Requirement of a Membrane Potential for the Posttranslational Transfer of Proteins into Mitochondsria

Posttranslational transfer of most precursor proteins into mitochondria is dependent on energization of the mitochondria. Experiments were carried out to determine whether the membrane potential or the intramitochondrial ATP is the immediate energy source. Transfer in vitro of precursors to the ADP/ATP carrier and to ATPase subunit 9 into isolated Neurospora mitochondria was investigated. Under conditions where the level of intramitochondrial ATP was high and the membrane potential was dissipated, import and processing of these precursor proteins did not take place. On the other hand, precursors were taken up and processed when the intramitochondrial ATP level was low, but the membrane potential was not dissipated. We conclude that a membrane potential is involved in the import of those mitochondrial precursor proteins which require energy for intracellular translocatio

Intercomparison Exercise for Heavy Metals in PM10

The Joint Research Centre (JRC) has carried out an Intercomparison Exercise (IE) for the determination of heavy metals in particulate matter (PM10). The IE focussed on Lead (Pb), Arsenic (As), Nickel (Ni) and Cadmium (Cd), the heavy metals regulated by the 1st and 4th Daughter Directives for Air Pollution. Copper (Cu), Chromium (Cr) and Zinc (Zn), the elements included in the EMEP programme together with Aluminium (Al), Cobalt (Co), Iron (Fe), Manganese (Mn) and Vanadium (V) were also tested. Fourteen Laboratories, generally members of the Network of Air Quality Reference Laboratories (AQUILA), participated in the IE. The participants mainly used microwave digestion with nitric acid and hydrogen peroxide and Inductively Coupled Plasma Mass Spectrometry (ICP-MS) or Graphite Furnace Atomic Absorption Spectrometry (GF-AAS) for analysis as recommended in the reference method (EN 14902). However, a few participants used other methods: Energy Dispersive X-ray Fluorescence (EDXRF), Atomic Emission Spectrometry (ICP-AES) and Voltammetry for analysis and vaporisation on hot plate before microwave digestion, Soxhlet extraction, high pressure or cold Hydrogen Fluoride methods for digestion. Each participant received 5 samples to be analysed: a liquid sample prepared by dilution of a Certified Reference Material (CRM), a solution of a dust CRM sample digested by the JRC13F, a sub-sample of a dust CRM that each participating laboratory had to digest and analyse, a solution prepared by JRC after digestion of an exposed filter and a pair of filters (one blank filter and one exposed filter) to be digested and analysed by each participant. For 89 % of all types of samples, the DQOs of the 1st and 4th European Directives (uncertainty of 25 % for Pb and 40 % for As, Cd and Ni) were met. All together, this is a very good score. The best results were obtained for the liquid CRM, dust CRM digested by JRC, dust CRM and filter digested by JRC with 92, 90, 96 and 93 % of DQOs being met, respectively. It was found that the DQOs were not met if the difference of acidity between test samples and participant calibration standards was high. Conversely, only 76 % of DQOs were met for the filter to be digested by each participant with (about 85 % for Cd and Ni, 73/64 % for Pb and As, the most difficult element to determine). The worst results were associated with special events: explosion in microwave oven during digestion for two participants, a wrong dilution factor used by one participant and a huge contamination in the blank filter for another participant. Among the two explosions, one of them was probably the effect of a lack of temperature control in the digestion vessel. For the other explosion, the microwave digestion and the digestion program advised by EN 14902 is to be questioned. Moreover, satisfactory results were obtained using Soxhlet extraction, high pressure method and cold Hydrogen Fluoride digestion methods which are not presented in EN 14902. The DQOs of As and Cd could not be met with EDXRF whose limit of detection was too high for these two elements and for Cd using Voltammetry which suffered a strong interference for this element. Regarding the methods of analysis, apart the points mentioned just before about EDXRF and Voltammetry, good results were observed using ICP-OES for Cd, Ni and Pb. A few discrepancies were also registered for GF-AAS and ICP-MS but they were created by the special events or acidity problem mentioned before. This shows that even though GF-AAS and ICP-MS are found suitable, the implementation by each participant may be responsible for important mistakes.JRC.H.4-Transport and air qualit

The future of Cybersecurity in Italy: Strategic focus area

This volume has been created as a continuation of the previous one, with the aim of outlining a set of focus areas and actions that the Italian Nation research community considers essential. The book touches many aspects of cyber security, ranging from the definition of the infrastructure and controls needed to organize cyberdefence to the actions and technologies to be developed to be better protected, from the identification of the main technologies to be defended to the proposal of a set of horizontal actions for training, awareness raising, and risk management

