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1. Event reconstruction in a liquid xenon Time Projection Chamber with an optically-open field cage

Author

Stiegler, T., Sangiorgio, S., Brodsky, J.P., Heffner, M., Kharusi, S. Al, Anton, G., Arnquist, I.J., Badhrees, I., Barbeau, P.S., Beck, D., Belov, V., Bhatta, T., Bolotnikov, A., Breur, P.A., Brown, E., Brunner, T., Caden, E., Cao, G.F., Cao, L., Chambers, C., Chana, B., Charlebois, S.A., Chiu, M., Cleveland, B., Coon, M., Craycraft, A., Dalmasson, J., Daniels, T., Darroch, L., De St. Croix, A., Mesrobian-Kabakian, A. Der, Deslandes, K., DeVoe, R., Di Vacri, M.L., Dilling, J., Ding, Y.Y., Dolinski, M.J., Dragone, A., Echevers, J., Edaltafar, F., Elbeltagi, M., Fabris, L., Fairbank, D., Fairbank, W., Farine, J., Ferrara, S., Feyzbakhsh, S., Gallina, G., Gautam, P., Giacomini, G., Goeldi, D., Gornea, R., Gratta, G., Hansen, E.V., Hoppe, E.W., Hößl, J., House, A., Hughes, M., Iverson, A., Jamil, A., Jewell, M.J., Jiang, X.S., Karelin, A., Kaufman, L.J., Koffas, T., Krücken, R., Kuchenkov, A., Kumar, K.S., Lan, Y., Larson, A., Leach, K.G., Lenardo, B.G., Leonard, D.S., Li, G., Li, S., Li, Z., Licciardi, C., Lv, P., MacLellan, R., Massacret, N., McElroy, T., Medina-Peregrina, M., Michel, T., Mong, B., Moore, D.C., Murray, K., Nakarmi, P., Natzke, C.R., Newby, R.J., Ni, K., Ning, Z., Njoya, O., Nolet, F., Nusair, O., Odgers, K., Odian, A., Oriunno, M., Orrell, J.L., Ortega, G.S., Ostrovskiy, I., Overman, C.T., Parent, S., Piepke, A., Pocar, A., Pratte, J.-F., Radeka, V., Raguzin, E., Rasiwala, H., Rescia, S., Retière, F., Richman, M., Robinson, A., Rossignol, T., Rowson, P.C., Roy, N., Saldanha, R., Skarpaas, K., VIII, Soma, A.K., St-Hilaire, G., Stekhanov, V., Sun, X.L., Tarka, M., Thibado, S., Tidball, A., Todd, J., Totev, T.I., Tsang, R., Tsang, T., Vachon, F., Veeraraghavan, V., Viel, S., Visser, G., Vivo-Vilches, C., Vuilleumier, J.-L., Wagenpfeil, M., Wager, T., Walent, M., Wang, Q., Wei, W., Wen, L.J., Wichoski, U., Worcester, M., Wu, S.X., Wu, W.H., Wu, X., Xia, Q., Yang, H., Yang, L., Zeldovich, O., Zhao, J., Zhou, Y., and Ziegler, T.

Published
2021
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2. Measurements of electron transport in liquid and gas Xenon using a laser-driven photocathode

