Activation of peroxisome proliferator-activated receptor beta/delta inhibits lipopolysaccharide-induced cytokine production in adipocytes by lowering nuclear factor-kappaB activity via extracellular signal-related kinase 1/2.

OBJECTIVE: Chronic activation of the nuclear factor-kappaB (NF-kappaB) in white adipose tissue leads to increased production of pro-inflammatory cytokines, which are involved in the development of insulin resistance. It is presently unknown whether peroxisome proliferator-activated receptor (PPAR) beta/delta activation prevents inflammation in adipocytes. RESEARCH DESIGN AND METHODS AND RESULTS: First, we examined whether the PPARbeta/delta agonist GW501516 prevents lipopolysaccharide (LPS)-induced cytokine production in differentiated 3T3-L1 adipocytes. Treatment with GW501516 blocked LPS-induced IL-6 expression and secretion by adipocytes and the subsequent activation of the signal transducer and activator of transcription 3 (STAT3)-Suppressor of cytokine signaling 3 (SOCS3) pathway. This effect was associated with the capacity of GW501516 to impede LPS-induced NF-kappaB activation. Second, in in vivo studies, white adipose tissue from Zucker diabetic fatty (ZDF) rats, compared with that of lean rats, showed reduced PPARbeta/delta expression and PPAR DNA-binding activity, which was accompanied by enhanced IL-6 expression and NF-kappaB DNA-binding activity. Furthermore, IL-6 expression and NF-kappaB DNA-binding activity was higher in white adipose tissue from PPARbeta/delta-null mice than in wild-type mice. Because mitogen-activated protein kinase-extracellular signal-related kinase (ERK)1/2 (MEK1/2) is involved in LPS-induced NF-kappaB activation in adipocytes, we explored whether PPARbeta/delta prevented NF-kappaB activation by inhibiting this pathway. Interestingly, GW501516 prevented ERK1/2 phosphorylation by LPS. Furthermore, white adipose tissue from animal showing constitutively increased NF-kappaB activity, such as ZDF rats and PPARbeta/delta-null mice, also showed enhanced phospho-ERK1/2 levels. CONCLUSIONS: These findings indicate that activation of PPARbeta/delta inhibits enhanced cytokine production in adipocytes by preventing NF-kappaB activation via ERK1/2, an effect that may help prevent insulin resistance.

Melanin-based coloration is a nondirectionally selected sex-specific signal of offspring development in the Alpine swift

Two mutually exclusive hypotheses have been put forward to explain the evolution and adaptive function of melanin-based color traits. According to sexual selection theory melanism is a directionally selected signal of individual quality, whereas theory on the maintenance of genetic polymorphism proposes that alternative melanin-based variants achieve equal fitness. Alpine swift (Apus melba) males and females have a conspicuous patch of white feathers on the breast with their rachis varying continuously from white to black, and hence the breast varies from white to striated. If this trait is a sexually selected signal of quality, its expression should be condition dependent and the degree of melanism directionally selected. If variation in melanism is a polymorphism, its expression should be genetically determined and fitness of melanin-based variants equal. We experimentally tested these predictions by exchanging eggs or hatchlings between randomly chosen nests and by estimating survival and reproduction in relation to melanism. We found that breast melanism is heritable and that the environment and body condition do not significantly influence its expression. Between 5 and 50 days of age nestlings were heavier and their wings longer when breast feathers of their biological father were blacker, and they also fledged at a younger age. This shows that aspects of offspring quality covary positively with the degree of melanism. However, this did not result in directional selection because nestling survival and recruitment in the local breeding population were not associated with father breast melanism. Furthermore, adult survival, age at first reproduction and probability of skipping reproduction did not covary with the degree of melanism. Genetic variation in breast melanism is therefore maintained either because nonmelanic males achieve fitness similar to melanic males via a different route than producing fast-growing offspring, or because the advantage of producing fast-growing offspring is not sufficiently pronounced to result in directional selection.

BPSK to ASK signal conversion using injection-locked oscillators-Part I: theory

This paper presents a new method and circuit for the conversion of binary phase-shift keying (BPSK) signals into amplitude shift keying signals. The basic principles of the conversion method are the superharmonic injection and locking of oscillator circuits, and interference phenomena. The first one is used to synchronize the oscillators, while the second is used to generate an amplitude interference pattern that reproduces the original phase modulation. When combined with an envelope detector, the proposed converter circuit allows the coherent demodulation of BPSK signals without need of any explicit carrier recovery system. The time response of the converter circuit to phase changes of the input signal, as well as the conversion limits, are discussed in detail.

