Anti-tumor activity mediated by protein and peptide transduction of HIV viral protein R (Vpr)

Peptides that are capable of traversing the cell membrane, via protein transduction domains (PTDs), are attractive either directly as drugs or indirectly as carriers for the delivery of therapeutic molecules. One such PTD, a HIV-1 Tat derived peptide has successfully delivered a variety of "cargoes" including proteins, peptides and nucleic acids into cells. There also exists other naturally occurring membrane permeable peptides which have potential as PTDs. Specifically, one of the accessory proteins of HIV (viral protein R; i.e., Vpr), which is important in controlling viral pathogenesis, possesses cell transduction domain characteristics. Related to these characteristics, Vpr has also been demonstrated to induce cell cycle arrest and host/target cell apoptosis, suggesting a potential anticancer activity for this protein. In this report we assessed the ability of Vpr protein or peptides, with or without conjugation to a PTD, to mediate anti-cancer activity against several tumor cell lines. Specifically, several Vpr peptides spanning carboxy amino acids 65-83 induced significant (i.e., greater than 50%) in vitro growth inhibition/toxicity of murine B16.F10 melanoma cells. Likewise, in in vitro experiments with other tumor cell lines, conjugation of Vpr to the Tat derived PTD and transfection of this construct into cells enhanced the induction of in vitro apoptosis by this protein when compared to the effects of transfection of cells with unconjugated Vpr. These results underscore the potential for Vpr based reagents as well as PTDs to enhance anti-tumor activity, and warrants further examination of Vpr protein and derived peptides as potential therapeutic agents against progressive cell proliferative diseases such as cancer. ©2009 Landes Bioscience

A covariant regulator for entanglement entropy: proofs of the Bekenstein bound and QNEC

While von Neumann entropies for subregions in quantum field theory universally contain ultraviolet divergences, differences between von Neumann entropies are finite and well-defined in many physically relevant scenarios. We demonstrate that such a notion of entropy differences can be rigorously defined in quantum field theory in a general curved spacetime by introducing a novel, covariant regulator for the entropy based on the modular crossed product. This regulator associates a type II von Neumann algebra to each spacetime subregion, resulting in well-defined renormalized entropies. This prescription reproduces formulas for entropy differences that coincide with heuristic formulas widely used in the literature, and we prove that it satisfies desirable properties such as unitary invariance and concavity. As an application, we provide proofs of the Bekenstein bound and the quantum null energy condition, formulated directly in terms of vacuum-subtracted von Neumann entropies.Comment: 6 pages + appendices, 2 figure

STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease

Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of STING prevented IRF3 phosphorylation by ethanol or ER stress, and absence of IRF3 prevented hepatocyte apoptosis. The pathogenic role of IRF3 in ALD was independent of inflammation or Type-I interferons. Thus, STING and IRF3 are key determinants of ALD, linking ER stress signaling with the mitochondrial pathway of hepatocyte apoptosis

Biodistribution and function of extracellular miRNA-155 in mice

Circulating miRNAs can be found in extracellular vesicles (EV) and could be involved in intercellular communication. Here, we report the biodistribution of EV associated miR-155 using miR-155 KO mouse model. Administration of exosomes loaded with synthetic miR-155 mimic into miR-155 KO mice resulted in a rapid accumulation and clearance of miR-155 in the plasma with subsequent distribution in the liver, adipose tissue, lung, muscle and kidney (highest to lowest, respectively). miR-155 expression was detected in isolated hepatocytes and liver mononuclear cells of recipient KO mice suggesting its cellular uptake. In vitro, exosome-mediated restoration of miR-155 in Kupffer cells from miR-155 deficient mice augmented their LPS-induced MCP1 mRNA increase. The systemic delivery of wild type plasma to miR-155 KO mice also resulted in a rapid accumulation of miR-155 in the circulation and distribution to the liver and adipose tissue. In summary, our results demonstrate tissue biodistribution and biologic function of EV-associated miR-155

Metabolic Networks of Sodalis glossinidius: A Systems Biology Approach to Reductive Evolution

Background: Genome reduction is a common evolutionary process affecting bacterial lineages that establish symbiotic or pathogenic associations with eukaryotic hosts. Such associations yield highly reduced genomes with greatly streamlined metabolic abilities shaped by the type of ecological association with the host. Sodalis glossinidius, the secondary endosymbiont of tsetse flies, represents one of the few complete genomes available of a bacterium at the initial stages of this process. In the present study, genome reduction is studied from a systems biology perspective through the reconstruction and functional analysis of genome-scale metabolic networks of S. glossinidius. Results: The functional profile of ancestral and extant metabolic networks sheds light on the evolutionary events underlying transition to a host-dependent lifestyle. Meanwhile, reductive evolution simulations on the extant metabolic network can predict possible future evolution of S. glossinidius in the context of genome reduction. Finally, knockout simulations in different metabolic systems reveal a gradual decrease in network robustness to different mutational events for bacterial endosymbionts at different stages of the symbiotic association. Conclusions: Stoichiometric analysis reveals few gene inactivation events whose effects on the functionality of S. glossinidius metabolic systems are drastic enough to account for the ecological transition from a free-living to hostdependent lifestyle. The decrease in network robustness across different metabolic systems may be associated with th