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The nuclear pore complex (NPC) mediates trafficking between the cytoplasm and nucleoplasm. It also plays key roles in other nuclear processes such as chromatin silencing, transcriptional regulation, and DNA damage repair. Nucleoporins, the structural components of the NPC, have been linked to a multitude of cancers through chromosomal translocations generating fusion proteins, changes in protein expression levels, and single point mutations. Only a small number of nucleoporins have been linked to tumorigenesis thus far, and these proteins-Nup62, Nup88, Nup98, Nup214, Nup358/RanBP2, and Tpr-line the trafficking pathway and are particularly associated with mRNA export. Overexpression of several associated nuclear export factors, most also involved in various stages of mRNA export, has been linked to cancers as well. Some oncogenic nucleoporin mutants are mislocalized to either the cytoplasm or nucleoplasm while others are incorporated into the NPC, and in all these cases they are thought to misregulate signaling pathways and transcription through either altered or diminished nucleoporin functionality. Intriguingly, many viruses target the same cancer-linked nucleoporins, often causing their degradation or mislocalization, implying that these viruses exploit some of the same weaknesses as the oncogenic defects.

Type I interferons (IFNs) play an important role in direct antiviral defense as well as linking the innate and adaptive immune responses. On dendritic cells (DCs), IFNs facilitate their activation and contribute to CD8(+) and CD4(+) T cell priming. However, the precise molecular mechanism by which IFNs regulate maturation and immunogenicity of DCs in vivo has not been studied in depth. Here we show that, after in vivo stimulation with the TLR ligand poly IC, IFNs dominate transcriptional changes in DCs. In contrast to direct TLR3/mda5 signaling, IFNs are required for upregulation of all pathways associated with DC immunogenicity. In addition, metabolic pathways, particularly the switch from oxidative phosphorylation to glycolysis, are also regulated by IFNs and required for DC maturation. These data provide evidence for a metabolic reprogramming concomitant with DC maturation and offer a novel mechanism by which IFNs modulate DC maturation.

Senescence is a form of cellular aging that limits the proliferative capacity of cells. Senescence can be triggered by different stress stimuli, such as DNA damage or oncogene activation. Two recent articles published in Cell have uncovered an unexpected role for cellular senescence during development, as a process that contributes to remodeling and patterning of the embryo. These findings are exciting and have important implications for the understanding of normal developmental and the evolutionary origin of senescence.

Adherent cells, crawling slugs, peeling paint, sessile liquid drops, bearings and many other living and non-living systems apply forces to solid substrates. Traction force microscopy (TFM) provides spatially-resolved measurements of interfacial forces through the quantification and analysis of the deformation of an elastic substrate. Although originally developed for adherent cells, TFM has no inherent size or force scale, and can be applied to a much broader range of mechanical systems across physics and biology. In this paper, we showcase the wide range of applicability of TFM, describe the theory, and provide experimental details and code so that experimentalists can rapidly adopt this powerful technique.

Passive immunotherapy represents a promising therapeutic intervention for a number of neoplastic, chronic inflammatory, and infectious diseases, with several monoclonal antibodies currently under development or already in use in the clinic. While Fab-antigen interactions play a crucial role in the activity of an antibody, it has become clear that Fc-mediated effector functions are involved during antibody-mediated activities in vivo. A complete understanding of the contributions of effector activities mediated by an antibody during its in vivo function is required for the development of antibodies with improved therapeutic efficacies. Animal models that are commonly used for the preclinical evaluation of antibodies include murine and non-human primate species, whose Fc gamma Rs present substantial structural, functional, and genetic variation compared with their human counterparts. Therefore, the use of such animal models provides limited information on the role of human IgG Fc-Fc gamma R interactions during the in vivo activities of antibodies intended for human therapeutics. In this chapter, we describe the development and evaluation of an Fc gamma R-humanized mouse model for the study of human Fc gamma R function in vivo. In this model, endogenous mouse Fc gamma R genes have been deleted and human Fc gamma Rs are expressed as transgenes that faithfully recapitulate the unique pattern of human Fc gamma R expression. Evaluation of the in vivo activities of a number of cytotoxic or therapeutic antibodies using Fc gamma R-humanized mice provided useful insights into human IgG Fc effector function. This mouse model has become a vital preclinical model for testing therapeutic human antibodies to treat malignancies, autoimmunity, inflammation, and infectious disease.

The nematode Caenorhabditis elegans has served as a fruitful setting for cell death research for over three decades. A conserved pathway of four genes, egl-1/BH3-only, ced-9/Bcl-2, ced-4/Apaf-1, and ced-3/caspase, coordinates most developmental cell deaths in C elegans. However, other cell death forms, programmed and pathological, have also been described in this animal. Some of these share morphological and/or molecular similarities with the canonical apoptotic pathway, while others do not. Indeed, recent studies suggest the existence of an entirely novel mode of programmed developmental cell destruction that may also be conserved beyond nematodes. Here, we review evidence for these noncanonical pathways. We propose that different cell death modalities can function as backup mechanisms for apoptosis, or as tailor-made programs that allow specific dying cells to be efficiently cleared from the animal.

While many physiological effects of estrogens (E) are due to regulation of gene transcription by liganded estrogen receptors (ERs), several effects are also mediated, at least in part, by rapid non-genomic actions of E. Though the relative importance of rapid versus genomic effects in the central nervous system is controversial, we showed previously that membrane-limited effects of E. initiated by an estradiol bovine serum albumin conjugate (E2-BSA), could potentiate transcriptional effects of 17 beta-estradiol from an estrogen response element (ERE)-reporter in neuroblastoma cells. Here, using specific inhibitors and activators in a pharmacological approach, we show that activation of phosphatidylinositol-3-phosphate kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways, dependent on a G alpha(q) coupled receptor signaling are important in this transcriptional potentiation. We further demonstrate, using ER alpha phospho-deficient mutants, that E2-BSA mediated phosphorylation of ER alpha is one mechanism to potentiate transcription from an ERE reporter construct. This study provides a possible mechanism by which signaling from the membrane is coupled to transcription in the nucleus, providing an integrated view of hormone signaling in the brain. (C) 2013 Elsevier Ltd. All rights reserved.

Background & aim: The dopaminergic pathways have been implicated in the etiology of drug addictions. The aim of this study was to determine if variants in dopaminergic genes are associated with heroin addiction. Materials & methods: The study includes 828 former heroin addicts and 232 healthy controls, of predominantly European ancestry. Ninety seven SNPs (13 genes) were analyzed. Results: Nine nominally significant associations were observed at CSNK1E, ANKK1, DRD2 and DRD3. Conclusion: The results support our previous report of association of CSNK1E SNP rs1534891 with protection from heroin addiction. CSNK1E interacts with circadian rhythms and DARPP-32 and has been implicated in negative regulation of sensitivity to opioids in rodents. It may be a target for drug addiction treatment.