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1.
Cell ; 137(5): 961-71, 2009 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-19490899

RESUMEN

It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal ganglia. In the striatum, a part of the basal ganglia affected in humans with a speech deficit due to a nonfunctional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one nonfunctional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans.


Asunto(s)
Sustitución de Aminoácidos , Ganglios Basales/metabolismo , Evolución Biológica , Factores de Transcripción Forkhead/metabolismo , Vocalización Animal , Animales , Dendritas/metabolismo , Dopamina/metabolismo , Expresión Génica , Heterocigoto , Humanos , Lenguaje , Depresión Sináptica a Largo Plazo , Ratones , Vías Nerviosas , Plasticidad Neuronal , Habla
2.
J Neurochem ; 159(3): 525-542, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34379806

RESUMEN

Sepsis-associated encephalopathy (SAE) represents diverse cerebral dysfunctions in response to pathogen-induced systemic inflammation. Peripheral exposure to lipopolysaccharide (LPS), a component of the gram-negative bacterial cell wall, has been extensively used to model systemic inflammation. Our previous studies suggested that LPS led to hippocampal neuron death and synaptic destruction in vivo. However, the underlying roles of activated microglia in these neuronal changes remained unclear. Here, LPS from two different bacterial strains (Salmonella enterica or E. coli) were compared and injected in 14- to 16-month-old mice and evaluated for neuroinflammation and neuronal integrity in the hippocampus at 7 or 63 days post-injection (dpi). LPS injection resulted in persistent neuroinflammation lasting for seven days and a subsequent normalisation by 63 dpi. Of note, increases in proinflammatory cytokines, microglial morphology and microglial mean lysosome volume were more pronounced after E. coli LPS injection than Salmonella LPS at 7 dpi. While inhibitory synaptic puncta density remained normal, excitatory synaptic puncta were locally reduced in the CA3 region of the hippocampus at 63 dpi. Finally, we provide evidence that excitatory synapses coated with complement factor 3 (C3) decreased between 7 dpi and 63 dpi. Although we did not find an increase of synaptic pruning by microglia, it is plausible that microglia recognised and eliminated these C3-tagged synapses between the two time points of investigation. Since a region-specific decline of CA3 synapses has previously been reported during normal ageing, we postulate that systemic inflammation may have accelerated or worsened the CA3 synaptic changes in the ageing brain.


Asunto(s)
Envejecimiento/patología , Región CA3 Hipocampal/patología , Inflamación/patología , Sinapsis/patología , Animales , Femenino , Inmunohistoquímica , Lipopolisacáridos , Ratones , Ratones Endogámicos C57BL , Microglía/patología , Salmonella , Sepsis/patología , Sinaptosomas/patología
3.
PLoS Biol ; 16(4): e2005019, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29659570

RESUMEN

Animal welfare requires the adequate housing of animals to ensure health and well-being. The application of environmental enrichment is a way to improve the well-being of laboratory animals. However, it is important to know whether these enrichment items can be incorporated in experimental mouse husbandry without creating a divide between past and future experimental results. Previous small-scale studies have been inconsistent throughout the literature, and it is not yet completely understood whether and how enrichment might endanger comparability of results of scientific experiments. Here, we measured the effect on means and variability of 164 physiological parameters in 3 conditions: with nesting material with or without a shelter, comparing these 2 conditions to a "barren" regime without any enrichments. We studied a total of 360 mice from each of 2 mouse strains (C57BL/6NTac and DBA/2NCrl) and both sexes for each of the 3 conditions. Our study indicates that enrichment affects the mean values of some of the 164 parameters with no consistent effects on variability. However, the influence of enrichment appears negligible compared to the effects of other influencing factors. Therefore, nesting material and shelters may be used to improve animal welfare without impairment of experimental outcome or loss of comparability to previous data collected under barren housing conditions.