BPSK to ASK signal conversion using injection-locked oscillators-part II: experiment

This paper demonstrates the feasibility of a new circuit for the conversion of binary phase-shift keying signals into amplitude-shift keying signals. In its simplest form, the converter circuit is composed by a power divider, a couple of second harmonic injection-locked oscillators, and a power combiner. The operation of the converter circuit relies on the frequency synchronization of both oscillators and the generation of an interference pattern by combining their outputs, which reproduces the original phase modulation. Two prototypes of the converter have been implemented. The first one is a hybrid version working in the 400-530-MHz frequency range. The second one has been implemented using multichip-module technology, and is intended to work in the 1.8-2.2-GHz frequency range.

Microinductive signal conditioning with resonant differential filters: high-sensitivity biodetection applications

Inductive-based devices integrated with Si technology for biodetection applications are characterized, using simple resonant differential filter configurations. This has allowed the corroboration of the viability of the proposed circuits, which are characterized by their very high simplicity, for microinductive signal conditioning in high-sensitivity sensor devices. The simulation of these simple circuits predicts sensitivities of the differential output voltage which can achieve values in the range of 0.1-1 V/nH, depending on the coil parameters. These very high-sensitivity values open the possibility for the experimental detection of extremely small inductance changes in the devices. For real microinductive devices, both series resistance and parasitic capacitive components contribute to the decrease of the differential circuit sensitivity. Nevertheless, measurements performed using micro-coils fabricated with relatively high series resistance and coupling parasitic effects have allowed detection of changes in the range of 2 nH. which are compatible with biodetection applications with estimated detection limits below the picomolarity range.

Drift compensation of gas sensor array data by Orthogonal Signal Correction

Drift is an important issue that impairs the reliability of gas sensing systems. Sensor aging, memory effects and environmental disturbances produce shifts in sensor responses that make initial statistical models for gas or odor recognition useless after a relatively short period (typically few weeks). Frequent recalibrations are needed to preserve system accuracy. However, when recalibrations involve numerous samples they become expensive and laborious. An interesting and lower cost alternative is drift counteraction by signal processing techniques. Orthogonal Signal Correction (OSC) is proposed for drift compensation in chemical sensor arrays. The performance of OSC is also compared with Component Correction (CC). A simple classification algorithm has been employed for assessing the performance of the algorithms on a dataset composed by measurements of three analytes using an array of seventeen conductive polymer gas sensors over a ten month period.

c-Jun N-terminal kinase binding domain-dependent phosphorylation of mitogen-activated protein kinase kinase 4 and mitogen-activated protein kinase kinase 7 and balancing cross-talk between c-Jun N-terminal kinase and extracellular signal-regulated kinase pathways in cortical neurons

The c-Jun N-terminal kinase (JNK) is a mitogen-activated protein kinase (MAPK) activated by stress-signals and involved in many different diseases. Previous results proved the powerful effect of the cell permeable peptide inhibitor d-JNKI1 (d-retro-inverso form of c-Jun N-terminal kinase-inhibitor) against neuronal death in CNS diseases, but the precise features of this neuroprotection remain unclear. We here performed cell-free and in vitro experiments for a deeper characterization of d-JNKI1 features in physiological conditions. This peptide works by preventing JNK interaction with its c-Jun N-terminal kinase-binding domain (JBD) dependent targets. We here focused on the two JNK upstream MAPKKs, mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7), because they contain a JBD homology domain. We proved that d-JNKI1 prevents MKK4 and MKK7 activity in cell-free and in vitro experiments: these MAPKK could be considered not only activators but also substrates of JNK. This means that d-JNKI1 can interrupt downstream but also upstream events along the JNK cascade, highlighting a new remarkable feature of this peptide. We also showed the lack of any direct effect of the peptide on p38, MEK1, and extracellular signal-regulated kinase (ERK) in cell free, while in rat primary cortical neurons JNK inhibition activates the MEK1-ERK-Ets1/c-Fos cascade. JNK inhibition induces a compensatory effect and leads to ERK activation via MEK1, resulting in an activation of the survival pathway-(MEK1/ERK) as a consequence of the death pathway-(JNK) inhibition. This study should hold as an important step to clarify the strong neuroprotective effect of d-JNKI1.

