58 research outputs found

    TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control

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    The 18-kDa TSPO (translocator protein) localizes on the outer mitochondrial membrane (OMM) and participates in cholesterol transport. Here, we report that TSPO inhibits mitochondrial autophagy downstream of the PINK1-PARK2 pathway, preventing essential ubiquitination of proteins. TSPO abolishes mitochondrial relocation of SQSTM1/p62 (sequestosome 1), and consequently that of the autophagic marker LC3 (microtubule-associated protein 1 light chain 3), thus leading to an accumulation of dysfunctional mitochondria, altering the appearance of the network. Independent of cholesterol regulation, the modulation of mitophagy by TSPO is instead dependent on VDAC1 (voltage-dependent anion channel 1), to which TSPO binds, reducing mitochondrial coupling and promoting an overproduction of reactive oxygen species (ROS) that counteracts PARK2-mediated ubiquitination of proteins. These data identify TSPO as a novel element in the regulation of mitochondrial quality control by autophagy, and demonstrate the importance for cell homeostasis of its expression ratio with VDAC1

    The pharmacological regulation of cellular mitophagy

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    Small molecules are pharmacological tools of considerable value for dissecting complex biological processes and identifying potential therapeutic interventions. Recently, the cellular quality-control process of mitophagy has attracted considerable research interest; however, the limited availability of suitable chemical probes has restricted our understanding of the molecular mechanisms involved. Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (for example, FCCP/CCCP) and the use of antimycin A and oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis and therefore limit the scope for dissection of subtle, bioenergy-related regulatory phenomena. Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation. We have summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications

    A blind accuracy assessment of computer-modeled forensic facial reconstruction using computed tomography data from live subjects.

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    A computer modeling system for facial reconstruction has been developed that employs a touch-based application to create anatomically accurate facial models focusing on skeletal detail. This article discusses the advantages and disadvantages of the system and illustrates its accuracy and reliability with a blind study using computed tomography (CT) data of living individuals. Three-dimensional models of the skulls of two white North American adults (one male, one female) were imported into the computer system. Facial reconstructions were produced by two practitioners following the Manchester method. Two posters were produced, each including a face pool of five surface model images and the facial reconstruction. The face pool related to the sex, age, and ethnic group of the target individual and included the surface model image of the target individual. Fifty-two volunteers were asked to choose the face from the face pool that most resembled each reconstruction. Both reconstructions received majority percentage hit rates that were at least 50% greater than any other face in the pool. The combined percentage hit rate was 50% above chance (70%). A quantitative comparison of the facial morphology between the facial reconstructions and the CT scan models of the subjects was carried out using Rapidform(™) 2004 PP2-RF4. The majority of the surfaces of the facial reconstructions showed less than 2.5 mm error and 90% of the male face and 75% of the female face showed less than 5 mm error. Many of the differences between the facial reconstructions and the facial scans were probably the result of positional effects caused during the CT scanning procedure, especially on the female subject who had a fatter face than the male subject. The areas of most facial reconstruction error were at the ears and nasal tip

    The permissibility of using somatic cell nuclear transfer techniques on nonhuman animals

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    Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Includes bibliographical references (leaves 79-81).Issued also on microfiche from Lange Micrographics.Somatic cell nuclear transfer is the process of cloning that produced Dolly. In order to clone an animal using somatic cell nuclear transfer, a donor cell is collected from an animal that one wants to clone and placed in a culture with a very low concentration of nutrients. This starves the cell and causes it to stop dividing and causes it to switch off its active genes. Next an egg cell is collected [from a member of the same or compatible species] and the nucleus containing the DNA is removed. The two cells are then placed next to each other in a culture and an electric pulse fuses them together. A second electric pulse-which simulates the spark of fertilization-activates the cell and starts division. After about six days the resulting embryo is placed into a surrogate mother. When the gestation period is completed the clone is born. In this thesis I consider the permissibility of using this techniques to clone non-human animals

