Through their many and varied metabolic functions, mitochondria power life. Paradoxically, mitochondria also have a central role in apoptotic cell death. Upon induction of mitochondrial apoptosis, mitochondrial outer membrane permeabilization (MOMP) usually commits a cell to die. Apoptotic signalling downstream of MOMP involves cytochrome c release from mitochondria and subsequent caspase activation. As such, targeting MOMP in order to manipulate cell death holds tremendous therapeutic potential across different diseases, including neurodegenerative diseases, autoimmune disorders and cancer. In this Review, we discuss new insights into how mitochondria regulate apoptotic cell death. Surprisingly, recent data demonstrate that besides eliciting caspase activation, MOMP engages various pro-inflammatory signalling functions. As we highlight, together with new findings demonstrating cell survival following MOMP, this pro-inflammatory role suggests that mitochondria-derived signalling downstream of pro-apoptotic cues may also have non-lethal functions. Finally, we discuss the importance and roles of mitochondria in other forms of regulated cell death, including necroptosis, ferroptosis and pyroptosis. Collectively, these new findings offer exciting, unexplored opportunities to target mitochondrial regulation of cell death for clinical benefit.

Mitochondria as multifaceted regulators of cell death.

volume 30 number 5 may 2012 nature biotechnology 24 repeat units for recognition of a specific set of 24 contiguous nucleotides at the target sites (Supplementary Fig. 1). For each pair of TALEN genes, one TALEN gene (half of the pair) was under the control of the 35S promoter of cauliflower mosaic virus and the other gene was driven by the maize ubiquitin 1 promoter, comprising a specific TALEN pair in a single plasmid (Supplementary Fig. 2). Each plasmid also contained a marker gene for hygromycin resistance. These constructs were introduced pathogen’s nutritional needs and enhance its persistence2,14. The Os11N3 promoter contains an effector-binding element (EBE) for AvrXa7, overlapping with another EBE for PthXo3 and with the TATA box (Fig. 1a and Supplementary Fig. 1). We deployed two pairs of designer TALENs (pair 1 and pair 2) independently to induce mutations in these overlapping EBEs of the Os11N3 promoter and thus to interfere with the virulence function of AvrXa7 and PthXo3, but not the developmental function of Os11N3 (Supplementary Fig. 1 and Supplementary Note). The TALE repetitive regions used for nuclease fusions included the native AvrXa7 and three designer TALE repetitive regions custom synthesized using a modular assembly method8. Each designer TALEN contained To the Editor: Transcription activator–like (TAL) effectors of Xanthomonas oryzae pv. oryzae (Xoo) contribute to pathogen virulence by transcriptionally activating specific rice disease-susceptibility (S) genes1,2. TAL effector nucleases (TALENs)—fusion proteins derived from the DNA recognition repeats of native or customized TAL effectors and the DNA cleavage domains of FokI3–5—have been used to create site-specific gene modifications in plant cells6,7, yeast8, animals9–12 and even human pluripotent cells13. Here, we exploit TALEN technology to edit a specific S gene in rice to thwart the virulence strategy of X. oryzae and thereby engineer heritable genome modifications for resistance to bacterial blight, a devastating disease in a crop that feeds half of the world’s population. We targeted the rice bacterial blight susceptibility gene Os11N3 (also called OsSWEET14) for TALEN-based disruption. This rice gene encodes a member of the SWEET sucrose-efflux transporter family and is hijacked by X. oryzae pv. oryzae, using its endogenous TAL effectors AvrXa7 or PthXo3, to activate the gene and thus divert sugars from the plant cell so as to satisfy the High-efficiency TALEN-based gene editing produces disease-resistant rice

/pdf/high-efficiency-talen-based-gene-editing-produces-disease-22m4hnufsc.pdf

High-efficiency TALEN-based gene editing produces disease-resistant rice

https://www.cell.com/cell/pdf/S0092-8674(10)00892-5.pdf

Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin Lymphoma

Stretchable electronics provide a foundation for applications that exceed the scope of conventional wafer and circuit board technologies due to their unique capacity to integrate with soft materials and curvilinear surfaces. The range of possibilities is predicated on the development of device architectures that simultaneously offer advanced electronic function and compliant mechanics. Here we report that thin films of hard electronic materials patterned in deterministic fractal motifs and bonded to elastomers enable unusual mechanics with important implications in stretchable device design. In particular, we demonstrate the utility of Peano, Greek cross, Vicsek and other fractal constructs to yield space-filling structures of electronic materials, including monocrystalline silicon, for electrophysiological sensors, precision monitors and actuators, and radio frequency antennas. These devices support conformal mounting on the skin and have unique properties such as invisibility under magnetic resonance imaging. The results suggest that fractal-based layouts represent important strategies for hard-soft materials integration.