Author

Njoya, O., Tsang, T., Tarka, M., Fairbank, W., Kumar, K.S., Rao, T., Wager, T., Kharusi, S. Al, Anton, G., Arnquist, I.J., Badhrees, I., Barbeau, P.S., Beck, D., Belov, V., Bhatta, T., Brodsky, J.P., Brown, E., Brunner, T., Caden, E., Cao, G.F., Cao, L., Cen, W.R., Chambers, C., Chana, B., Charlebois, S.A., Chiu, M., Cleveland, B., Coon, M., Craycraft, A., Dalmasson, J., Daniels, T., Darroch, L., Daugherty, S.J., De St. Croix, A., Der Mesrobian-Kabakian, A., DeVoe, R., Di Vacri, M.L., Dilling, J., Ding, Y.Y., Dolinski, M.J., Dragone, A., Echevers, J., Elbeltagi, M., Fabris, L., Fairbank, D., Farine, J., Ferrara, S., Feyzbakhsh, S., Fontaine, R., Fucarino, A., Gallina, G., Gautam, P., Giacomini, G., Goeldi, D., Gornea, R., Gratta, G., Hansen, E.V., Heffner, M., Hoppe, E.W., Hößl, J., House, A., Hughes, M., Iverson, A., Jamil, A., Jewell, M.J., Jiang, X.S., Karelin, A., Kaufman, L.J., Kodroff, D., Koffas, T., Krücken, R., Kuchenkov, A., Lan, Y., Larson, A., Leach, K.G., Lenardo, B.G., Leonard, D.S., Li, G., Li, S., Li, Z., Licciardi, C., Lin, Y.H., Lv, P., MacLellan, R., McElroy, T., Medina-Peregrina, M., Michel, T., Mong, B., Moore, D.C., Murray, K., Nakarmi, P., Natzke, C.R., Newby, R.J., Ning, Z., Nolet, F., Nusair, O., Odgers, K., Odian, A., Oriunno, M., Orrell, J.L., Ortega, G.S., Ostrovskiy, I., Overman, C.T., Parent, S., Piepke, A., Pocar, A., Pratte, J.-F., Radeka, V., Raguzin, E., Rescia, S., Retière, F., Richman, M., Robinson, A., Rossignol, T., Rowson, P.C., Roy, N., Runge, J., Saldanha, R., Sangiorgio, S., Skarpaas, K., VIII, Soma, A.K., St-Hilaire, G., Stekhanov, V., Stiegler, T., Sun, X.L., Todd, J., Tolba, T., Totev, T.I., Tsang, R., Vachon, F., Veeraraghavan, V., Viel, S., Visser, G., Vivo-Vilches, C., Vuilleumier, J.-L., Wagenpfeil, M., Walent, M., Wang, Q., Ward, M., Watkins, J., Weber, M., Wei, W., Wen, L.J., Wichoski, U., Wu, S.X., Wu, W.H., Wu, X., Xia, Q., Yang, H., Yang, L., Yen, Y.-R., Zeldovich, O., Zhao, J., Zhou, Y., and Ziegler, T.

Published
2020
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3. Characterization of the Hamamatsu VUV4 MPPCs for nEXO

