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1.
PLoS Pathog ; 16(10): e1008999, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33057424

RESUMEN

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus known to cause epidemics resulting in predominantly symptomatic infections, which in rare cases cause long term debilitating arthritis and arthralgia. Significant progress has been made in understanding the roles of canonical RNA sensing pathways in the host recognition of CHIKV; however, less is known regarding antagonism of CHIKV by cytosolic DNA sensing pathways like that of cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING). With the use of cGAS or STING null cells we demonstrate that the pathway restricts CHIKV replication in fibroblasts and immune cells. We show that DNA accumulates in the cytoplasm of infected cells and that CHIKV blocks DNA dependent IFN-ß transcription. This antagonism of DNA sensing is via an early autophagy-mediated degradation of cGAS and expression of the CHIKV capsid protein is sufficient to induce cGAS degradation. Furthermore, we identify an interaction of CHIKV nsP1 with STING and map the interaction to 23 residues in the cytosolic loop of the adaptor protein. This interaction stabilizes the viral protein and increases the level of palmitoylated nsP1 in cells. Together, this work supports previous publications highlighting the relevance of the cGAS-STING pathway in the early detection of (+)ssRNA viruses and provides direct evidence that CHIKV interacts with and antagonizes cGAS-STING signaling.


Asunto(s)
Virus Chikungunya/inmunología , Interferón Tipo I/inmunología , Proteínas de la Membrana/inmunología , Nucleotidiltransferasas/inmunología , Aedes , Animales , Autofagia/inmunología , Técnicas de Cultivo de Célula , Virus Chikungunya/fisiología , Células HEK293 , Humanos , Inmunidad Innata , Interferón Tipo I/metabolismo , Interferón beta/inmunología , Interferón beta/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Transcripción Genética , Proteínas Virales/metabolismo , Replicación Viral
2.
Eur J Pharmacol ; 221(2-3): 275-80, 1992 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-1426006

RESUMEN

The effect of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists on the generalized tonic-clonic convulsions and wet-dog shakes induced by the intraperitoneal (i.p.) or the intrahippocampal (i.h., stereotaxic microinjection into the CA1 region) administration of 4-aminopyridine (4-AP) was studied in rats. Pretreatment with NMDA competitive and non-competitive antagonists resulted in potent protection against the motor effects of both the i.p. and the i.h. administration of 4-AP. MK-801 (0.25 mg/kg i.p.) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP, 0.8 nmol intracerebroventricular, i.c.v.) showed the most powerful anticonvulsive effect, since they prevented the occurrence of generalized tonic convulsions and the death of the animals in convulsions after i.p. 4-AP. The i.c.v. injection (10 nmol) of the NMDA competitive antagonists 2-amino-5-phosphonopentanoate (AP-5) and 2-amino-5-phosphonoheptanoate (AP-7) also showed a clear though less potent protective effect. Similarly, the frequency of wet-dog shakes induced by i.h. 4-AP was markedly decreased by pretreating the animals with i.p. MK-801 or with i.c.v. CPP or AP-7. However, the co-injection of CPP with 4-AP failed to protect against the occurrence of wet-dog shakes. The i.c.v. pretreatment with the unselective antagonist, kynurenate (up to 68 nmol) or with the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (0.5 nmol), did not significantly modify the effects of 4-AP when administered either i.p. or i.h. We conclude that NMDA receptors are involved in the mechanism of the convulsive activity induced by 4-AP, probably because this drug induces the release of glutamate.


Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , 4-Aminopiridina/farmacología , Conducta Animal/efectos de los fármacos , N-Metilaspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Convulsiones/prevención & control , Aminoácidos/farmacología , Animales , Masculino , Piperazinas/farmacología , Ratas , Receptores de N-Metil-D-Aspartato/fisiología
3.
An Esp Pediatr ; 37(2): 140-4, 1992 Aug.
Artículo en Español | MEDLINE | ID: mdl-1384409

RESUMEN

The XYY syndrome presents with a wide variation in the clinical features, both of the physical and behavioral nature. We report two new cases which illustrate this statement. The first case presented with aggressive behaviour and cryptorchidism. The second case was associated with pathological short height, pubertal delay and cardiac features (extrasystoles and short PR interval). We revise some of the aspects of XYY syndrome.