Asunto(s)
Bienestar del Animal/ética , Ambiente Controlado , Comportamiento de Nidificación/fisiología , Bienestar del Animal/economía , Animales , Metabolismo Energético/fisiología , Femenino , Pruebas de Función Cardíaca/métodos , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Nocicepción/fisiología
4.
Sensors (Basel) ; 21(3)2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33535491

RESUMEN

As demonstrated by earlier studies, pre-hospital triage with trans-telephonic electrocardiogram (TTECG) and direct referral for catheter therapy shows great value in the management of out-of-hospital chest pain emergencies. It does not only improve in-hospital mortality in ST-segment elevation myocardial infarction, but it has also been identified as an independent predictor of higher in-hospital survival rate. Since TTECG-facilitated triage shortens both transport time and percutaneous coronary intervention (PCI)-related procedural time intervals, it was hypothesized that even high-risk patients with acute coronary syndrome (ACS) and cardiogenic shock (CS) might also benefit from TTECG-based triage. Here, we decided to examine our database for new triage- and left ventricular (LV) function-related parameters that can influence in-hospital mortality in ACS complicated by CS. ACS patients were divided into two groups, namely, (1) hospital death patients (n = 77), and (2) hospital survivors (control, n = 210). Interestingly, TTECG-based consultation and triage of CS and ACS patients were confirmed as significant independent predictors of lower hospital mortality risk (odds ratio (OR) 0.40, confidence interval (CI) 0.21-0.76, p = 0.0049). Regarding LV function and blood chemistry, a good myocardial reperfusion after PCI (high area at risk (AAR) blush score/AAR LV segment number; OR 0.85, CI 0.78-0.98, p = 0.0178) and high glomerular filtration rate (GFR) value at the time of hospital admission (OR 0.97, CI 0.96-0.99, p = 0.0042) were the most crucial independent predictors of a decreased risk of in-hospital mortality in this model. At the same time, a prolonged time interval between symptom onset and hospital admission, successful resuscitation, and higher peak creatine kinase activity were the most important independent predictors for an increased risk of in-hospital mortality. In ACS patients with CS, (1) an early TTECG-based teleconsultation and triage, as well as (2) good myocardial perfusion after PCI and a high GFR value at the time of hospital admission, appear as major independent predictors of a lower in-hospital mortality rate.


Asunto(s)
Síndrome Coronario Agudo , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Síndrome Coronario Agudo/diagnóstico , Mortalidad Hospitalaria , Humanos , Factores de Riesgo , Choque Cardiogénico/diagnóstico , Resultado del Tratamiento
5.
J Neurochem ; 155(6): 650-661, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-31872431

RESUMEN

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder causing memory loss, language problems and behavioural disturbances. AD is associated with the accumulation of fibrillar amyloid-ß (Aß) and the formation of neurofibrillary tau tangles. Fibrillar Aß itself represents a danger-associated molecular pattern, which is recognized by specific microglial receptors. One of the key players is formation of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, whose activation has been demonstrated in AD patient brains and transgenic animal models of AD. Here, we investigated whether Aß oligomers or protofibrils that represent lower molecular aggregates prior to Aß deposition are able to activate the NLRP3 inflammasome and subsequent interleukin-1 beta (IL-1ß) release by microglia. In our study, we used Aß preparations of different sizes: small oligomers and protofibrils of which the structure was confirmed by atomic force microscopy. Primary microglial cells from C57BL/6 mice were treated with the respective Aß preparations and NLRP3 inflammasome activation, represented by caspase-1 cleavage, IL-1ß production, and apoptosis-associated speck-like protein containing a CARD speck formation was analysed. Both protofibrils and low molecular weight Aß aggregates induced a significant increase in IL-1ß release. Inflammasome activation was confirmed by apoptosis-associated speck-like protein containing a CARD speck formation and detection of active caspase-1. The NLRP3 inflammasome inhibitor MCC950 completely inhibited the Aß-induced immune response. Our results show that the NLRP3 inflammasome is activated not only by fibrillar Aß aggregates as reported before, but also by lower molecular weight Aß oligomers and protofibrils, highlighting the possibility that microglial activation by these Aß species may initiate innate immune responses in the central nervous system prior to the onset of Aß deposition. Cover Image for this issue: https://doi.org/10.1111/jnc.14773.


