayesian B-spline Bias-reduction model, and highlight differences with the previously used method. Differences in UN IGME U5MR estimates as published in 2012 and those published in 2013 are presented and decomposed into differences due to the updated database and differences due to the new estimation method to explain and motivate changes in estimates.

Findings

Compared to the previously used method, the new UN IGME estimation method is based on a different trend fitting method that can track (recent) changes in U5MR more closely. The new method provides U5MR estimates that account for data quality issues. Resulting differences in U5MR point estimates between the UN IGME 2012 and 2013 publications are small for the majority of countries but greater than 10 deaths per 1,000 live births for 33 countries in 2011 and 19 countries in 1990. These differences can be explained by the updated database used, the curve fitting method as well as accounting for data quality issues. Changes in the number of deaths were less than 10% on the global level and for the majority of MDG regions.

Conclusions

The 2013 UN IGME estimates provide the most recent assessment of levels and trends in U5MR based on all available data and an improved estimation method that allows for closer-to-real-time monitoring of changes in the U5MR and takes account of data quality issues.     

Msh2 Acts in Medium-Spiny Striatal Neurons as an Enhancer of CAG Instability and Mutant Huntingtin Phenotypes in Huntington's Disease Knock-In Mice

The CAG trinucleotide repeat mutation in the Huntington's disease gene (HTT) exhibits age-dependent tissue-specific expansion that correlates with disease onset in patients, implicating somatic expansion as a disease modifier and potential therapeutic target. Somatic HTT CAG expansion is critically dependent on proteins in the mismatch repair (MMR) pathway. To gain further insight into mechanisms of somatic expansion and the relationship of somatic expansion to the disease process in selectively vulnerable MSNs we have crossed HTT CAG knock-in mice (HdhQ111) with mice carrying a conditional (floxed) Msh2 allele and D9-Cre transgenic mice, in which Cre recombinase is expressed specifically in MSNs within the striatum. Deletion of Msh2 in MSNs eliminated Msh2 protein in those neurons. We demonstrate that MSN-specific deletion of Msh2 was sufficient to eliminate the vast majority of striatal HTT CAG expansions in HdhQ111 mice. Furthermore, MSN-specific deletion of Msh2 modified two mutant huntingtin phenotypes: the early nuclear localization of diffusely immunostaining mutant huntingtin was slowed; and the later development of intranuclear huntingtin inclusions was dramatically inhibited. Therefore, Msh2 acts within MSNs as a genetic enhancer both of somatic HTT CAG expansions and of HTT CAG-dependent phenotypes in mice. These data suggest that the selective vulnerability of MSNs may be at least in part contributed by the propensity for somatic expansion in these neurons, and imply that intervening in the expansion process is likely to have therapeutic benefit.     

Chronic alcohol exposure alters behavioral and synaptic plasticity of the rodent prefrontal cortex

In the present study, we used a mouse model of chronic intermittent ethanol (CIE) exposure to examine how CIE alters the plasticity of the medial prefrontal cortex (mPFC). In acute slices obtained either immediately or 1-week after the last episode of alcohol exposure, voltage-clamp recording of excitatory post-synaptic currents (EPSCs) in mPFC layer V pyramidal neurons revealed that CIE exposure resulted in an increase in the NMDA/AMPA current ratio. This increase appeared to result from a selective increase in the NMDA component of the EPSC. Consistent with this, Western blot analysis of the postsynaptic density fraction showed that while there was no change in expression of the AMPA GluR1 subunit, NMDA NR1 and NRB subunits were significantly increased in CIE exposed mice when examined immediately after the last episode of alcohol exposure. Unexpectedly, this increase in NR1 and NR2B was no longer observed after 1-week of withdrawal in spite of a persistent increase in synaptic NMDA currents. Analysis of spines on the basal dendrites of layer V neurons revealed that while the total density of spines was not altered, there was a selective increase in the density of mushroom-type spines following CIE exposure. Examination of NMDA-receptor mediated spike-timing-dependent plasticity (STDP) showed that CIE exposure was associated with altered expression of long-term potentiation (LTP). Lastly, behavioral studies using an attentional set-shifting task that depends upon the mPFC for optimal performance revealed deficits in cognitive flexibility in CIE exposed mice when tested up to 1-week after the last episode of alcohol exposure. Taken together, these observations are consistent with those in human alcoholics showing protracted deficits in executive function, and suggest these deficits may be associated with alterations in synaptic plasticity in the mPFC.     

Efficient, chemoselective synthesis of immunomicelles using single-domain antibodies with a C-terminal thioester

Background  

Classical bioconjugation strategies for generating antibody-functionalized nanoparticles are non-specific and typically result in heterogeneous compounds that can be compromised in activity. Expression systems based on self-cleavable intein domains allow the generation of recombinant proteins with a C-terminal thioester, providing a unique handle for site-specific conjugation using native chemical ligation (NCL). However, current methods to generate antibody fragments with C-terminal thioesters require cumbersome refolding procedures, effectively preventing application of NCL for antibody-mediated targeting and molecular imaging.     

Estimating the frequency of Asian cytochrome B haplotypes in standard European and local Spanish pig breeds

Mitochondrial DNA has been widely used to perform phylogenetic studies in different animal species. In pigs, genetic variability at the cytochrome B gene and the D-loop region has been used as a tool to dissect the genetic relationships between different breeds and populations. In this work, we analysed four SNP at the cytochrome B gene to infer the Asian (A1 and A2 haplotypes) or European (E1 and E2 haplotypes) origins of several European standard and local pig breeds. We found a mixture of Asian and European haplotypes in the Canarian Black pig (E1, A1 and A2), German Piétrain (E1, A1 and A2), Belgian Piétrain (E1, A1), Large White (E1 and A1) and Landrace (E1 and A1) breeds. In contrast, the Iberian (Guadyerbas, Ervideira, Caldeira, Campanario, Puebla and Torbiscal strains) and the Majorcan Black pig breeds only displayed the E1 haplotype. Our results show that the introgression of Chinese pig breeds affected most of the major European standard breeds, which harbour Asian haplotypes at diverse frequencies (15–56%). In contrast, isolated local Spanish breeds, such as the Iberian and Majorcan Black pig, only display European cytochrome B haplotypes, a feature that evidences that they were not crossed with other Chinese or European commercial populations. These findings illustrate how geographical confinement spared several local Spanish breeds from the extensive introgression event that took place during the 18th and 19th centuries in Europe.