Challenges of future multimedia QoE monitoring for internet service providers

The ever-increasing network traffic and user expectations at reduced cost make the delivery of high Quality of Experience (QoE) for multimedia services more vital than ever in the eyes of Internet Service Providers (ISPs). Real-time quality monitoring, with a focus on the user, has become essential as the first step in cost-effective provisioning of high quality services. With the recent changes in the perception of user privacy, the rising level of application-layer encryption and the introduction and deployment of virtualized networks, QoE monitoring solutions need to be adapted to the fast changing Internet landscape. In this contribution, we provide an overview of state-of-the-art quality monitoring models and probing technologies, and highlight the major challenges ISPs have to face when they want to ensure high service quality for their customers

Epigenetic polypharmacology: from combination therapy to multitargeted drugs

The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed

Histone Deacetylase and Microtubules as Targets for the Synthesis of Releasable Conjugate Compounds

Design and synthesis of an HDAC inhibitor and its merger with three tubulin binders to create releasable conjugate compounds is described. The biological evaluation includes: a) in vitro reactivity with glutathione, b) antiproliferative activity, c) cell cycle analysis and d) quantification of protein acetylation. The cellular pharmacology study indicated that the HDAC-inhibitor-drug conjugates retained antimitotic and proapoptotic activity with a reduced potenc

Comparison of Therapeutic Effects between Pulsed and Continuous Wave 810-nm Wavelength Laser Irradiation for Traumatic Brain Injury in Mice

Background and Objective Transcranial low-level laser therapy (LLLT) using near-infrared light can efficiently penetrate through the scalp and skull and could allow non-invasive treatment for traumatic brain injury (TBI). In the present study, we compared the therapeutic effect using 810-nm wavelength laser light in continuous and pulsed wave modes in a mouse model of TBI. Study Design/Materials and Methods TBI was induced by a controlled cortical-impact device and 4-hours post-TBI 1-group received a sham treatment and 3-groups received a single exposure to transcranial LLLT, either continuous wave or pulsed at 10-Hz or 100-Hz with a 50% duty cycle. An 810-nm Ga-Al-As diode laser delivered a spot with diameter of 1-cm onto the injured head with a power density of 50-mW/cm2 for 12-minutes giving a fluence of 36-J/cm2. Neurological severity score (NSS) and body weight were measured up to 4 weeks. Mice were sacrificed at 2, 15 and 28 days post-TBI and the lesion size was histologically analyzed. The quantity of ATP production in the brain tissue was determined immediately after laser irradiation. We examined the role of LLLT on the psychological state of the mice at 1 day and 4 weeks after TBI using tail suspension test and forced swim test. Results The 810-nm laser pulsed at 10-Hz was the most effective judged by improvement in NSS and body weight although the other laser regimens were also effective. The brain lesion volume of mice treated with 10-Hz pulsed-laser irradiation was significantly lower than control group at 15-days and 4-weeks post-TBI. Moreover, we found an antidepressant effect of LLLT at 4-weeks as shown by forced swim and tail suspension tests. Conclusion The therapeutic effect of LLLT for TBI with an 810-nm laser was more effective at 10-Hz pulse frequency than at CW and 100-Hz. This finding may provide a new insight into biological mechanisms of LLLT.National Institutes of Health (U.S.) (NIH grant R01AI050875)Center for Integration of Medicine and Innovative Technology (DAMD17-02-2-0006)United States. Dept. of Defense. Congressionally Directed Medical Research Programs (W81XWH-09-1-0514)United States. Air Force Office of Scientific Research (Military Photomedicine Program (FA9950-04-1-0079))Japan. Ministry of Education, Culture, Sports, Science and TechnologyJapan Society for the Promotion of Scienc

Macroeconomic models for assessing the transition towards a circular economy: a systematic review

The Circular Economy (CE) paradigm has gained traction in both academic discourse and industrial practice. While a transition towards a CE is generally associated with more sustainable futures, less is known about its socio-economic feasibility. This article provides a systematic literature review of contributions to macroeconomic modelling which evaluate environmental and socio-economic impacts of CE interventions (classified in terms of closing supply chains, resource efficiency, residual waste management, and product lifetime extension). Differences in modelling approaches (Leontief input-output, macroeconometric input-output, and computable general equilibrium), and underlying assumptions relating to changes in final demand and technology, are found to be significant drivers of differences in the modelled outcomes of CE interventions. Through this review, various research gaps are identified, including addressing the challenges to sectoral and regional disaggregation (allowing for the modelling of international trade-offs), broader consideration of societal issues beyond GDP and employment (such as environmental, gender or transnational justice), and consideration of broader modelling dynamics (such as rebound effects, the interplay between demand and distribution, and real-financial interactions)