Facilitation of spatial working memory performance following intra-prefrontal cortical administration of the adrenergic alpha1 agonist phenylephrine.

RATIONALE: Spatial working memory is dependent on the appropriate functioning of the prefrontal cortex (PFC). PFC activity can be modulated by noradrenaline (NA) released by afferent projections from the locus coeruleus. The coreuleo-cortical NA system could therefore be a target for cognitive enhancers of spatial working memory. Of the three classes of NA receptor potentially involved, the α2 and α1 classes seem most significant, though agents targeting these receptors have yielded mixed results. This may be partially due to the use of behavioural assays that do not translate effectively from the laboratory to the clinical setting. Use of a paradigm with improved translational potential may be essential to resolve these discrepancies. OBJECTIVES: The objective of this study was to assess the effects of PFC-infused α2 and α1 adrenergic receptor agonists on spatial working memory performance in the touchscreen continuous trial-unique non-matching to location (cTUNL) task in rats. METHODS: Young male rats were trained in the cTUNL paradigm. Cannulation of the mPFC allowed direct administration of GABA agonists for task validation, and phenylephrine and guanfacine to determine the effects of adrenergic agonists on task performance. RESULTS: Infusion of muscimol and baclofen resulted in a delay-dependent impairment. Administration of the α2 agonist guanfacine had no effect, whilst infusion of the α1 agonist phenylephrine significantly improved working memory performance. CONCLUSIONS: Spatial working memory as measured in the rat cTUNL task is dependent on the mPFC. Enhancement of noradrenergic signalling enhanced performance in this paradigm, suggesting a significant role for the α1 receptor in this facilitation.This work was supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA inkind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). CJH was funded by Wellcome Trust grant 089703/Z/09/Z.This is the final version of the article. It first appeared from Springer via http://link.springer.com/article/10.1007/s00213-015-4038-

NAIL COSMETICS

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66131/1/j.1365-4362.1992.tb01368.x.pd

Predicting Phenotypic Diversity and the Underlying Quantitative Molecular Transitions

During development, signaling networks control the formation of multicellular patterns. To what extent quantitative fluctuations in these complex networks may affect multicellular phenotype remains unclear. Here, we describe a computational approach to predict and analyze the phenotypic diversity that is accessible to a developmental signaling network. Applying this framework to vulval development in C. elegans, we demonstrate that quantitative changes in the regulatory network can render ~500 multicellular phenotypes. This phenotypic capacity is an order-of-magnitude below the theoretical upper limit for this system but yet is large enough to demonstrate that the system is not restricted to a select few outcomes. Using metrics to gauge the robustness of these phenotypes to parameter perturbations, we identify a select subset of novel phenotypes that are the most promising for experimental validation. In addition, our model calculations provide a layout of these phenotypes in network parameter space. Analyzing this landscape of multicellular phenotypes yielded two significant insights. First, we show that experimentally well-established mutant phenotypes may be rendered using non-canonical network perturbations. Second, we show that the predicted multicellular patterns include not only those observed in C. elegans, but also those occurring exclusively in other species of the Caenorhabditis genus. This result demonstrates that quantitative diversification of a common regulatory network is indeed demonstrably sufficient to generate the phenotypic differences observed across three major species within the Caenorhabditis genus. Using our computational framework, we systematically identify the quantitative changes that may have occurred in the regulatory network during the evolution of these species. Our model predictions show that significant phenotypic diversity may be sampled through quantitative variations in the regulatory network without overhauling the core network architecture. Furthermore, by comparing the predicted landscape of phenotypes to multicellular patterns that have been experimentally observed across multiple species, we systematically trace the quantitative regulatory changes that may have occurred during the evolution of the Caenorhabditis genus

A Phase I Dose Escalation Trial of Gemcitabine with Radiotherapy for Breast Cancer in the Treatment of Unresectable Chest Wall Recurrences

