Publications by authors named "Andre d"

82 Publications

Phytochrome B and PHYTOCHROME INTERACTING FACTOR8 modulate seasonal growth in trees.

New Phytol 2021 Mar 18. Epub 2021 Mar 18.

Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, 901 83, Sweden.

The seasonally synchronized annual growth cycle that is regulated mainly by photoperiod and temperature cues is a crucial adaptive strategy for perennial plants in boreal and temperate ecosystems. Phytochrome B (phyB), as a light and thermal sensor, has been extensively studied in Arabidopsis. However, the specific mechanisms for how the phytochrome photoreceptors control the phenology in tree species remain poorly understood. We characterized the functions of PHYB genes and their downstream PHYTOCHROME INTERACTING FACTOR (PIF) targets in the regulation of shade avoidance and seasonal growth in hybrid aspen trees. We show that while phyB1 and phyB2, as phyB in other plants, act as suppressors of shoot elongation during vegetative growth, they act as promoters of tree seasonal growth. Furthermore, while the Populus homologs of both PIF4 and PIF8 are involved in the shade avoidance syndrome (SAS), only PIF8 plays a major role as a suppressor of seasonal growth. Our data suggest that the PHYB-PIF8 regulon controls seasonal growth through the regulation of FT and CENL1 expression while a genome-wide transcriptome analysis suggests how, in Populus trees, phyB coordinately regulates SAS responses and seasonal growth cessation.
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http://dx.doi.org/10.1111/nph.17350DOI Listing
March 2021

Androglobin gene expression patterns and FOXJ1-dependent regulation indicate its functional association with ciliogenesis.

J Biol Chem 2021 Jan-Jun;296:100291. Epub 2021 Jan 13.

Section of Medicine, Department of Endocrinology, Metabolism and Cardiovascular System, University of Fribourg, Fribourg, Switzerland. Electronic address:

Androglobin (ADGB) represents the latest addition to the globin superfamily in metazoans. The chimeric protein comprises a calpain domain and a unique circularly permutated globin domain. ADGB expression levels are most abundant in mammalian testis, but its cell-type-specific expression, regulation, and function have remained unexplored. Analyzing bulk and single-cell mRNA-Seq data from mammalian tissues, we found that-in addition to the testes-ADGB is prominently expressed in the female reproductive tract, lungs, and brain, specifically being associated with cell types forming motile cilia. Correlation analysis suggested coregulation of ADGB with FOXJ1, a crucial transcription factor of ciliogenesis. Investigating the transcriptional regulation of the ADGB gene, we characterized its promoter using epigenomic datasets, exogenous promoter-dependent luciferase assays, and CRISPR/dCas9-VPR-mediated activation approaches. Reporter gene assays revealed that FOXJ1 indeed substantially enhanced luciferase activity driven by the ADGB promoter. ChIP assays confirmed binding of FOXJ1 to the endogenous ADGB promoter region. We dissected the minimal sequence required for FOXJ1-dependent regulation and fine mapped the FOXJ1 binding site to two evolutionarily conserved regions within the ADGB promoter. FOXJ1 overexpression significantly increased endogenous ADGB mRNA levels in HEK293 and MCF-7 cells. Similar results were observed upon RFX2 overexpression, another key transcription factor in ciliogenesis. The complex transcriptional regulation of the ADGB locus was illustrated by identifying a distal enhancer, responsible for synergistic regulation by RFX2 and FOXJ1. Finally, cell culture studies indicated an ADGB-dependent increase in the number of ciliated cells upon overexpression of the full-length protein, confirming a ciliogenesis-associated role of ADGB in mammals.
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http://dx.doi.org/10.1016/j.jbc.2021.100291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949040PMC
January 2021

Acute Iatrogenic Agranulocytosis: A Rare and Dire Case of an Adverse Drug Reaction to Be Aware.

Case Rep Hematol 2020 19;2020:6125626. Epub 2020 Nov 19.

Hospital Central Do Funchal, Madeira Island, Funchal, Portugal.

Background: Iatrogenic agranulocytosis (IA), by nonchemotherapeutic drugs, is a rare adverse event, resulting in a neutrophil count under 0.5 × 10 cells/L with fever or other suggestive signs of infection.

Methods: This paper discusses the possible mechanisms responsible for agranulocytosis induced by nonchemotherapeutic drugs. It also describes three cases as well as potential ways to handle such iatrogenic situations.

Conclusion: Neutropenia under 0.1 × 10 cells/L predispose patients to potentially fatal infections. Empiric broad-spectrum antibiotic and hematopoietic growth factors may be helpful in shortening hospitalization and prevent further infectious complications. Not all drugs associated with IA require frequent hematological monitoring, except medications such as clozapine, ticlopidine, and antithyroids.
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http://dx.doi.org/10.1155/2020/6125626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690997PMC
November 2020

Cell Death in Cells Overlying Lateral Root Primordia Facilitates Organ Growth in Arabidopsis.

Curr Biol 2020 02 16;30(3):455-464.e7. Epub 2020 Jan 16.

