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In mammals, plasma concentrations of amino acids (AA) are affected by nutritional or pathologic conditions. Alterations in AA profiles have been reported as a result of a deficiency of any one of the essential AA, a dietary imbalance of AA or an insufficient intake of protein. In recent years, evidence has accumulated that AA availability regulates the expression of several genes involved in the regulation of a number of cellular functions or AA metabolism. Nevertheless, the molecular mechanisms involved in the AA regulation of mammalian gene expression are limited, particularly the signaling pathways mediating the AA response. This work provides a better understanding of the signaling pathways involved in the AA control of gene expression. We studied the expression of C/EBP homologous protein (CHOP) and asparagine synthetase (AS) in response to deprivation of a single AA and investigated the possible link between protein synthesis inhibition due to amino acid limitation and gene expression. We have shown the following: 1) several mechanisms are involved in the AA control of gene expression. When omitted from the culture medium, each AA can activate one (or several) specific signaling pathways leading to the regulation of one specific pattern of genes. 2) AA limitation by itself can induce gene expression independently of a cellular stress due to protein synthesis inhibition. Together, these results suggest that AA control of gene expression involves several specific mechanisms by which one AA (or one group of AA) can activate one signaling pathway and thus alter one specific pattern of gene expression. [ABSTRACT FROM AUTHOR]

Summary: The reversible phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α) is a highly conserved signal implicated in the cellular adaptation to numerous stresses such as the one caused by amino acid limitation. In response to dietary amino acid deficiency, the brain-specific activation of the eIF2α kinase GCN2 leads to food intake inhibition. We report here that GCN2 is rapidly activated in the mediobasal hypothalamus (MBH) after consumption of a leucine-deficient diet. Furthermore, knockdown of GCN2 in this particular area shows that MBH GCN2 activity controls the onset of the aversive response. Importantly, pharmacological experiments demonstrate that the sole phosphorylation of eIF2α in the MBH is sufficient to regulate food intake. eIF2α signaling being at the crossroad of stress pathways activated in several pathological states, our study indicates that hypothalamic eIF2α phosphorylation could play a critical role in the onset of anorexia associated with certain diseases. [Copyright &y& Elsevier]

Parketal.(14)showedthatATF4canberegulatedbymTORC1 through a posttranscriptional mechanism independently of eIF2 phosphorylationandproposedthatATF4isalsoacentral regulator of AA homeostasis under nonstress conditions where demand for protein synthesis (and consequently for AAs) can nonetheless fluctuate. In addition to these well-characterized signaling pathways, several studies using transcription profiling reveal that other nonidentified signaling mechanisms could be involved in the regulation of gene expression in response to AA limitation (6). The most studied mechanism of sensing AA insufficiency is the pathway involving the protein kinase GCN2 that is activated upon free-tRNA accumulation after AA limitation. [Extracted from the article]

Currently, mitral valve repair (MVr) success for primary mitral regurgitation relies mainly on surgeon's expertise and major heterogeneities are observe concerning MVr rate, technics, and results. MVr success is estimated by a morphological echocardiographic assessment after aortic unclamping. To date, coaptation forces have been poorly characterized. We developed a device allowing a precise morphologic and qualitative assessment of coaptation. A first prototype allowing three-dimensional mapping of coaptation forces was developed and a provisional patent was filed. A number of features informed the design of the new device, including force sensitivity, flexibility, and biocompatibility. Varying sensing technologies were screened (including piezo-electric, piezo-resistive, and resistive sensors), and a specific device to hold the sensor was designed and prototyped. The first generation of prototype was tested on a porcine ex vivo beating heart model. The device was inserted between the mitral leaflet through a left atrial incision between two running sutures. The sensor was positioned and connected to a custom-made acquisition system. The coaptation signal was recorded in normal valves and after creation of a posterior central prolapse. We were able to obtain precise surface mapping of mitral coaptation forces in this model. The coaptation signal was notably more intense in the normal valve compare to the prolapsed valve in otherwise similar hemodynamic conditions (Fig. 1). A mapping of coaptation forces along the entire mitral valve surface can be achieved with the method and device we have developed. This technology may be useful to assist surgeons during MVr while providing real-time objective measurement in support of the conventional intraoperative morphological assessment. An extensive development roadmap has been developed and is being put in place to move our invention toward clinical trials. [ABSTRACT FROM AUTHOR]