Author

Gallina, G., Giampa, P., Retière, F., Kroeger, J., Zhang, G., Ward, M., Margetak, P., Li, G., Tsang, T., Doria, L., Al Kharusi, S., Alfaris, M., Anton, G., Arnquist, I.J., Badhrees, I., Barbeau, P.S., Beck, D., Belov, V., Bhatta, T., Blatchford, J., Brodsky, J.P., Brown, E., Brunner, T., Cao, G.F., Cao, L., Cen, W.R., Chambers, C., Charlebois, S.A., Chiu, M., Cleveland, B., Coon, M., Craycraft, A., Dalmasson, J., Daniels, T., Darroch, L., Daugherty, S.J., De St. Croix, A., Der Mesrobian-Kabakian, A., DeVoe, R., Dilling, J., Ding, Y.Y., Dolinski, M.J., Dragone, A., Echevers, J., Elbeltagi, M., Fabris, L., Fairbank, D., Fairbank, W., Farine, J., Feyzbakhsh, S., Fontaine, R., Gautam, P., Giacomini, G., Gornea, R., Gratta, G., Hansen, E.V., Heffner, M., Hoppe, E.W., Hößl, J., House, A., Hughes, M., Ito, Y., Iverson, A., Jamil, A., Jewell, M.J., Jiang, X.S., Karelin, A., Kaufman, L.J., Kodroff, D., Koffas, T., Krücken, R., Kuchenkov, A., Kumar, K.S., Lan, Y., Larson, A., Lenardo, B.G., Leonard, D.S., Li, S., Li, Z., Licciardi, C., Lin, Y.H., Lv, P., MacLellan, R., McElroy, T., Medina-Peregrina, M., Michel, T., Mong, B., Moore, D.C., Murray, K., Nakarmi, P., Newby, R.J., Ning, Z., Njoya, O., Nolet, F., Nusair, O., Odgers, K., Odian, A., Oriunno, M., Orrell, J.L., Ortega, G.S., Ostrovskiy, I., Overman, C.T., Parent, S., Piepke, A., Pocar, A., Pratte, J.-F., Qiu, D., Radeka, V., Raguzin, E., Rescia, S., Richman, M., Robinson, A., Rossignol, T., Rowson, P.C., Roy, N., Saldanha, R., Sangiorgio, S., Skarpaas, K., VIII, Soma, A.K., St-Hilaire, G., Stekhanov, V., Stiegler, T., Sun, X.L., Tarka, M., Todd, J., Tolba, T., Totev, T.I., Tsang, R., Vachon, F., Veeraraghavan, V., Visser, G., Vuilleumier, J.-L., Wagenpfeil, M., Walent, M., Wang, Q., Watkins, J., Weber, M., Wei, W., Wen, L.J., Wichoski, U., Wu, S.X., Wu, W.H., Wu, X., Xia, Q., Yang, H., Yang, L., Yen, Y.-R., Zeldovich, O., Zhao, J., Zhou, Y., and Ziegler, T.

Published
2019
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8. Out- Of- Pocket health expenditure and household consumption patterns in Benin: Is there a crowding out effect?

Author

Hilaire Gbodja Houeninvo, Venant Cossi Celestin Quenum, and Melain Modeste Senou

Subjects
Health shocks, Consumption patterns, Out of Pocket, Crowding out effect, SURE, Benin, Medicine (General), R5-920
Abstract

Abstract Health shocks are common and have serious consequences for households in developing countries where health insurance is lacking. In this study, we examine whether out-of-pocket health expenditures crowd out household consumption of non-healthcare necessities, such as education items in Benin using a sample of 14,952 households from the global vulnerability and food security analysis survey. We estimated a system of conditional Engel curves with three stage least squared (3SLS) and seemingly unrelated regression (SURE) for seven categories of goods using the Quadratic Almost Ideal Demand System (QUAIDS) in the form of budget shares corresponding to proportions of total non-health expenditure. Findings show that out of pocket health expenditure leads households to spend more on health care that in fine crowd out expenditure in other necessity goods such as education item. These findings highlight the need for social protection programs to mitigate the impact of health shocks on vulnerable households in Benin.

Published
2023
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12. Developing and implementing National Health Insurance: learnings from the first try in Benin

Author

Kefilath Bello, Jean-Paul Dossou, Hashim Hounkpatin, and Hilaire Gbodja Houeninvo

Subjects
Medicine (General), R5-920, Infectious and parasitic diseases, RC109-216
Abstract

Methods We used a case study design, framed by the policy triangle of Walt and Gilson. We collected data through document review, quantitative data extraction from routine information, and interviews with 20 key informants. We performed a content analysis using both complementarily deductive and inductive analysis.Results This study confirms the keen interest for national health insurance scheme in Benin among various stakeholders. Compared with user fee exemption policies, it is considered as more sustainable, with a more reliable financing, and a greater likelihood to facilitate population’s access to quality healthcare without financial hardships.Exempting the poor from paying health insurance premiums was however considered as an equitable mean to facilitate the extension of the health insurance to informal sector workers.The whole arrangements failed to deliver appropriate skills, tools, coordination and incentives to drive the policy implementers to make individual and organisational changes necessary to adjust to the objectives and values of the reform. These deficiencies compromised the implementation fidelity with unintended effects such as low subscription rate, low services utilisation and sustainability threats.Conclusion Supporting countries in documenting policy processes will ease learning across their tries for progressing towards Universal Health Coverage, as more than one try will be necessary.