Umeå Plant Science Centre, Department of Plant Physiology, Umeå University, 901 87 Umeå, Sweden. Electronic address:

Plant organ growth is widely accepted to be determined by cell division and cell expansion, but, unlike that in animals, the contribution of cell elimination has rarely been recognized. We investigated this paradigm during Arabidopsis lateral root formation, when the lateral root primordia (LRP) must traverse three overlying cell layers within the parent root. A subset of LRP-overlying cells displayed the induction of marker genes for cell types undergoing developmental cell death, and their cell death was detected by electron, confocal, and light sheet microscopy techniques. LRP growth was delayed in cell-death-deficient mutants lacking the positive cell death regulator ORESARA1/ANAC092 (ORE1). LRP growth was restored in ore1-2 knockout plants by genetically inducing cell elimination in cells overlying the LRP or by physically killing LRP-overlying cells by ablation with optical tweezers. Our results support that, in addition to previously discovered mechanisms, cell elimination contributes to regulating lateral root emergence.
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http://dx.doi.org/10.1016/j.cub.2019.11.078DOI Listing
February 2020

Index of suspicion with appropriate timing of CT scan helps prevent missed diagnosis in urologic trauma.

Med J Malaysia 2018 08;73(4):255-256

Hospital Kajang, Department of General Surgery, Selangor, Malaysia.

Ureteric and bladder injuries are uncommon, difficult to diagnose and rarely occur in isolation. Diagnosis is often delayed or missed at presentation. Therefore, high clinical suspicion and appropriate timing of computed tomography (CT) are of paramount importance. We report two cases (ureteropelvic junction avulsion and ruptured dome of bladder) whereby the presentations were subtle and would have been missed if not for high clinical suspicion. This article discusses the problems associated with these urologic injuries, as well as how to develop a high index of suspicion based on the pattern of anatomical disruption, mechanism of injury, physiological abnormality and comorbidity.
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August 2018

Influence of the periprostatic adipose tissue in obesity-associated mouse urethral dysfunction and oxidative stress: Effect of resveratrol treatment.

Eur J Pharmacol 2018 Oct 11;836:25-33. Epub 2018 Aug 11.

Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas 13084-971, Brazil.

Obese mice display overactive bladder (OAB) associated with impaired urethra smooth muscle (USM) function. In this study, we evaluated the role of the adipose tissue surrounding the urethra and prostate in obese mice (here referred as periprostatic adipose tissue; PPAT) to the USM dysfunction. Male C57BL6/JUnib mice fed with either a standard-chow or high-fat diet to induce obesity were used. In PPAT, histological analysis, and qPCR analysis for gp91phox, tumor necrosis factor-α (TNF-α) and superoxide dismutase (SOD) were conducted. In USM, concentration-response curves to contractile and relaxing agents, as well as measurements of reactive-oxygen species and nitric oxide (NO) levels were performed. The higher PPAT area in obese mice was accompanied by augmented gp91phox (NOX2) and TNF-α expressions, together with decreased SOD1 expression. In USM of obese group, the contractile responses to phenylephrine and vasopressin were increased, whereas the relaxations induced with glyceryl trinitrate were reduced. The reactive-oxygen species and NO levels in USM of obese mice were increased and decreased, respectively. A higher SOD expression was also detected in obese group whilst no changes in the gp91phox levels were observed. We next evaluated the effects of the antioxidant resveratrol (100 mg/kg/day, two-weeks, PO) in the functional alterations and NO levels of obese mice. Resveratrol treatment in obese mice reversed both the functional USM dysfunction and the reduced NO production. Our data show that PPAT exerts a local inflammatory response and increases oxidative stress that lead to urethral dysfunction. Resveratrol could be an auxiliary option to prevent obesity-associated urethral dysfunction.
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http://dx.doi.org/10.1016/j.ejphar.2018.08.010DOI Listing
October 2018

Epigallocatechin-3-gallate protects against the exacerbation of allergic eosinophilic inflammation associated with obesity in mice.

Int Immunopharmacol 2018 Sep 20;62:212-219. Epub 2018 Jul 20.

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil. Electronic address:

Obesity is linked to worse asthma symptoms. Epigallocatechin-3-gallate (EGCG) reduces airway inflammation, but no study investigated the effects of EGCG on obesity-associated asthma. We aimed here to evaluate the effects of EGCG on allergen-induced airway inflammation in high-fat diet-fed mice. Male C57Bl/6 mice maintained on either standard-chow or high-fat diet for 12 weeks were treated or not with EGCG (10 mg/kg/day, gavage, two weeks). Animals were intranasally challenged with ovalbumin (OVA). In lung tissue and bronchoalveolar lavage fluid (BALF), cell counting and markers of inflammation and oxidative stress were evaluated. High-fat diet-fed mice exhibited significantly higher body weight and epididymal fat mass compared with lean group. EGCG treatment reduced by 20% the epididymal fat mass in obese mice (P < 0.05). The OVA-induced increases of total cells and eosinophils in lung tissue of obese mice were significantly reduced EGCG treatment. The increased levels of TNF-α, IL-4, IL-5 and eotaxin in BALF of obese mice were normalized by EGCG. Likewise, the enhanced expression of inducible nitric oxide synthase (iNOS) and nitric oxide metabolite (NOx) levels in obese mice were normalized by EGCG. Reactive‑oxygen species (ROS) and superoxide dismutase (SOD) levels were elevated and reduced, respectively, in lung tissue of obese mice, both of which were restored by EGCG. In lean mice, EGCG had no significant effect in evaluated parameter (body measures, and inflammatory and oxidative markers). EGCG turns to normal the levels of inflammatory and oxidative stress markers in lungs of obese mice, suggesting it could be an option to attenuate obesity-related asthma.
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http://dx.doi.org/10.1016/j.intimp.2018.06.028DOI Listing
September 2018

Loss of Neuroglobin Expression Alters Cdkn1a/Cdk6-Expression Resulting in Increased Proliferation of Neural Stem Cells.

