PrPC regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells

The prion protein (PrP) plays a key role in prion disease pathogenesis. Although the misfolded and pathologic variant of this protein (PrP^SC) has been studied in depth, the physiological role of PrP^C remains elusive and controversial. PrP^C is a cell‐surface glycoprotein involved in multiple cellular functions at the plasma membrane, where it interacts with a myriad of partners and regulates several intracellular signal transduction cascades. However, little is known about the gene expression changes modulated by PrP^C in animals and in cellular models. In this article, we present PrP^C‐dependent gene expression signature in N2a cells and its implication in the most overrepresented functions: cell cycle, cell growth and proliferation, and maintenance of cell shape. PrP^C over‐expression enhances cell proliferation and cell cycle re‐entrance after serum stimulation, while PrP^C silencing slows down cell cycle progression. In addition, MAP kinase and protein kinase B (AKT) pathway activation are under the regulation of PrP^C in asynchronous cells and following mitogenic stimulation. These effects are due in part to the modulation of epidermal growth factor receptor (EGFR) by PrP^C in the plasma membrane, where the two proteins interact in a multimeric complex. We also describe how PrP^C over‐expression modulates filopodia formation by Rho GTPase regulation mainly in an AKT‐Cdc42‐N‐WASP‐dependent pathway.

     

Developmental and Regional Expression of NMDA Receptor Subtypes Containing the NR2D Subunit in Rat Brain

Abstract: The regional and developmental expression of NMDA receptors containing the NR2D subunit was analyzed on the level of the subunit mRNA and protein in rat brain. RNase protection experiments indicated that among two proposed splice variants of the NR2D subunit, only the NR2D-2 subunit is expressed. The regional distribution of the NR2D subunit protein was visualized with a newly developed NR2D-2 subunit-specific antiserum on brain sections using the histoblot technique. In adult brain, NR2D immunoreactivity was mainly restricted to diencephalic, mesencephalic, and brainstem structures. During postnatal development, the NR2D subunit was detected transiently in certain regions, such as the ventro-basal complex of the thalamus, hippocampus, inferior colliculus, and brainstem reticular formation, suggesting that NR2D subunit-containing receptors play a role in these brain areas only during development. The level of NR2D subunit mRNA and protein decreased during late postnatal development. However, significant levels of NR2D subunit mRNA and protein were present in adulthood, in particular, in the globus pallidus, thalamus, subthalamic nuclei, and superior colliculus. These results indicate a functional relevance for NMDA receptors containing the NR2D subunit in the developing and adult brain, although its expression in the adult brain is less prominent and restricted to a few brain areas.     

The Arf GAP CNT-2 regulates the apoptotic fate in C. elegans asymmetric neuroblast divisions

During development, all cells make the decision to live or die. Although the molecular mechanisms that execute the apoptotic program are well defined, less is known about how cells decide whether to live or die. In C.?elegans, this decision is linked to how cells divide asymmetrically [1, 2]. Several classes of molecules are known to regulate asymmetric cell divisions in metazoans, yet these molecules do not appear to control C.?elegans divisions that produce apoptotic cells [3]. We identified CNT-2, an Arf GTPase-activating protein (GAP) of the AGAP family, as a novel regulator of this type of neuroblast division. Loss of CNT-2 alters daughter cell size and causes the apoptotic cell to adopt the fate of its sister cell, resulting in extra neurons. CNT-2's Arf GAP activity is essential for its function in these divisions. The N terminus of CNT-2, which contains?a GTPase-like domain that defines the AGAP class of Arf GAPs, negatively regulates CNT-2's function. We provide evidence that CNT-2 regulates receptor-mediated endocytosis and consider the implications of its role in asymmetric cell divisions.     

The Genome-wide Patterns of Variation Expose Significant Substructure in a Founder Population

Although high-density SNP genotyping platforms generate a momentum for detailed genome-wide association (GWA) studies, an offshoot is a new insight into population genetics. Here, we present an example in one of the best-known founder populations by scrutinizing ten distinct Finnish early- and late-settlement subpopulations. By determining genetic distances, homozygosity, and patterns of linkage disequilibrium, we demonstrate that population substructure, and even individual ancestry, is detectable at a very high resolution and supports the concept of multiple historical bottlenecks resulting from consecutive founder effects. Given that genetic studies are currently aiming at identifying smaller and smaller genetic effects, recognizing and controlling for population substructure even at this fine level becomes imperative to avoid confounding and spurious associations. This study provides an example of the power of GWA data sets to demonstrate stratification caused by population history even within a seemingly homogeneous population, like the Finns. Further, the results provide interesting lessons concerning the impact of population history on the genome landscape of humans, as well as approaches to identify rare variants enriched in these subpopulations.     

