Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

Mitochondrial Membrane Permeabilization in Cell Death

In the last decade, basic cancer research has produced remarkable advances in our understanding of cancer biology and cancer genetics. Among the most important of these advances is the realization that apoptosis and the genes that control it have a profound effect on the malignant phenotype. For example, it is now clear that some oncogenic mutations disrupt apoptosis, leading to tumor initiation, progression or metastasis. Conversely, compelling evidence indicates that other oncogenic changes promote apoptosis, thereby producing selective pressure to override apoptosis during multistage carcinogenesis. Finally, it is now well documented that most cytotoxic anticancer agents induce apoptosis, raising the intriguing possibility that defects in apoptotic programs contribute to treatment failure. Because the same mutations that suppress apoptosis during tumor development also reduce treatment sensitivity, apoptosis provides a conceptual framework to link cancer genetics with cancer therapy. An intense research effort is uncovering the underlying mechanisms of apoptosis such that, in the next decade, one envisions that this information will produce new strategies to exploit apoptosis for therapeutic benefit.

Apoptosis in cancer

For over three decades, a mainstay and goal of clinical oncology has been the development of therapies promoting the effective elimination of cancer cells by apoptosis. This programmed cell death process is mediated by several signalling pathways (referred to as intrinsic and extrinsic) triggered by multiple factors, including cellular stress, DNA damage and immune surveillance. The interaction of apoptosis pathways with other signalling mechanisms can also affect cell death. The clinical translation of effective pro-apoptotic agents involves drug discovery studies (addressing the bioavailability, stability, tumour penetration, toxicity profile in non-malignant tissues, drug interactions and off-target effects) as well as an understanding of tumour biology (including heterogeneity and evolution of resistant clones). While tumour cell death can result in response to therapy, the selection, growth and dissemination of resistant cells can ultimately be fatal. In this Review, we present the main apoptosis pathways and other signalling pathways that interact with them, and discuss actionable molecular targets, therapeutic agents in clinical translation and known mechanisms of resistance to these agents.

Targeting apoptosis in cancer therapy

BCL-2 was the first anti-death gene discovered, a milestone with far reaching implications for tumor biology. Multiple members of the human Bcl-2 family of apoptosis-regulating proteins have been identified, including six antiapoptotic, three structurally similar proapoptotic proteins and several structurally diverse proapoptotic interacting proteins that operate as upstream agonists or antagonists. These proteins, in turn, are regulated through myriad post-translational modifications and interactions with other proteins. Bcl-2-family proteins regulate all major types of cell death, including apoptosis, necrosis and autophagy, thus operating as nodal points at the convergence of multiple pathways with broad relevance to oncology. Experimental therapies targeting Bcl-2-family mRNAs or proteins are currently in clinical testing, raising hopes that a new class of anticancer drugs may soon be available.

Bcl-2 family proteins and cancer.

During the past decade a plethora of studies have unravelled the multiple roles of nitric oxide (NO) in airway physiology and pathophysiology. In the respiratory tract, NO is produced by a wide variety of cell types and is generated via oxidation of l-arginine that is catalyzed by the enzyme NO synthase (NOS). NOS exists in three distinct isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) have been shown to be modulators of bronchomotor tone. On the other hand, NO derived from iNOS seems to be a proinflammatory mediator with immunomodulatory effects. The concentration of this molecule in exhaled air is abnormal in activated states of different inflammatory airway diseases, and its monitoring is potentially a major advance in the management of, e.g., asthma. Finally, the production of NO under oxidative stress conditions secondarily generates strong oxidizing agents (reactive nitrogen species) that may modulate the development of chronic inflammatory airway diseases and/or amplify the inflammatory response. The fundamental mechanisms driving the altered NO bioactivity under pathological conditions still need to be fully clarified, because their regulation provides a novel target in the prevention and treatment of chronic inflammatory diseases of the airways.

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Nitric Oxide in Health and Disease of the Respiratory System

Self-cooling materials, such as food containers for transporting perishable food items, and methods for producing and using the materials are disclosed. The materials include a reactant adapted to produce an endothermic reaction upon hydration of the reactant by ambient water vapor. Proper handling of items that need to be kept cold can be difficult during transport of the items. For example, ice cream can begin to melt while being taken home from the store and re-freezing can give the ice cream a different texture. Proper, handling of food is important to minimize spoiling of the food and prevent foodbome illnesses, both of which may be associated with growth of bacteria, or other germs.

Self-cooling containers and wraps

Symbologies for encoding data, as well as methods of encoding and decoding thereof are described. The symbologies may have a plurality of pixels arranged in a plurality of patterns on or in a substrate. Furthermore, each of the plurality of pixels may have one or more optical properties that each provides one or more types of non-interacting data.

Orthogonal encoding for tags

Cellular uptake and in situ binding of a peptide agonist for calmodulin.

In some examples, a method to monitor an animal may include determining a physiological status of the animal based on a tattoo that includes intelligent ink injected into skin of the animal. The method may also include recording the physiological status of the animal. The method may also include, in response to the physiological status indicating a physiological event or condition, triggering an alert to address the physiological event or condition.

Tattoo and tattoo applicator for animal lifecycle monitoring

Embodiments described herein provide for terahertz tags and methods of making and using them. A tag may include a terahertz reflective material; and a saturated hygroscopic material positioned on the terahertz reflective material. A tag may include a terahertz reflective material; and an anhydrous hygroscopic material positioned on the terahertz reflective material. A humidity sensor may include a terahertz reflective material; and an anhydrous hygroscopic material positioned on the terahertz reflective material. A temperature sensor may include a terahertz reflective material; an anhydrous hygroscopic material positioned on the terahertz reflective material; and a polymer overlay having thermally controlled water permeability disposed on the anhydrous hygroscopic material. Some embodiments relate to a tag identification device configured to transmit an incident signal toward the tag, and to receive a reply signal from the tag in response to the incident signal.

Michael Keoni Manion

Papers

Self-cooling containers and wraps

Orthogonal encoding for tags

Cellular uptake and in situ binding of a peptide agonist for calmodulin.

Tattoo and tattoo applicator for animal lifecycle monitoring

Terahertz frequency tags and methods for their preparation and use