Stem Cells Dev 2018 03 27;27(6):378-390. Epub 2018 Feb 27.

1 Protein Chemistry, Proteomics and Epigenetic Signaling, University of Antwerp , Antwerp, Belgium .

In the quest to unravel its functional significance, neuroglobin (Ngb), a brain-specific neuroprotective protein, has recently been proposed as an actor in neurodevelopment. As neural stem cells (NSCs) are fundamental during brain development, the present study aimed at investigating the role of Ngb in the growth and proliferation of NSCs by comparing an Ngb-floxed (Ngb-)NSC line, equivalent to the wild-type cellular situation, with an in-house created Ngb knockout (Ngb-)NSC line. Ngb-NSCs were characterized by an increased growth and proliferation capacity in vitro, supported by RNA sequencing and western blot results reporting the downregulation of Cdkn1a and the upregulation of Cdk6, both enhancing the cell cycle. Based on additional gene ontology enrichment and pathway analyses, we hypothesize that the loss of Ngb affects multiple cellular signaling pathways with the most important being the Akt-Tp53 axis.
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http://dx.doi.org/10.1089/scd.2017.0097DOI Listing
March 2018

High-fat diet-induced obesity impairs insulin signaling in lungs of allergen-challenged mice: Improvement by resveratrol.

Sci Rep 2017 12 11;7(1):17296. Epub 2017 Dec 11.

Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

Insulin resistance plays an important role in obesity-associated asthma exacerbations. Using a murine model of allergic airway inflammation, we evaluated the insulin signaling transmission in lungs of obese compared with lean mice. We further evaluated the effects of the polyphenol resveratrol in the pulmonary insulin signaling. In lean mice, insulin stimulation significantly increased phosphorylations of AKT, insulin receptor substrate 1 (IRS-1) and insulin receptor β (IRβ) in lung tissue and isolated bronchi (p < 0.05), which were impaired in obese group. Instead, obese mice displayed increased tyrosine nitrations of AKT, IRβ and IRS-1 (p < 0.05). Two-week therapy of obese mice with resveratrol (100 mg/kg/day) restored insulin-stimulated AKT, IRS-1 and IRβ phosphorylations, and simultaneously blunted the tyrosine nitration of these proteins. Additionally, the c-Jun N-terminal kinase (JNK) and inhibitor of NF-κB Kinase (IκK) phosphorylations were significantly increased in obese group, an effect normalized by resveratrol. In separate experiments, the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine (20 mg/kg/day, three weeks) mimicked the protective effects exerted by resveratrol in lungs of obese mice. Lungs of obese mice display nitrosative-associated impairment of insulin signaling, which is reversed by resveratrol. Polyphenols may be putative drugs to attenuate asthma exacerbations in obese individuals.
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http://dx.doi.org/10.1038/s41598-017-17558-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725490PMC
December 2017

Hearing Without Neuroglobin.

Neuroscience 2017 Dec 13;366:138-148. Epub 2017 Oct 13.

Department of Nuclear Medicine, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.

Neuroglobin (Ngb) is a member of the globin family of respiratory proteins, which was recently observed in many neurons of the auditory pathways. Up to now, however, nothing was known about the role of Ngb in hearing processes. We therefore studied auditory function by recording distortion-product otoacoustic emissions (DPOAE) and auditory brainstem responses (ABRs) in wild-type (C57BL/6N) and Ngb-knockout mice. In KO mice, DPOAE thresholds were moderately augmented in the range of 5-18 kHz, reaching statistical significance at 8 and 10 kHz, while the ABR thresholds were not different between groups. The activation of the efferent system by an additional noise given to the contralateral ear resulted in an increased f2-f1-emission level only in WT animals. A noise exposure resulted in similar acute threshold shifts in the DPOAE and ABR of both animal groups. The recovery of hearing function, expressed by decreased DPOAE thresholds, was not significantly different between groups after four days and after four weeks. ABR recordings showed that threshold shifts elicited by noise-trauma were slightly better revised in wild-type mice. While ABR amplitudes were similar in both groups before noise overexposure, four weeks after trauma a moderate but statistically significant decrease of the latest peak-to-peak response amplitude (originating in the inferior colliculus) was observed in KO mice. Our results suggest that the lack of Ngb, at least in the model used in the present study, results in only marginal deficits in hearing ability. A putative functional role of Ngb in the efferent system warrants further studies.
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http://dx.doi.org/10.1016/j.neuroscience.2017.10.010DOI Listing
December 2017

Development of Simple QSPR Models for the Prediction of the Heat of Decomposition of Organic Peroxides.

Mol Inform 2017 10 12;36(10). Epub 2017 Apr 12.

Chimie ParisTech, PSL Research University, CNRS, Institut de Recherche de Chimie Paris (IRCP), F-75005, Paris, France.

