AMBRA1 controls the translation of immune-specific genes in T lymphocytes.

T cell receptor (TCR) engagement causes a global cellular response that entrains signaling pathways, cell cycle regulation, and cell death. The molecular regulation of mRNA translation in these processes is poorly understood. Using a whole-genome CRISPR screen for regulators of CD95 (FAS/APO-1)-mediated T cell death, we identified AMBRA1, a protein previously studied for its roles in autophagy, E3 ubiquitin ligase activity, and cyclin regulation.

Narrative Review: Pyoderma Gangrenosum.

Pyoderma gangrenosum (PG) is a skin lesion, characteristically a neutrophilic dermatosis, that can be complicated by rapid progression, necrosis, and ulceration. This is an important pathology to be discussed given that there are no established criteria for diagnosis or treatment. This review aims to elucidate characteristics and variations of PG that distinguish it from other ulcerative skin lesions.

Inferior Vena Cava Filters and Complications: A Systematic Review.

Inferior vena cava (IVC) filters have been used since the 1960s to treat patients with acute risk of pulmonary embolism (PE) to prevent migration of thrombus by trapping it within the filter. Traditional usage has been in patients with contraindication to anticoagulation that carry a significant mortality risk. In this systematic review, we sought to evaluate complications associated with placement of inferior vena cava filters based on published data from the past 20 years.

Early B cell factor 4 modulates FAS-mediated apoptosis and promotes cytotoxic function in human immune cells.

Apoptosis is a genetically regulated program of cell death that plays a key role in immune disease processes. We identified EBF4, a little-studied member of the early B cell factor (EBF) family of transcription factors, in a whole-genome CRISPR screen for regulators of Fas/APO-1/CD95-mediated T cell death. Loss of EBF4 increases the half-life of the c-FLIP protein, and its presence in the Fas signaling complex impairs caspase-8 cleavage and apoptosis.

GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans.

Inborn errors of immunity (IEIs) unveil regulatory pathways of human immunity. We describe a new IEI caused by mutations in the GTPase of the immune-associated protein 6 (GIMAP6) gene in patients with infections, lymphoproliferation, autoimmunity, and multiorgan vasculitis. Patients and Gimap6-/- mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)-containing lipids.

Mucus sialylation determines intestinal host-commensal homeostasis.

Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation.

Evaluation of In Vitro Activity of the Class I PI3K Inhibitor Buparlisib (BKM120) in Pediatric Bone and Soft Tissue Sarcomas.

Pediatric bone and soft tissue sarcomas often display increased Akt phosphorylation through up regulation of insulin-like growth factor (IGF1) signaling. Additionally, Akt signaling has been linked to resistance to IGF1 receptor (IGF1R) and mTOR (mammalian target of rapamycin) inhibitors in sarcoma, further demonstrating the role of Akt in tumor survival. This suggests targeting components of the PI3K/Akt pathway may be an effective therapeutic strategy.

Structure-activity relationship study of E6 as a novel necroptosis inducer.

Necroptosis inducers represent a promising potential treatment for drug-resistant cancer. We herein describe the structure modification of E6, which was identified recently as a potent and selective necroptosis inducer. The studies described herein demonstrate for the first time that functionalized biphenyl derivatives possess necroptosis inducer activity.

Phosphoproteomic profiling reveals IL6-mediated paracrine signaling within the Ewing sarcoma family of tumors.

Unlabelled: Members of the Ewing sarcoma family of tumors (ESFT) contain tumor-associated translocations that give rise to oncogenic transcription factors, most commonly EWS/FLI1. EWS/FLI1 plays a dominant role in tumor progression by modulating the expression of hundreds of target genes. Here, the impact of EWS/FLI1 inhibition, by RNAi-mediated knockdown, on cellular signaling was investigated using mass spectrometry-based phosphoproteomics to quantify global changes in phosphorylation.

Snail1 controls epithelial-mesenchymal lineage commitment in focal adhesion kinase-null embryonic cells.

Mouse embryonic cells isolated from focal adhesion kinase (FAK)-null animals at embryonic day 7.5 display multiple defects in focal adhesion remodeling, microtubule dynamics, mechanotransduction, proliferation, directional motility, and invasion. To date, the ability of FAK to modulate cell function has been ascribed largely to its control of posttranscriptional signaling cascades in this embryonic cell population.

Oncogenic fusion protein EWS/FLI1 down-regulates gene expression by both transcriptional and posttranscriptional mechanisms.

Ewing family tumors are characterized by a translocation between the RNA binding protein EWS and one of five ETS transcription factors, most commonly FLI1. The fusion protein produced by the translocation has been thought to act as an aberrant transcription factor, leading to changes in gene expression and cellular transformation. In this study, we investigated the specific processes EWS/FLI1 utilizes to alter gene expression.

