Impact of cigarette smoke on physical-chemical and molecular proprieties of human skin in an ex vivo model.

BACKGROUND: This is a study about the skin ageing exposome, focusing on the effect of cigarette smoke. Human living skin explants (HSE) were exposed to cigarette smoke (CS) of two cigarettes for 2 hours using a custom-made exposure chamber, the Pollubox® . Effects on the surface physico-chemistry and molecular properties of the skin were analyzed and reported for the first time. BASIC PROCEDURES: To this end, transcriptomic study followed by immunohistochemistry, MDA (Malondialdehyde Dosage), and surface physio-chemistry data: surface free energy determination, TEWL (Trans Epidermal Water Loss), skin pH and FT-IR (Fourier Transform-Infrared) spectroscopy of the explant were collected from untreated and treated HSE. MAIN FINDINGS: Results showed a decrease of the total surface free energy of the treated HSE. This decrease reflected higher interactions with polar compounds from the environment and consequently a decrease of the surface hydrophobicity. Additionally, an increase of TEWL and skin pH was observed after treatment. The transcriptomic analysis showed downregulation of mitochondrial genes (PON2-NDUFA4L2-ATP1A1-ALDH2-PRODH) combined with an increase of MDA in CS-treated HSE. CONCLUSIONS: CS-induced oxidation of lipids at HSE surface alters the skin barrier: interactions with polar products are enhanced and the lipid chain packing at the surface is modified. Consequently, skin permeability could increase which correlated with repression of CA9 and AQP1 genes. Beside activation of AHR-NRF2 pathway in CS-exposed HSE, our results suggested that mitochondrial functions were strongly impacted and oxidized lipids failed to be eliminated promoting skin barrier alteration. A mitophagy activity was suggested through the confirmation of PINK1 accumulation in the epidermis by immunostaining.

Ultrasound-stimulated Brownian ratchet enhances diffusion of molecules retained in hydrogels.

We demonstrate that low-frequency ultrasonic stimulation applied directly to a hydrogel, at energy levels below the cavitation threshold, can control the release of a therapeutic molecule. The hydrogel that contained the molecules was enclosed within a hollow acoustic horn. The harmonic modes in the acoustic horn combined with the physical gel structure to induce a flashing ratchet that released all of the retained molecules in less than 90 s at an intensity of 1.5 W cm-2 (applied energy of 135 J cm-2, ultrasound center frequency of 27.9 ±â€¯1.5 kHz). In contrast, ultrasound is used currently as a remote stimulus for drug-delivery systems, at energy levels above the cavitation threshold. The low-energy flashing ratchet approach that we describe is applicable to drive the diffusion of molecules in a range of gels that are ubiquitous in biomedical systems, including for example in drug delivery, molecule identification and separation systems.

A Wearable Low-Power Sensing Platform for Environmental and Health Monitoring: The Convergence Project.

The low-power sensing platform proposed by the Convergence project is foreseen as a wireless, low-power and multifunctional wearable system empowered by energy-efficient technologies. This will allow meeting the strict demands of life-style and healthcare applications in terms of autonomy for quasi-continuous collection of data for early-detection strategies. The system is compatible with different kinds of sensors, able to monitor not only health indicators of individual person (physical activity, core body temperature and biomarkers) but also the environment with chemical composition of the ambient air (NOx, COx, NHx particles) returning meaningful information on his/her exposure to dangerous (safety) or pollutant agents. In this article, we introduce the specifications and the design of the low-power sensing platform and the different sensors developed in the project, with a particular focus on pollutant sensing capabilities and specifically on NO2 sensor based on graphene and CO sensor based on polyaniline ink.

Gene expression comparison reveals distinct basal expression of HOX members and differential TNF-induced response between brain- and spinal cord-derived microvascular endothelial cells.

