Not all effort is equal: the role of the anterior cingulate cortex in different forms of effort-reward decisions

Sherpa Romeo green journal; open accessThe rat anterior cingulate cortex (ACC) mediates effort-based decision making when the task requires the physical effort of climbing a ramp. Normal rats will readily climb a barrier leading to high reward whereas rats with ACC lesions will opt instead for an easily obtained small reward. The present study explored whether the role of ACC in cost-benefit decisions extends beyond climbing by testing its role in ramp climbing as well as two novel cost-benefit decision tasks, one involving the physical effort of lifting weights and the other the emotional cost of overcoming fear (i.e., "courage"). As expected, rats with extensive ACC lesions tested on a ramp-climbing task were less likely to choose a high-reward/high-effort arm than sham controls. However, during the first few trials, lesioned rats were as likely as controls to initially turn into the high-reward arm (HRA) but far less likely to actually climb the barrier, suggesting that the role of the ACC is not in deciding which course of action to pursue, but rather in maintaining a course of action in the face of countervailing forces. In the effort-reward decision task involving weight lifting, some lesion animals behaved like controls while others avoided the HRA. However, the results were not statistically significant and a follow-up study using incremental increasing effort failed to show any difference between lesion and control groups. The results suggest that the ACC is not needed for effort-reward decisions involving weight lifting but may affect motor abilities. Finally, a courage task explored the willingness of rats to overcome the fear of crossing an open, exposed arm to obtain a high reward. Both sham and ACC-lesioned animals exhibited equal tendencies to enter the open arm. However, whereas sham animals gradually improved on the task, ACC-lesioned rats did not. Taken together, the results suggest that the role of the ACC in effort-reward decisions may be limited to certain tasks.Ye

Plant dispersal by teal (Anas crecca) in the Camargue: duck guts are more important than their feet

12 páginas, 3 figuras, 4 tablas.1. Migratory waterbirds are major vectors for the dispersal of aquatic plants. However, quantitative field studies of the frequency of transport are scarce, and the relative importance of internal and external transport remains unclear. 2. We quantified and compared the rates of internal and external transport of aquatic plant propagules by teal (Anas crecca) in the Camargue (southern France), inspecting the lower gut contents of birds that had been shot (n = 366) and washing birds that had been live-trapped (n = 68) during the winters of 2006–2007 and 2007–2008. 3. Intact propagules (n = 902) of 21 plant taxa were recorded in the rectum of teal, of which 16 germinated or were shown to be viable. Intact propagules were recorded in the rectum of 20% of teal, with up to 171 propagules per individual bird. Chara oogonia were most abundant (60% of intact propagules), suggesting that small size favours internal transport. Eleocharis palustris, Juncus spp. and Potamogeton pusillus (17, 7 and 6% of intact propagules, respectively) were also very abundant. 4. Intact propagules (n = 12) of 10 plant taxa were found on the outside of live teal, and four of these taxa later germinated. Intact propagules were found on 18% of teal. No teal was found to carry more than one propagule externally. There was no difference in size between propagules transported internally and externally. 5. Teal are major dispersers of plants within the Camargue, despite being highly granivorous. Contrary to widespread assumptions in the literature, endozoochory by ducks appears to be a much more important mode of dispersal for aquatic plants than exozoochory. We found no evidence of changes in the probability of plant propagule dispersal at a landscape scale over the course of the winter, so propagule production and zoochory appear to be decoupled over time in aquatic systems.A.-L. Brochet is funded by a Doctoral grant from Office National de la Chasse et de la Faune Sauvage, with additional funding from a research agreement between ONCFS, the Tour du Valat, Laboratoire de Biométrie et de Biologie Evolutive (UMR 5558 CNRS Université Lyon 1) and the Doñana Biological Station (CSIC). This work also received funding from the Agence Nationale de la Recherche through the Santé Environnement – Santé Travail scheme (contract number 2006-SEST-22).Peer reviewe