Quantitative structure-property relationships represent alternative method to experiments to access the estimation of physico-chemical properties of chemicals for screening purpose at R&D level but also to gather missing data in regulatory context. In particular, such predictions were encouraged by the REACH regulation for the collection of data, provided that they are developed respecting the rigorous principles of validation proposed by OECD. In this context, a series of organic peroxides, unstable chemicals which can easily decompose and may lead to explosion, were investigated to develop simple QSPR models that can be used in a regulatory framework. Only constitutional and topological descriptors were employed to achieve QSPR models predicting the heat of decomposition, which could be used without any time consuming preliminary structure calculations at quantum chemical level. To validate the models, the original experimental dataset was divided into a training and a validation set according to two methods of partitioning, one based on the property value and the other based on the structure of the molecules by the mean of PCA. Four QSPR models were developed upon the type of descriptors and the methods of partitioning. The 2 models issuing from the PCA based method were highlighted as they presented good predictive power and they are easier to apply than our previous quantum chemical based model, since they do not need any preliminary calculations.
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http://dx.doi.org/10.1002/minf.201700024DOI Listing
October 2017

Critical re-evaluation of neuroglobin expression reveals conserved patterns among mammals.

Neuroscience 2016 Nov 16;337:339-354. Epub 2016 Aug 16.

Institute of Molecular Genetics, Johannes Gutenberg-University Mainz, D-55099 Mainz, Germany. Electronic address:

Neuroglobin (Ngb) is a respiratory protein that is almost exclusively expressed in the vertebrate nervous system. Despite many years of research, the exact function and even the expression sites of Ngb are still a matter of debate. However, to investigate hypotheses surrounding the potential roles of Ngb, a detailed knowledge of its major and minor expression sites is indispensable. We have therefore evaluated Ngb expression by extensive bioinformatic analysis using publicly available transcriptome data (RNA-Seq). During mammalian brain development, we observed low embryonic expression of Ngb mRNA and an increase after birth, arguing against a role of Ngb in fetal hypoxia tolerance. In adult mouse brain, we found highest Ngb mRNA levels in the hypothalamus, where expression was up to 100-fold stronger than in cerebral cortex, cerebellum or hippocampus, as confirmed by qRT-PCR and Western blotting. High Ngb expression in the hypothalamus was found conserved in humans and other mammals. Thus, Ngb mRNA is expressed at a basal level in many mammalian brain regions, but shows distinctive regional peaks. RNA-Seq analysis further revealed only low levels of Ngb mRNA in retina and testes and no signal in standard tumor cell lines, thus raising questions concerning previous studies and functional hypotheses. In conclusion, this broad-scale expression study may point to distinct Ngb functions for high- and low-expressing cells and tissues and argues against a single, generic role of Ngb as an oxygen supplier or as an endogenous protectant in all nerve cells.
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http://dx.doi.org/10.1016/j.neuroscience.2016.07.042DOI Listing
November 2016

Therapy with resveratrol attenuates obesity-associated allergic airway inflammation in mice.

Int Immunopharmacol 2016 Sep 22;38:298-305. Epub 2016 Jun 22.

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil. Electronic address:

Obesity and insulin resistance have been associated with deterioration in asthma outcomes. High oxidative stress and deficient activation of AMP-activated protein kinase (AMPK) have emerged as important regulators linking insulin resistance and inflammation. This study aimed to evaluate the effects of resveratrol on obesity-associated allergic pulmonary inflammation. Male C57/Bl6 mice fed with high-fat diet to induce obesity (obese group) or standard-chow diet (lean group) were treated or not with resveratrol (100mg/kg/day, two weeks). Mice were sensitized and challenged with ovalbumin (OVA). At 48h thereafter, bronchoalveolar lavage fluid was performed, and lungs collected for morphological studies and Western blot analysis. Treatment of obese mice with resveratrol significantly reduced hyperglycemia and insulin resistance, as well as the body measures (body mass, fat mass, % fat, and body area). OVA-challenge promoted a higher increase in pulmonary eosinophil infiltration in obese compared with lean mice, which was nearly abrogated by resveratrol treatment. Resveratrol markedly increased the phosphorylated AMPK expression in lung tissues of obese compared with lean mice. Resveratrol reduced the p47phox expression and reactive-oxygen species (ROS) production, and elevated the superoxide dismutase (SOD) levels in lung tissues of obese mice. The increased pulmonary levels of TNF-α and inducible nitric oxide synthase (iNOS) in obese mice were also normalized after resveratrol treatment. In lean mice, resveratrol failed to affect the levels of fasting glucose, p47phox, ROS levels, TNF-α, iNOS and phosphorylated AMPK. Resveratrol exhibits protective effects in obesity-associated lung inflammation that is accompanied by local AMPK activation and antioxidant property.
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http://dx.doi.org/10.1016/j.intimp.2016.06.017DOI Listing
September 2016

Chronic treatment with resveratrol improves overactive bladder in obese mice via antioxidant activity.

Eur J Pharmacol 2016 Oct 15;788:29-36. Epub 2016 Jun 15.

Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas 13084-971, Brazil. Electronic address:

The objective of the present work was to evaluate whether oral intake with resveratrol ameliorates overactive bladder in high-fat fed mice. Male C57BL6 mice fed with standard chow or high-fat diet to induce obesity received a two-week therapy with resveratrol (100mg/kg, given as a daily gavage). Weight and metabolic profile, together with cystometry and in vitro bladder contractions were evaluated. Measurements of gp91phox and SOD1 mRNA expressions and reactive-oxygen species (ROS) in bladder tissues, and serum TBARS were performed. Obese mice exhibited increases in body weight and epididymal fat mass, which were significantly reduced by oral treatment with resveratrol. Cystometric study in obese mice showed increases in non-voiding contractions, post-voiding pressure and voiding frequency that were reversed by resveratrol treatment. Likewise, the in vitro bladder overactivity in response to electrical-field stimulation (80V, 1-32Hz) or carbachol (1nM to 10mM) were normalized by resveratrol. The gp91phox and SOD1 mRNA expressions in bladder tissues were markedly higher in obese mice compared with lean group. In addition, ROS levels in bladder tissues and serum lipid peroxidation (TBARS assay) were markedly higher in obese compared with lean mice, all of which were reduced by resveratrol treatment. In lean group, resveratrol had no effect in any parameter evaluated. Our results show that two-week therapy of obese mice with resveratrol reduces the systemic and bladder oxidative stress, and greatly ameliorated the cystometry alterations and in vitro bladder overactivity. Resveratrol treatment could be an option to prevent obesity-associated overactive bladder.
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http://dx.doi.org/10.1016/j.ejphar.2016.06.017DOI Listing
October 2016

METACASPASE9 modulates autophagy to confine cell death to the target cells during Arabidopsis vascular xylem differentiation.

Biol Open 2016 Jan 6;5(2):122-9. Epub 2016 Jan 6.

Umeå Plant Science Centre, Department of Plant Physiology, Umeå University, Umeå 90187, Sweden

We uncovered that the level of autophagy in plant cells undergoing programmed cell death determines the fate of the surrounding cells. Our approach consisted of using Arabidopsis thaliana cell cultures capable of differentiating into two different cell types: vascular tracheary elements (TEs) that undergo programmed cell death (PCD) and protoplast autolysis, and parenchymatic non-TEs that remain alive. The TE cell type displayed higher levels of autophagy when expression of the TE-specific METACASPASE9 (MC9) was reduced using RNAi (MC9-RNAi). Misregulation of autophagy in the MC9-RNAi TEs coincided with ectopic death of the non-TEs, implying the existence of an autophagy-dependent intercellular signalling from within the TEs towards the non-TEs. Viability of the non-TEs was restored when AUTOPHAGY2 (ATG2) was downregulated specifically in MC9-RNAi TEs, demonstrating the importance of autophagy in the spatial confinement of cell death. Our results suggest that other eukaryotic cells undergoing PCD might also need to tightly regulate their level of autophagy to avoid detrimental consequences for the surrounding cells.
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http://dx.doi.org/10.1242/bio.015529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823987PMC
January 2016

Target Therapy in Lung Cancer.

Adv Exp Med Biol 2016 ;893:127-136

Unit of Thoracic Surgery, Chefarzt der neuen Klinik für Thoraxchirurgie am Kantonsspital, St. Gallen, Switzerland.

Lung cancer is an extremely heterogeneous disease, with well over 50 different histological variants recognized under the fourth revision of the World Health Organization (WHO) typing system. Because these variants have differing genetic and biological properties correct classification of lung cancer is necessary to assure that lung cancer patients receive optimum management. Due to the recent understanding that histologic typing and EGFR mutation status are important for target the therapy in lung adenocarcinoma patients there was a great need for a new classification that addresses diagnostic issues and strategic management to allow for molecular testing in small biopsy and cytology specimens. For this reason and in order to address advances in lung cancer treatment an international multidisciplinary classification was proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS), further increasing the histological heterogeneity and improving the existing WHO-classification. Is now the beginning of personalized therapy era that is ideally finalized to treat each individual case of lung cancer in different way.
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http://dx.doi.org/10.1007/978-3-319-24223-1_6DOI Listing
May 2016

Prediction of the thermal decomposition of organic peroxides by validated QSPR models.

J Hazard Mater 2014 Jul 13;276:216-24. Epub 2014 May 13.

Institut de Recherche de Chimie Paris, Chimie ParisTech CNRS, 11 rue P. et M. Curie, Paris 75005, France; Institut Universitaire de France, 103 Boulevard Saint Michel, Paris F-75005, France.

Organic peroxides are unstable chemicals which can easily decompose and may lead to explosion. Such a process can be characterized by physico-chemical parameters such as heat and temperature of decomposition, whose determination is crucial to manage related hazards. These thermal stability properties are also required within many regulatory frameworks related to chemicals in order to assess their hazardous properties. In this work, new quantitative structure-property relationships (QSPR) models were developed to predict accurately the thermal stability of organic peroxides from their molecular structure respecting the OECD guidelines for regulatory acceptability of QSPRs. Based on the acquisition of 38 reference experimental data using DSC (differential scanning calorimetry) apparatus in homogenous experimental conditions, multi-linear models were derived for the prediction of the decomposition heat and the onset temperature using different types of molecular descriptors. Models were tested by internal and external validation tests and their applicability domains were defined and analyzed. Being rigorously validated, they presented the best performances in terms of fitting, robustness and predictive power and the descriptors used in these models were linked to the peroxide bond whose breaking represents the main decomposition mechanism of organic peroxides.
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http://dx.doi.org/10.1016/j.jhazmat.2014.05.009DOI Listing
July 2014

Accuracy of a Novel Noninvasive Multisensor Technology to Estimate Glucose in Diabetic Subjects During Dynamic Conditions.

J Diabetes Sci Technol 2014 Jan 1;8(1):54-63. Epub 2014 Jan 1.