Published
2022
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16. Perinatal changes of I(h) in phrenic motoneurons

Author

Di Pasquale, E., Tell, F., Ptak, K., Monteau, R., Hilaire, G., Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de neurophysiologie cellulaire (LNPC), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), and Dumonceaud, Corinne

Subjects
MESH: Phrenic Nerve, Patch-Clamp Techniques, MESH: Rats, MESH: Respiratory Muscles, Cesium, MESH: Rats, Sprague-Dawley, MESH: Animals, Newborn, Membrane Potentials, Rats, Sprague-Dawley, MESH: Respiratory Center, Fetus, MESH: Cesium, MESH: Patch-Clamp Techniques, Animals, MESH: Membrane Potentials, MESH: Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Motor Neurons, Cardiovascular Agents, MESH: Fetus, Respiratory Center, Respiratory Muscles, Rats, Phrenic Nerve, Pyrimidines, Animals, Newborn, MESH: Pyrimidines, Respiratory Mechanics, MESH: Respiratory Mechanics, MESH: Cardiovascular Agents, MESH: Motor Neurons
Abstract

The hyperpolarization-activated cationic current (I(h)) was characterized and its maturation studied on phrenic motoneurons (PMNs), from reduced preparations of foetal (E18 and E21) and newborn (P0-P3) rats, using the whole-cell patch-clamp technique. In voltage-clamp mode, 2-s hyperpolarizing steps (5-mV, -50 to -110 mV) elicited a noninactivating inward current, blocked by external application of Cs+ or ZD 7288. At -110 mV, Ih current density averaged 0.67 +/- 0.41 pA/pF at E18, reached a transient peak at E21 (1.38 +/- 0.11 pA/pF) and decreased at P0-P3 (0.77 +/- 0.22 pA/pF). V1/2 was similar at E18 and E21 (-79 mV) but was significantly hyperpolarized at P0-P3 (-90 mV). The time constant of activation was voltage-dependent, and significantly faster at E21. Reversal potential was similar at all ages when estimated by extrapolation or tail current procedures. It was positively shifted by 25 +/- 6 mV when external potassium was raised from 3 to 10 m M, suggesting a similar sensitivity to K+ from E18 to P0-3. Cs(+) or ZD 7288 applications on PMNs at rest in current-clamp mode, in a partitioned chamber, induced a 10 +/- 2 mV hyperpolarization at E18 and E21, and an 8 +/- 2 mV hyperpolarization at P0-3. The area of the central respiratory drive potential or current was increased by 33 and 31%, respectively, at E21, but was not significantly modified at E18 and P0-3. Our data suggest a critical period during the perinatal maturation of Ih during which it is transiently upregulated and attenuates the influence of the central respiratory drive on PMNs just prior to birth.

Published
2001

17. Cellular and synaptic effect of substance P on neonatal phrenic motoneurons

Author

Ptak, K., Konrad, M., Di Pasquale, E., Tell, F., Hilaire, G., Monteau, R., Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de neurophysiologie cellulaire (LNPC), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Groupe d'étude des réseaux moteurs - GERM (GERMG), and Dumonceaud, Corinne

Subjects
MESH: Phrenic Nerve, Patch-Clamp Techniques, Potassium Channels, MESH: Substance P, MESH: Rats, Action Potentials, Cesium, Tetrodotoxin, Substance P, Receptors, N-Methyl-D-Aspartate, MESH: Animals, Newborn, Membrane Potentials, MESH: Synapses, MESH: Spinal Cord, MESH: Cesium, MESH: Patch-Clamp Techniques, Animals, MESH: Membrane Potentials, MESH: Receptors, Neurokinin-1, MESH: Animals, MESH: Receptors, Neurokinin-2, 4-Aminopyridine, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Action Potentials, Decerebrate State, Motor Neurons, MESH: Receptors, N-Methyl-D-Aspartate, Tetraethylammonium, Cobalt, Receptors, Neurokinin-2, MESH: Potassium Channels, Receptors, Neurokinin-1, MESH: Tetrodotoxin, Rats, Phrenic Nerve, MESH: Cobalt, 2-Amino-5-phosphonovalerate, Animals, Newborn, Spinal Cord, MESH: 4-Aminopyridine, MESH: Decerebrate State, MESH: Tetraethylammonium, Synapses, MESH: Brain Stem, MESH: 2-Amino-5-phosphonovalerate, MESH: Motor Neurons, Brain Stem
Abstract