The purpose of this study was to determine the maximum tolerated dose (MTD) of gemcitabine when given concurrently with standard radiotherapy for the treatment of chest wall recurrences, and to compare actuarial rates of local-regional control with those achieved in historical controls. Patients with unresectable chest wall recurrences were enrolled in a phase I trial of concurrent gemcitabine and radiotherapy. Gemcitabine was increased at 150 mg/m 2 /week increments, starting at 300 mg/m 2 /week. Radiotherapy was delivered to the chest wall and regional nodes to a total of 60 to 70 Gy in 2 Gy daily fractions. Treatment toxicity was assessed and a comparison of treatment outcome was performed between study patients and historical groups treated with either radiotherapy alone or excision followed by radiotherapy. The dose-limiting toxicities of neutropenia and thrombocytopenia occurred at the second planned dose of 450 mg/m 2 /week after accrual of only six patients, resulting in a MTD of 300 mg/m 2 /week. Myelosuppression and skin desquamation were commonly observed. Actuarial rates of local-regional control were 100%, 50%, and 90% at 2 years for the gemcitabine with radiotherapy, radiotherapy alone, and excision followed by radiotherapy groups, respectively ( p  = 0.105). The difference among the Kaplan–Meier curves for overall local-regional control was statistically significant at p  = 0.007 in favor of combined gemcitabine and radiotherapy. The MTD of gemcitabine is 300 mg/m 2 /week when gemcitabine is delivered concurrently with radiotherapy for unresectable chest wall failures. This novel approach suggests excellent local-regional control when compared to historical controls. A phase II trial is warranted. Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75565/1/j.1075-122X.2004.21305.x.pd

Probability that a chromosome is lost without trace under the neutral Wright-Fisher model with recombination

I describe an analytical approximation for calculating the short-term probability of loss of a chromosome under the neutral Wright-Fisher model with recombination. I also present an upper and lower bound for this probability. Exact analytical calculation of this quantity is difficult and computationally expensive because the number of different ways in which a chromosome can be lost, grows very large in the presence of recombination. Simulations indicate that the probabilities obtained using my approximate formula are always comparable to the true expectations provided that the number of generations remains small. These results are useful in the context of an algorithm that we recently developed for simulating Wright-Fisher populations forward in time. C++ programs that can efficiently calculate these formulas are available on request.Comment: Additional Information, Padhukasahasram et al. 2008, Genetics, FORWSIM algorith

Consistency of Published Results on the Pathogen Batrachochytrium dendrobatidis in Madagascar: Formal Comment on Kolby et al. Rapid Response to Evaluate the Presence of Amphibian Chytrid Fungus (Batrachochytrium dendrobatidis) and Ranavirus in Wild Amphibian Populations in Madagascar

判型：B5，平成4年１１月30日[目次]バブル消えて思うこと新任教官紹介及び挨拶一番古い新しい大学維管束植物の遺伝子発現機構の解析のための基礎的研究留学感想トピックス学生サークル紹介学生部だより保健管理センターだより卒業生だよりへルン文

Recognizing detachment-mode seafloor spreading in the deep geological past.

Large-offset oceanic detachment faults are a characteristic of slow- and ultraslow-spreading ridges, leading to the formation of oceanic core complexes (OCCs) that expose upper mantle and lower crustal rocks on the seafloor. The lithospheric extension accommodated by these structures is now recognized as a fundamentally distinct “detachment-mode” of seafloor spreading compared to classical magmatic accretion. Here we demonstrate a paleomagnetic methodology that allows unequivocal recognition of detachment-mode seafloor spreading in ancient ophiolites and apply this to a potential Jurassic detachment fault system in the Mirdita ophiolite (Albania). We show that footwall and hanging wall blocks either side of an inferred detachment have significantly different magnetizations that can only be explained by relative rotation during seafloor spreading. The style of rotation is shown to be identical to rolling hinge footwall rotation documented recently in OCCs in the Atlantic, confirming that detachment-mode spreading operated at least as far back as the Jurassic