Too much of a good thing

Culture of primary lymphocytes at physiological oxygen levels better maintains intracellular redox state.     

Too much of a good thing: mechanisms of gene action in Down syndrome

The molecular mechanisms underlying the specific traits in individuals with Down syndrome (DS) have been postulated to derive either from nonspecific perturbation of balanced genetic programs, or from the simple, mendelian-like influence of a small subset of genes on chromosome 21. However, these models do not provide a comprehensive explanation for experimental or clinical observations of the effects of trisomy 21. DS is best viewed as a complex genetic disorder, where the specific phenotypic manifestations in a given individual are products of genetic, environmental and stochastic influences. Mouse models that recapitulate both the genetic basis for and the phenotypic consequences of trisomy provide an experimental system to define these contributions.     

Too much of a good thing: resource provisioning alters infectious disease dynamics in wildlife

Provisioning of abundant food resources in human-altered landscapes can have profound effects on wildlife ecology, with important implications for pathogen transmission. While empirical studies have quantified the effects of provisioning on host behaviour and immunology, the net interactive effect of these components on host–pathogen dynamics is unknown. We use simple compartmental models to investigate how provisioning-induced changes to host demography, contact behaviour and immune defence influence pathogen invasion and persistence. We show that pathogen invasion success and equilibrium prevalence depend critically on how provisioning affects host immune defence and that moderate levels of provisioning can lead to drastically different outcomes of pathogen extinction or maximizing prevalence. These results highlight the need for further empirical studies to fully understand how provisioning affects pathogen transmission in urbanized environments.     

Too much of a good thing: the Prl-3 in p53's oyster

In this issue of Molecular Cell, Basak et al. (2008) identify Prl-3 as a p53-inducible gene acting in DNA damage-induced cell-cycle arrest. Both deletion and overexpression of Prl-3 can be cytostatic, adding to a growing list of genes whose expression must be carefully titrated for proper cell proliferation.     

Methamphetamine induces chronic corticostriatal depression: too much of a bad thing

Leading theories of drug addiction propose that repeated drug exposure produces a long-lasting homeostatic dysregulation in brain reward processing that is normalized by drug readministration. In this issue of Neuron, Bamford and colleagues describe a novel neurobiological substrate that may contribute to this effect.     

Too much of a good thing: the role of protein kinase CK2 in tumorigenesis and prospects for therapeutic inhibition of CK2

CK2 is a highly conserved protein serine/threonine kinase that is ubiquitously distributed in eukaryotes, constitutively active and has been implicated in multiple cellular functions, as well as in tumorigenesis and transformation. Elevated CK2 activity has been associated with the malignant transformation of several tissues and is associated with aggressive tumor behaviour. While the precise roles of CK2 in tumorigenesis remain incompletely understood, mounting evidence suggests a role for CK2 in the protection of cells from apoptosis via the regulation of tumor suppressor and oncogene activity. Consequently, CK2 has emerged as a potential therapeutic target, and strategies to inhibit CK2 have been ongoing in pre-clinical trials. This review will focus on published evidence highlighting the molecular mechanisms by which CK2 functions in the promotion of tumorigenesis, as well as review current strategies being used to inhibit CK2.     

Too much of a good thing: sea ice extent may have forced emperor penguins into refugia during the last glacial maximum

The relationship between population structure and demographic history is critical to understanding microevolution and for predicting the resilience of species to environmental change. Using mitochondrial DNA from extant colonies and radiocarbon‐dated subfossils, we present the first microevolutionary analysis of emperor penguins (Aptenodytes forsteri) and show their population trends throughout the last glacial maximum (LGM, 19.5–16 kya) and during the subsequent period of warming and sea ice retreat. We found evidence for three mitochondrial clades within emperor penguins, suggesting that they were isolated within three glacial refugia during the LGM. One of these clades has remained largely isolated within the Ross Sea, while the two other clades have intermixed around the coast of Antarctica from Adélie Land to the Weddell Sea. The differentiation of the Ross Sea population has been preserved despite rapid population growth and opportunities for migration. Low effective population sizes during the LGM, followed by a rapid expansion around the beginning of the Holocene, suggest that an optimum set of sea ice conditions exist for emperor penguins, corresponding to available foraging area.     

Antipodal effects of p25 on synaptic plasticity, learning, and memory--too much of a good thing is bad

Elevated activity of the Cdk5/p25 complex has been implicated in the pathogenesis of Alzheimer's disease. The report by Fischer and colleagues in this issue of Neuron describes a dichotomous role for the activator protein p25 in synaptic plasticity, learning, and memory, whereby transient expression in transgenic mice produces beneficial effects, but prolonged expression is detrimental. This work demonstrates the complexity of Cdk5/p25 in neuronal function and shows that dysregulation of a factor involved in plasticity can cause neurodegeneration.     

When habitat management can be a bad thing: effects of habitat quality,isolation and climate on a declining grassland butterfly

The conservation of most temperate grassland habitats and their characteristic fauna and flora requires regular low-intensive forms of land-use to counteract natural succession. Although many species tolerate moderate disturbance regimes, some are known to be susceptible to grazing or mowing, thereby causing a management dilemma. One of these species is the Woodland Ringlet butterfly, Erebia medusa. In this study, we analysed which environmental factors determine the occurrence of E. medusa in the Diemel Valley (Central Germany). Furthermore, we conducted microclimatic measurements during the winter months to investigate the role of the litter layer as a microclimatic buffer. Patch occupancy in the Diemel Valley was well explained by the amount of litter present in a patch and connectivity to other inhabited patches. The role of local climatic conditions could not be clarified, due to inter-correlations with connectivity. During the winter, the air temperature inside the litter layer was significantly less variable than above it. We conclude that the current distribution of E. medusa in the Diemel Valley is caused by the combined effect of habitat quality and connectivity, and perhaps also by climatic factors. The importance of the litter layer reflects the dependence of E. medusa on low-intensive or absent land-use. In addition, the litter layer possibly constitutes an essential habitat element, as it buffers temperature fluctuations and thus probably reduces the energy consumption of overwintering larvae. Given the species’ preference for abandoned grasslands, the conservation of E. medusa requires a low-intensity habitat management, for example, by rotational grazing or mowing of small parts of the sites. On the landscape level, the preservation of well-connected habitat networks is important.     

The ACR20 and defining a threshold for response in rheumatic diseases: too much of a good thing

In the past 20 years great progress has been made in the development of multidimensional outcome measures (such as the Disease Activity Score and ACR20) to evaluate treatments in rheumatoid arthritis, a process disseminated throughout rheumatic diseases. These outcome measures have standardized the assessment of outcomes in trials, making it possible to evaluate and compare the efficacy of treatments. The methodologic advances have included the selection of pre-existing outcome measures that detected change in a sensitive fashion (in rheumatoid arthritis, this was the Core Set Measures). These measures were then combined into a single multidimensional outcome measure and such outcome measures have been widely adopted in trials and endorsed by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) and regulatory agencies. The secular improvement in treatment for patients with rheumatoid arthritis has been facilitated in part by these major methodologic advancements. The one element of this effort that has not optimized measurement of outcomes nor made it easier to detect the effect of treatments is the dichotomization of continuous measures of response, creating responders and non-responder definitions (for example, ACR20 responders; EULAR good responders). Dichotomizing response sacrifices statistical power and eliminates variability in response. Future methodologic work will need to focus on improving multidimensional outcome measurement without arbitrarily characterizing some patients as responders while labeling others as non-responders.