BACKGROUND: The heterogeneity of endothelial cell types underlies their remarkable ability to sub-specialize and provide specific requirements for a given vascular bed. Here, we compared rat microvascular endothelial cells (MECs) derived from the brain and spinal cord in both basal and inflammatory conditions. METHODS: We used whole rat genome microarrays to compare, at different time points, basal and TNF-α-induced gene expression of rat MECs from in vitro models of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). Validation at both messenger RNA (mRNA) and protein levels was performed on freshly extracted microvessels (MVs) from the brain and spinal cord (BMVs and SCMVs, respectively), as these were considered the closest in vivo tissues to cultured MECs. RESULTS: Most of the genes encoding adhesion/tight junction molecules and known endothelial markers were similarly expressed in brain and spinal cord MECs (BMECs and SCMECs, respectively). However, one striking finding was the higher expression of several Hox genes, which encode transcription factors involved in positional identity. The differential expression of Hoxa9 and Hoxb7 at the mRNA levels as well as protein levels was confirmed in BMVs and SCMVs. Although the TNF-α response was in general higher in BMECs than in SCMECs at 12 h, the opposite was observed at 48 h. Furthermore, we found that expression of Tnfrsf1a and Tnfrsf1b encoding the TNF receptor super-family member 1a/TNFR1 and 1b/TNFR2, respectively, were constitutively higher in BMVs compared to SCMVs. However, only Tnfrsf1b was induced in SCMECs in response to TNF-α at 24 and 48 h. CONCLUSIONS: Our results support a role for HOX members in defining the positional identities of MECs in vivo. Our data also suggest that the delayed transcriptional activation upon TNF-α treatment in SCMECs results from the requirement of the TNF-induced expression of Tnfrsf1b. In contrast, its high basal expression in BMECs might be sufficient to confer an immediate and efficient TNF-α response.

Expansion of functionally anergic CD21-/low marginal zone-like B cell clones in hepatitis C virus infection-related autoimmunity.

Homeostasis of peripheral B cell subsets is disturbed during chronic hepatitis C virus (HCV) infection, leading to the occurrence of autoimmunity and B cell lymphoproliferation. However, mechanisms by which HCV causes lymphoproliferation remain controversial. We report in this article on the elevated number of clonal CD21(-/low)IgM(+)CD27(+) marginal zone (MZ)-like B cells, which correlates with autoimmunity and lymphoproliferation in HCV patients. We found an increase in autoreactive BCRs using V(H)1-69 and V(H)4-34 genes in CD21(-/low) MZ B cells. CD21(-/low) MZ B cells showed impaired calcium-mediated signaling, did not upregulate activation markers, and did not proliferate in response to BCR triggering. CD21(-/low) MZ B cells also were prone to dying faster than their CD21(+) counterparts, suggesting that these B cells were anergic. CD21(-/low) MZ B cells, in contrast, remained responsive to TLR9 stimulation. Gene array analyses revealed the critical role of Early growth response 2 and Cbl-b in the induction of anergy. Therefore, HCV patients who display high frequencies of unresponsive CD21(-/low) MZ B cells are more susceptible to developing autoimmunity and/or lymphoproliferation. These cells remain in peripheral blood controlled by functional anergy instead of being eliminated, and chronic antigenic stimulation through TLR stimulation may create a favorable environment for breaking tolerance and activating these cells.

Electromagnetic fields applied to the reduction of abdominal obesity.

INTRODUCTION: According to various researches, abdominal obesity increases the risks of cancers or cardio-vascular diseases. OBJECTIVE: To evaluate the reduction of waistline and the evolution of biological parameters on patients after 12 sessions of a new medical device called REDUSTIM(®) associating alternate low frequency electromagnetic fields and controlled micropressure. METHODS: Two studies were made: a double-blind randomized study performed on 28 patients with a waistline > 88 cm/35 inches for women and > 102 cm/40 inches for men for a period of 6 weeks and a functional analysis on DNA chips performed on 11 patients showing proven overweight. RESULTS: Following our studies a statistically significant reduction of waistline of more than 6 cm after 12 sessions has been observed, and the biological assessments performed before and after the treatments showed both a highly significant reduction of transaminases level and the device mechanism on the stimulation of insensitive muscle contractions. CONCLUSIONS: Facing an alarming increase in overweight and obesity and considering the current therapeutic gear offering various results, it seems interesting to propose an efficient technique for the reduction of abdominal obesity. The clinical study demonstrated the safety and efficiency of the device for the reduction of abdominal obesity. Treatment showed itself efficient with patients who were not committed to any weight loss program.

APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-κB activation.

Apolipoprotein E4 (APOEε4) is the major allelic risk factor for late-onset sporadic Alzheimer's disease (sAD). Inflammation is increasingly considered as critical in sAD initiation and progression. Identifying brain molecular mechanisms that could bridge these two risk factors remain unelucidated. Leveraging induced pluripotent stem cell (iPSC)-based strategies, we demonstrate that APOE controls inflammation in human astrocytes by regulating Transgelin 3 (TAGLN3) expression and, ultimately, nuclear factor κB (NF-κB) activation. We uncover that APOE4 specifically downregulates TAGLN3, involving histone deacetylases activity, which results in low-grade chronic inflammation and hyperactivated inflammatory responses. We show that APOE4 exerts a dominant negative effect to prime astrocytes toward a pro-inflammatory state that is pharmacologically reversible by TAGLN3 supplementation. We further confirm that TAGLN3 is downregulated in the brain of patients with sAD. Our findings highlight the APOE-TAGLN3-NF-κB axis regulating neuroinflammation in human astrocytes and reveal TAGLN3 as a molecular target to modulate neuroinflammation, as well as a potential biomarker for AD.

Temporal transcriptomic analysis of human primary keratinocytes exposed to ß-naphthoflavone highlights the protective efficacy of skin to environmental pollutants.

The skin covers almost the entire body and plays an important role in detoxification and elimination of xenobiotics. These processes are initiated following the binding of xenobiotics to the aryl hydrocarbon receptor (AhR), which leads to the expression of several detoxification enzymes. To gain some insights on their impacts on skin cells over time, a temporal transcriptional analysis using gene expression arrays was performed in human primary epidermal keratinocyte (HEK) cells exposed for 6, 24 and 48 h to ß-naphthoflavone (ßNF), a potent agonist of AhR. Our results demonstrated that expression of genes related to xenobiotic, inflammation, and extracellular matrix remodeling was increased upon ßNF treatment from 6 h onwards. In contrast, the anti-oxidative response was seen mainly starting at 24 h. While some of the genes controlled by the epidermal differentiation complex was induced as soon as 6 h, expression of most of the S100 related genes located within the same chromosomal locus and keratin genes was increased at later times (24 and 48 h). Altogether our transcriptomic data highlight that following ßNF exposure, HEK cells elicited a protective xenobiotic response together with the activation of inflammation and keratinocyte regeneration. Later on these processes were followed by the stimulation of anti-oxidant activity and terminal differentiation.

Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions.