Experiments were carried out on the in vitro brainstem-spinal cord preparation of the newborn rat to analyse the effects of substance P (SP) on phrenic motoneuron (PMN) activity. In current-clamp mode, SP significantly depolarized PMNs, increased their input resistance, decreased the rheobase current and shifted the firing frequency-intensity relationships leftwards, but did not affect spike frequency adaptation or single spike configuration. The neurokinin receptor agonist NK1 had SP-mimetic effects, whereas the NK3 and NK2 receptor agonists were less effective and ineffective, respectively. In a tetrodotoxin-containing aCSF, only SP or the NK1 receptor agonist were still active. No depolarization was observed when the NK1 receptor agonist was applied in the presence of muscarine. In voltage-clamp mode, SP or the NK1 receptor agonist produced an inward current (ISP) which was not significantly reduced by extracellular application of tetraethylammonium, Co2+, 4-aminopyridine or Cs+. In aCSF containing tetrodotoxin, Co2+ and Cs+, ISP was blocked by muscarine. No PMN displayed any M-type potassium current but only a current showing no voltage sensitivity over the range -100 to 0 mV, reversing near the expected EK +, hence consistent with a leak current. SP application to the spinal cord only (using a partitioned chamber) significantly increased the phrenic activity. Pretreatment with the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP5) decreased the C4 discharge duration and blocked the effect of SP, thus exhibiting an NMDA potentiation by SP. In conclusion, SP modulates postsynaptically the response of phrenic motoneurons to the inspiratory drive through the reduction of a leak conductance and the potentiation of the NMDA component of the synaptic input.

Published
2000

18. Changes in serotonin metabolism may elicit obstructive apnoea in the newborn rat

Author

Hilaire, G, Morin, D, Lajard, A M, and Monteau, R

Subjects
Serotonin, Electromyography, Tryptophan, Infant, Hydroxyindoleacetic Acid, Respiratory Muscles, Rats, 5-Hydroxytryptophan, Rats, Sprague-Dawley, Sleep Apnea Syndromes, Animals, Newborn, Animals, Humans, Injections, Intraperitoneal, Sudden Infant Death, Research Article
Abstract

1. Experiments were performed on anaesthetized newborn rats (aged 3-10 days) to know whether an increase in central serotonin levels might favour the occurrence of obstructive apnoeas as previously suggested by in vitro results from our group. 2. The levels of serotonin (5-HT), its precursor 5-hydroxytryptophan (5-HTP) and its metabolite, 5-hydroxyindole-acetic acid (5-HIAA), were analysed in cerebrospinal fluid samples collected at the level of the obex prior to and after intraperitoneal injection of L-tryptophan (50 mg kg-1) in sixty-eight anaesthetized newborn rats (control rats prior to injection and injected rats 15, 30 and 45 min after the injection). A significant increase in 5-HT and 5-HTP levels occurred 30 min after the injection, attesting to the activation of 5-HT biosynthesis. 3. The EMG activity of both the genioglossus and the diaphragm was recorded before and after L-tryptophan load (50 mg kg-1) in twenty-two newborn rats. After the injection of L-tryptophan, the amplitude of the integrated genioglossus activity decreased, or was even abolished, either during a few respiratory cycles or for long periods in twenty-one out of twenty-two animals. Recovery of the genioglossus activity occurred within 45-60 min. 4. The thoracic respiratory movements and the resulting upper airway pressure changes were recorded before and after L-tryptophan injection (50 mg kg-1) in sixty-two animals. In some litters (n = 7), most of the animals (21/25) displayed, within 20-40 min of the injection, recurrent episodes of obstructive apnoea often followed by central ones. These respiratory difficulties became severe and drastic, and led in two instances to respiratory distress and death. Lower doses of L-tryptophan (10 mg kg-1) did not induce any respiratory disorders unless these were potentiated by pargyline treatment (50 mg kg-1, n = 7). The obstructive apnoeas liable to occur after an L-tryptophan load (50 mg kg-1) were prevented by blocking the 5-HT receptor with methysergide (50 mg kg-1, n = 5) or by blocking the 5-HT biosynthesis by applying p-chlorophenylalanine (PCPA) pretreatment at birth (300 mg kg-1, n = 7). In other litters (n = 6), none of the eighteen newborn rats tested were affected by L-tryptophan, however, In five young adult rats, L-tryptophan again had no effect.4+ ĕ