Human skin penetration of a copper tripeptide in vitro as a function of skin layer

We study a set of 28 GRB light-curves detected between 15 December 2002 and 9 June 2003 by the anti-coincidence shield of the spectrometer (SPI) of INTEGRAL. During this period it has detected 50 bursts, that have been confirmed by other instruments, with a time resolution of 50 ms. First, we derive the basic characteristics of the bursts: various duration measures, the count peak flux and the count fluence. Second, a sub-sample of 11 bursts with 12 individual, well-separated pulses is studied. We fit the pulse shape with a model by Kocevski et al. (2003) and find that the pulses are quite self-similar in shape. There is also a weak tendency for the pulses with steep power-law decays to be more asymmetric. Third, the variability of the complex light-curves is studied by analyzing their power-density-spectra (PDS) and their RMS variability.
The averaged PDS, of the whole sample, is a power-law with index of $1.60\pm0.05$ and a break between 1–2 Hz. Fourth, we also discuss the background and noise levels. We found that the background noise has a Gaussian distribution and its power is independent of frequency, i.e., it is white noise. However, it does not follow a Poisson statistic since on average the variance is ~1.6 larger than the mean. We discuss our results in context of the current theoretical picture in which GRBs are created in an anisotropic, highly relativistic outflow from collapsing massive stars. Finally, we note that the exact behaviour of the instrument is not yet known and therefore the above results should be treated as preliminary.

Human skin penetration of a copper tripeptide in vitro as a function of skin layer

Objective and designSkin retention and penetration by copper applied as glycyl-L-histidyl-L-lysine cuprate diacetate was evaluated in vitro in order to assess its potential for its transdermal delivery as an anti-inflammatory agent.Materials and methodsFlow-through diffusion cells with 1 cm(2) exposure area were used under infinite dose conditions. 0.68% aq. copper tripeptide as permeant was applied on isolated stratum corneum, heat-separated epidermis and dermatomed skin and receptor fluid collected over 48 h in 4 h intervals using inductively coupled plasma mass spectrometry to analyze for copper in tissues and receptor fluid.ResultsThe permeability coefficient of the compound through dermatomed skin was 2.43 ± 0.51 × 10(-4) cm/h; 136.2 ± 17.5 μg/cm(2) copper permeated 1 cm(2) of that tissue over 48 h, while 97 ± 6.6 μg/cm(2) were retained as depot.ConclusionsCopper as tripeptide was delivered in potentially therapeutically effective amounts for inflammatory disease

JunB Inhibits ER Stress and Apoptosis in Pancreatic Beta Cells

Cytokines contribute to pancreatic β-cell apoptosis in type 1 diabetes (T1D) by modulation of β-cell gene expression networks. The transcription factor Activator Protein-1 (AP-1) is a key regulator of inflammation and apoptosis. We presently evaluated the function of the AP-1 subunit JunB in cytokine-mediated β-cell dysfunction and death. The cytokines IL-1β+IFN-γ induced an early and transitory upregulation of JunB by NF-κB activation. Knockdown of JunB by RNA interference increased cytokine-mediated expression of inducible nitric oxide synthase (iNOS) and endoplasmic reticulum (ER) stress markers, leading to increased apoptosis in an insulin-producing cell line (INS-1E) and in purified rat primary β-cells. JunB knockdown β-cells and junB−/− fibroblasts were also more sensitive to the chemical ER stressor cyclopiazonic acid (CPA). Conversely, adenoviral-mediated overexpression of JunB diminished iNOS and ER markers expression and protected β-cells from cytokine-induced cell death. These findings demonstrate a novel and unexpected role for JunB as a regulator of defense mechanisms against cytokine- and ER stress-mediated apoptosis