/pdf/fractal-design-concepts-for-stretchable-electronics-2ydcxe2ozo.pdf

Fractal design concepts for stretchable electronics

Triggering of tumour cell apoptosis is the foundation of many cancer therapies. Death receptors of the tumour necrosis factor (TNF) superfamily have been largely characterized, as have the signals that are generated when these receptors are activated. TNF-related apoptosis-inducing ligand (TRAIL) receptors (TRAILR1 and TRAILR2) are promising targets for cancer therapy. Herein we review what is known about the molecular control of TRAIL-mediated apoptosis, the role of TRAIL in carcinogenesis and the potential therapeutic utility of recombinant TRAIL and agonistic antibodies against TRAILR1 and TRAILR2.

http://dipbsf.uninsubria.it/monti/BFPN%202009/TRAIL-2008.pdf?origin=publication_detail

The TRAIL apoptotic pathway in cancer onset, progression and therapy

An Fcγ Receptor-Dependent Mechanism Drives Antibody-Mediated Target-Receptor Signaling in Cancer Cells

http://zhiyuan.sjtu.edu.cn/file/course/20131031092244_Ma%20Xiaojing-Discussion.pdf

TWEAK Attenuates the Transition from Innate to Adaptive Immunity

Supplementary Figure 1: Metabolites plasma concentrations (MPR and oxo-4-HPR) determined in mice after single oral treatment of 4 doses of Bio-nFeR: 10, 50, 100 and 200 mg/Kg. The analysis was performed after 0, 24, 48 h. Supplementary Figure 2: Evaluation of the 50% inhibitory concentration (IC50) of BionFeR and NCI-FeR formulation was done on a representative lung cancer stem cell line (LCSC). The cells were exposed to the indicated drug doses (0-30 M) and cell viability was evaluated by CellTiter-Glo after 72 hours. Supplementary Figure 3: A) Sphingomyelin-Ceramide (SM-CER) and SphingomyelinDihydro-Ceramide (SM-DH-CER) content in lung (LC), melanoma (MEL) and colon (CRC) tumors treated with Bio-nFeR at single 100-150 mg/Kg administration were quantified through Ultra High Performance Liquid Chromatography (UHPLC), normalized to control and plotted as fold change. B) Quantification of Glucosyl-Ceramide (GLC-CER) and Glucosyl-Dihydro-Ceramide (GLC-DH-CER) in the same samples as in A, normalized to control and plotted as fold change. Supplementary Figure 4: Cancer stem cell marker expression in CSC-culture conditions and in CSC-derived xenografts. A) Flow cytometry analysis of Aldefluor in (left panels) and CD44v6 (middle and right panels) in the indicated CSC and xenograft samples. B) Immunoblot analysis of CSC antigens c-Kit and SOX-2 in the indicated control (-) or BionFeR treated (+) melanoma xenografts. -actin blot was used for equal loading control. Supplementary Figure 5: Growth curves of lung CSC-derived xenografts in control mice or mice treated with Bio-nFeR or NCI-FeR at 100 mg/kg dose for the indicated times. Mean± standard error is shown. *P<0.05

Becky Yang

Papers

An Fcγ Receptor-Dependent Mechanism Drives Antibody-Mediated Target-Receptor Signaling in Cancer Cells

TWEAK Attenuates the Transition from Innate to Adaptive Immunity

Supplementary Figure 3

TRAF2 Sets a Threshold for Extrinsic Apoptosis by Tagging Caspase-8 with a Ubiquitin Shutoff Timer

Cooperation of the proapoptotic receptor agonist rhApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin lymphoma xenografts