Published
1993

19. Phox2a Gene, A6 Neurons, and Noradrenaline Are Essential for Development of Normal Respiratory Rhythm in Mice.

Author

Viemari, J. C., Bévengut, M., Burnet, H., Coulon, P., Pequignot, J. M., Tiveron, M. C., and Hilaire, G.

Subjects
NEURONS, NORADRENALINE, RESPIRATORY organs, NERVOUS system, MICE, NEUROSCIENCES
Abstract

Although respiration is vital to the survival of all mammals from the moment of birth, little is known about the genetic factors controlling the prenatal maturation of this physiological process. Here we investigated the role of the Phox2a gene that encodes for a homeodomain protein involved in the generation of noradrenergic A6 neurons in the maturation of the respiratory network. First, comparisons of the respiratory activity of fetuses delivered surgically from heterozygous Phox2a pregnant mice on gestational day 18 showed that the mutants had impaired in vivo ventilation, in vitro respiratory-like activity, and in vitro respiratory responses to central hypoxia and noradrenaline. Second, pharmacological studies on wild-type neonates showed that endogenous noradrenaline released from pontine A6 neurons potentiates rhythmic respiratory activity via α1 medullary adrenoceptors. Third, transynaptic tracing experiments in which rabies virus was injected into the diaphragm confirmed that A6 neurons were connected to the neonatal respiratory network. Fourth, blocking the α1 adrenoceptors in wild-type dams during late gestation with daffy injections of the α1 adrenoceptor antagonist prazosin induced in vivo and in vitro neonatal respiratory deficits similar to those observed in Phox2a mutants. These results suggest that noradrenaline, A6 neurons, and the Phox2a gene, which is crucial for the generation of A6 neurons, are essential for development of normal respiratory rhythm in neonatal mice. Metabolic noradrenaline disorders occurring during gestation therefore may induce neonatal respiratory deficits, in agreement with the catecholamine anomalies reported in victims of sudden infant death syndrome. [ABSTRACT FROM AUTHOR]

Published
2004
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48. Prevalence of HTLV-I Infection and Its Association with Tuberculosis among Patients at an Urban Clinic in Haiti.

Author

Walsh KF, Lee MH, Brejt JA, Reust MJ, Juste MJ, Hilaire G, Pape JW, Koenig S, and Dupnik K

Abstract

This retrospective case-control study examined the prevalence of HTLV-I and its association with tuberculosis among urban clinic patients in Haiti. Prevalence of HTLV-I among tuberculosis cases was 2.1% and among controls was 2.4%. Prevalence of HLTV-I was higher in females than males (odds ratio [OR] 2.45, P = 0.020). HTLV-I prevalence in those ≥ 50 years was 8.4% compared with 1.3% in those < 50 (OR 6.74, P < 0.001). We found no association between HTLV-I and tuberculosis in this population.

Published
2022
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49. Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader-Willi syndrome.