BACKGROUND: Several cases of myopathies have been observed in the horse Norman Cob breed. Muscle histology examinations revealed that some families suffer from a polysaccharide storage myopathy (PSSM). It is assumed that a gene expression signature related to PSSM should be observed at the transcriptional level because the glycogen storage disease could also be linked to other dysfunctions in gene regulation. Thus, the functional genomic approach could be conducted in order to provide new knowledge about the metabolic disorders related to PSSM. We propose exploring the PSSM muscle fiber metabolic disorders by measuring gene expression in relationship with the histological phenotype. RESULTS: Genotypying analysis of GYS1 mutation revealed 2 homozygous (AA) and 5 heterozygous (GA) PSSM horses. In the PSSM muscles, histological data revealed PAS positive amylase resistant abnormal polysaccharides, inflammation, necrosis, and lipomatosis and active regeneration of fibers. Ultrastructural evaluation revealed a decrease of mitochondrial number and structural disorders. Extensive accumulation of an abnormal polysaccharide displaced and partially replaced mitochondria and myofibrils. The severity of the disease was higher in the two homozygous PSSM horses.Gene expression analysis revealed 129 genes significantly modulated (p < 0.05). The following genes were up-regulated over 2 fold: IL18, CTSS, LUM, CD44, FN1, GST01. The most down-regulated genes were the following: mitochondrial tRNA, SLC2A2, PRKCalpha, VEGFalpha. Data mining analysis showed that protein synthesis, apoptosis, cellular movement, growth and proliferation were the main cellular functions significantly associated with the modulated genes (p < 0.05). Several up-regulated genes, especially IL18, revealed a severe muscular inflammation in PSSM muscles. The up-regulation of glycogen synthase kinase-3 (GSK3beta) under its active form could be responsible for glycogen synthase (GYS1) inhibition and hypoxia-inducible factor (HIF1alpha) destabilization. CONCLUSION: The main disorders observed in PSSM muscles could be related to mitochondrial dysfunctions, glycogenesis inhibition and the chronic hypoxia of the PSSM muscles.

Beyond the 3' end: experimental validation of extended transcript isoforms.

High throughput EST and full-length cDNA sequencing have revealed extensive variations at the 3' ends of mammalian transcripts. Whether all of these changes are biologically meaningful has been the subject of controversy, as such, results may reflect in part transcription or polyadenylation leakage. We selected here a set of tandem poly(A) sites predicted from EST/cDNA sequence analysis that (i) are conserved between human and mouse, (ii) produce alternative 3' isoforms with unusual size features and (iii) are not documented in current genome databases, and we submitted these sites to experimental validation in mouse tissues. Out of 86 tested poly(A) sites from 44 genes, 84 were individually confirmed using a specially devised RT-PCR strategy. We then focused on validating the exon structure between distant tandem poly(A) sites separated by over 3 kb, and between stop codons and alternative poly(A) sites located at 4.5 kb or more, using a long-distance RT-PCR strategy. In most cases, long transcripts spanning the whole poly(A)-poly(A) or stop-poly(A) distance were detected, confirming that tandem sites were part of the same transcription unit. Given the apparent conservation of these long alternative 3' ends, different regulatory functions can be foreseen, depending on the location where transcription starts.

Long-Term Pantethine Treatment Counteracts Pathologic Gene Dysregulation and Decreases Alzheimer's Disease Pathogenesis in a Transgenic Mouse Model.

The low-molecular weight thiol pantethine, known as a hypolipidemic and hypocholesterolemic agent, is the major precursor of co-enzyme A. We have previously shown that pantethine treatment reduces amyloid-ß (Aß)-induced IL-1ß release and alleviates pathological metabolic changes in primary astrocyte cultures. These properties of pantethine prompted us to investigate its potential benefits in vivo in the 5XFAD (Tg) mouse model of Alzheimer's disease (AD).1.5-month-old Tg and wild-type (WT) male mice were submitted to intraperitoneal administration of pantethine or saline control solution for 5.5 months. The effects of such treatments were investigated by performing behavioral tests and evaluating astrogliosis, microgliosis, Αß deposition, and whole genome expression arrays, using RNAs extracted from the mice hippocampi. We observed that long-term pantethine treatment significantly reduced glial reactivity and Αß deposition, and abrogated behavioral alteration in Tg mice. Moreover, the transcriptomic profiles revealed that after pantethine treatment, the expression of genes differentially expressed in Tg mice, and in particular those known to be related to AD, were significantly alleviated. Most of the genes overexpressed in Tg compared to WT were involved in inflammation, complement activation, and phagocytosis and were found repressed upon pantethine treatment. In contrast, pantethine restored the expression of a significant number of genes involved in the regulation of Αß processing and synaptic activities, which were downregulated in Tg mice. Altogether, our data support a beneficial role for long-term pantethine treatment in preserving CNS crucial functions altered by Aß pathogenesis in Tg mice and highlight the potential efficiency of pantethine to alleviate AD pathology.

