Extracellular high-mobility group box (HMGB)1 mediates inflammation during sterile and infectious injury and contributes importantly to disease pathogenesis. The first critical step in the release of HMGB1 from activated immune cells is mobilization from the nucleus to the cytoplasm, a process dependent upon hyperacetylation within two HMGB1 nuclear localization sequence (NLS) sites. The inflammasomes mediate the release of cytoplasmic HMGB1 in activated immune cells, but the mechanism of HMGB1 translocation from nucleus to cytoplasm was previously unknown. Here, we show that pharmacological inhibition of JAK/STAT1 inhibits LPS-induced HMGB1 nuclear translocation. Conversely, activation of JAK/STAT1 by type 1 interferon (IFN) stimulation induces HMGB1 translocation from nucleus to cytoplasm. Mass spectrometric analysis unequivocally revealed that pharmacological inhibition of the JAK/STAT1 pathway or genetic deletion of STAT1 abrogated LPS-or type 1 IFN-induced HMGB1 acetylation within the NLS sites. Together, these results identify a critical role of the JAK/STAT1 pathway in mediating HMGB1 cytoplasmic accumulation for subsequent release, suggesting that the JAK/STAT1 pathway is a potential drug target for inhibiting HMGB1 release.damage-associated molecular pattern | cytokine | pathogen-associated molecular pattern | innate immunity | therapy H igh-mobility group box 1 (HMGB1), a ubiquitous DNAbinding protein, is a promiscuous sensor driving nucleic acidmediated immune responses and a pathogenic inflammatory mediator in sepsis, arthritis, colitis, and other disease syndromes (1-5). Immune cells actively release HMGB1 after activation by exposure to pathogen-associated molecular patterns or damageassociated molecular patterns, including lipopolysaccharide (LPS) and inflammasome agonists (1, 6, 7). High levels of extracellular HMGB1 accumulate in patients with infectious and sterile inflammatory diseases. Extracellular disulfide HMGB1 stimulates macrophages to release TNF and other inflammatory mediators by binding and signaling through Toll-like receptor (TLR)4. Reduced HMGB1 facilitates immune cell migration by interacting with the receptor for advanced glycation end products (RAGE) and CXCL12 (8-12), a process regulated by posttranslational redox-dependent mechanisms. Administration of neutralizing anti-HMGB1 mAbs or other HMGB1 antagonists significantly reduces the severity of inflammatory disease, promotes bacterial clearance during Pseudomonas aeruginosa or Salmonella typhimurium infection and attenuates memory impairment in sepsis survivors (1,(13)(14)(15). Together, these and other findings indicate the importance of a mechanistic understanding of HMGB1 release from activated immune cells and the regulatory signaling pathways controlling these processes.Most cytokines harbor a leader peptide that facilitates secretion through the endoplasmic reticulum-Golgi exocytotic route. HMGB1, which lacks a leader peptide, is released via unconventional protein secretion pathways (1, 6, 7). In quiescent cells, most ...
When patients with VT and structural heart disease have no VT or nonclinical VT only inducible at the end of ablation or their condition is too unstable to undergo final programmed stimulation, NIPS should be considered in the following days to further define risk of recurrence. If clinical VT is inducible at NIPS, repeat ablation may be considered because recurrence over the following year is high.
Our data show a significant correlation between the CI and CVP estimates obtained from the BEAT examination and that from a PAC. BEAT provides a noninvasive method of evaluating cardiac function and volume status. Bedside echocardiography is teachable and should become a part of future critical care curricula.
Spinobulbar muscular atrophy and Huntington's disease are caused by polyglutamine expansion in the androgen receptor and huntingtin, respectively, and their pathogenesis has been associated with abnormal nuclear localization and aggregation of truncated forms of these proteins. Here we show, in diverse cell types, that glucocorticoids can up-or down-modulate aggregation and nuclear localization of expanded polyglutamine polypeptides derived from the androgen receptor and huntingtin through specific regulation of gene expression. Wild-type glucocorticoid receptor (GR), as well as C-terminal deletion derivatives, suppressed the aggregation and nuclear localization of these polypeptides, whereas mutations within the DNA binding domain and N terminus of GR abolished this activity. Surprisingly, deletion of a transcriptional regulatory domain within the GR N terminus markedly increased aggregation and nuclear localization of the expanded polyglutamine proteins. Thus, aggregation and nuclear localization of expanded polyglutamine proteins are regulated cellular processes that can be modulated by a well-characterized transcriptional regulator, the GR. Our findings suggest approaches to study the molecular pathogenesis and selective neuronal degeneration of polyglutamine expansion diseases.
This study identifies factors associated with prehospital management of anaphylaxis for children, which highlight that epinephrine administration may be occurring with considerable delay. Increased awareness and education of caregivers, patients, and medical professionals are necessary to provide optimal management.
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