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1. Transcription factor induction of vascular blood stem cell niches in vivo

Author

Hagedorn, Elliott J., Perlin, Julie R., Freeman, Rebecca J., Wattrus, Samuel J., Han, Tianxiao, Mao, Clara, Kim, Ji Wook, Fernández-Maestre, Inés, Daily, Madeleine L., D’Amato, Christopher, Fairchild, Michael J., Riquelme, Raquel, Li, Brian, Ragoonanan, Dana A.V.E., Enkhbayar, Khaliun, Henault, Emily L., Wang, Helen G., Redfield, Shelby E., Collins, Samantha H., Lichtig, Asher, Yang, Song, Zhou, Yi, Kunar, Balvir, Gomez-Salinero, Jesus Maria, Dinh, Thanh T., Pan, Junliang, Holler, Karoline, Feldman, Henry A., Butcher, Eugene C., van Oudenaarden, Alexander, Rafii, Shahin, Junker, J. Philipp, and Zon, Leonard I.

Published
2023
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2. Transcription factor induction of vascular blood stem cell niches in vivo

Author

Hagedorn, Elliott J, Perlin, Julie R, Freeman, Rebecca J, Wattrus, Samuel J, Han, Tianxiao, Mao, Clara, Kim, Ji Wook, Fernández-Maestre, Inés, Daily, Madeleine L, D'Amato, Christopher, Fairchild, Michael J, Riquelme, Raquel, Li, Brian, Ragoonanan, Dana A V E, Enkhbayar, Khaliun, Henault, Emily L, Wang, Helen G, Redfield, Shelby E, Collins, Samantha H, Lichtig, Asher, Yang, Song, Zhou, Yi, Kunar, Balvir, Gomez-Salinero, Jesus Maria, Dinh, Thanh T, Pan, Junliang, Holler, Karoline, Feldman, Henry A, Butcher, Eugene C, van Oudenaarden, Alexander, Rafii, Shahin, Junker, J Philipp, Zon, Leonard I, Hagedorn, Elliott J, Perlin, Julie R, Freeman, Rebecca J, Wattrus, Samuel J, Han, Tianxiao, Mao, Clara, Kim, Ji Wook, Fernández-Maestre, Inés, Daily, Madeleine L, D'Amato, Christopher, Fairchild, Michael J, Riquelme, Raquel, Li, Brian, Ragoonanan, Dana A V E, Enkhbayar, Khaliun, Henault, Emily L, Wang, Helen G, Redfield, Shelby E, Collins, Samantha H, Lichtig, Asher, Yang, Song, Zhou, Yi, Kunar, Balvir, Gomez-Salinero, Jesus Maria, Dinh, Thanh T, Pan, Junliang, Holler, Karoline, Feldman, Henry A, Butcher, Eugene C, van Oudenaarden, Alexander, Rafii, Shahin, Junker, J Philipp, and Zon, Leonard I

Abstract

The hematopoietic niche is a supportive microenvironment composed of distinct cell types, including specialized vascular endothelial cells that directly interact with hematopoietic stem and progenitor cells (HSPCs). The molecular factors that specify niche endothelial cells and orchestrate HSPC homeostasis remain largely unknown. Using multi-dimensional gene expression and chromatin accessibility analyses in zebrafish, we define a conserved gene expression signature and cis-regulatory landscape that are unique to sinusoidal endothelial cells in the HSPC niche. Using enhancer mutagenesis and transcription factor overexpression, we elucidate a transcriptional code that involves members of the Ets, Sox, and nuclear hormone receptor families and is sufficient to induce ectopic niche endothelial cells that associate with mesenchymal stromal cells and support the recruitment, maintenance, and division of HSPCs in vivo. These studies set forth an approach for generating synthetic HSPC niches, in vitro or in vivo, and for effective therapies to modulate the endogenous niche.