Self-heating study of bulk acoustic wave resonators under high RF power.

The present work first provides an experimental technique to study self-heating of bulk acoustic wave (BAW) resonators under high RF power in the gigahertz range. This study is specially focused on film bulk acoustic wave resonators and solidly mounted resonators processed onto silicon wafers and designed for wireless systems. Precisely, the reflection coefficient of a one-port device is measured while up to several watts are applied and power leads to electrical drifts of impedances. In the following, we describe how absorbed power can be determined from the incident one in real time. Therefore, an infrared camera held over the radio frequency micro electromechanical system (RF-MEMS) surface with an exceptional spatial resolution reaching up to 2 microm/pixels gives accurate temperature mapping of resonators after emissivity correction. From theoretical point of view, accurate three-dimensional (3-D) structures for finite-element modeling analyses are carried out to know the best materials and architectures to use for enhancing power handling. In both experimental and theoretical investigations, comparison is made between film bulk acoustic wave resonators and solidly mounted resonators. Thus, the trend in term of material, architecture, and size of device for power application such as in transmission path of a transceiver is clearly identified.

Correction: Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer's disease: Alleviation by pantethine.

[This corrects the article DOI: 10.1371/journal.pone.0175369.].

Gene expression analysis reveals early changes in several molecular pathways in cerebral malaria-susceptible mice versus cerebral malaria-resistant mice.

BACKGROUND: Microarray analyses allow the identification and assessment of molecular signatures in whole tissues undergoing pathological processes. To better understand cerebral malaria pathogenesis, we investigated intra-cerebral gene-expression profiles in well-defined genetically cerebral malaria-resistant (CM-R) and CM-susceptible (CM-S) mice, upon infection by Plasmodium berghei ANKA (PbA). We investigated mouse transcriptional responses at early and late stages of infection by use of cDNA microarrays. RESULTS: Through a rigorous statistical approach with multiple testing corrections, we showed that PbA significantly altered brain gene expression in CM-R (BALB/c), and in CM-S (CBA/J and C57BL/6) mice, and that 327 genes discriminated between early and late infection stages, between mouse strains, and between CM-R and CM-S mice. We further identified 104, 56, 84 genes with significant differential expression between CM-R and CM-S mice on days 2, 5, and 7 respectively. The analysis of their functional annotation indicates that genes involved in metabolic energy pathways, the inflammatory response, and the neuroprotection/neurotoxicity balance play a major role in cerebral malaria pathogenesis. In addition, our data suggest that cerebral malaria and Alzheimer's disease may share some common mechanisms of pathogenesis, as illustrated by the accumulation of beta-amyloid proteins in brains of CM-S mice, but not of CM-R mice. CONCLUSION: Our microarray analysis highlighted marked changes in several molecular pathways in CM-S compared to CM-R mice, particularly at early stages of infection. This study revealed some promising areas for exploration that may both provide new insight into the knowledge of CM pathogenesis and the development of novel therapeutic strategies.

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer's disease: Alleviation by pantethine.

Astrocytes play critical roles in central nervous system homeostasis and support of neuronal function. A better knowledge of their response may both help understand the pathophysiology of Alzheimer's disease (AD) and implement new therapeutic strategies. We used the 5xFAD transgenic mouse model of AD (Tg thereafter) to generate astrocyte cultures and investigate the impact of the genotype on metabolic changes and astrocytes activation. Metabolomic analysis showed that Tg astrocytes exhibited changes in the glycolytic pathway and tricarboxylic acid (TCA) cycle, compared to wild type (WT) cells. Tg astrocytes displayed also a prominent basal inflammatory status, with accentuated reactivity and increased expression of the inflammatory cytokine interleukin-1 beta (IL-1ß). Compensatory mechanisms were activated in Tg astrocytes, including: i) the hexose monophosphate shunt with the consequent production of reducing species; ii) the induction of hypoxia inducible factor-1 alpha (HIF-1α), known to protect against amyloid-ß (Aß) toxicity. Such events were associated with the expression by Tg astrocytes of human isoforms of both amyloid precursor protein (APP) and presenilin-1 (PS1). Similar metabolic and inflammatory changes were induced in WT astrocytes by exogenous Aß peptide. Pantethine, the vitamin B5 precursor, known to be neuroprotective and anti-inflammatory, alleviated the pathological pattern in Tg astrocytes as well as WT astrocytes treated with Aß. In conclusion, our data enlighten the dual pathogenic/protective role of astrocytes in AD pathology and the potential protective role of pantethine.

