Up-regulation of the levels of expression and function of a constitutively active mutant of the hamster alpha1B-adrenoceptor by ligands that act as inverse agonists.

The alpha1-adrenergic agonist phenylephrine stimulated phospholipase D (PLD) activity in Rat 1 fibroblasts transfected to express either the wild-type hamster alpha1B-adrenoceptor or a constitutively active mutant (CAM) form of this receptor. The EC50 for agonist stimulation of PLD activity was substantially lower at the CAM receptor than at the wild-type receptor as previously noted for phenylephrine stimulation of phosphoinositidase C activity. Sustained treatment of cells expressing the CAM alpha1B-adrenoceptor with phentolamine resulted in a marked up-regulation in levels of this receptor with half-maximal effects produced within 24 h and with an EC50 of approx. 40 nM. Such an up-regulation could be produced with a range of other ligands generally viewed as alpha1-adrenoceptor antagonists but equivalent treatment of cells expressing the wild-type alpha1B-adrenoceptor was unable to mimic these effects. After sustained treatment of the CAM alpha1B-adrenoceptor expressing cells with phentolamine, basal PLD activity was increased and phenylephrine was now able to stimulate PLD activity to greater levels than in vehicle-treated CAM alpha1B-adrenoceptor-expressing cells. The EC50 for phenylephrine stimulation of PLD activity was not altered, however, by phentolamine pretreatment and the associated up-regulation of the receptor. After phentolamine-induced up-regulation of basal PLD activity, a range of alpha1-antagonists were shown to possess the characteristics of inverse agonists of the CAM alpha1B-adrenoceptor as they were able to substantially decrease the elevated basal PLD activity.

The role of moral values in the economic analysis of crime: A general equilibrium approach

In this paper, we develop a general equilibrium model of crime and show thatlaw enforcement has different roles depending on the equilibrium characterization and the value of social norms. When an economy has a unique stable equilibrium where a fraction of the population is productive and the remaining predates, the government can choose an optimal law enforcement policy to maximize a welfare function evaluated at the steady state. If such steady state is not unique, law enforcement is still relevant but in a completely different way because the steady state that prevails depends on the initial proportions of productive and predator individuals in the economy. The relative importance of these proportions can be changed through law enforcement policy.

Potencial de alimentação de Chrysoperla externa (Hagen, 1861) (Neuroptera, Chrysopidae) em diferentes densidades de Uroleucon ambrosiae (Thomas, 1878) (Hemiptera, Aphididae)

Feeding potential of Chrysoperla externa (Hagen) (Neuroptera, Chrysopidae) in different densities of Uroleucon ambrosiae (Thomas) (Hemiptera, Aphididae). The feeding potential of 2nd and 3rd instar larvae of Chrysoperla externa (Hagen, 1861) in relation to different densities of 30, 40 and 50 nymphs of Uroleucon ambrosiae (Thomas, 1878) at 3rd and 4th instars was evaluated. The treatments were individualized into 2.5 cm in diameter and 8.5 cm tall flat bottom glass vials and maintained in a controlled environmental chamber at 25±2 ºC temperature, 70±10% RH and 14 h photophase. A completely randomized experimental design with 10 replications was used. The consumption of the prey nymphs by the predator larvae was evaluated after 1, 2, 4, 8, 16 and 24 h from the beginning of the experiment and at every subsequent 24 h period until 2nd instar larvae molted or 3rd instar larvae pupated. Results have shown that for 2nd instar larvae, during the 1 h to 24 h period, there was a decreasing prey consumption at the 30 and 40 prey densities. However an increase in the consumption at the 50 prey density was observed. After this period, C. externa larvae presented a progressive increase on nymphs consumption as a function of the prey density. The same occurred with de 3rd instar predator larvae in all treatments. When daily mean consumption was evaluated the predator/prey ratio was 1:23, 1:27 and 1:33 for 2nd instar larvae and 1:27, 1:33 and 1:41 for 3rd instar larvae at 30, 40 and 50 nymph densities, respectively.

IL-28A (IFN-λ2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease.