Asunto(s)
Aberraciones Cromosómicas Sexuales/genética , Cariotipo XYY/genética , Adolescente , Agresión , Estatura , Complejos Cardíacos Prematuros , Niño , Criptorquidismo , Humanos , Hipercinesia , Masculino , Polimorfismo Genético , Pubertad Tardía , Aberraciones Cromosómicas Sexuales/fisiopatología , Aberraciones Cromosómicas Sexuales/psicología , Síndrome
4.
Clin Genet ; 38(2): 128-38, 1990 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-2208764

RESUMEN

We report on the case of a male who from the start of life displayed vesicular lesions; on the trunk these were clustered and on the limbs they adopted a linear configuration. After biopsy of one such lesion, the histopathological study was compatible with a diagnosis of incontinentia pigmenti (IP). In the following months, hyperkeratotic lesions appeared which later became pigmented. The mother and other female members of the family also showed different degrees of alteration related to the same disease. The karyotype study showed the existence of 47,XXY (Klinefelter syndrome). The exceptional nature of this case is that although it is the third case reported in the literature of a male affected by incontinentia pigmenti with a previous family history, it is the only one combining this characteristic with the presence of a 47,XXY karyotype.


Asunto(s)
Incontinencia Pigmentaria/genética , Aberraciones Cromosómicas Sexuales/genética , Cromosoma X , Adulto , Femenino , Tamización de Portadores Genéticos , Humanos , Lactante , Cariotipificación , Masculino , Linaje , Anomalías Dentarias/genética
5.
Eur J Pharmacol ; 178(3): 275-84, 1990 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-2340861

RESUMEN

The behavioral and electrographic effects of 4-aminopyridine (4-AP) administered i.p. or microinjected into the hippocampal CA1 region (i.h.) were studied in rats. The modification of such effects by the systemic administration of the Ca2+ antagonist dihydropyridine, nifedipine, was also studied. 4-AP i.p. (5 mg/kg) induced generalized tonic convulsions in 74% of the animals and death in 13%. Convulsions were characterized by electrical discharges of relatively short duration in all structures studied (frontal cortex, amygdala, dorsal hippocampus and dorsal raphe). Limbic seizures and frequent wet-dog shakes were observed when 4-AP was administered i.h. (2-4 nmol) and this behavior was correlated with hippocampal discharges, which rapidly propagated to the other structures. Pretreatment with nifedipine (7.5-50 mg/kg s.c.) markedly potentiated the effects of 4-AP. The percentage of rats that died during generalized convulsion after i.p. 4-AP increased to 56-87% and the frequency of wet-dog shakes increased after i.h. microinjection of 4-AP. Moreover, nifedipine-treated rats showed long-lasting (greater than 60 min) continuous discharges in all structures studied (status epilepticus). These results are discussed in the light of the possible participation of Ca2+ channels in the convulsant effect of 4-AP and its potentiation by nifedipine.


Asunto(s)
4-Aminopiridina/farmacología , Conducta Animal/efectos de los fármacos , Nifedipino/farmacología , Convulsiones/inducido químicamente , Animales , Sinergismo Farmacológico , Electroencefalografía , Hipocampo/anatomía & histología , Masculino , Microinyecciones , Ratas , Ratas Endogámicas , Convulsiones/fisiopatología
7.
An Esp Pediatr ; 18(2): 113-7, 1983 Feb.
Artículo en Español | MEDLINE | ID: mdl-6881733

RESUMEN

Two patients with partial deletion of the short arm of number 4 chromosome are reported and their phenotypes and genetic characteristics are discussed. The genetic work up of both patients are compared concluding that a deletion of a part of the short arm of one of the 4th pair respective of the chromosome segment which is missing, is sufficient to produce this syndrome.


Asunto(s)
Anomalías Múltiples/genética , Aberraciones Cromosómicas/genética , Deleción Cromosómica , Cromosomas Humanos 4-5 , Discapacidad Intelectual/genética , Trastornos de los Cromosomas , Cara , Humanos , Recién Nacido , Cariotipificación , Masculino , Fenotipo , Síndrome
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