Incorporating Field Studies into Species Distribution and Climate Change Modelling: A Case Study of the Koomal Trichosurus vulpecula hypoleucus (Phalangeridae)

Species distribution models (SDMs) are an effective way of predicting the potential distribution of species and their response to environmental change. Most SDMs apply presence data to a relatively generic set of predictive variables such as climate. However, this weakens the modelling process by overlooking the responses to more cryptic predictive variables. In this paper we demonstrate a means by which data gathered from an intensive animal trapping study can be used to enhance SDMs by combining field data with bioclimatic modelling techniques to determine the future potential distribution for the koomal (Trichosurus vulpecula hypoleucus). The koomal is a geographically isolated subspecies of the common brushtail possum, endemic to south-western Australia. Since European settlement this taxon has undergone a significant reduction in distribution due to its vulnerability to habitat fragmentation, introduced predators and tree/shrub dieback caused by a virulent group of plant pathogens of the genus Phytophthora. An intensive field study found: 1) the home range for the koomal rarely exceeded 1 km in in length at its widest point; 2) areas heavily infested with dieback were not occupied; 3) gap crossing between patches (>400 m) was common behaviour; 4) koomal presence was linked to the extent of suitable vegetation; and 5) where the needs of koomal were met, populations in fragments were demographically similar to those found in contiguous landscapes. We used this information to resolve a more accurate SDM for the koomal than that created from bioclimatic data alone. Specifically, we refined spatial coverages of remnant vegetation and dieback, to develop a set of variables that we combined with selected bioclimatic variables to construct models. We conclude that the utility value of an SDM can be enhanced and given greater resolution by identifying variables that reflect observed, species-specific responses to landscape parameters and incorporating these responses into the model.     

Age-related effect induced by oxidative stress on the cerebral glutathione system

In the forebrain from male Wistar rats aged 5, 15 and 25 months, age-related putative alterations in the glutathione system (reduced and oxidized glutathione; redox index) were chronically induced by the administration in drinking water of free radical generators (hydrogen peroxide, ferrous chloride) or of inhibitors of endogenous free radical defenses (diethyl-dithio-carbamate, an inhibitor of superoxide dismutase activity). In hydrogen peroxide administered rats, both reduced glutathione and the cerebral glutathione redox index markedly declined as a function of aging, whereas oxidized glutathione consistently increased. In contrast, chronic iron intake failed to modify the reduced glutathione in forebrain from the rats of the different ages tested, whereas the oxidized glutathione was increased in the older brains. The chronic intake of diethyl-dithio-carbamate enhanced the concentrations of reduced glutathione in the forebrains from the rats of the different ages tested, the oxidized glutathione being unchanged. In 15-month-old rats submitted to chronic oxidative stress, ergot alkaloids (and particularly dihydroergocriptine) interfered with cerebral glutathione system, while papaverine was always ineffective. The comprehensive analysis of the data indicates that: (a) both the type of oxidative stress and the age of the animals modulate the cerebral responsiveness to the putative modifiers in the level of tissue free radicals; (b) aging magnifies the cerebral alterations induced by oxidative stress; the (c) cerebral glutathione system may be modified by metabolic rather than by circulatory interferences; (d) a balance between the various cerebral antioxidant defenses is present, the perturbation of an antioxidant system resulting in the compensatory modified activity of component(s) of another system.     

Remote Monitoring of Inhaled Bronchodilator Use and Weekly Feedback about Asthma Management: An Open-Group,Short-Term Pilot Study of the Impact on Asthma Control

Objective

Adequate symptom control is a problem for many people with asthma. We asked whether weekly email reports on monitored use of inhaled, short-acting bronchodilators might improve scores on composite asthma-control measures.

Methods

Through an investigational electronic medication sensor attached to each participant''s inhaler, we monitored 4 months'' use of inhaled, short-acting bronchodilators. Participants completed surveys, including the Asthma Control Test^TM (ACT), to assess asthma control at entry and monthly thereafter. After the first month, participants received weekly email reports for 3 months. The reports summarized inhaled bronchodilator use during the preceding week and provided suggestions derived from National Asthma Education and Prevention Program (NAEPP) guidelines. Paired t-tests and random-effects mixed models were implemented to assess changes in primary asthma endpoints.

Results

Thirty individuals participated in the 4-month study; 29 provided complete asthma control information. Mean age was 36.8 years (range: 19–74 years); 52% of respondents were female. Mean ACT scores were 17.6 (Standard Deviation [SD]  = 3.35) at entry and 18.4 (SD = 3.60) at completion of the first month. No significant difference appeared between ACT values at entry and completion of the first month (p = 0.66); however, after participants began receiving email reports and online information about their inhaler use, mean ACT scores increased 1.40 points (95% CI: 0.61, 2.18) for each subsequent study month. Significant decreases occurred in 2-week histories of daytime symptoms (β = −1.35, 95% CI: −2.65, −0.04) and nighttime symptoms (β = −0.84, 95% CI: −1.25, −0.44); no significant change in activity limitation (β = −0.21, 95% CI: −0.69, 0.26) was observed. Participants reported increased awareness and understanding of asthma patterns, level of control, bronchodilator use (timing, location) and triggers, and improved preventive practices.

Conclusions

Weekly email reports and access to online charts summarizing remote monitoring of inhaled bronchodilator frequency and location were associated with improved asthma control and a decline in day-to-day asthma symptoms.     

Decision science for effective management of populations subject to stochasticity and imperfect knowledge

Many species are threatened by human activity through processes such as habitat modification, water management, hunting, and introduction of invasive species. These anthropogenic threats must be mitigated as efficiently as possible because both time and money available for mitigation are limited. For example, it is essential to address the type and degree of uncertainties present to derive effective management strategies for managed populations. Decision science provides the tools required to produce effective management strategies that can maximize or minimize the desired objective(s) based on imperfect knowledge, taking into account stochasticity. Of particular importance are questions such as how much of available budgets should be invested in reducing uncertainty and which uncertainties should be reduced. In such instances, decision science can help select efficient environmental management actions that may be subject to stochasticity and imperfect knowledge. Here, we review the use of decision science in environmental management to demonstrate the utility of the decision science framework. Our points are illustrated using examples from the literature. We conclude that collaboration between theoreticians and practitioners is crucial to maximize the benefits of decision science’s rational approach to dealing with uncertainty.