Identification of a minimal promoter sequence for the human N-acetyltransferase Type I gene that binds AP-1 (activator protein 1) and YY-1 (Yin and Yang 1)

Human N-acetyltransferase Type I (NAT1) catalyses the acetylation of many aromatic amine and hydrazine compounds and it has been implicated in the catabolism of folic acid. The enzyme is widely expressed in the body, although there are considerable differences in the level of activity between tissues. A search of the mRNA databases revealed the presence of several NAT1 transcripts in human tissue that appear to be derived from different promoters. Because little is known about NAT1 gene regulation, the present study was undertaken to characterize one of the putative promoter sequences of the NAT1 gene located just upstream of the coding region. We show with reverse-transcriptase PCR that mRNA transcribed from this promoter (Promoter 1) is present in a variety of human cell-lines, but not in quiescent peripheral blood mononuclear cells. Using deletion mutant constructs, we identified a 20 bp sequence located 245 bases upstream of the translation start site which was sufficient for basal NAT1 expression. It comprised an AP-1 (activator protein 1)-binding site, flanked on either side by a TCATT motif. Mutational analysis showed that the AP-1 site and the 3' TCATT sequence were necessary for gene expression, whereas the 5' TCATT appeared to attenuate promoter activity. Electromobility shift assays revealed two specific bands made up by complexes of c-Fos/Fra, c-Jun, YY-1 (Yin and Yang 1) and possibly Oct-1. PMA treatment enhanced expression from the NAT1 promoter via the AP-1-binding site. Furthermore, in peripheral blood mononuclear cells, PMA increased endogenous NAT1 activity and induced mRNA expression from Promoter I, suggesting that it is functional in vivo.

A model of seller holdout

We model a buyer who wishes to combine objects owned by two separate sellers in order to realize higher value. Sellers are able to avoid entering into negotiations with the buyer, so that the order in which they negotiate is endogenous. Holdout occurs if at least one of the sellers is not present in the first round of negotiations. We demonstrate that complementarity of the buyer's technology is a necessary condition for equilibrium holdout. Moreover, a rise in complementarity leads to an increased likelihood of holdout, and an increased efficiency loss. Applications include patents, the land assembly problem, and mergers.

Naloxone fails to antagonize initial hypoalgesic effect of a manual therapy treatment for lateral epicondylalgia

Background: Recent research has shown that Mulligan's Mobilization With Movement treatment technique for the elbow (MWM), a peripheral joint mobilization technique, produces a substantial and immediate pain relief in chronic lateral epicondylalgia (48% increase in pain-free grip strength).(1) This hypoalgesic effect is far greater than that previously reported with spinal manual therapy treatments, prompting speculation that peripheral manual therapy treatments may differ in mechanism of action to spinal manual therapy techniques. Naloxone antagonism and tolerance studies, which employ widely accepted tests for the identification of endogenous opioid-mediated pain control mechanisms, have shown that spinal manual therapy-induced hypoalgesia does not involve an opioid mechanism. Objective: The aim of this study was to evaluate the effect of naloxone administration on the hypoalgesic effect of MWM. Methods: A randomized, controlled trial evaluated the effect of administering naloxone, saline, or no-substance control injection on the MWM-induced hypoalgesia in 18 participants with lateral epicondylalgia. Pain-free grip strength, pressure pain threshold, thermal pain threshold, and upper limb neural tissue provocation test 2b were the outcome measures. Results: The results demonstrated that the initial hypoalgesic effect of the MWM was not antagonized by naloxone, suggesting a nonopioid mechanism of action. Conclusions: The studied peripheral mobilization treatment technique appears to have a similar effect profile to previously studied spinal manual therapy techniques, suggesting a nonopioid-mediated hypoalgesia following manual therapy.

Real exchange rate and elasticity of labour supply in a balance-of-payments-constrained macrodynamics

A macrodynamic model is proposed in which the real exchange rate and the elasticity of labour supply interact defining different trajectories of growth and income distribution in a developing economy. Growth depends on imports of capital goods which are paid with exports (there are no capital flows) and hence is constrained by equilibrium in current account. The role of the elasticity of labour supply is to prevent the real exchange rate from appreciating as the economy grows, thereby sustaining international competitiveness. The model allows for endogenous technological change and considers the impact of migration from the subsistence to the modern sector on the cumulative (Kaldor-Verdoorn) process of learning.