FDA Critical Path Initiatives: Opportunities for Generic Drug Development

FDA’s critical path initiative documents have focused on the challenges involved in the development of new drugs. Some of the focus areas identified apply equally to the production of generic drugs. However, there are scientific challenges unique to the development of generic drugs as well. In May 2007, FDA released a document “Critical Path Opportunities for Generic Drugs” that identified some of the specific challenges in the development of generic drugs. The key steps in generic product development are usually characterization of the reference product, design of a pharmaceutically equivalent and bioequivalent product, design of a consistent manufacturing process and conduct of the pivotal bioequivalence study. There are several areas of opportunity where scientific progress could accelerate the development and approval of generic products and expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. These areas include the use of quality by design to develop bioequivalent products, more efficient bioequivalence methods for systemically acting drugs (expansion of BCS waivers, highly variable drugs), and development of new bioequivalence methods for locally acting drugs

Circulating microRNAs as novel biomarkers for diabetes mellitus.

Diabetes mellitus is characterized by insulin secretion from pancreatic β cells that is insufficient to maintain blood glucose homeostasis. Autoimmune destruction of β cells results in type 1 diabetes mellitus, whereas conditions that reduce insulin sensitivity and negatively affect β-cell activities result in type 2 diabetes mellitus. Without proper management, patients with diabetes mellitus develop serious complications that reduce their quality of life and life expectancy. Biomarkers for early detection of the disease and identification of individuals at risk of developing complications would greatly improve the care of these patients. Small non-coding RNAs called microRNAs (miRNAs) control gene expression and participate in many physiopathological processes. Hundreds of miRNAs are actively or passively released in the circulation and can be used to evaluate health status and disease progression. Both type 1 diabetes mellitus and type 2 diabetes mellitus are associated with distinct modifications in the profile of miRNAs in the blood, which are sometimes detectable several years before the disease manifests. Moreover, circulating levels of certain miRNAs seem to be predictive of long-term complications. Technical and scientific obstacles still exist that need to be overcome, but circulating miRNAs might soon become part of the diagnostic arsenal to identify individuals at risk of developing diabetes mellitus and its devastating complications

From Dynamic Expression Patterns to Boundary Formation in the Presomitic Mesoderm

The segmentation of the vertebrate body is laid down during early embryogenesis. The formation of signaling gradients, the periodic expression of genes of the Notch-, Fgf- and Wnt-pathways and their interplay in the unsegmented presomitic mesoderm (PSM) precedes the rhythmic budding of nascent somites at its anterior end, which later develops into epithelialized structures, the somites. Although many in silico models describing partial aspects of somitogenesis already exist, simulations of a complete causal chain from gene expression in the growth zone via the interaction of multiple cells to segmentation are rare. Here, we present an enhanced gene regulatory network (GRN) for mice in a simulation program that models the growing PSM by many virtual cells and integrates WNT3A and FGF8 gradient formation, periodic gene expression and Delta/Notch signaling. Assuming Hes7 as core of the somitogenesis clock and LFNG as modulator, we postulate a negative feedback of HES7 on Dll1 leading to an oscillating Dll1 expression as seen in vivo. Furthermore, we are able to simulate the experimentally observed wave of activated NOTCH (NICD) as a result of the interactions in the GRN. We esteem our model as robust for a wide range of parameter values with the Hes7 mRNA and protein decays exerting a strong influence on the core oscillator. Moreover, our model predicts interference between Hes1 and HES7 oscillators when their intrinsic frequencies differ. In conclusion, we have built a comprehensive model of somitogenesis with HES7 as core oscillator that is able to reproduce many experimentally observed data in mice

In Vivo Methods for the Assessment of Topical Drug Bioavailability

This paper reviews some current methods for the in vivo assessment of local cutaneous bioavailability in humans after topical drug application. After an introduction discussing the importance of local drug bioavailability assessment and the limitations of model-based predictions, the focus turns to the relevance of experimental studies. The available techniques are then reviewed in detail, with particular emphasis on the tape stripping and microdialysis methodologies. Other less developed techniques, including the skin biopsy, suction blister, follicle removal and confocal Raman spectroscopy techniques are also described