Summary: To insure an adequate supply of nutrients, omnivores choose among available food sources. This process is exemplified by the well-characterized innate aversion of omnivores to otherwise nutritious foods of imbalanced amino acid content. We report that brain-specific inactivation of GCN2, a ubiquitously expressed protein kinase that phosphorylates translation initiation factor 2 α (eIF2α) in response to intracellular amino acid deficiency, impairs this aversive response. GCN2 inactivation also diminishes phosphorylated eIF2α levels in the mouse anterior piriform cortex following consumption of an imbalanced meal. An ancient intracellular signal transduction pathway responsive to amino acid deficiency thus affects feeding behavior by activating a neuronal circuit that biases consumption against imbalanced food sources. [Copyright &y& Elsevier]

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The CHOP gene is transcriptionally induced by amino acid starvation. We have previously identified a genomic cis-acting element (amino acid response element (AARE)) involved in the transcriptional activation of the human CHOP gene by leucine starvation and shown that it binds the activating transcription factor 2 (ATF2). The present study was designed to identify other transcription factors capable of binding to the CHOP AARE and to establish their role with regard to induction of the gene by amino acid deprivation. Electrophoretic mobility shift assay and transient transfection experiments show that several transcription factors that belong to the C/EBP or ATF families bind the AARE sequence and activate transcription. Among all these transcription factors, only ATF4 and ATF2 are involved in the amino acid control of CHOP expression. We show that inhibition of ATF2 or ATF4 expression impairs the transcriptional activation of CHOP by amino acid starvation. The transacting capacity of ATF4 depends on its expression level and that of ATF2 on its phosphorylation state. In response to leucine starvation, ATF4 expression and ATF2 phosphorylation are increased. However, induction of ATF4 expression by the endoplasmic reticulum stress pathway does not fully activate the AARE-dependent transcription. Taken together our results demonstrate that at least two pathways, one leading to ATF4 induction and one leading to ATF2 phosphorylation, are necessary to induce CHOP expression by amino acid starvation. This work was extended to the regulation of other amino acid regulated genes and suggests that ATF4 and ATF2 are key components of the amino acid control of gene expression. [ABSTRACT FROM AUTHOR]

Provides an understanding at the mechanisms involved in the amino acid regulation of gene expression. Regulation of amino acid metabolism and homeostasis; Posttranscriptional regulation of gene expression by amino acid availability; Transcriptional activation of mammalian genes by amino acid starvation; Signaling pathway of amino acid.

Objective. – To study the impact of an original education program on compliance to hormone replacement therapy (HRT) in post-menopausal women.Methods. – Data were obtained from 1,192 post-menopausal women (age: 53 ± 5 years) included in the study with an onset less than six months: E2 gel (n = 791) or patch (n = 401) + progestins, and randomized in either educational program (Ep = 600) or regular verbal counselling (VC = 592). A patient is considered bad compliant with HRT when she prematurely stopped the study, whatever the reason of the cessation. The groups EP and VC are homogeneous for the age distribution, the HRT regimen, the date of onset and the climateric symptoms scores.Results. – There is a significant difference between EP and VC groups in compliance, respectively 86 and 81% (p < 0.027). This difference is partially explained by the significant improvement in the patch subgroups (EP: 86% versus VC: 77%, p = 0.028). The trend observed in the gel group is not significant (EP: 85% and VC: 82%) due to the high level of compliance usually noticed in women treated with the gel and the verbal counselling. The significative difference in the compliance observed during the verbal counselling between the continuous (76%) and the sequential (86%, p = 0.001) HRT regimen disappears with the educational program (continuous: 84% and sequential: 87%, NS).Conclusion. – This first large study on the HRT compliance in France, using a patient educational material, validates its efficacy to reach a better compliance than with regular verbal counselling. Even though in the daily practice, about 40% of the patients discontinue the treatment during the first year, 81% of the women followed in this study continue to receive the HRT after nine months of use. The original educational program of the COMET study improves significatively this high compliance (+ 5% from the verbal counselling). Thus, the combination of the doctor verbal counselling and an educational material is desirable to obtain a good compliance with HRT. [Copyright &y& Elsevier]