Forward-looking versus recursive-dynamic modeling in climate policy analysis: A comparison

This paper develops a multi-regional general equilibrium model for climate policy analysis based on the latest version of the MIT Emissions Prediction and Policy Analysis (EPPA) model. We develop two versions so that we can solve the model either as a fully inter-temporal optimization problem (forward-looking, perfect foresight) or recursively. The standard EPPA model on which these models are based is solved recursively, and it is necessary to simplify some aspects of it to make inter-temporal solution possible. The forward-looking capability allows one to better address economic and policy issues such as borrowing and banking of GHG allowances, efficiency implications of environmental tax recycling, endogenous depletion of fossil resources, international capital flows, and optimal emissions abatement paths among others. To evaluate the solution approaches, we benchmark each version to the same macroeconomic path, and then compare the behavior of the two versions under a climate policy that restricts greenhouse gas emissions. We find that the energy sector and CO(2) price behavior are similar in both versions (in the recursive version of the model we force the inter-temporal theoretical efficiency result that abatement through time should be allocated such that the CO(2) price rises at the interest rate.) The main difference that arises is that the macroeconomic costs are substantially lower in the forward-looking version of the model, since it allows consumption shifting as an additional avenue of adjustment to the policy. On the other hand, the simplifications required for solving the model as an optimization problem, such as dropping the full vintaging of the capital stock and fewer explicit technological options, likely have effects on the results. Moreover, inter-temporal optimization with perfect foresight poorly represents the real economy where agents face high levels of uncertainty that likely lead to higher costs than if they knew the future with certainty. We conclude that while the forward-looking model has value for some problems, the recursive model produces similar behavior in the energy sector and provides greater flexibility in the details of the system that can be represented. (C) 2009 Elsevier B.V. All rights reserved.

Microdistribution of juveniles and adults of the mud crab Panopeus americanus (Brachyura, Panopeidae) in a remnant mangrove area in the southwest Atlantic

The distribution and density of a population of the narrowback mud crab Panopeus americanus were evaluated, with emphasis on the different developmental stages (juveniles and adults) and sexes. Specimens were collected in a remnant human-impacted mangrove at Araca on the northern coast of Sao Paulo, Brazil, at two-month intervals from January through July 2006, using 1m x 1m sample plots randomly distributed in the intertidal zone. The population was abundant, with a mean density of 14.3 +/- 9.3 individuals/m(2). Larger individuals were more abundant in the upper and middle intertidal zones, whereas smaller crabs were predominant in the lower intertidal and thus remained submerged longer. Males and juveniles were homogeneously distributed. Females preferred regions farther from the waterline. A clustered distribution pattern suggested gregarious behaviour and settling of juveniles in the vicinity of the adults` habitats, in an adaptive process as a function of tidal rhythms.

Nestmate recognition in the stingless bee Frieseomelitta varia (Hymenoptera, Apidae, Meliponini): sources of chemical signals

Social insects use cuticular lipids for nestmate recognition. These lipids are chiefly hydrocarbons that can be endogenously produced or acquired from the environment. Although these compounds are already described as coming from different sources for different groups of social insects, nothing is known about the source of cuticular hydrocarbons in stingless bees. We used behavioural recognition tests and cuticle chemical investigation to elucidate the role of endogenous and environmentally based cues for nestmate recognition in the stingless bee Frieseomelitta varia. We found that although newly emerged workers present specific cuticle patterns according to their nest origin, these compounds are not used for nestmate recognition, since newly emerged workers are broadly accepted in different colonies. The cerumen used in nest construction played an important role in recognition behaviour. Twenty minutes of contact with foreign cerumen was sufficient to increase the rejection rates of nestmates and separate the groups of workers according to their chemical profile. On the other hand, tests of feeding on a common diet showed no effect on chemical cuticle pattern or recognition behaviour. (C) 2010 The Association for the Study of Animal Behaviour. Published by Elsevier Ltd. All rights reserved.

Maternal investment in egg production: environmental and population-specific effects on offspring performance in the snapping shrimp Alpheus nuttingi (Schmitt, 1924) (Decapoda, Alpheidae)

Among marine invertebrates, the overall biomass invested in egg production varies widely within populations, which can result from the interaction of endogenous and exogenous factors. Species that have constant reproduction throughout the year can be good models to study the influence of environmental factors on reproductive processes. We conducted a seasonal comparison of egg production in the intertidal snapping shrimp Alpheus nuttingi, which shows a continuous reproductive pattern, to examine the hypothesis that differences in egg production are driven by environmental conditions and population features. This population showed an uncommon strategy, characterized by females that produce eggs of varying sizes within their clutches, with reduced egg volume when the number of eggs is higher (Spring-Summer). In these seasons, higher temperatures and greater food availability may allow the production of more eggs compared to the Autumn-Winter seasons. Compared to other alpheid shrimps, this population produces small eggs, but in larger numbers. Despite the higher fecundity, the reproductive output is relatively low, this production being supported by the large size of females from the southern Atlantic region. Our findings showed that the egg production of A. nuttingi was greatly influenced by environmental factors. Therefore, this shrimp, and probably other decapods that possess continuous reproduction, adopt different reproductive strategies during the year. (C) Koninklijke Brill NV, Leiden, 2010.