Asunto(s)
Péptidos beta-Amiloides/metabolismo , Amiloide/metabolismo , Microglía/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Animales Recién Nacidos , Supervivencia Celular/fisiología , Inflamasomas/metabolismo , Ratones , Ratones Endogámicos C57BL
6.
Mamm Genome ; 31(1-2): 30-48, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32060626

RESUMEN

The collaborative cross (CC) is a large panel of mouse-inbred lines derived from eight founder strains (NOD/ShiLtJ, NZO/HILtJ, A/J, C57BL/6J, 129S1/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Here, we performed a comprehensive and comparative phenotyping screening to identify phenotypic differences and similarities between the eight founder strains. In total, more than 300 parameters including allergy, behavior, cardiovascular, clinical blood chemistry, dysmorphology, bone and cartilage, energy metabolism, eye and vision, immunology, lung function, neurology, nociception, and pathology were analyzed; in most traits from sixteen females and sixteen males. We identified over 270 parameters that were significantly different between strains. This study highlights the value of the founder and CC strains for phenotype-genotype associations of many genetic traits that are highly relevant to human diseases. All data described here are publicly available from the mouse phenome database for analyses and downloads.


Asunto(s)
Ratones Endogámicos/genética , Fenotipo , Animales , Ratones de Colaboración Cruzada/genética , Bases de Datos Genéticas , Femenino , Estudios de Asociación Genética , Genotipo , Masculino , Ratones , Sitios de Carácter Cuantitativo , Especificidad de la Especie
7.
J Inherit Metab Dis ; 42(5): 839-849, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31111503

RESUMEN

Triosephosphate isomerase (TPI) deficiency is a fatal genetic disorder characterized by hemolytic anemia and neurological dysfunction. Although the enzyme defect in TPI was discovered in the 1960s, the exact etiology of the disease is still debated. Some aspects indicate the disease could be caused by insufficient enzyme activity, whereas other observations indicate it could be a protein misfolding disease with tissue-specific differences in TPI activity. We generated a mouse model in which exchange of a conserved catalytic amino acid residue (isoleucine to valine, Ile170Val) reduces TPI specific activity without affecting the stability of the protein dimer. TPIIle170Val/Ile170Val mice exhibit an approximately 85% reduction in TPI activity consistently across all examined tissues, which is a stronger average, but more consistent, activity decline than observed in patients or symptomatic mouse models that carry structural defect mutant alleles. While monitoring protein expression levels revealed no evidence for protein instability, metabolite quantification indicated that glycolysis is affected by the active site mutation. TPIIle170Val/Ile170Val mice develop normally and show none of the disease symptoms associated with TPI deficiency. Therefore, without the stability defect that affects TPI activity in a tissue-specific manner, a strong decline in TPI catalytic activity is not sufficient to explain the pathological onset of TPI deficiency.


Asunto(s)
Anemia Hemolítica Congénita no Esferocítica/patología , Errores Innatos del Metabolismo de los Carbohidratos/patología , Dominio Catalítico/genética , Triosa-Fosfato Isomerasa/deficiencia , Triosa-Fosfato Isomerasa/genética , Anemia Hemolítica Congénita no Esferocítica/enzimología , Animales , Conducta Animal , Errores Innatos del Metabolismo de los Carbohidratos/enzimología , Modelos Animales de Enfermedad , Estabilidad de Enzimas , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación , Multimerización de Proteína
8.
Nucleic Acids Res ; 45(6): 3031-3045, 2017 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-27923998