    TERRORISM AND JUST WAR TRADITION: ISSUES OF COMPATIBILITY

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    In simplest terms, I intend to argue in this dissertation that at least some types of terrorism are permissible within a Just War framework. There are two forms that this argument can take. There is the weak form that concludes that at least some types of terrorism are permissible within a Just War framework but leaves open the question of the justifiability of any formulation of Just War Theory. There is also the strong form of the argument that at least some types of terrorism are permissible within a Just War framework and that the Just War Tradition is the correct moral theory to govern martial actions, and therefore concludes that at least some types of terrorism are permissible. In my dissertation, I am arguing for the weaker claim and leaving open the question of the correctness of any formulation of Just War Theory. If Just War Tradition is correct and I am successful in demonstrating that at least some types of terrorism are permissible within a Just War framework, then I will have shown that at least some types of terrorism are permissible. As I have said, though, my project is not to argue to defend any version of Just War Theory that Just War Tradition is correct but rather to merely to demonstrate that at least some types of terrorism are permissible within a Just War framework. When evaluating any use of force within the scope of a Just War framework, two questions need to be addressed: (1) was it appropriate to engage in the use of force (jus ad bellum considerations), and (2) was the force used appropriately (jus in bello considerations). It is within the scope of these two questions that most of the objections to terrorism arise. In my dissertation, I argue that a terrorist campaign or action can meet key standards of jus ad bellum and jus in bello implicit in Just War Theory. I show how these standards can be met in response to two central objections to terrorism, that terrorists lack the authority to make war, and that the random targeting of civilians renders terrorism unjustifiable. iii I approach the question whether it is appropriate for terrorists to engage in the use of violent force from the perspective of a Lockean theory of individual sovereignty. I show that the authority to engage in martial activities rests with governments because that authority has been granted them by those individuals who have come together to form the community over which the government has been given authority. Individuals who have delegated authority to the government, however, have not alienated their right to engage in martial activities. Instead, they have suspended exercising their right to engage in martial activities contingent upon the governments’ using that authority appropriately. When governments fail to use their delegated authority appropriately, then individuals can once again exercise their rights. This includes coming together to form new communities—non-governmental organizations—through which to exercise their power, including their right of self-defense. I deal with the second question, the appropriateness of terrorist tactics, e.g. intentionally targeting members of civilian populations, by arguing that many more members of the civilian population are combatants than most people realize. I argue that anyone who is dangerous in the martial sense, where the martial sense of dangerousness is understood as having one’s behavior purposely directed in support or military or other martial activities makes one a combatant

    New species of Australian chiton from Queensland, Enoplochiton torri

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    Volume: 20Start Page: 27End Page: 3

    CO2 : mineral reaction in a natural analogue for CO2 storage : implications for modeling

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    Geochemical models of CO2 injection into reservoir sandstones often predict the growth of minerals that will permanently store the CO2 in solid form, and injection experiments record significant fluctuations in porewater chemistry on a short time scale. Yet the proportion of CO2 reaction may be small, even over geological time scales. A southern North Sea (UK) gas accumulation with a high natural CO2 content (c. 50%) forms a natural analogue to engineered storage, and provides a calibration point for geochemical models of CO2–rock reaction. In the analogue site, the carbonate mineral dawsonite has formed in only trace amounts (0.4 ± 0.3% solid volume) despite exposure to high levels of CO2 for 50 Myr or more. It is calculated that only 2.4 (± 0.9)% of the CO2 present within the structure is currently locked up as dawsonite, and a similar quantity in solution in the porewaters. Comparison of stable O and C isotopes with a neighboring field with low CO2 content gas suggests that up to 0.7 (± 2)% solid volume dolomite cement is associated with the CO2 charge, equivalent to 0–25% of the total CO2. The remaining 70–95% of the CO2 is present as a free phase, after tens of millions of years. Consequently, geological storage of anthropogenic CO2 in reservoirs similar to the Rotliegend Group must rely on physical containment and not mineral sequestration. The Rotliegend Group is still an excellent candidate for a CO2 storage reservoir, though using physical trapping mechanisms and not chemical ones
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