Geographical variation in offspring size effects across generations

Offspring size is thought to strongly affect offspring fitness and many studies have shown strong offspring size/fitness relationships in marine and terrestrial organisms. This relationship is strongly mitigated by local environmental conditions and the optimal offspring size that mothers should produce will vary among different environments. It is assumed that offspring size will consistently affect the same traits among populations but this assumption has not been tested. Here I use a common garden experiment to examine the effects of offspring size on subsequent performance for the marine bryozoan Bugula neritina using larvae from two very different populations. The local conditions at one population (Williamstown) favour early reproduction whereas the other population (Pt. Wilson) favours early growth. Despite being placed in the same habitat, the effects of parental larval size were extremely variable and crossed generations. For larvae from Williamstown, parental larval size positively affected initial colony growth and larval size in the next generation. For larvae from the other population, parental larval size positively affected colony fecundity and negatively affected larval size in the next generation. Traditionally, exogenous factors have been viewed as the sole source of variation in offspring size/fitness relationship but these results show that endogenous factors (maternal source population) can also cause variation in this crucial relationship. It appears offspring size effects can be highly variable among populations and organisms can adapt to local conditions without changing the size of their offspring.

Central substance P NK(1) receptors are involved in fever induced by LPS but not by IL-1 beta and CCL3/MIP-1 alpha in rats

Substance P (SP) is a neuropeptide that can modulate inflammatory mediator release through activation of NK(1) receptors (NK(1)R). Some studies have also suggested the involvement of SP in lipopolysaccharide (LPS)-induced fever. However, the precise contribution of this neuropeptide to the pathways activated during fever is unknown. In this study we investigated the effect of a selective NK(1)R antagonist, SR140333B, on the febrile response induced by LPS and cytokines. Our results show that the systemic injection of SR140333B did not modify the fever induced by LPS at a dose that is able to reduce protein extravasation induced by SP in the skin. On the other hand, intracerebroventricular administration of 5R140333B significantly reduced the fever induced by peripheral injection of LPS. These data emphasize an important role for SP in the central nervous system during the febrile response to LPS, and are reinforced by the fact that intracerebroventricular injection of SP also induced fever in a dose-dependent manner in captopril-treated rats. Considering that the febrile response can result from the generation of several endogenous pyrogens, among them interleukin (IL)-1 beta and macrophage inflammatory protein-1 alpha (CCL3/MIP-1 alpha), we also examined the effect of SR140333B on the fever induced by these cytokines which act through prostaglandin-dependent and independent mechanisms, respectively. Surprisingly, SR140333B did not modify the febrile response to IL-1 beta or CCL3/MIP-1 alpha. Altogether these data suggest that the central action of SP is essential for LPS-, but not for IL-1 beta- or CCL3/MIP-1 alpha-induced fever. (C) 2011 Elsevier B.V. All rights reserved.

Insights into the organization of dorsal spinal cord pathways from an evolutionarily conserved raldh2 intronic enhancer

Comparative studies of the tetrapod raldh2 (aldh1a2) gene, which encodes a retinoic acid (RA) synthesis enzyme, have led to the identification of a dorsal spinal cord enhancer. Enhancer activity is directed dorsally to the roof plate and dorsal-most (dl1) interneurons through predicted Tcf- and Cdx-homeodomain binding sites and is repressed ventrally via predicted Tgif homeobox and ventral Lim-homeodomain binding sites. Raldh2 and Math1/Cath1 expression in mouse and chicken highlights a novel, transient, endogenous Raldh2 expression domain in dl1 interneurons, which give rise to ascending circuits and intraspinal commissural interneurons, suggesting roles for RA in the ontogeny of spinocerebellar and intraspinal proprioceptive circuits. Consistent with expression of raldh2 in the dorsal interneurons of tetrapods, we also found that raldh2 is expressed in dorsal interneurons throughout the agnathan spinal cord, suggesting ancestral roles for RA signaling in the ontogenesis of intraspinal proprioception.