Published
2023

3. Transcription factor induction of vascular blood stem cell niches in vivo

Author

CMM Sectie Molecular Cancer Research, Cancer, Hubrecht Institute with UMC, Hagedorn, Elliott J., Perlin, Julie R., Freeman, Rebecca J., Wattrus, Samuel J., Han, Tianxiao, Mao, Clara, Kim, Ji Wook, Fernández-Maestre, Inés, Daily, Madeleine L., D'Amato, Christopher, Fairchild, Michael J., Riquelme, Raquel, Li, Brian, Ragoonanan, Dana A.V.E., Enkhbayar, Khaliun, Henault, Emily L., Wang, Helen G., Redfield, Shelby E., Collins, Samantha H., Lichtig, Asher, Yang, Song, Zhou, Yi, Kunar, Balvir, Gomez-Salinero, Jesus Maria, Dinh, Thanh T., Pan, Junliang, Holler, Karoline, Feldman, Henry A., Butcher, Eugene C., van Oudenaarden, Alexander, Rafii, Shahin, Junker, J. Philipp, Zon, Leonard I., CMM Sectie Molecular Cancer Research, Cancer, Hubrecht Institute with UMC, Hagedorn, Elliott J., Perlin, Julie R., Freeman, Rebecca J., Wattrus, Samuel J., Han, Tianxiao, Mao, Clara, Kim, Ji Wook, Fernández-Maestre, Inés, Daily, Madeleine L., D'Amato, Christopher, Fairchild, Michael J., Riquelme, Raquel, Li, Brian, Ragoonanan, Dana A.V.E., Enkhbayar, Khaliun, Henault, Emily L., Wang, Helen G., Redfield, Shelby E., Collins, Samantha H., Lichtig, Asher, Yang, Song, Zhou, Yi, Kunar, Balvir, Gomez-Salinero, Jesus Maria, Dinh, Thanh T., Pan, Junliang, Holler, Karoline, Feldman, Henry A., Butcher, Eugene C., van Oudenaarden, Alexander, Rafii, Shahin, Junker, J. Philipp, and Zon, Leonard I.

Published
2023

6. Transcription factor induction of vascular blood stem cell niches in vivo

Author

Hagedorn, Elliott J., primary, Perlin, Julie R., additional, Freeman, Rebecca J., additional, Wattrus, Samuel J., additional, Han, Tianxiao, additional, Mao, Clara, additional, Kim, Ji Wook, additional, Fernández-Maestre, Inés, additional, Daily, Madeleine L., additional, D’Amato, Christopher, additional, Fairchild, Michael J., additional, Riquelme, Raquel, additional, Li, Brian, additional, Ragoonanan, Dana A.V.E., additional, Enkhbayar, Khaliun, additional, Henault, Emily L., additional, Wang, Helen G., additional, Redfield, Shelby E., additional, Collins, Samantha H., additional, Lichtig, Asher, additional, Yang, Song, additional, Zhou, Yi, additional, Kunar, Balvir, additional, Gomez-Salinero, Jesus Maria, additional, Dinh, Thanh T., additional, Pan, Junliang, additional, Holler, Karoline, additional, Feldman, Henry A., additional, Butcher, Eugene C., additional, van Oudenaarden, Alexander, additional, Rafii, Shahin, additional, Philipp Junker, J., additional, and Zon, Leonard I., additional

Published
2021
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7. Long-term exposure to high-altitude chronic hypoxia during gestation induces neonatal pulmonary hypertension at sea level

Author

Herrera, Emilio A., Riquelme, Raquel A., Ebensperger, German, Reyes, Roberto V., Ulloa, Cesar E., Cabello, Gertrudis, Krause, Bernardo J., Parer, Julian T., Giussani, Dino A., and Llanos, Anibal J.

Subjects
Hypoxia -- Complications and side effects, Hypoxia -- Research, Infants (Newborn) -- Health aspects, Pregnant women -- Health aspects, Pulmonary hypertension -- Risk factors, Pulmonary hypertension -- Diagnosis, Pulmonary hypertension -- Research, Biological sciences
Abstract