Conservation of alternative polyadenylation patterns in mammalian genes.

BACKGROUND: Alternative polyadenylation is a widespread mechanism contributing to transcript diversity in eukaryotes. Over half of mammalian genes are alternatively polyadenylated. Our understanding of poly(A) site evolution is limited by the lack of a reliable identification of conserved, equivalent poly(A) sites among species. We introduce here a working definition of conserved poly(A) sites as sites that are both (i) properly aligned in human and mouse orthologous 3' untranslated regions (UTRs) and (ii) supported by EST or cDNA data in both species. RESULTS: We identified about 4800 such conserved poly(A) sites covering one third of the orthologous gene set studied. Characteristics of conserved poly(A) sites such as processing efficiency and tissue-specificity were analyzed. Conserved sites show a higher processing efficiency but no difference in tissular distribution when compared to non-conserved sites. In general, alternative poly(A) sites are species-specific and involve minor, non-conserved sites that are unlikely to play essential roles. However, there are about 500 genes with conserved tandem poly(A) sites. A significant fraction of these conserved tandems display a conserved arrangement of major/minor sites in their 3' UTR, suggesting that these alternative 3' ends may be under selection. CONCLUSION: This analysis allows us to identify potential functional alternative poly(A) sites and provides clues on the selective mechanisms at play in the appearance of multiple poly(A) sites and their maintenance in the 3' UTRs of genes.

High Seebeck Coefficient of Porous Silicon: Study of the Porosity Dependence.

In-plane Seebeck coefficient of porous Si free-standing membranes of different porosities was accurately measured at room temperature. Quasi-steady-state differential Seebeck coefficient method was used for the measurements. A detailed description of our home-built setup is presented. The Seebeck coefficient was proved to increase with increasing porosity up to a maximum of ~1 mV/K for the ~50 % porosity membrane, which is more than a threefold increase compared to the starting highly doped bulk c-Si substrate. By further increasing porosity and after a maximum is reached, the Seebeck coefficient sharply decreases and stabilizes at ~600 µV/K. The possible mechanisms that determine this behaviour are discussed, supported by structural characterization and photoluminescence measurements. The decrease in nanostructure size and increase in carrier depletion with increasing porosity, together with the complex structure and morphology of porous Si, are at the origin of complex energy filtering and phonon drag effects. All the above contribute to the observed anomalous behaviour of thermopower as a function of porosity and will be discussed.

Temporal gene profiling of the 5XFAD transgenic mouse model highlights the importance of microglial activation in Alzheimer's disease.

BACKGROUND: The 5XFAD early onset mouse model of Alzheimer's disease (AD) is gaining momentum. Behavioral, electrophysiological and anatomical studies have identified age-dependent alterations that can be reminiscent of human AD. However, transcriptional changes during disease progression have not yet been investigated. To this end, we carried out a transcriptomic analysis on RNAs from the neocortex and the hippocampus of 5XFAD female mice at the ages of one, four, six and nine months (M1, M4, M6, M9). RESULTS: Our results show a clear shift in gene expression patterns between M1 and M4. At M1, 5XFAD animals exhibit region-specific variations in gene expression patterns whereas M4 to M9 mice share a larger proportion of differentially expressed genes (DEGs) that are common to both regions. Analysis of DEGs from M4 to M9 underlines the predominance of inflammatory and immune processes in this AD mouse model. The rise in inflammation, sustained by the overexpression of genes from the complement and integrin families, is accompanied by an increased expression of transcripts involved in the NADPH oxidase complex, phagocytic processes and IFN-γ related pathways. CONCLUSIONS: Overall, our data suggest that, from M4 to M9, sustained microglial activation becomes the predominant feature and point out that both detrimental and neuroprotective mechanisms appear to be at play in this model. Furthermore, our study identifies a number of genes already known to be altered in human AD, thus confirming the use of the 5XFAD strain as a valid model for understanding AD pathogenesis and for screening potential therapeutic molecules.