The small RNA PhrS stimulates synthesis of the Pseudomonas aeruginosa quinolone signal.

Quorum sensing, a cell-to-cell communication system based on small signal molecules, is employed by the human pathogen Pseudomonas aeruginosa to regulate virulence and biofilm development. Moreover, regulation by small trans-encoded RNAs has become a focal issue in studies of virulence gene expression of bacterial pathogens. In this study, we have identified the small RNA PhrS as an activator of PqsR synthesis, one of the key quorum-sensing regulators in P. aeruginosa. Genetic studies revealed a novel mode of regulation by a sRNA, whereby PhrS uses a base-pairing mechanism to activate a short upstream open reading frame to which the pqsR gene is translationally coupled. Expression of phrS requires the oxygen-responsive regulator ANR. Thus, PhrS is the first bacterial sRNA that provides a regulatory link between oxygen availability and quorum sensing, which may impact on oxygen-limited growth in P. aeruginosa biofilms.

Role of peroxynitrite in the redox regulation of cell signal transduction pathways.

Peroxynitrite is a potent oxidant and nitrating species formed from the reaction between the free radicals nitric oxide and superoxide. An excessive formation of peroxynitrite represents an important mechanism contributing to cell death and dysfunction in multiple cardiovascular pathologies, such as myocardial infarction, heart failure and atherosclerosis. Whereas initial works focused on direct oxidative biomolecular damage as the main route of peroxynitrite toxicity, more recent evidence, mainly obtained in vitro, indicates that peroxynitrite also behaves as a potent modulator of various cell signal transduction pathways. Due to its ability to nitrate tyrosine residues, peroxynitrite affects cellular processes dependent on tyrosine phosphorylation. Peroxynitrite also exerts complex effects on the activity of various kinases and phosphatases, resulting in the up- or downregulation of signalling cascades, in a concentration- and cell-dependent manner. Such roles of peroxynitrite in the redox regulation of key signalling pathways for cardiovascular homeostasis, including protein kinase B and C, the MAP kinases, Nuclear Factor Kappa B, as well as signalling dependent on insulin and the sympatho-adrenergic system are presented in detail in this review.

Estimation of the parameters of the gravitational-wage signal of a coalescing binary system

The statistical theory of signal detection and the estimation of its parameters are reviewed and applied to the case of detection of the gravitational-wave signal from a coalescing binary by a laser interferometer. The correlation integral and the covariance matrix for all possible static configurations are investigated numerically. Approximate analytic formulas are derived for the case of narrow band sensitivity configuration of the detector.

Divergent signal-to-noise ratio and stochastic resonance in monostable systems

We present a class of systems for which the signal-to-noise ratio always increases when increasing the noise and diverges at infinite noise level. This new phenomenon is a direct consequence of the existence of a scaling law for the signal-to-noise ratio and implies the appearance of stochastic resonance in some monostable systems. We outline applications of our results to a wide variety of systems pertaining to different scientific areas. Two particular examples are discussed in detail.

Manipulating the sensitivity of signal-induced repression: quantification and consequences of altered brinker gradients.

Traditionally, the analysis of gene regulatory regions suffered from the caveat that it was restricted to artificial contexts (e.g. reporter constructs of limited size). With the advent of the BAC recombineering technique, genomic constructs can now be generated to test regulatory elements in their endogenous environment. The expression of the transcriptional repressor brinker (brk) is negatively regulated by Dpp signaling. Repression is mediated by small sequence motifs, the silencer elements (SEs), that are present in multiple copies in the regulatory region of brk. In this work, we manipulated the SEs in the brk locus. We precisely quantified the effects of the individual SEs on the Brk gradient in the wing disc by employing a 1D data extraction method, followed by the quantification of the data with reference to an internal control. We found that mutating the SEs results in an expansion of the brk expression domain. However, even after mutating all predicted SEs, repression could still be observed in regions of maximal Dpp levels. Thus, our data point to the presence of additional, low affinity binding sites in the brk locus.

Effect of the output of the system in signal detection

We analyze the consequences that the choice of the output of the system has in the efficiency of signal detection. It is shown that the output signal and the signal-to-noise ratio (SNR), used to characterize the phenomenon of stochastic resonance, strongly depend on the form of the output. In particular, the SNR may be enhanced for an adequate output.