RESUMEN

An interplay between the nucleosome binding proteins H1 and HMGN is known to affect chromatin dynamics, but the biological significance of this interplay is still not clear. We find that during embryonic stem cell differentiation loss of HMGNs leads to down regulation of genes involved in neural differentiation, and that the transcription factor OLIG2 is a central node in the affected pathway. Loss of HMGNs affects the expression of OLIG2 as well as that of OLIG1, two transcription factors that are crucial for oligodendrocyte lineage specification and nerve myelination. Loss of HMGNs increases the chromatin binding of histone H1, thereby recruiting the histone methyltransferase EZH2 and elevating H3K27me3 levels, thus conferring a repressive epigenetic signature at Olig1&2 sites. Embryonic stem cells lacking HMGNs show reduced ability to differentiate towards the oligodendrocyte lineage, and mice lacking HMGNs show reduced oligodendrocyte count and decreased spinal cord myelination, and display related neurological phenotypes. Thus, the presence of HMGN proteins is required for proper expression of neural differentiation genes during embryonic stem cell differentiation. Specifically, we demonstrate that the dynamic interplay between HMGNs and H1 in chromatin epigenetically regulates the expression of OLIG1&2, thereby affecting oligodendrocyte development and myelination, and mouse behavior.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diferenciación Celular/genética , Epigénesis Genética , Proteínas HMGN/fisiología , Histonas/metabolismo , Proteínas del Tejido Nervioso/genética , Oligodendroglía/citología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular , Células Madre Embrionarias/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Femenino , Proteína HMGN1/genética , Proteína HMGN1/fisiología , Proteína HMGN2/genética , Proteína HMGN2/fisiología , Masculino , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/metabolismo , Factor de Transcripción 2 de los Oligodendrocitos
9.
Biochem Biophys Res Commun ; 503(4): 2770-2777, 2018 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-30100055

RESUMEN

Heterozygous missense mutations in the human VCP gene cause inclusion body myopathy associated with Paget disease of bone and fronto-temporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS). The exact molecular mechanisms by which VCP mutations cause disease manifestation in different tissues are incompletely understood. In the present study, we report the comprehensive analysis of a newly generated R155C VCP knock-in mouse model, which expresses the ortholog of the second most frequently occurring human pathogenic VCP mutation. Heterozygous R155C VCP knock-in mice showed decreased plasma lactate, serum albumin and total protein concentrations, platelet numbers, and liver to body weight ratios, and increased oxygen consumption and CD8+/Ly6C + T-cell fractions, but none of the typical human IBMPFD or ALS pathologies. Breeding of heterozygous mice did not yield in the generation of homozygous R155C VCP knock-in animals. Immunoblotting showed identical total VCP protein levels in human IBMPFD and murine R155C VCP knock-in tissues as compared to wild-type controls. However, while in human IBMPFD skeletal muscle tissue 70% of the total VCP mRNA was derived from the mutant allele, in R155C VCP knock-in mice only 5% and 7% mutant mRNA were detected in skeletal muscle and brain tissue, respectively. The lack of any obvious IBMPFD or ALS pathology could thus be a consequence of the very low expression of mutant VCP. We conclude that the increased and decreased fractions of the R155C mutant VCP mRNA in man and mice, respectively, are due to missense mutation-induced, divergent alterations in the biological half-life of the human and murine mutant mRNAs. Furthermore, our work suggests that therapy approaches lowering the expression of the mutant VCP mRNA below a critical threshold may ameliorate the intrinsic disease pathology.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Demencia Frontotemporal/genética , Genes Letales , Distrofia Muscular de Cinturas/genética , Mutación , Miositis por Cuerpos de Inclusión/genética , Osteítis Deformante/genética , Proteína que Contiene Valosina/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Antígenos Ly/genética , Antígenos Ly/metabolismo , Encéfalo/metabolismo , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Modelos Animales de Enfermedad , Femenino , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/patología , Regulación de la Expresión Génica , Técnicas de Sustitución del Gen , Heterocigoto , Humanos , Masculino , Ratones , Ratones Transgénicos , Músculo Esquelético/metabolismo , Distrofia Muscular de Cinturas/metabolismo , Distrofia Muscular de Cinturas/patología , Miositis por Cuerpos de Inclusión/metabolismo , Miositis por Cuerpos de Inclusión/patología , Osteítis Deformante/metabolismo , Osteítis Deformante/patología , Transducción de Señal , Especificidad de la Especie , Proteína que Contiene Valosina/metabolismo
10.
Int J Cancer ; 136(10): 2293-303, 2015 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-25348795