IL-28 (IFN-λ) cytokines exhibit potent antiviral and antitumor function but their full spectrum of activities remains largely unknown. Recently, IL-28 cytokine family members were found to be profoundly down-regulated in allergic asthma. We now reveal a novel role of IL-28 cytokines in inducing type 1 immunity and protection from allergic airway disease. Treatment of wild-type mice with recombinant or adenovirally expressed IL-28A ameliorated allergic airway disease, suppressed Th2 and Th17 responses and induced IFN-γ. Moreover, abrogation of endogenous IL-28 cytokine function in IL-28Rα(-/-) mice exacerbated allergic airway inflammation by augmenting Th2 and Th17 responses, and IgE levels. Central to IL-28A immunoregulatory activity was its capacity to modulate lung CD11c(+) dendritic cell (DC) function to down-regulate OX40L, up-regulate IL-12p70 and promote Th1 differentiation. Consistently, IL-28A-mediated protection was absent in IFN-γ(-/-) mice or after IL-12 neutralization and could be adoptively transferred by IL-28A-treated CD11c(+) cells. These data demonstrate a critical role of IL-28 cytokines in controlling T cell responses in vivo through the modulation of lung CD11c(+) DC function in experimental allergic asthma. →See accompanying Closeup by Michael R Edwards and Sebastian L Johnston http://dx.doi.org/10.1002/emmm.201100143.

Biometal muscles to restore contractile function of weak heart

Objectives: Existing VADs are single-ventricle pumps needing anticoagulation. We developed a bi-ventricular external assist device that partially reproduces the physiological muscle function of the heart. This artificial muscle could wrap the heart and improve its contractile force.Methods: The device has a carbon fiber skeleton fitting a 30-40kg patient's heart, to which a Nitinol based artificial muscle is connected. The artificial muscle wraps both ventricles. The Nitinol fibers are woven on a Kevlar mesh surrounding each ventricle. The fibers are electrically driven with a dedicated control unit developed for this purpose. We assessed hemodynamic performances of this device using a previously described dedicated bench test. Volume ejected and pressure gradient have been measured with afterload ranging from 10 to 50mmHg.Results: With an afterload of 50mmHg the system has an ejection fraction of 4% on the right side and 5% on the left side. The system is able to generate a systolic ejection of 2.2mL on the right side and 3.25mL on the left side. With an afterload of 25mmHg the results are reduced of about 20%. The activation frequency can reach 80/minute resulting in a total volume displacement of 176mL/minute on the right side and 260mL/minute on the left side.Conclusions: These preliminary studies confirmed the possibility of improving the ejection fraction of a failing heart using artificial muscle for external cardiac compression avoiding anticoagulation therapy. This device could be helpful in weaning cardio-pulmonary bypass and/or for short-term cardio-circulatory support in pediatric population with cardiac failure.

A comment on the Nash program and the theory of implementation

The mechanisms in the Nash program for cooperative games are madecompatible with the framework of the theory of implementation. This is donethrough a reinterpretation of the characteristic function that avoids feasibilityproblems, thereby allowing an analysis that focuses exclusively on the payoff space. In this framework, we show that the core is the only majorcooperative solution that is Maskin monotonic. Thus, implementation of mostcooperative solutions must rely on refinements of the Nash equilibrium concept(like most papers in the Nash program do). Finally, the mechanisms in theNash program are adapted into the model.

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts.

TGF-β and myostatin are the two most important regulators of muscle growth. Both growth factors have been shown to signal through a Smad3-dependent pathway. However to date, the role of Smad3 in muscle growth and differentiation is not investigated. Here, we demonstrate that Smad3-null mice have decreased muscle mass and pronounced skeletal muscle atrophy. Consistent with this, we also find increased protein ubiquitination and elevated levels of the ubiquitin E3 ligase MuRF1 in muscle tissue isolated from Smad3-null mice. Loss of Smad3 also led to defective satellite cell (SC) functionality. Smad3-null SCs showed reduced propensity for self-renewal, which may lead to a progressive loss of SC number. Indeed, decreased SC number was observed in skeletal muscle from Smad3-null mice showing signs of severe muscle wasting. Further in vitro analysis of primary myoblast cultures identified that Smad3-null myoblasts exhibit impaired proliferation, differentiation and fusion, resulting in the formation of atrophied myotubes. A search for the molecular mechanism revealed that loss of Smad3 results in increased myostatin expression in Smad3-null muscle and myoblasts. Given that myostatin is a negative regulator, we hypothesize that increased myostatin levels are responsible for the atrophic phenotype in Smad3-null mice. Consistent with this theory, inactivation of myostatin in Smad3-null mice rescues the muscle atrophy phenotype.

Loss of ATF2 function leads to cranial motoneuron degeneration during embryonic mouse development.