We determined whether postnatal pulmonary hypertension induced by 70% of pregnancy at high altitude (HA) persists once the offspring return to sea level and investigated pulmonary vascular mechanisms operating under these circumstances. Pregnant ewes were divided into two groups: conception, pregnancy, and delivery at low altitude (580 m, LLL) and conception at low altitude, pregnancy at HA (3,600 m) from 30% of gestation until delivery, and return to lowland (LHL). Pulmonary arterial pressure (PAP) was measured in vivo. Vascular reactivity and morphometry were assessed in small pulmonary arteries (SPA). Protein expression of vascular mediators was determined. LHL lambs had higher basal PAP and a greater increment in PAP after [N.sup.G]-nitro-L-arginine methyl ester (20.9 [+ or -] 1.1 vs. 13.7 [+ or -] 0.5 mmHg; 39.9 [+ or -] 5.0 vs. 18.3 [+ or -] 1.3 mmHg, respectively). SPA from LHL had a greater maximal contraction to [K.sup.+] (1.34 [+ or -] 0.05 vs. 1.16 [+ or -] 0.05 N/m), higher sensitivity to endothelin-1 and nitroprusside, and persistence of dilatation following blockade of soluble guanylate cyclase. The heart ratio of the right ventricle-to-left ventricle plus septum was higher in the LHL relative to LLL. The muscle area of SPA (29.3 [+ or -] 2.9 vs. 21.1 [+ or -] 1.7%) and the protein expression of endothelial nitric oxide synthase (1.7 [+ or -] 0.1 vs. 1.1 [+ or -] 0.2), phosphodiesterase (1.4 [+ or -] 0.1 vs. 0.7 [+ or -] 0.1), and [Ca.sup.2+]-activated [K.sup.+] channel (0.76 [+ or -] 0.16 vs. 0.30 [+ or -] 0.01) were greater in LHL compared with LLL lambs. In contrast, LHL had decreased heme oxygenase-1 expression (0.82 [+ or -] 0.26 vs. 2.22 [+ or -] 0.44) and carbon monoxide production (all P < 0.05). Postnatal pulmonary hypertension induced by 70% of pregnancy at HA promotes cardiopulmonary remodeling that persists at sea level. pulmonary hypoxic vasoconstriction; pulmonary vascular reactivity; nitric oxide; pulmonary vasodilators; pulmonary vasoconstrictors doi: 10.1152/ajpregu.00123.2010

Published
2010

8. High-altitude chronic hypoxia during gestation and after birth modifies cardiovascular responses in newborn sheep

Author

Herrera, Emilio A., Pulgar, Victor M., Riquelme, Raquel A., Sanhueza, Emilia M., Reyes, Roberto V., Ebensperger, German, Parer, Julian T., Valdez, Enrique A., Ginssani, Dino A., Blanco, Carlos E., Hanson, Mark A., and Llanos, Anibal J.

Subjects
Hypoxia -- Research, Cardiovascular system -- Research, Lambs -- Research, Lambs -- Health aspects, Pulmonary hypertension -- Research, Pulmonary hypertension -- Risk factors, Biological sciences
Abstract

Perinatal exposure to chronic hypoxia induces sustained pulmonary hypertension and structural and functional changes in both pulmonary and systemic vascular beds. The aim of this study was to analyze consequences of high-altitude chronic hypoxia during gestation and early after birth in pulmonary and femoral vascular responses in newborn sheep. Lowland (LLNB; 580 m) and highland (HLNB; 3,600 m) newborn lambs were cathetherized under general anesthesia and submitted to acute sustained or stepwise hypoxic episodes. Contractile and dilator responses of isolated pulmonary and femoral small arteries were analyzed in a wire myograph. Under basal conditions, HLNB had a higher pulmonary arterial pressure (PAP; 20.2 [+ or -] 2.4 vs. 13.6 [+ or -] 0.5 mmHg, P < 0.05) and cardiac output (342 [+ or -] 23 vs. 279 [+ or -] 13 ml x [min.sup.-1] x [kg.sup.-1], P < 0.05) compared with LLNB. In small pulmonary arteries, HLNB showed greater contractile capacity and higher sensitivity to nitric oxide. In small femoral arteries, HLNB had lower maximal contraction than LLNB with higher maximal response and sensitivity to noradrenaline and phenylephrine. In acute superimposed hypoxia, HLNB reached higher PAP and femoral vascular resistance than LLNB. Graded hypoxia showed that average PAP was always higher in HLNB compared with LLNB at any P[O.sub.2]. Newborn lambs from pregnancies at high altitude have stronger pulmonary vascular responses to acute hypoxia associated with higher arterial contractile status. In addition, systemic vascular response to acute hypoxia is increased in high-altitude newborns, associated with higher arterial adrenergic responses. These responses determined in intrauterine life and early after birth could be adaptive to chronic hypoxia in the Andean altiplano. hypoxemia; pulmonary hypertension; vascular reactivity; neonatal lamb; highlands doi:10.1152/ajpregu.00909.2006