RESUMEN

Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR-34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted transgenesis to analyze the function of miR-34a in vivo. We generated mice with a constitutive deletion of the miR-34a gene. These mice were devoid of mir-34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re-expression of miR-34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR-34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR-34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR-34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR-34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re-express miR-34a in tumors could, therefore, represent an efficient therapeutic option.


Asunto(s)
Neoplasias Cerebelosas/patología , Cerebelo/metabolismo , Meduloblastoma/patología , MicroARNs/genética , MicroARNs/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Regulación Neoplásica de la Expresión Génica , Técnicas de Inactivación de Genes , Humanos , Meduloblastoma/genética , Meduloblastoma/metabolismo , Ratones , Ratones Transgénicos , Fenotipo , Transducción de Señal
11.
PLoS Genet ; 8(12): e1003071, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23236288

RESUMEN

The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species.


Asunto(s)
Drosophila , Redes Reguladoras de Genes , Dolor Nociceptivo , Fosfolípidos , Transducción de Señal , Animales , Capsaicina/toxicidad , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Fosfatidilinositol 3-Quinasa Clase Ib/fisiología , Drosophila/genética , Drosophila/fisiología , Calor , Humanos , Hipersensibilidad/genética , Ratones , Neuronas Aferentes/metabolismo , Dolor Nociceptivo/inducido químicamente , Dolor Nociceptivo/genética , Dolor Nociceptivo/fisiopatología , Fosfolípidos/genética , Fosfolípidos/metabolismo , Fosfolípidos/fisiología , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/fisiología , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/fisiología
12.
J Biol Chem ; 288(23): 16690-16703, 2013 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-23620591

RESUMEN

The nuclei of most vertebrate cells contain members of the high mobility group N (HMGN) protein family, which bind specifically to nucleosome core particles and affect chromatin structure and function, including transcription. Here, we study the biological role of this protein family by systematic analysis of phenotypes and tissue transcription profiles in mice lacking functional HMGN variants. Phenotypic analysis of Hmgn1(tm1/tm1), Hmgn3(tm1/tm1), and Hmgn5(tm1/tm1) mice and their wild type littermates with a battery of standardized tests uncovered variant-specific abnormalities. Gene expression analysis of four different tissues in each of the Hmgn(tm1/tm1) lines reveals very little overlap between genes affected by specific variants in different tissues. Pathway analysis reveals that loss of an HMGN variant subtly affects expression of numerous genes in specific biological processes. We conclude that within the biological framework of an entire organism, HMGNs modulate the fidelity of the cellular transcriptional profile in a tissue- and HMGN variant-specific manner.


Asunto(s)
Regulación de la Expresión Génica/fisiología , Proteínas HMGN/metabolismo , Transcripción Genética/fisiología , Animales , Proteínas HMGN/genética , Ratones , Ratones Mutantes , Especificidad de Órganos/fisiología
13.
J Biomed Sci ; 21: 68, 2014 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-25084970