Div. Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA, USA

The purpose of this study was to determine whether an approach of multisensor technology with integrated data analysis in an armband system (SenseWear® Pro Armband, SWA) can provide estimates of plasma glucose concentration in diabetes. In all, 41 subjects with diabetes participated. On day 1 subjects underwent an oral glucose tolerance test (OGTT) and on day 2 a 60-minute treadmill test (TT). SWA plasma glucose estimates were compared against reference peripheral venous glucose concentrations. A continuous glucose monitoring device (CGM) was also placed on each subject to serve as a reference for clinical comparison. Pearson coefficient, Clarke error grid (CEG), and mean absolute relative difference (MARD) analyses were used to compare the performance of plasma glucose estimation. There were significant correlations between plasma glucose concentrations estimated by the SWA and the reference plasma glucose concentration during the OGTT (r = .65, P < .05) and the TT (r = .91, P < .05). CEG analysis revealed that during the OGTT, 93% of plasma glucose concentration readings were in the clinically acceptable zone A+B for the SWA and 95% for the CGM. During the TT, the SWA had 96% of readings in zone A+B, compared to 97% for the CGM. During OGTTs, MARDs for the SWA and CGM were 26% and 18%, respectively. During TTs, MARDs were 16% and 12%, respectively. Plasma glucose concentration estimation by the SWA's noninvasive multisensor approach appears to be feasible and its performance in estimating glucose approaches that of a CGM. The success of this pilot study suggests that multisensor technology holds promising potential for the development of a wearable, noninvasive, painless glucose monitor.
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http://dx.doi.org/10.1177/1932296813516182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454109PMC
January 2014

Are you bleeding? Validation of a machine-learning algorithm for determination of blood volume status: application to remote triage.

J Appl Physiol (1985) 2014 Mar 9;116(5):486-94. Epub 2014 Jan 9.

Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth, Texas;

Due to limited remote triage monitoring capabilities, combat medics cannot currently distinguish bleeding soldiers from those engaged in combat unless they have physical access to them. The purpose of this study was to test the hypothesis that low-level physiological signals can be used to develop a machine-learning algorithm for tracking changes in central blood volume that will subsequently distinguish central hypovolemia from physical activity. Twenty-four subjects underwent central hypovolemia via lower body negative pressure (LBNP), and a supine-cycle exercise protocol. Exercise workloads were determined by matching heart rate responses from each LBNP level. Heart rate and stroke volume (SV) were measured via Finometer. ECG, heat flux, skin temperature, galvanic skin response, and two-axis acceleration were obtained from an armband (SenseWear Pro2) and used to develop a machine-learning algorithm to predict changes in SV as an index of central blood volume under both conditions. The algorithm SV was retrospectively compared against Finometer SV. A model was developed to determine whether unknown data points could be correctly classified into these two conditions using leave-one-out cross-validation. Algorithm vs. Finometer SV values were strongly correlated for LBNP in individual subjects (mean r = 0.92; range 0.75-0.98), but only moderately correlated for exercise (mean r = 0.50; range -0.23-0.87). From the first level of LBNP/exercise, the machine-learning algorithm was able to distinguish between LBNP and exercise with high accuracy, sensitivity, and specificity (all ≥90%). In conclusion, a machine-learning algorithm developed from low-level physiological signals could reliably distinguish central hypovolemia from exercise, indicating that this device could provide battlefield remote triage capabilities.
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http://dx.doi.org/10.1152/japplphysiol.00012.2013DOI Listing
March 2014

Metformin attenuates the exacerbation of the allergic eosinophilic inflammation in high fat-diet-induced obesity in mice.

PLoS One 2013 24;8(10):e76786. Epub 2013 Oct 24.

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

A positive relationship between obesity and asthma has been well documented. The AMP-activated protein kinase (AMPK) activator metformin reverses obesity-associated insulin resistance (IR) and inhibits different types of inflammatory responses. This study aimed to evaluate the effects of metformin on the exacerbation of allergic eosinophilic inflammation in obese mice. Male C57BL6/J mice were fed for 10 weeks with high-fat diet (HFD) to induce obesity. The cell infiltration and inflammatory markers in bronchoalveolar lavage (BAL) fluid and lung tissue were evaluated at 48 h after ovalbumin (OVA) challenge. HFD obese mice displayed peripheral IR that was fully reversed by metformin (300 mg/kg/day, two weeks). OVA-challenge resulted in higher influx of total cell and eosinophils in lung tissue of obese mice compared with lean group. As opposed, the cell number in BAL fluid of obese mice was reduced compared with lean group. Metformin significantly reduced the tissue eosinophil infiltration and prevented the reduction of cell counts in BAL fluid. In obese mice, greater levels of eotaxin, TNF-α and NOx, together with increased iNOS protein expression were observed, all of which were normalized by metformin. In addition, metformin nearly abrogated the binding of NF-κB subunit p65 to the iNOS promoter gene in lung tissue of obese mice. Lower levels of phosphorylated AMPK and its downstream target acetyl CoA carboxylase (ACC) were found in lung tissue of obese mice, which were restored by metformin. In separate experiments, the selective iNOS inhibitor aminoguanidine (20 mg/kg, 3 weeks) and the anti-TNF-α mAb (2 mg/kg) significantly attenuated the aggravation of eosinophilic inflammation in obese mice. In conclusion, metformin inhibits the TNF-α-induced inflammatory signaling and NF-κB-mediated iNOS expression in lung tissue of obese mice. Metformin may be a good pharmacological strategy to control the asthma exacerbation in obese individuals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076786PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811997PMC
August 2014

[Alzheimer's disease and anaesthesia: potential relationships and clinical implications].