Published
2007

10. Vasodilator tone in the llama fetus: the role of nitric oxide during normoxemia and hypoxemia

Author

Sanhueza, Emilia M., Riquelme, Raquel A., Herrera, Emilio A., Giussani, Dino A., Blanco, Carlos A., Hanson, Mark A., and Llanos, Anibal J.

Subjects
Hypoxia -- Research, Blood flow -- Research, Blood pressure -- Research, Vasodilators -- Research, Biological sciences
Abstract

The fetal llama responds to hypoxemia, with a marked peripheral vasoconstriction but, unlike the sheep, with little or no increase in cerebral blood flow. We tested the hypothesis that the role of nitric oxide (NO) may be increased during hypoxemia in this species, to counterbalance a strong vasoconstrictor effect. Ten fetal llamas were operated under general anesthesia. Mean arterial pressure (MAP), heart rate, cardiac output, total vascular resistance, blood flows, and vascular resistances in cerebral, carotid and femoral vascular beds were determined. Two groups were studied, one with nitric oxide synthase (NOS) blocker [N.sup.G]-nitro-L-arginine methyl ester (L-NAME), and the other with 0.9% NaCl (control group), during normoxemia, hypoxemia, and recovery. During normoxemia, L-NAME produced an increase in fetal MAP and a rapid bradycardia. Cerebral, carotid, and femoral vascular resistance increased and blood flow decreased to carotid and femoral beds, while cerebral blood flow did not change significantly. However, during hypoxemia cerebral and carotid vascular resistance fell by 44% from its value in normoxemia after L-NAME, although femoral vascular resistance progressively increased and remained high during recovery. We conclude that in the llama fetus: 1) NO has an important role in maintaining a vasodilator tone during both normoxemia and hypoxemia in cerebral and femoral vascular beds and 2) during hypoxemia, NOS blockade unmasked the action of other vasodilator agents that contribute, with nitric oxide, to preserving blood flow and oxygen delivery to the tissues. [N.sup.G]-nitro-L-arginine methyl ester; arterial pressure; blood flow; vascular resistance; hypoxia

Published
2005

15. GRIP1 in GABAergic synapses

Author

Li, Rong-Wen, Serwanski, David R., Miralles, Celia P., Li, Xuejing, Charych, Erik, Riquelme, Raquel, Huganir, Richard L., and de Blas, Angel L.

Published
2005
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16. Chemoreflex and endocrine components of cardiovascular responses to acute hypoxemia in the llama fetus

Author

Giussani, Dino A., Riquelme, Raquel A., Moraga, Fernando A., McGarrigle, Hugh H.G., Gaete, Cristian R., Sanhueza, Emilia M., Hanson, Mark A., and Llanos, Anibal J.

Subjects
Llamas -- Physiological aspects, Hypoxia -- Physiological aspects, Carotid body -- Physiological aspects, Biological sciences
Abstract

Llamas have a low ventilatory sensitivity to hypoxia because of their exposure to chronic during early life. To determine whether llama fetuses also have a blunted carotid chemoreflex response, cardiovascular responses of intact and chronically instrumented fetuses during hypoxemia were examined. The intact fetuses exhibited intense vasoconstriction relative to the chronically instrumented fetal llamas. It was concluded that vasoconstriction is a consequence of chronic exposure to hypoxia of high altitude.