The AP-1 family transcription factor ATF2 is essential for development and tissue maintenance in mammals. In particular, ATF2 is highly expressed and activated in the brain and previous studies using mouse knockouts have confirmed its requirement in the cerebellum as well as in vestibular sense organs. Here we present the analysis of the requirement for ATF2 in CNS development in mouse embryos, specifically in the brainstem. We discovered that neuron-specific inactivation of ATF2 leads to significant loss of motoneurons of the hypoglossal, abducens and facial nuclei. While the generation of ATF2 mutant motoneurons appears normal during early development, they undergo caspase-dependent and independent cell death during later embryonic and foetal stages. The loss of these motoneurons correlates with increased levels of stress activated MAP kinases, JNK and p38, as well as aberrant accumulation of phosphorylated neurofilament proteins, NF-H and NF-M, known substrates for these kinases. This, together with other neuropathological phenotypes, including aberrant vacuolisation and lipid accumulation, indicates that deficiency in ATF2 leads to neurodegeneration of subsets of somatic and visceral motoneurons of the brainstem. It also confirms that ATF2 has a critical role in limiting the activities of stress kinases JNK and p38 which are potent inducers of cell death in the CNS.

GLUT8 is dispensable for embryonic development but influences hippocampal neurogenesis and heart function.

GLUT8 is a glucose transporter isoform expressed at high levels in testis; at intermediate levels in the brain, including the hippocampus; and at lower levels in the heart and several other tissues. GLUT8 is located in an intracellular compartment and does not appear to translocate to the cell surface, except in blastocysts, where insulin has been reported to induce its surface expression. Here, we generated mice with inactivation of the glut8 gene. We showed that expression of GLUT8 was not required for normal embryonic development and that glut8-/- mice had normal postnatal development, glucose homeostasis, and response to mild stress. Adult glut8-/- mice showed increased proliferation of hippocampal cells but no defect in memory acquisition and retention. Absence of GLUT8 from the heart did not alter heart size and morphology but led to an increase in P-wave duration, which was not associated with abnormal Nav1.5 Na+ channel or connexin expression. Thus, absence of GLUT8 expression in the mouse caused complex but mild physiological alterations.

Zapfen-Stäbchen-Dystrophie durch eine neue reinerbige RPE65-Mutation in Leberscher kongenitaler Amaurose Cone-Rod Dystrophy Caused by a Novel Homozygous RPE65 Mutation in Leber Congenital Amaurosis.

Background: The aim of this study was to describe an unexpected phenotype in a family with Leber congenital amaurosis (LCA) due to a retinal pigment epithelium-specific protein 65 kDa (RPE65) homozygous mutation. History and Signs: We analyzed a family from Yemen in which 3 individuals were affected with LCA. Linkage analysis using markers flanking the known LCA genes was done, followed by direct sequencing of RPE65. Therapy and Outcome: Severe visual impairment and night blindness were observed during infancy. We observed photophobia only in the 8-year-old patient. The youngest affected had bilateral hyperopia of + 3.50 and visual acuity of 1/60. The oldest two had visual acuity limited to hand movements in the right eye (OD) and counting fingers in the left eye (OS) for the oldest and of 5/60 OD, 6/60 OS for the other. They showed disc pallor, attenuated vessels, white flecks in the retina mid-periphery and bull's eye maculopathy. ERGs of the oldest child were completely unresponsive. Genomic sequencing identified a novel homozygous missense mutation, IVS2-3C > G, in the second RPE65 intron. Conclusions: We identified a novel LCA-related homozygous RPE65 mutation associated with a severe clinical presentation including an early and severe cone dysfunction. This is in contrast with the presentation associated with other RPE65 mutations predominantly causing rod-cone dystrophy with residual visual function.

Heritability of left ventricular structure and function in Caucasian families.

AIMS: The aim of this study was to investigate the heritability as well as genetic and environmental correlations of left ventricular (LV) structural and functional traits in complex pedigrees of a Caucasian population. METHODS AND RESULTS: We randomly recruited 459 white European subjects from 52 families (50% women; mean age 45 years). LV structure was measured by M-mode and 2D echocardiography and LV function was measured by conventional Doppler and tissue Doppler imaging (TDI). Other measurements included blood pressure, anthropometric, and biochemical measurements. We estimated the heritability of LV traits while adjusting for covariables, including sex, age, body height and weight, systolic and diastolic blood pressures, and heart rate. With full adjustment, heritability of LV mass was 0.23 (P= 0.025). The TDI-derived mitral annular velocities Ea and Aa showed moderate heritability (h(2)= 0.36 and 0.53, respectively), whereas the mitral inflow A peak had weak heritability (h(2) = 0.25) and the E peak was not heritable (h(2) = 0.11). We partitioned the total phenotypic correlation when it reached significance, into a genetic and an environmental component. The genetic correlations were 0.61 between the E and Ea peaks and 0.90 between the A and Aa peaks. CONCLUSION: Our study demonstrated moderate heritability for LV mass as well as the mitral annular Ea and Aa peaks. We also found significant genetic correlations between the E and Ea peaks and between the A and Aa peaks. Our current findings support the ongoing research to map and detect genetic variants that contribute to the variation in LV mass and other LV structural and functional phenotypes.