Diel vertical migration: Modelling light-mediated mechanisms

Light is generally regarded as the most likely cue used by zooplankton to regulate their vertical movements through the water column. However, the way in which light is used by zooplankton as a cue is not well understood. In this paper we present a mathematical model of diel vertical migration which produces vertical distributions of zooplankton that vary in space and time. The model is used to predict the patterns of vertical distribution which result when animals are assumed to adopt one of three commonly proposed mechanisms for vertical swimming. First, we assume zooplankton tend to swim towards a preferred intensity of light. We then assume zooplankton swim in response to either the rate of change in light intensity or the relative rate of change in light intensity. The model predicts that for all three mechanisms movement is fastest at sunset and sunrise and populations are primarily influenced by eddy diffusion at night in the absence of a light stimulus. Daytime patterns of vertical distribution differ between the three mechanisms and the reasons for the predicted differences are discussed. Swimming responses to properties of the light field are shown to be adequate for describing diel vertical migration where animals congregate in near surface waters during the evening and reside at deeper depths during the day. However, the model is unable to explain how some populations halt their ascent before reaching surface waters or how populations re-congregate in surface waters a few hours before sunrise, a phenomenon which is sometimes observed in the held. The model results indicate that other exogenous or endogenous factors besides light may play important roles in regulating vertical movement.

A transgenic mouse model that recapitulates the clinical features of both neonatal and adult forms of the skin disease epidermolytic hyperkeratosis

Keratins are the major structural proteins of keratinocytes, which are the most abundant cell type in the mammalian epidermis. Mutations in epidermal keratin genes have been shown to cause severe blistering skin abnormalities. One such disease, epidermolytic hyperkeratosis (EHK), also known as bullous congenital ichthyosiform erythroderma, occurs as a result of mutations in highly conserved regions of keratins K1 and K10. Patients with EHK first exhibit erythroderma with severe blistering, which later is replaced by thick patches of scaly skin. To assess the effect of a mutated K1 gene on skin biology and to produce an animal model for EHK, we removed 60 residues from the 2B segment of HK1 and observed the effects of its expression in the epidermis of transgenic mice. Phenotypes of the resultant mice closely resembled those observed in the human disease, first with epidermal blisters, then later with hyperkeratotic lesions. In neonatal mice homozygous for the transgene, the skin was thicker, with an increased labeling index, and the spinous cells showed a collapse of the keratin filament network around the nuclei, suggesting that a critical concentration of the mutant HK1, over the endogenous MK1, was required to disrupt the structural integrity of the spinous cells. Additionally, footpad epithelium, which is devoid of hair follicles, showed blistering in the spinous layer, suggesting that hair follicles can stabilize or protect the epidermis from trauma. Blisters were not evident in adult mice, but instead they showed a thick, scaly hyperkeratotic skin with increased mitosis, resulting in an increased number of corneocytes and granular cells. Irregularly shaped keratohyalin granules were also observed. To date, this is the only transgenic model to show the typical morphology found in the adult form of EHK.

The shoot controls zeatin riboside export from pea roots. Evidence from the branching mutant rms4

The rms4 mutant of pea (Pisum sativum L.) was used in grafting studies and cytokinin analyses of the root xylem sap to provide evidence that, at least for pea, the shoot can modify the import of cytokinins from the root. The rms4 mutation, which confers a phenotype with increased branching in the shoot, causes a very substantial decrease (down to 40-fold less) in the concentration of zeatin riboside (ZR) in the xylem sap of the roots. Results from grafts between wild-type (WT) and rms4 plants indicate that the concentration of cytokinins in the xylem sap of the roots is determined almost entirely by the genotype of the shoot. WT scions normalize the cytokinin concentration in the sap of rms4 mutant roots, whereas mutant scions cause WT roots to behave like those of self-grafted mutant plants. The mechanism whereby rms4 shoots of pea cause a down-regulation in the export of cytokinins from the roots is unknown at this time. However, our data provide evidence that the shoot transmits a signal to the roots and thereby controls processes involved in the regulation of cytokinin biosynthesis in the root.

HUMAN CHOLESTERYL ESTER TRANSFER PROTEIN EXPRESSION ENHANCES THE MOUSE SURVIVAL RATE IN AN EXPERIMENTAL SYSTEMIC INFLAMMATION MODEL: A NOVEL ROLE FOR CETP

Mice expressing human cholesteryl ester transfer protein (huCETP) are more resistant to Escherichia coli bacterial wall LIPS because death rates 5 days after intraperitoneal inoculation of LIPS were higher in wild-type than in huCETP(+/-) mice, whereas all huCETP(+/+) mice remained alive. After LIPS inoculation, plasma concentrations of TNF-alpha and IL-6 increased less in huCETP(+/+) than in wild-type mice. LPS in vitro elicited lower TNF-alpha production by CETP expressing than by wild-type macrophages. In addition, TNF-alpha production by RAW 264.7 murine macrophages increased on incubation with LPS but decreased in a dose-dependent manner when human CETP was added to the medium. Human CETP in vitro enhanced the LIPS binding to plasma high-density lipoprotein/low-density lipoprotein. The liver uptake of intravenous infused C-14-LPS from Salmonella typhimurium was greater in huCETP(+/+) than in wild-type mice. Present data indicate for the first time that CETP is an endogenous component involved in the first line of defense against an exacerbated production of proinflammatory mediators.