Published
1996

18. Transcription Factor Induction of Ectopic Vascular Blood Stem Cell Niches In Vivo

Author

Hagedorn, Elliott J., primary, Perlin, Julie R., primary, Freeman, Rebecca J., primary, Mao, Clara, primary, Fernández-Maestre, Inés, primary, Daily, Madeleine L., primary, D'Amato, Christopher R., primary, Wattrus, Samuel J., primary, Han, Tianxiao, primary, Fairchild, Michael J., primary, Riquelme, Raquel, primary, Li, Brian, primary, Redfield, Shelby E., primary, Collins, Samantha H., primary, Lichtig, Asher, primary, Yang, Song, primary, Zhou, Yi, primary, Kunar, Balvir, primary, Gomez-Salinero, Jesus M, primary, Dinh, Theresa T., primary, Pan, Junliang, primary, Holler, Karoline, primary, Butcher, Eugene, primary, Van Oudenaarden, Alexander, primary, Rafii, Shahin, primary, Junker, Jan Philipp, primary, and Zon, Leonard I, primary

Published
2019
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22. Generation of mouse-zebrafish hematopoietic tissue chimeric embryos for hematopoiesis and host-pathogen interaction studies

Author

Parada-Kusz, Margarita, primary, Penaranda, Cristina, additional, Hagedorn, Elliott J., additional, Clatworthy, Anne, additional, Nair, Anil V., additional, Henninger, Jonathan E., additional, Ernst, Christoph, additional, Li, Brian, additional, Riquelme, Raquel, additional, Jijon, Humberto, additional, Villablanca, Eduardo J., additional, Zon, Leonard I., additional, Hung, Deborah, additional, and Allende, Miguel L., additional

Published
2018
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23. Generation of Mouse-Zebrafish Hematopoietic Tissue Chimeric Embryos for Hematopoiesis and Host-Pathogen Interaction Studies

Author

Parada-Kusz, Margarita, primary, Clatworthy, Anne, additional, Hagedorn, Elliott J., additional, Penaranda, Cristina, additional, Nair, Anil V., additional, Henninger, Jonathan E., additional, Ernst, Christoph, additional, Li, Brian, additional, Riquelme, Raquel, additional, Jijon, Humberto, additional, Villablanca, Eduardo J., additional, Zon, Leonard I., additional, Hung, Deborah, additional, and Allende, Miguel L., additional

Published
2017
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25. Genome-Wide RNA Tomography of the Hematopoietic Stem Cell Niche in Zebrafish Reveals Unexpected Functional Macrophage-Stem Cell Interactions

Author

Hagedorn, Elliott J, primary, Perlin, Julie R, additional, Mao, Clara, additional, Li, Brian, additional, D'Amato, Christopher, additional, Riquelme, Raquel, additional, Collins, Samantha, additional, Holler, Karo, additional, van Oudenaarden, Alexander, additional, Junker, Jan Philipp, additional, and Zon, Leonard I., additional

Published
2016
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28. Acciones neurotróficas del factor de crecimiento similar a la insulina de tipo I en el oído interno

Author

Rodriguez-de la Rosa, Lourdes, Contreras, Julio, Cediel, Rafael, León, Yolanda, Sánchez-Calderón, Hortensia, Murillo-Cuesta, Silvia, Riquelme, Raquel, and Varela-Nieto, Isabel