Melatonin improves glucose homeostasis and endothelial vascular function in high-fat diet-fed insulin-resistant mice.

Obesity and insulin resistance represent a problem of utmost clinical significance worldwide. Insulin-resistant states are characterized by the inability of insulin to induce proper signal transduction leading to defective glucose uptake in skeletal muscle tissue and impaired insulin-induced vasodilation. In various pathophysiological models, melatonin interacts with crucial molecules of the insulin signaling pathway, but its effects on glucose homeostasis are not known. In a diet-induced mouse model of insulin resistance and normal chow-fed control mice, we sought to assess the effects of an 8-wk oral treatment with melatonin on insulin and glucose tolerance and to understand underlying mechanisms. In high-fat diet-fed mice, but not in normal chow-fed control mice, melatonin significantly improved insulin sensitivity and glucose tolerance, as evidenced by a higher rate of glucose infusion to maintain euglycemia during hyperinsulinemic clamp studies and an attenuated hyperglycemic response to an ip glucose challenge. Regarding underlying mechanisms, we found that melatonin restored insulin-induced vasodilation to skeletal muscle, a major site of glucose utilization. This was due, at least in part, to the improvement of insulin signal transduction in the vasculature, as evidenced by increased insulin-induced phosphorylation of Akt and endoethelial nitric oxide synthase in aortas harvested from melatonin-treated high-fat diet-fed mice. In contrast, melatonin had no effect on the ability of insulin to promote glucose uptake in skeletal muscle tissue in vitro. These data demonstrate for the first time that in a diet-induced rodent model of insulin resistance, melatonin improves glucose homeostasis by restoring the vascular action of insulin.

Running versus strength-based warm-up : acute effects on isometric knee extension function

This study investigated the influence of two warm-up protocols on neural and contractile parameters of knee extensors. A series of neuromuscular tests including voluntary and electrically evoked contractions were performed before and after running- (R (WU); slow running, athletic drills, and sprints) and strength-based (S (WU); bilateral 90 degrees back squats, Olympic lifting movements and reactivity exercises) warm ups (duration ~40 min) in ten-trained subjects. The estimated overall mechanical work was comparable between protocols. Maximal voluntary contraction torque (+15.6%; P < 0.01 and +10.9%; P < 0.05) and muscle activation (+10.9 and +12.9%; P < 0.05) increased to the same extent after R (WU) and S (WU), respectively. Both protocols caused a significant shortening of time to contract (-12.8 and -11.8% after R (WU) and S (WU); P < 0.05), while the other twitch parameters did not change significantly. Running- and strength-based warm ups induce similar increase in knee extensors force-generating capacity by improving the muscle activation. Both protocols have similar effects on M-wave and isometric twitch characteristics.

Expression and function of interleukin-7 in secondary and tertiary lymphoid organs.

Interleukin-7 (IL-7) is known since many years as stromal-cell derived cytokine that plays a key role for the adaptive immune system. It promotes lymphocyte development in the bone marrow and thymus as well as naive and memory T cell homeostasis in the periphery. More recently, IL-7 reporter mice and other approaches have led to the further characterization of the various stromal cell sources of IL-7 in secondary lymphoid organs (SLO) and other tissues. We will review these advances along with a discussion of the regulation of IL-7 and its receptor, and compare the biological effects IL-7 has on adaptive as well as innate immune cells in SLO. Finally, we will review the role of IL-7 in development of SLO and tertiary lymphoid tissues that frequently are associated with sites of chronic inflammation.

Solving higher-dimensional continuous time stochastic control problems by value function regression

The paper develops a method to solve higher-dimensional stochasticcontrol problems in continuous time. A finite difference typeapproximation scheme is used on a coarse grid of low discrepancypoints, while the value function at intermediate points is obtainedby regression. The stability properties of the method are discussed,and applications are given to test problems of up to 10 dimensions.Accurate solutions to these problems can be obtained on a personalcomputer.