Background: An increase in protein intake exerts a stimulating effect on protein kinetics in children, young adults, and healthy elderly persons. However, there are few data on the response to such dietary changes in malnourished elderly subjects, despite important medical implications in this population. Objective: The objective of this study was to determine the metabolic response to short-term nutritional supplementation in moderately malnourished elderly subjects. Design: The influence of 10 d of supplementation (1.67 MJ/d and 30 g protein/d) on body composition, resting energy expenditure, and whole-body protein kinetics was studied in 17 malnourished elderly patients and 12 healthy young adults. A control group of 6 malnourished elderly patients received no supplementation. Results: Supplemented elderly subjects had a significantly greater fat-free mass gain than did unsupplemented elderly subjects (1.3 and 0.1 kg, respectively; age effect, P < 0.05; diet effect, P < 0.02) and a significantly greater increase in fasting rate of protein synthesis than did young supplemented subjects (0.6 and 0.2 g x kg FFM-1 x 11 h-1; age effect, P < 0.05). The net protein balance in the supplemented elderly subjects in the fed state was positively correlated with protein intake (r2 = 0.46) and in the fasted state was negatively correlated with protein intake (r2 = 0.27). The sum of these regressions is a line with increasingly positive net diurnal protein balance produced by increasing protein intake. Conclusion: These data provide evidence of a short-term anabolic response of protein metabolism to dietary supplementation in malnourished elderly patients that is likely to improve muscle strength and functional status. Copyright © 2000 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

The present paper reports for the first time on the fabrication of highly efficient solar cells based on a perovskite layer produced by a sequential deposition method coupling thermal evaporation and slot-die coating. Thermally evaporated PbI 2 films were converted into perovskite by slot-die coating a solution containing the organic MA and FA cations. Careful optimization of the coating parameters resulted in uniform double-cation perovskite films with an optical band gap of 1.64 eV. This work highlights the need for a DMSO (Dimethyl Sulfoxide) vapor treatment performed on the evaporated PbI 2 film to obtain high-quality perovskite layers after the conversion step. Thus, a simple and short pre-treatment has been designed to induce the formation of porous PbI 2 (DMSO) x complex phases enabling a fast and complete perovskite conversion process. Thereby, the champion device delivers a power conversion efficiency of 19.8% with enhanced short-circuit current, open-circuit voltage, and fill factor compared to control devices without treatment. [Display omitted] • For the first time, wide bandgap mixed halide perovskite is deposited using thermal evaporation coupling slot-die coating. • A DMSO vapor treatment is applied to the evaporated PbI 2 precursor film to ease the perovskite formation. • A champion power conversion efficiency of 19.8% for perovskite solar cells is achieved using this deposition technique. [ABSTRACT FROM AUTHOR]

The mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth and metabolism. It controls many cell functions by integrating nutrient availability and growth factor signals. Amino acids, and in particular leucine, are among the main positive regulators of mTORC1 signaling. The current model for the regulation of mTORC1 by amino acids involves the movement of mTOR to the lysosome mediated by the Rag-GTPases. Here, we have examined the control of mTORC1 signaling and mTOR localization by amino acids and leucine in serum-fed cells, because both serum growth factors (or, e.g., insulin) and amino acids are required for full activation of mTORC1 signaling. We demonstrate that mTORC1 activity does not closely correlate with the lysosomal localization of mTOR. In particular, leucine controls mTORC1 activity without any detectable modification of the lysosomal localization of mTOR, indicating that the signal(s) exerted by leucine is likely distinct from those exerted by other amino acids. In addition, knock-down of the Rag-GTPases attenuated the inhibitory effect of amino acid- or leucine-starvation on the phosphorylation of mTORC1 targets. Furthermore, data from cells where Rag expression has been knocked down revealed that leucine can promote mTORC1 signaling independently of the lysosomal localization of mTOR. Our data complement existing models for the regulation of mTORC1 by amino acids and provide new insights into this important topic. [ABSTRACT FROM AUTHOR]

Abstract: CHOP encodes a ubiquitous transcription factor that is one of the most important components in the network of stress-inducible transcription. In particular, this factor is known to mediate cell death in response to stress. The focus of this work is to study its pivotal role in the control of cell viability according to the duration of a stress like amino acid starvation. We show that during the first 6h of starvation, CHOP upregulates a number of autophagy genes but is not involved in the first steps of the autophagic process. By contrast, when the amino acid starvation is prolonged (16–48h), we demonstrated that CHOP has a dual role in both inducing apoptosis and limiting autophagy through the transcriptional control of specific target genes. Overall, this study reveals a novel regulatory role for CHOP in the crosstalk between autophagy and apoptosis in response to stress. [Copyright &y& Elsevier]

Abstract: In mammals, metabolic adaptations are required to cope with episodes of protein deprivation and malnutrition. Consequently, mammals have to adjust physiological functions involved in the adaptation to amino acid availability. Part of this regulation involves the modulation of the expression of numerous genes. In particular, it has been shown that amino acids by themselves can modify the expression of target genes. This review describes the regulation of amino acids homeostasis and the their role as signal molecules. The recent advances in the understanding of the molecular mechanisms involved in the control of mammalian gene expression in response to amino acid limitation will be described. [Copyright &y& Elsevier]

Abstract: There is a growing body of evidence that suggests that amino acids play an important role in controlling gene expression, but the cell specificity of the amino-acid-mediated regulation of gene expression in mammals remains unknown. Using a model of muscle cells (C2C12) at two stages of differentiation, i.e. myoblasts and myotubes, we employed transcriptional profiling to show that amino-acid deficiency does not regulate the same set of gene in differentiated and non-differentiated cells. Furthermore, in myotubes, the GCN2 pathway is not activated by amino-acid starvation due to an amino-acid supply from intracellular proteolysis associated with a low GCN2 expression. [Copyright &y& Elsevier]

The integrated stress response (ISR) is defined as a highly conserved response to several stresses that converge to the induction of the activating transcription factor 4 (ATF4). Because an uncontrolled response may have deleterious effects, cells have elaborated several negative feedback loops that attenuate the ISR. In the present study, we describe how induction of the human homolog of Drosophila tribbles (TRB3) attenuates the ISR by a negative feedback mechanism. To investigate the role of TRB3 in the control of the ISR, we used the regulation of gene expression by amino acid limitation as a model. The enhanced production of ATF4 upon amino acid starvation results in the induction of a large number of target genes like CHOP (CAAT/enhancer-binding protein-homologous protein), asparagine synthetase (ASNS), or TRB3. We demonstrate that TRB3 overexpression inhibits the transcriptional induction of CHOP and ASNS whereas TRB3 silencing induces the expression of these genes both under normal and stressed conditions. In addition, transcriptional profiling experiments show that TRB3 affects the expression of many ISR-regulated genes. Our results also suggest that TRB3 and ATF4 belong to the same protein complex bound to the sequence involved in the ATF4-dependent regulation of gene expression by amino acid limitation. Collectively, our data identify TRB3 as a negative feedback regulator of the ATF4-dependent transcription and participates to the fine regulation of the ISR. [ABSTRACT FROM AUTHOR]