Ann Fr Anesth Reanim 2011 Jan 30;30(1):37-46. Epub 2010 Nov 30.

Service d'anesthésie réanimation I, groupe hospitalier Pellegrin, CHU de Bordeaux, université Victor-Segalen Bordeaux 2, 146, rue Léo-Saignat, 33076 Bordeaux cedex, France.

Alzheimer's disease is the most common form of dementia. As the aging population increases, Alzheimer's disease is becoming a major concern of Public Health. Many molecular lesions have been detected in Alzheimer's disease, but physiopathology is still poorly understood. If the neurotoxicity of anaesthetics in human remains debatable, perioperative period is certainly a high-risk factor for cognitive impairment, especially in elderly population. Large clinical studies are required to develop new strategies for perioperative management in such patients, including the adjustment of anaesthesia techniques. Before that, information of patient and its relatives and a particular attention for elderly during anaesthesia and perioperative period should be considered.
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http://dx.doi.org/10.1016/j.annfar.2010.10.013DOI Listing
January 2011

Physical inactivity in patients with COPD, a controlled multi-center pilot-study.

Respir Med 2010 Jul 18;104(7):1005-11. Epub 2010 Feb 18.

Pulmonary Rehabilitation and Respiratory Division, UZ Gasthuisberg, Leuven, Belgium.

Background: Physical activity (PA) has been reported to be reduced in severe chronic obstructive pulmonary disease (COPD). Studies in moderate COPD are currently scarce. The aim of the present study was to investigate physical activity in daily life in patients with COPD (n=70) and controls (n=30).

Methods: A multi-center controlled study was conducted. PA was assessed using a multisensor armband device (SenseWear, BodyMedia, Pittsburgh, PA) and is reported as the average number of steps per day, and the time spent in mild and moderate physical activity.

Results: Patients suffered from mild (n=9), moderate (n=28), severe (n=23) and very severe (n=10) COPD. The time spent in activities with mild (80 + or - 69 min vs 160 + or - 89 min, p<0.0001) and moderate intensity (24 + or - 29 min vs 65 + or - 70 min; p<0.0036) was reduced in patients compared to controls. The number of steps reached 87 + or - 34%, 71 + or - 32%, 49 + or - 34% and 29 + or - 20% of control values in GOLD-stages I to IV respectively. The time spent in activities at moderate intensity was 53 + or - 47%, 41 + or - 45%, 31 + or - 47% and 22 + or - 34% of the values obtained in controls respectively with increasing GOLD-stage. These differences reached statistical significance as of GOLD stage II (p<0.05). No differences were observed among centers.

Conclusions: Physical activity is reduced early in the disease progression (as of GOLD-stage II). Reductions in physical activities at moderate intensity seem to precede the reduction in the amount of physical activities at lower intensity.
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http://dx.doi.org/10.1016/j.rmed.2010.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471783PMC
July 2010

Mechanisms determining safety and performance of brain stimulating electrodes.

Annu Int Conf IEEE Eng Med Biol Soc 2009 ;2009:689-92

Department of Engineering Science and Mechanics at the Pennsylvania State University, University Park, PA 16802 USA.

Electrical current is widely used to interact with or stimulate neural systems. Current transduction from device to tissue is mediated at the electrode-tissue interface by capacitive charge and electrochemistry. This charge-passing-capacity is frequency dependent. While safety parameters have been established for high-frequencies, safety has not been fully determined for novel materials and pulse frequencies significantly lower than 100 Hz. We are explicitly interested in safety parameters and performance of charge passing at low frequencies (<<100 Hz) for neural systems. We present a visual study of pH during charge passing for electrodeposited iridium oxide electrodes. Clear reaction-diffusion waves are observed that extend many hundreds of micrometers from the electrode surface.
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http://dx.doi.org/10.1109/IEMBS.2009.5334136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606912PMC
April 2010

Orientational ordering in the low-temperature stable phases of deuterated thiophene.

Acta Crystallogr B 2008 Oct 15;64(Pt 5):589-95. Epub 2008 Sep 15.

Laboratoire Léon Brillouin, CEA, CNRS UMR12, CEA-Saclay, 91191 Gif-sur-Yvette Cedex, France.

The stable structures of deuterated thiophene C(4)D(4)S were investigated at 155 (phase III), 115 (phase IV), 100 and 1.5 K (phase V) by neutron powder diffraction. At 155 K, thiophene is orthorhombic with space group Pbnm. Although there is some degree of in-plane orientational disorder, molecules begin to order along two symmetrically equivalent main orientations. At 115 K the structure is incommensurate, with a wavevector q approximately 0.55a*. At 100 K and below, there is a doubling of the a cell parameter and the structure space group is P2(1). For the first time, it is shown that, unlike C(4)H(4)S, phase V of C(4)D(4)S is not an orientational glass: thiophene molecules are perfectly ordered and are oriented within the molecular plane along two alternating directions, corresponding to the two main orientations observed at 155 K. This ordering probably originates in the slowing down of the in-plane reorientational dynamics upon deuteration.
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http://dx.doi.org/10.1107/S0108768108015103DOI Listing
October 2008

[Harassment of personnel in contact with the public: from experiencing aggressive behaviour to preventing it].

