SIRT6-dependent functional switch via K494 modifications of RE-1 silencing transcription factor.

RE-1 silencing transcription factor (REST) is a key repressor of neural genes. REST is upregulated under stress signals, aging and neurodegenerative diseases, but although it is upregulated, its function is lost in Alzheimer's Disease. However, why it becomes inactive remains unclear.

Early Functional Status Change After Cardiopulmonary Resuscitation in a Pediatric Heart Center: A Single-Center Retrospective Study.

Children with cardiac disease are at significantly higher risk for in-hospital cardiac arrest (CA) compared with those admitted without cardiac disease. CA occurs in 2-6% of patients admitted to a pediatric intensive care unit (ICU) and 4-6% of children admitted to the pediatric cardiac-ICU. Treatment of in-hospital CA with cardiopulmonary resuscitation (CPR) results in return of spontaneous circulation in 43-64% of patients and survival rate that varies from 20 to 51%.

Evaluation and validation of a prediction model for extubation success in very preterm infants.

Objective: To perform an external validation of a publicly available model predicting extubation success in very preterm infants.

Study Design: Retrospective study of infants born <1250 g at a single center. Model performance evaluated using the area under the receiver operating characteristic curve (AUROC) and comparing observed and expected probabilities of extubation success, defined as survival ≥5 d without an endotracheal tube.

A comparison of high-flow nasal cannula versus non-invasive positive pressure ventilation for respiratory support in infants following cardiac surgery.

Background: Following cardiac surgery, infants often remain endotracheally intubated upon arrival to the cardiac ICU. High-flow nasal cannula and non-invasive positive pressure ventilation are used to support patients following extubation. There are limited data on the superiority of either mode to prevent extubation failure.

Repurposing Hsp90 inhibitors as antibiotics targeting histidine kinases.

To address the growing need for new antimicrobial agents, we explored whether inhibition of bacterial signaling machinery could inhibit bacterial growth. Because bacteria rely on two-component signaling systems to respond to environmental changes, and because these systems are both highly conserved and mediated by histidine kinases, inhibiting histidine kinases may provide broad spectrum antimicrobial activity. The histidine kinase ATP binding domain is conserved with the ATPase domain of eukaryotic Hsp90 molecular chaperones.

Single nucleotide changes in the human Igamma1 and Igamma4 promoters underlie different transcriptional responses to CD40.

Analysis of subclass-specific germline transcription in activated peripheral B cells revealed a highly biased expression pattern of the four Igamma transcripts to signals through CD40 and IL-4. This difference was most pronounced when comparing the profile of Igamma1 and Igamma4 transcripts and was not expected given the very high degree of sequence conservation between promoters. In this report, the influence of sequence differences on the regulation of the Igamma1 and Igamma4 promoters has been investigated given the highly muted transcriptional activity of the Igamma4 promoter.

c-Rel plays a key role in deficient activation of B cells from a non-X-linked hyper-IgM patient.

Our previous results demonstrated that B cells from a patient (pt1) with non-X-linked hyper-IgM syndrome (HIGM) possess an atypical CD23(lo) phenotype that is unaffected by CD40-mediated activation. To investigate the molecular mechanism underlying defective CD23 expression in pt1 B cells, we used lymphoblastoid cell lines that express LMP1 under the control of a tetracycline-inducible promoter (LCL(tet)). Our analysis revealed that the CD23(lo) phenotype in the pt1-LCL(tet) cells is a direct consequence of diminished CD23 transcription.

Use of chromatin immunoprecipitation (ChIP) to detect transcription factor binding to highly homologous promoters in chromatin isolated from unstimulated and activated primary human B cells.

The Chromatin Immunoprecipiation (ChIP) provides a powerful technique for identifying the in vivo association of transcription factors with regulatory elements. However, obtaining meaningful information for promoter interactions is extremely challenging when the promoter is a member of a class of highly homologous elements. Use of PCR primers with small numbers of mutations can limit cross-hybridization with non-targeted sequences and distinguish a pattern of binding for factors with the regulatory element of interest.

A novel NF-kappa B-regulated site within the human I gamma 1 promoter requires p300 for optimal transcriptional activity.

Transcriptional activation of germline (GL) promoters occurs through binding of NF-kappaB to three evolutionarily conserved sites within a CD40 response region in the human and mouse GL Igamma and Iepsilon promoters. Here we identify and characterize a novel NF-kappaB binding site (kappaB6) within the human GL Igamma1 promoter that plays an essential role in basal- and CD40-induced transcription. This site is adjacent to identified CREB/activating transcription factor (ATF) sites, present in the Igamma1 but not the Igamma3 promoter, which are important for the amplification of transcription.

Maintenance of the CD40-related immunodeficient response in hyper-IgM B cells immortalized with a LMP1-regulated mini-EBV.

Our previous investigation of a patient (pt1) with non-X-linked hyper-immunoglobulin M syndrome revealed a CD40-mediated defect in B cell activation that resulted in low CD23 expression and absence of germ-line transcription and class-switch recombination. These deficiencies were complemented in vitro by a high threshold of sustained signaling through CD40. To further analyze the signaling defect in pt1 B cells, two types of Epstein-Barr virus lymphoblastoid cell lines (LCLs) were generated that either constitutively expressed the viral transforming protein latent membrane protein-1 (LMP1; pt1-LCL) or expressed it under the control of a tet-inducible promoter (pt1-LCL(tet)).