Role of kinase-independent and -dependent functions of FAK in endothelial cell survival and barrier function during embryonic development.

Focal adhesion kinase (FAK) is essential for vascular development as endothelial cell (EC)-specific knockout of FAK (conditional FAK knockout [CFKO] mice) leads to embryonic lethality. In this study, we report the differential kinase-independent and -dependent functions of FAK in vascular development by creating and analyzing an EC-specific FAK kinase-defective (KD) mutant knockin (conditional FAK knockin [CFKI]) mouse model. CFKI embryos showed apparently normal development through embryonic day (E) 13.

Conserved herpesviral kinase promotes viral persistence by inhibiting the IRF-3-mediated type I interferon response.

A conserved herpesviral kinase, designated ORF36 in murine gamma-herpesvirus 68 (MHV-68), plays multiple vital roles in the viral life cycle. Here, we show by screening mutant viruses that ORF36 counteracts the antiviral type I interferon (IFN) response. ORF36 specifically binds to the activated form of interferon regulatory factor 3 (IRF-3) in the nucleus, inhibiting IRF-3 interaction with the cotranscriptional activator CBP and thereby suppressing the recruitment of RNA polymerase II to the interferon beta promoter.

Role of focal adhesion kinase Ser-732 phosphorylation in centrosome function during mitosis.

Focal adhesion kinase (FAK) is the major cytoplasmic tyrosine kinase in focal adhesions and a critical mediator of integrin signaling in a variety of cells, including endothelial cells (ECs). Here we describe a new function for FAK in the regulation of centrosome functions in a Ser-732 phosphorylation-dependent manner during mitosis. Deletion of FAK in primary ECs causes increases in centrosome numbers, multipolar and disorganized spindles, and unaligned chromosomes during mitosis.

Cardiac developmental defects and eccentric right ventricular hypertrophy in cardiomyocyte focal adhesion kinase (FAK) conditional knockout mice.

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that plays an important role in integrin-mediated signal transduction. To explore the role and mechanisms of FAK in cardiac development, we inactivated FAK in embryonic cardiomyocytes by crossing the floxed FAK mice with myosin light chain-2a (MLC2a) Cre mice, which expressed Cre as early as embryonic day 9.5 in the heart.

Abstinent adolescent marijuana users show altered fMRI response during spatial working memory.

Marijuana is the most widely used illicit substance among teenagers, yet little is known about the possible neural influence of heavy marijuana use during adolescence. We previously demonstrated an altered functional magnetic resonance imaging (fMRI) activity related to spatial working memory (SWM) among adolescents who were heavy users of after an average of 8 days of abstinence, but the persisting neural effects remain unclear. To characterize the potentially persisting neurocognitive effects of heavy marijuana use in adolescence, we examined fMRI response during SWM among abstinent marijuana-using teens.

Depressive symptoms in adolescents: associations with white matter volume and marijuana use.

Background: Depressed mood has been associated with decreased white matter and reduced hippocampal volumes. However, the relationship between brain structure and mood may be unique among adolescents who use marijuana heavily. The goal of this study was to examine the relationship between white matter and hippocampal volumes and depressive symptoms among adolescent marijuana users and controls.

In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro.

The in vitro scratch assay is an easy, low-cost and well-developed method to measure cell migration in vitro. The basic steps involve creating a "scratch" in a cell monolayer, capturing the images at the beginning and at regular intervals during cell migration to close the scratch, and comparing the images to quantify the migration rate of the cells. Compared to other methods, the in vitro scratch assay is particularly suitable for studies on the effects of cell-matrix and cell-cell interactions on cell migration, mimic cell migration during wound healing in vivo and are compatible with imaging of live cells during migration to monitor intracellular events if desired.

Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis.

Focal adhesion kinase (FAK) is a critical mediator of signal transduction by integrins and growth factor receptors in a variety of cells including endothelial cells (ECs). Here, we describe EC-specific knockout of FAK using a Cre-loxP approach. In contrast to the total FAK knockout, deletion of FAK specifically in ECs did not affect early embryonic development including normal vasculogenesis.

Signal transduction pathways: targets for green and black tea polyphenols.

Tea is one of the most popular beverages consumed in the world and has been demonstrated to have anti-cancer activity in animal models. Research findings suggest that the polyphenolic compounds, (-)-epigallocatechin-3-gallate found primarily in green tea, and theaflavin-3,3'-digallate, a major component of black tea, are the two most effective anti-cancer factors found in tea. Several mechanisms to explain the chemopreventive effects of tea have been presented but others and we suggest that tea components target specific cell-signaling pathways responsible for regulating cellular proliferation or apoptosis.