Skeletal muscle alterations and exercise performance decrease in erythropoietin-deficient mice: a comparative study.

BACKGROUND: Erythropoietin (EPO) is known to improve exercise performance by increasing oxygen blood transport and thus inducing a higher maximum oxygen uptake (VO2max). Furthermore, treatment with (or overexpression of) EPO induces protective effects in several tissues, including the myocardium. However, it is not known whether EPO exerts this protective effect when present at physiological levels. Given that EPO receptors have been identified in skeletal muscle, we hypothesized that EPO may have a direct, protective effect on this tissue. Thus, the objectives of the present study were to confirm a decrease in exercise performance and highlight muscle transcriptome alterations in a murine EPO functional knock-out model (the EPO-d mouse). METHODS: We determined VO2max peak velocity and critical speed in exhaustive runs in 17 mice (9 EPO-d animals and 8 inbred controls), using treadmill enclosed in a metabolic chamber. Mice were sacrificed 24h after a last exhaustive treadmill exercise at critical speed. The tibialis anterior and soleus muscles were removed and total RNA was extracted for microarray gene expression analysis. RESULTS: The EPO-d mice's hematocrit was about 50% lower than that of controls (p<0.05) and their performance level was about 25% lower (p<0.001). A total of 1583 genes exhibited significant changes in their expression levels. However, 68 genes were strongly up-regulated (normalized ratio>1.4) and 115 were strongly down-regulated (normalized ratio<0.80). The transcriptome data mining analysis showed that the exercise in the EPO-d mice induced muscle hypoxia, oxidative stress and proteolysis associated with energy pathway disruptions in glycolysis and mitochondrial oxidative phosphorylation. CONCLUSIONS: Our results showed that the lack of functional EPO induced a decrease in the aerobic exercise capacity. This decrease was correlated with the hematocrit and reflecting poor oxygen supply to the muscles. The observed alterations in the muscle transcriptome suggest that physiological concentrations of EPO exert both direct and indirect muscle-protecting effects during exercise. However, the signaling pathway involved in these protective effects remains to be described in detail.

Acoustic, piezoelectric, and dielectric nonlinearities of AlN in coupled resonator filters for high RF power levels.

Coupled resonator filters (CRFs) are the new generation of BAW filters recently designed for the front-end modules of mobile transmission systems. Looking for designers' requirements, CRF devices have been characterized and modeled. The model based on equivalent circuits relies on material constants such as stiffness and electro-coupling coefficients, and works only for linear-mode propagation. Because of their positions between antennas and power amplifiers, they often work under high RF power, inducing nonlinear response in the AlN piezoelectric layer. In this work, we analyze for the first time the nonlinear behavior of AlN material particularly for coupled BAW resonators. To characterize the nonlinear effects in CRFs, we measure the 1-dB gain compression point (P1dB) and the intercept point (IP(3)). Then, we develop a nonlinear model of CRFs using harmonic balance (HB) simulation in commercially available software. The HB environment allows fitting simulations to measurements in terms of P(1dB) and IP(3). We find that a high RF power induces nonlinear changes in the material constants' real parts: elastic stiffness c(33) (4.9%), piezoelectric e(33) (17.4%), and permittivity ϵ(33) (5.2%). These nonlinear variations of material constants describe the nonlinear behavior of CRF devices using the same deposit process for AlN material.