Abstract

6 páginas, 4 figuras.-- et al., [ES]: [Introducción]: La pérdida de audición constituye una de las deficiencias sensoriales invalidantes más frecuentes en el mundo desarrollado. En la actualidad se estudian diferentes abordajes terapéuticos, entre los que se incluyen el tratamiento con células madre, la manipulación genética y la protección farmacológica. [Objetivo]: Evaluar el papel del factor de crecimiento similar a la insulina de tipo I (IGF-I) en el desarrollo, el mantenimiento y la reparación de la función auditiva. [Desarrollo]: El desarrollo del oído interno depende de la adecuada coordinación de los procesos celulares de proliferación, diferenciación, neurogénesis y muerte celular programada, que se encuentran regulados por distintos factores entre los que se encuentra el IGF-I. Durante la embriogénesis del oído interno, este factor se expresa abundantemente y es fundamental para la supervivencia celular y el mantenimiento de los precursores neuronales. El estudio del ratón nulo Igf-1¿/¿ ha puesto de manifiesto su importancia en el desarrollo y mantenimiento funcional del oído interno. Los ratones deficientes en este gen presentan alteraciones morfológicas que se corresponden con graves deficiencias funcionales, confirmadas mediante el análisis de los potenciales evocados auditivos de tronco cerebral. El déficit de IGF-I en humanos también se acompaña de hipoacusia sensorial profunda. [Conclusión]: En este escenario, se perfila el IGF-I como un factor clave para el desarrollo de la función auditiva y un candidato para la terapia regenerativa del oído interno., [EN]: [Introduction]: Loss of hearing constitutes one of the most frequent disabling sensory impairments in the developed world. Different therapeutic approaches are currently being studied, including treatment with stem cells, genetic manipulation and pharmacological protection. [Aim]: To evaluate the role played by insulin-like growth factor-I (IGF-I) in the development, maintenance and repair of auditory functioning. [Development]: Proper development of the inner ear is dependent on a suitable coordination of the cell processes of proliferation, differentiation, neurogenesis and programmed cell death, which are regulated by different factors, one of which is IGF-I. During the embryogenesis of the inner ear, this factor is expressed in abundance and is essential for cell survival and maintaining neuronal precursors. Studies conducted in Igf-1–/– null mice have highlighted its importance in the development and continued functioning of the inner ear. Mice with a deficit in this gene display morphological disorders that correspond to severe functional deficiencies, which are confirmed by analysing brainstem auditory evoked potentials. A deficit of IGF-I in humans is also accompanied by profound sensory hypoacusis. [Conclusions]: In a scenario like this, IGF-I appears as a key factor in the development of auditory functioning and a candidate for regenerative therapy of the inner ear., Trabajo financiado en parte gracias a los siguientes proyectos de investigación: FIS03/203, BMC03-07751, PIO05, BFU05, CAM IV PRICIT, y a la colaboración de la empresa DIGNA Biotech. H. Sánchez-Calderón disfruta de un contrato posdoctoral I3P del CSIC.

Published
2007

29. Sensorineural hearing loss in insulin-like growth factor I-null mice: A new model of human deafness

Author

Cediel, Rafael, Riquelme, Raquel, Contreras, Julio, and Varela-Nieto, Isabel

Subjects
otorhinolaryngologic diseases
Abstract

It has been reported that mutations in the gene encoding human insulin-like growth factor-I (IGF-I) cause syndromic hearing loss. To study the precise role of IGF-I in auditory function and to hypothesize the possible morphological and electrophysiological changes that may occur in the human inner ear, we have analysed the auditory brainstem response in a mouse model of IGF-I deficiency. We show here that homozygous Igf-1-/- mice present an all-frequency involved bilateral sensorineural hearing loss. Igf-1-/- mice also present a delayed response to acoustic stimuli; this increases along the auditory pathway, indicating a contribution of the central nervous system to the hearing loss in Igf-1-/- mice. These results support the use of the Igf-1-/- mouse as a new model for the study of human syndromic deafness. © The Authors (2006)., This work was supported in part by grants from Ministerio de Educación (BMC03 ⁄ 07751-C03-02), Fondo de Investigaciones Sanitarias (G03 ⁄ 203) and Comunidad de Madrid (SAL ⁄ 0873 ⁄ 2004). R.R and A.D. were supported by postdoctoral contracts of Comunidad de Madrid and the I3P CSIC programme, respectively.

Published
2006

30. Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex

Author

García-Díaz, Beatriz, primary, Riquelme, Raquel, additional, Varela-Nieto, Isabel, additional, Jiménez, Antonio Jesús, additional, de Diego, Isabel, additional, Gómez-Conde, Ana lsabel, additional, Matas-Rico, Elisa, additional, Aguirre, José Ángel, additional, Chun, Jerold, additional, Pedraza, Carmen, additional, Santín, Luis Javier, additional, Fernández, Oscar, additional, Rodríguez de Fonseca, Fernando, additional, and Estivill-Torrús, Guillermo, additional

Published
2014
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31. A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice

Author

Ministerio de Ciencia e Innovación (España), Fundación Mutua Madrileña, Digna Biotech, Riquelme, Raquel, Cediel, Rafael, Contreras, Julio, Rodriguez-de la Rosa, Lourdes, Murillo-Cuesta, Silvia, Hernández-Sánchez, Catalina, Zubeldia, José M., Cerdán, Sebastián, Varela-Nieto, Isabel, Ministerio de Ciencia e Innovación (España), Fundación Mutua Madrileña, Digna Biotech, Riquelme, Raquel, Cediel, Rafael, Contreras, Julio, Rodriguez-de la Rosa, Lourdes, Murillo-Cuesta, Silvia, Hernández-Sánchez, Catalina, Zubeldia, José M., Cerdán, Sebastián, and Varela-Nieto, Isabel

Abstract

Insulin-like growth factor-I (IGF-I) belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1(-/-) null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss) is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1(+/+) and null Igf1(-/-) mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR) recordings and in vivo MRI brain imaging. Igf1(-/-) null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1(+/+) wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1(-/-) null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to prevent or ameliorate ag

Published
2010

32. Store-operated channels in the pulmonary circulation of high- and low-altitude neonatal lambs

Author

Parrau, Daniela, primary, Ebensperger, Germán, additional, Herrera, Emilio A., additional, Moraga, Fernando, additional, Riquelme, Raquel A., additional, Ulloa, César E., additional, Rojas, Rodrigo T., additional, Silva, Pablo, additional, Hernandez, Ismael, additional, Ferrada, Javiera, additional, Diaz, Marcela, additional, Parer, Julian T., additional, Cabello, Gertrudis, additional, Llanos, Aníbal J., additional, and Reyes, Roberto V., additional

Published
2013
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33. Optimizing the stimuli to evoke the amplitude modulation following response (AMFR) in neonates

Author

Riquelme, Raquel and Riquelme, Raquel

Abstract

[Objective]: The goal was to identify stimulus features that enhance the detection of the amplitude modulation following response (AMFR) in neonates. The features explored were (1) envelope type, sinusoidal versus a half-wave rectified sinusoid (transposed); (2) best modulation frequency; and (3) spectral content, i.e., tone versus band-pass noise. [Design]: Results are based on recordings from 149 babies (80 babies in the neonatal intensive care unit and 69 newborn infants). All had passed hearing screening based on the click-evoked ABR. Babies were not sedated. We used carrier frequencies of approximately 500, 1000, 2000, and 4000 Hz and modulation frequencies between ∼25 and 98 Hz. For the noise stimuli, we used band-pass noise at center frequencies of 500, 1000, 2000, and 4000 Hz. All stimuli were presented through insert earphones delivered simultaneously to both ears, at intensities ranging from 20 to70 dB SPL. Magnitude squared coherence, phase coherence, and spectral criteria were used to detect criterion AMFRs. We analyzed four measures: (1) percent of satisfied runs; (2) the amplitude of criterion AMFR; (3) time to detect a criterion AMFR; and (4) response strength (e.g., the value of the magnitude squared coherence when it reached criterion minus the critical value it had to exceed for that number of averages all divided by the critical value). [Results]: (1) The AMFRs evoked by transposed tones were larger and detected faster than those to sinusoidal amplitude modulated tones. Consequently, remaining protocols all used the transposed envelopes. (2) The range of effective modulation frequencies was broad (41 to 88 Hz) across carrier frequencies. (3) The AMFRs evoked by transposed noise were faster and more efficient than those to transposed tones. [Conclusions]: In neonates, transposed tones are more effective than sinusoidal amplitude modulated tones in evoking the AMFR, modulation frequencies between 41 to 88 Hz are almost equally effective in evoking t

Published
2006

42. The auditory receptor of the epileptic hamster strain GPG/VALL

Author

Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología, Cantos, Raquel, Riquelme, Raquel, García Atares, Natividad, Sala Verdú, María Luisa, López García, Dolores Estilita, Rueda Puente, Joaquín, Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología, Cantos, Raquel, Riquelme, Raquel, García Atares, Natividad, Sala Verdú, María Luisa, López García, Dolores Estilita, and Rueda Puente, Joaquín

Published
1996

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