RESUMEN

BACKGROUND: Type I Bartter syndrome is a recessive human nephropathy caused by loss-of-function mutations in the SLC12A1 gene coding for the Na+-K+-2Cl- cotransporter NKCC2. We recently established the mutant mouse line Slc12a1I299F exhibiting kidney defects highly similar to the late-onset manifestation of this hereditary human disease. Besides the kidney defects, low blood pressure and osteopenia were revealed in the homozygous mutant mice which were also described in humans. Beside its strong expression in the kidney, NKCC2 has been also shown to be expressed in other tissues in rodents i.e. the gastrointestinal tract, pancreatic beta cells, and specific compartments of the ear, nasal tissue and eye. RESULTS: To examine if, besides kidney defects, further organ systems and/or metabolic pathways are affected by the Slc12a1I299F mutation as primary or secondary effects, we describe a standardized, systemic phenotypic analysis of the mutant mouse line Slc12a1I299F in the German Mouse Clinic. Slc12a1I299F homozygous mutant mice and Slc12a1I299F heterozygous mutant littermates as controls were tested at the age of 4-6 months. Beside the already published changes in blood pressure and bone metabolism, a significantly lower body weight and fat content were found as new phenotypes for Slc12a1I299F homozygous mutant mice. Small additional effects included a mild erythropenic anemia in homozygous mutant males as well as a slight hyperalgesia in homozygous mutant females. For other functions, such as immunology, lung function and neurology, no distinct alterations were observed. CONCLUSIONS: In this systemic analysis no clear primary effects of the Slc12a1I299F mutation appeared for the organs other than the kidneys where Slc12a1 expression has been described. On the other hand, long-term effects additional and/or secondary to the kidney lesions might also appear in humans harboring SLC12A1 mutations.


Asunto(s)
Síndrome de Bartter , Presión Sanguínea/genética , Mutación Missense , Miembro 1 de la Familia de Transportadores de Soluto 12 , Sustitución de Aminoácidos , Animales , Síndrome de Bartter/genética , Síndrome de Bartter/metabolismo , Síndrome de Bartter/patología , Huesos/metabolismo , Huesos/patología , Femenino , Homocigoto , Humanos , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/patología , Masculino , Ratones , Ratones Mutantes , Miembro 1 de la Familia de Transportadores de Soluto 12/genética , Miembro 1 de la Familia de Transportadores de Soluto 12/metabolismo
14.
Proc Natl Acad Sci U S A ; 108(44): 18150-5, 2011 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-22025726

RESUMEN

GABA(A) receptors are the major ionotropic inhibitory neurotransmitter receptors. The endocannabinoid system is a lipid signaling network that modulates different brain functions. Here we show a direct molecular interaction between the two systems. The endocannabinoid 2-arachidonoyl glycerol (2-AG) potentiates GABA(A) receptors at low concentrations of GABA. Two residues of the receptor located in the transmembrane segment M4 of ß(2) confer 2-AG binding. 2-AG acts in a superadditive fashion with the neurosteroid 3α, 21-dihydroxy-5α-pregnan-20-one (THDOC) and modulates δ-subunit-containing receptors, known to be located extrasynaptically and to respond to neurosteroids. 2-AG inhibits motility in CB(1)/CB(2) cannabinoid receptor double-KO, whereas ß(2)-KO mice show hypermotility. The identification of a functional binding site for 2-AG in the GABA(A) receptor may have far-reaching consequences for the study of locomotion and sedation.


Asunto(s)
Moduladores de Receptores de Cannabinoides/fisiología , Endocannabinoides , Receptores de GABA-A/fisiología , Aminoácidos/química , Animales , Locomoción , Ratones , Ratones Noqueados , Receptores de GABA-A/química
15.
J Electrocardiol ; 47(3): 294-9, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24636796

RESUMEN

BACKGROUND: The efficacy of the transtelephonic ECG system (TTECG) in the management of ST segment elevation myocardial infarction (STEMI) was examined with regard to the ambulance service- and percutaneous coronary intervention (PCI)-related delay times, the prehospital medical therapy and the in-hospital mortality rate. METHODS: The study was conducted as a collaborative effort between the University of Debrecen and the Hungarian National Ambulance Service. Altogether 397 patients were recruited in the TTECG group, while 378 patients transported to the PCI centre without TTECG served as controls. RESULTS: More accurate prehospital medical therapy was achieved in the TTECG group. The PCI-related delay times were significantly shorter, while the in-hospital mortality rate was significantly lower in the TTECG group than among the controls. CONCLUSIONS: The findings illustrate that TTECG is a valuable tool which may potentially improve the regional management of STEMI patients.