Author

Matarazzo V, Caccialupi L, Schaller F, Shvarev Y, Kourdougli N, Bertoni A, Menuet C, Voituron N, Deneris E, Gaspar P, Bezin L, Durbec P, Hilaire G, and Muscatelli F

Subjects
Animals, Disease Models, Animal, Gene Deletion, Mice, Nerve Tissue Proteins deficiency, Nuclear Proteins deficiency, Serotonin metabolism, Action Potentials, Apnea physiopathology, Nerve Tissue Proteins metabolism, Nuclear Proteins metabolism, Prader-Willi Syndrome physiopathology, Serotonergic Neurons pathology, Serotonin Plasma Membrane Transport Proteins metabolism
Abstract

Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder that presents with hypotonia and respiratory distress in neonates. The Necdin -deficient mouse is the only model that reproduces the respiratory phenotype of PWS (central apnea and blunted response to respiratory challenges). Here, we report that Necdin deletion disturbs the migration of serotonin (5-HT) neuronal precursors, leading to altered global serotonergic neuroarchitecture and increased spontaneous firing of 5-HT neurons. We show an increased expression and activity of 5-HT Transporter (SERT/Slc6a4) in 5-HT neurons leading to an increase of 5-HT uptake. In Necdin -KO pups, the genetic deletion of Slc6a4 or treatment with Fluoxetine, a 5-HT reuptake inhibitor, restored normal breathing. Unexpectedly, Fluoxetine administration was associated with respiratory side effects in wild-type animals. Overall, our results demonstrate that an increase of SERT activity is sufficient to cause the apneas in Necdin- KO pups, and that fluoxetine may offer therapeutic benefits to PWS patients with respiratory complications.

Published
2017
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50. Increasing brain protein O-GlcNAc-ylation mitigates breathing defects and mortality of Tau.P301L mice.

Author

Borghgraef P, Menuet C, Theunis C, Louis JV, Devijver H, Maurin H, Smet-Nocca C, Lippens G, Hilaire G, Gijsen H, Moechars D, and Van Leuven F

Subjects
Analysis of Variance, Animals, Blotting, Western, Female, Immunohistochemistry, Immunoprecipitation, Mice, Mice, Transgenic, Plethysmography, Pyrans chemical synthesis, Respiratory Mechanics drug effects, Thiazoles chemical synthesis, tau Proteins genetics, Brain metabolism, Nerve Tissue Proteins metabolism, Pyrans pharmacology, Respiratory Mechanics physiology, Tauopathies drug therapy, Tauopathies physiopathology, Thiazoles pharmacology, beta-N-Acetylhexosaminidases antagonists & inhibitors
Abstract

The microtubule associated protein tau causes primary and secondary tauopathies by unknown molecular mechanisms. Post-translational O-GlcNAc-ylation of brain proteins was demonstrated here to be beneficial for Tau.P301L mice by pharmacological inhibition of O-GlcNAc-ase. Chronic treatment of ageing Tau.P301L mice mitigated their loss in body-weight and improved their motor deficits, while the survival was 3-fold higher at the pre-fixed study endpoint at age 9.5 months. Moreover, O-GlcNAc-ase inhibition significantly improved the breathing parameters of Tau.P301L mice, which underpinned pharmacologically the close correlation of mortality and upper-airway defects. O-GlcNAc-ylation of brain proteins increased rapidly and stably by systemic inhibition of O-GlcNAc-ase. Conversely, biochemical evidence for protein Tau.P301L to become O-GlcNAc-ylated was not obtained, nor was its phosphorylation consistently or markedly affected. We conclude that increasing O-GlcNAc-ylation of brain proteins improved the clinical condition and prolonged the survival of ageing Tau.P301L mice, but not by direct biochemical action on protein tau. The pharmacological effect is proposed to be located downstream in the pathological cascade initiated by protein Tau.P301L, opening novel venues for our understanding, and eventually treating the neurodegeneration mediated by protein tau.

Published
2013
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