Sante Publique 2008 May-Jun;20 Suppl 3:S137-47

Echelon national de santé au travail, Caisse centrale de la mutualité sociale agricole, Les Mercuriales, 40, rue lean Jaurès, 93547 Bagnolet cedex, France.

The Agricultural Social Mutual Insurance System (MSA) has been mobilised to support a corporate approach in the perspective to decrease mortal acts of violence or aggression. The plan brought together the skills of all the companies' actors (management, hygiene committees, safety and working conditions committee, occupational health and safety at work, and salaried workers). The MSA occupational health departments carried out a situational inventory (through a survey of salaried workers exposed to the risk of aggression). An intervention methodology was addressed to the occupational medical practitioners (PECVAT Protocol). A corporate framework agreement has specified the plan that was developed by company and the actors concerned. Finally, an evaluation enabled them to define the level at which this prevention intervention should be implemented.
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http://dx.doi.org/10.3917/spub.083.0137DOI Listing
October 2008

Heterotrimeric G-protein subunit function in Candida albicans: both the alpha and beta subunits of the pheromone response G protein are required for mating.

Eukaryot Cell 2008 Sep 25;7(9):1591-9. Epub 2008 Jul 25.

NRC Biotechnology Research Institute, 6100 Royalmount Ave., Montreal, Quebec, Canada H4P 2R2.

A pheromone-mediated signaling pathway that couples seven-transmembrane-domain (7-TMD) receptors to a mitogen-activated protein kinase module controls Candida albicans mating. 7-TMD receptors are typically connected to heterotrimeric G proteins whose activation regulates downstream effectors. Two Galpha subunits in C. albicans have been identified previously, both of which have been implicated in aspects of pheromone response. Cag1p was found to complement the mating pathway function of the pheromone receptor-coupled Galpha subunit in Saccharomyces cerevisiae, and Gpa2p was shown to have a role in the regulation of cyclic AMP signaling in C. albicans and to repress pheromone-mediated arrest. Here, we show that the disruption of CAG1 prevented mating, inactivated pheromone-mediated arrest and morphological changes, and blocked pheromone-mediated gene expression changes in opaque cells of C. albicans and that the overproduction of CAG1 suppressed the hyperactive cell cycle arrest exhibited by sst2 mutant cells. Because the disruption of the STE4 homolog constituting the only C. albicans gene for a heterotrimeric Gbeta subunit also blocked mating and pheromone response, it appears that in this fungal pathogen the Galpha and Gbeta subunits do not act antagonistically but, instead, are both required for the transmission of the mating signal.
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http://dx.doi.org/10.1128/EC.00077-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2547078PMC
September 2008

Recent advances in free-living physical activity monitoring: a review.

J Diabetes Sci Technol 2007 Sep;1(5):760-7

BodyMedia Inc., Pittsburgh, Pennsylvania 15222, USA.

It has become clear recently that the epidemic of type 2 diabetes sweeping the globe is associated with decreased levels of physical activity and an increase in obesity. Incorporating appropriate and sufficient physical activity into one's life is an essential component of achieving and maintaining a healthy weight and overall health, especially for those with type II diabetes mellitus. Regular physical activity can have a positive impact by lowering blood glucose, helping the body to be more efficient at using insulin. There are other substantial benefits for patients with diabetes, including prevention of cardiovascular disease, hyperlipidemia, hypertension, and obesity. Several complications of utilizing a self-care treatment methodology involving exercise include (1) patients may not know how much activity that they engage in and (2) health-care providers do not have objective measurements of how much activity their patients perform. However, several technological advances have brought a variety of activity monitoring devices to the market that can address these concerns. Ranging from simple pedometers to multisensor devices, the different technologies offer varying levels of accuracy, comfort, and reliability. The key notion is that by providing feedback to the patient, motivation can be increased and targets can be set and aimed toward. Although these devices are not specific to the treatment of diabetes, the importance of physical activity in treating the disease makes an understanding of these devices important. This article reviews these physical activity monitors and describes the advantages and disadvantages of each.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769664PMC
http://dx.doi.org/10.1177/193229680700100522DOI Listing
September 2007

Sherlock Holmes: an expert's view of expertise.

Br J Psychol 2008 Feb;99(Pt 1):109-25

Université de Franche-Comté, France.

In recent years, there has been an intense research effort to understand the cognitive processes and structures underlying expert behaviour. Work in different fields, including scientific domains, sports, games and mnemonics, has shown that there are vast differences in perceptual abilities between experts and novices, and that these differences may underpin other cognitive differences in learning, memory and problem solving. In this article, we evaluate the progress made in the last years through the eyes of an outstanding, albeit fictional, expert: Sherlock Holmes. We first use the Sherlock Holmes character to illustrate expert processes as described by current research and theories. In particular, the role of perception, as well as the nature and influence of expert knowledge, are all present in the description of Conan Doyle's hero. In the second part of the article, we discuss a number of issues that current research on expertise has barely addressed. These gaps include, for example, several forms of reasoning, the influence of emotions on cognition, and the effect of age on experts' knowledge and cognitive processes. Thus, although nearly 120-year-old, Conan Doyle's books show remarkable illustrations of expert behaviour, including the coverage of themes that have mostly been overlooked by current research.
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http://dx.doi.org/10.1348/000712607X224469DOI Listing
February 2008