Asunto(s)
Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/cirugía , Electrocardiografía/estadística & datos numéricos , Servicios Médicos de Urgencia/estadística & datos numéricos , Mortalidad Hospitalaria , Intervención Coronaria Percutánea/mortalidad , Telemedicina/estadística & datos numéricos , Síndrome Coronario Agudo/mortalidad , Teléfono Celular/estadística & datos numéricos , Electrocardiografía/métodos , Femenino , Humanos , Hungría/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Medición de Riesgo , Tasa de Supervivencia , Resultado del Tratamiento , Listas de Espera/mortalidad
16.
Addict Biol ; 18(4): 678-88, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22994904

RESUMEN

The brain stress-response system is critically involved in the addiction process, stimulating drug consumption and the relapse to drug taking in abstinent addicts. At the same time, its functioning is affected by chronic drug exposure. Here, we have investigated the role of the endogenous opioid peptide dynorphin as a modulator of effects of long-term ethanol consumption on the brain stress-response system. Using the two-bottle choice paradigm, we demonstrate an enhanced ethanol preference in male dynorphin knockout mice. Exposure to mild foot shock increased ethanol consumption in wild-type control littermates, but not in dynorphin-deficient animals. Blood adrenocorticotropic hormone levels determined 5 minutes after the shock were not affected by the genotype. We also determined the neuronal reactivity after foot shock exposure using c-Fos immunoreactivity in limbic structures. This was strongly influenced by both genotype and chronic ethanol consumption. Long-term alcohol exposure elevated the foot shock-induced c-Fos expression in the basolateral amygdala in wild-type animals, but had the opposite effect in dynorphin-deficient mice. An altered c-Fos reactivity was also found in the periventricular nucleus, the thalamus and the hippocampus of dynorphin knockouts. Together these data suggest that dynorphin plays an important role in the modulation of the brain stress-response systems after chronic ethanol exposure.


Asunto(s)
Hormona Adrenocorticotrópica/metabolismo , Dinorfinas/fisiología , Etanol/farmacología , Sistema Límbico/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Estrés Fisiológico/fisiología , Adaptación Fisiológica/efectos de los fármacos , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/metabolismo , Análisis de Varianza , Animales , Conducta Adictiva/metabolismo , Dinorfinas/genética , Etanol/administración & dosificación , Femenino , Preferencias Alimentarias , Genotipo , Inmunoquímica , Sistema Límbico/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados/genética , Refuerzo en Psicología , Autoadministración , Caracteres Sexuales , Estrés Fisiológico/efectos de los fármacos , Tálamo/efectos de los fármacos , Tálamo/metabolismo
17.
Eur Heart J ; 33(24): 2994-6, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23242706

RESUMEN

AIMS: This research was performed to provide data on the specific needs and expectations of junior cardiologists across Europe from a professional medical organization characterized by the European Society of Cardiology (ESC). METHODS: The study was carried out using telephone interviews. The target respondents were based in a wide range of different locations within Europe and were identified by national groups of young cardiologists and trainees. A questionnaire was employed asking about information sources, membership of professional societies and related benefits. RESULTS: A total of 120 interviews were conducted. Websites and journals proved the most popular sources for professional information, consulted by .71 and 68% of respondents, respectively.With regard to the up to date best practice recommendations, guidelines documents were most common, mentioned by 63%. Overall, the ESC resources appeared within highest priority. The two main important tangible benefits expected from membership of professional societies were access to medical information, mostly journals and guidelines, and reduced financial congress requirements. Also, the most significant intangible benefit was networking. CONCLUSIONS: The ESC is widely respected by the junior cardiologists and trainees. Its congresses and guidelines are central to respondents' image of it as a large, well arranged, important, and impressive organization. The ESC is a competently placed institution to further develop its relationship with young cardiologists.


