The Journal of clinical investigation
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MS results from destruction of the protective myelin sheath surrounding axons, which prevents the transmission of nerve impulses. Precursors of oligodendrocytes, the cells capable of myelinating axons, are preserved in demyelinating lesions; however, why these precursors do not differentiate into mature oligodendrocytes and remyelinate axons is unknown. Contactin is a noncanonical Notch receptor ligand that mediates oligodendrocyte differentiation. ⋯ However, Notch1 intracellular domain coassociates with the nuclear transporter Importin beta but fails to show evidence of nuclear translocation. These cytoplasmic aggregates also contain TAT-interacting protein 30 kDa (TIP30), a proapoptotic factor, which inhibits nuclear transport and, consequently, Notch1-mediated oligodendrocyte differentiation and remyelination. These data target TIP30 as a new pathogenic factor in MS.
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Familial hemiplegic migraine type 1 (FHM1) is an autosomal dominant subtype of migraine with aura that is associated with hemiparesis. As with other types of migraine, it affects women more frequently than men. FHM1 is caused by mutations in the CACNA1A gene, which encodes the alpha1A subunit of Cav2.1 channels; the R192Q mutation in CACNA1A causes a mild form of FHM1, whereas the S218L mutation causes a severe, often lethal phenotype. ⋯ Further, female S218L and R192Q mutant mice were more susceptible to SD and neurological deficits than males. This sex difference was abrogated by ovariectomy and senescence and was partially restored by estrogen replacement, implicating ovarian hormones in the observed sex differences in humans with FHM1. These findings demonstrate that genetic and hormonal factors modulate susceptibility to SD and neurological deficits in FHM1 mutant mice, providing a potential mechanism for the phenotypic diversity of human migraine and aura.
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Recent evidence indicates that small noncoding RNA molecules known as microRNAs (miRNAs) can function as tumor suppressors and oncogenes. Mutation, misexpression, and altered mature miRNA processing are implicated in carcinogenesis and tumor progression. Because SNPs in pre-miRNAs could alter miRNA processing, expression, and/or binding to target mRNA, we conducted a systematic survey of common pre-miRNA SNPs and their surrounding regions and evaluated in detail the association of 4 of these SNPs with the survival of individuals with non-small cell lung cancer (NSCLC). ⋯ Furthermore, binding assays revealed that the rs11614913 SNP can affect binding of mature hsa-mir-196a2-3p to its target mRNA. Therefore, the rs11614913 SNP in hsa-mir-196a2 may be a prognostic biomarker for NSCLC. Further characterization of miRNA SNPs may open new avenues for the study of cancer and therapeutic interventions.
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Cigarette smoke (CS) inhalation causes an early inflammatory response in rodent airways by stimulating capsaicin-sensitive sensory neurons that express transient receptor potential cation channel, subfamily V, member 1 (TRPV1) through an unknown mechanism that does not involve TRPV1. We hypothesized that 2 alpha,beta-unsaturated aldehydes present in CS, crotonaldehyde and acrolein, induce neurogenic inflammation by stimulating TRPA1, an excitatory ion channel coexpressed with TRPV1 on capsaicin-sensitive nociceptors. We found that CS aqueous extract (CSE), crotonaldehyde, and acrolein mobilized Ca2+ in cultured guinea pig jugular ganglia neurons and promoted contraction of isolated guinea pig bronchi. ⋯ Treatment with CSE or aldehydes increased Ca2+ influx in TRPA1-transfected cells, but not in control HEK293 cells, and promoted neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE and aldehydes on Ca2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data identify alpha,beta-unsaturated aldehydes as the main causative agents in CS that via TRPA1 stimulation mediate airway neurogenic inflammation and suggest a role for TRPA1 in the pathogenesis of CS-induced diseases.
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Historical Article
The American Society for Clinical Investigation--the first 100 years.
The annual Atlantic City meeting of the Young Turks was an exciting event--an opportunity to hear great science, to explore career opportunities, and to meet and make friends. Though the 1950s, '60s, and '70s, the meetings remained relatively intimate, broadly covering the best in medicine and constantly growing until the participants outgrew the Atlantic City venue to eventually spawn the numerous specialty annual meetings that we have today.