Asunto(s)
Actitud del Personal de Salud , Cardiología , Almacenamiento y Recuperación de la Información/estadística & datos numéricos , Cuerpo Médico de Hospitales , Europa (Continente) , Humanos , Sociedades Médicas
18.
J Biol Chem ; 286(21): 18614-22, 2011 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-21467037

RESUMEN

ADAR2, an RNA editing enzyme that converts specific adenosines to inosines in certain pre-mRNAs, often leading to amino acid substitutions in the encoded proteins, is mainly expressed in brain. Of all ADAR2-mediated edits, a single one in the pre-mRNA of the AMPA receptor subunit GluA2 is essential for survival. Hence, early postnatal death of mice lacking ADAR2 is averted when the critical edit is engineered into both GluA2 encoding Gria2 alleles. Adar2(-/-)/Gria2(R/R) mice display normal appearance and life span, but the general phenotypic effects of global lack of ADAR2 have remained unexplored. Here we have employed the Adar2(-/-)/Gria2(R/R) mouse line, and Gria2(R/R) mice as controls, to study the phenotypic consequences of loss of all ADAR2-mediated edits except the critical one in GluA2. Our extended phenotypic analysis covering ∼320 parameters identified significant changes related to absence of ADAR2 in behavior, hearing ability, allergy parameters and transcript profiles of brain.


Asunto(s)
Adenosina Desaminasa/metabolismo , Edición de ARN/fisiología , Precursores del ARN/metabolismo , Adenosina Desaminasa/genética , Animales , Ratones , Ratones Noqueados , Especificidad de Órganos/fisiología , Precursores del ARN/genética , Proteínas de Unión al ARN , Receptores AMPA/genética , Receptores AMPA/metabolismo
19.
Mamm Genome ; 23(9-10): 611-22, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22926221

RESUMEN

Under the label of the German Mouse Clinic (GMC), a concept has been developed and implemented that allows the better understanding of human diseases on the pathophysiological and molecular level. This includes better understanding of the crosstalk between different organs, pleiotropy of genes, and the systemic impact of envirotypes and drugs. In the GMC, experts from various fields of mouse genetics and physiology, in close collaboration with clinicians, work side by side under one roof. The GMC is an open-access platform for the scientific community by providing phenotypic analysis in bilateral collaborations ("bottom-up projects") and as a partner and driver in international large-scale biology projects ("top-down projects"). Furthermore, technology development is a major topic in the GMC. Innovative techniques for primary and secondary screens are developed and implemented into the phenotyping pipelines (e.g., detection of volatile organic compounds, VOCs).


Asunto(s)
Modelos Animales , Animales , Alemania , Ratones , Fenotipo
20.
Methods ; 53(2): 120-35, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20708688

RESUMEN

Model organisms like the mouse are important tools to learn more about gene function in man. Within the last 20 years many mutant mouse lines have been generated by different methods such as ENU mutagenesis, constitutive and conditional knock-out approaches, knock-down, introduction of human genes, and knock-in techniques, thus creating models which mimic human conditions. Due to pleiotropic effects, one gene may have different functions in different organ systems or time points during development. Therefore mutant mouse lines have to be phenotyped comprehensively in a highly standardized manner to enable the detection of phenotypes which might otherwise remain hidden. The German Mouse Clinic (GMC) has been established at the Helmholtz Zentrum München as a phenotyping platform with open access to the scientific community (www.mousclinic.de; [1]). The GMC is a member of the EUMODIC consortium which created the European standard workflow EMPReSSslim for the systemic phenotyping of mouse models (http://www.eumodic.org/[2]).


Asunto(s)
Ratones Mutantes , Fenotipo , Animales , Conducta Animal , Análisis Químico de la Sangre/métodos , Catarata/patología , Pruebas de Función Renal/métodos , Ratones , Ratones Mutantes Neurológicos , Mutagénesis , Dimensión del Dolor/métodos , Dimensión del Dolor/normas , Estándares de Referencia , Urinálisis/métodos
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