Friendly fire Snook, Scott A; Snook, Scott A
2011., 20110919, 2011, 2000-01-01
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On April 14, 1994, two U.S. Air Force F-15 fighters accidentally shot down two U.S. Army Black Hawk Helicopters over Northern Iraq, killing all twenty-six peacekeepers onboard. In response to this ...disaster the complete array of military and civilian investigative and judicial procedures ran their course. After almost two years of investigation with virtually unlimited resources, no culprit emerged, no bad guy showed himself, no smoking gun was found. This book attempts to make sense of this tragedy--a tragedy that on its surface makes no sense at all.
The textbook description of mitochondrial respiratory complexes (RCs) views them as free-moving entities linked by the mobile carriers coenzyme Q (CoQ) and cytochrome c (cyt c). This model (known as ...the fluid model) is challenged by the proposal that all RCs except complex II can associate in supercomplexes (SCs). The proposed SCs are the respirasome (complexes I, III, and IV), complexes I and III, and complexes III and IV. The role of SCs is unclear, and their existence is debated. By genetic modulation of interactions between complexes I and III and III and IV, we show that these associations define dedicated CoQ and cyt c pools and that SC assembly is dynamic and organizes electron flux to optimize the use of available substrates.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The essential oxidoreductase Mia40/CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space. Here, we investigated the interactome of Mia40 thereby ...revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca(2+) signaling. Among the interaction partners of Mia40 is MICU1-the regulator of the mitochondrial Ca(2+) uniporter (MCU), which transfers Ca(2+) across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca(2+) uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca(2+) levels: the dimer associates with MCU at low levels of Ca(2+) and dissociates upon high Ca(2+) concentrations. Our findings support a model in which mitochondrial Ca(2+) uptake is regulated by a Ca(2+)-dependent remodeling of the uniporter complex.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at ...an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.
Without questioning the fact that to achieve efficiency emitters should pay for the true costs of their actions (a core principle of economic policies such as pollution taxes), we find sufficient ...evidence in the literature to demonstrate that many other policy instruments can be used in combination with taxes and permits to ensure that the transport needs of the present generation can be met without compromising the ability of future generations to meet any needs of their own.
The policies and policy aspects considered in this paper broadly fall into three categories: physical policies, soft policies, and knowledge policies. All three aim to bring about changes in consumers’ and firms’ behaviour, but in different ways. The first category includes policies with a physical infrastructure element: public transport, land use, walking and cycling, road construction, and freight transport. We also consider the particular challenges for mobility in developing countries, and how these may be addressed. Soft policies, on the other hand, are non-tangible aiming to bring about behavioural change by informing actors about the consequences of their transport choices, and potentially persuading them to change their behaviour. These measures include car sharing and car pooling, teleworking and teleshopping, eco-driving, as well as general information and advertising campaigns. Finally, knowledge policies emphasise the important role of investment in research and development for a sustainable model of mobility for the future.
The main findings can be summarised as follows.
An increase in the use of
public transport, combined with a decrease in the use of private cars, can reduce traffic congestion and, more importantly, carbon dioxide (CO
2) emissions, as public transport generally causes lower CO
2 emissions per passenger kilometre than private cars. Public transport fares are subsidised in most places, which can be justified by economies of scale and by the fact that public transport can reduce total road transport externalities. London, Singapore, Portland and Curitiba are all examples of good practice at government level, having achieved reliable, frequent and integrated public transport.
Policies to increase public transport use must be part of an
integrated policy. Integrated policy refers to integration across different modes of transport, different government objectives (such as the economy, health and the environment), considering the needs of different social groups, and coordinating action between the relevant government institutions. There is evidence that a lack of coordination can jeopardise the achievement of policy objectives.
A sustainable model for transport policy also requires integration with
land-use policies. These may be somewhat limited within the bounds of existing cities, but as cities grow and new cities are built, urban planners must put more emphasis on land use for sustainable transport in order to reduce congestion and CO
2 emissions. Sustainable land-use policy can direct urban development towards a form that allows public transport as well as walking and cycling to be at the core of urban mobility.
Walking and cycling, which improve general health and produce no tailpipe emissions, constitute an excellent alternative to motorised transport on short-distance trips within towns and cities. The policies which can incentivise walking and cycling include crime reduction to make streets safer, well-maintained and clean pavements, attractive street furniture, safe crossings with shorter waiting times, dedicated cycle paths, showers in offices, and lower speed limits, to name but a few.
Road construction and expansion used to be seen as one of the most promising ways to reduce traffic congestion. However, in the mid-1990s, the issue was reassessed and it was found that building and expanding roads, increased, rather than decreased, congestion, and ultimately induced higher levels of travel demand. The reason for this is that the extra capacity reduces the general cost of travelling and the less expensive the travel, the more it will be demanded. Regarding
freight modal shift, road transport is much more polluting than rail per tonne-km of goods transported and therefore a shift towards greater use of rail in freight transport is desirable. Inadequate infrastructure is the main obstacle preventing this modal shift taking place.
Developing countries face great mobility challenges: rural areas are often extremely poorly connected to transport infrastructure, such that, in contrast to the situation in developed countries, the benefits of road construction can strongly outweigh the total costs (including environmental ones). The main challenge, however, is to develop a solution to the problems arising from the combination of urbanisation and motorisation. Integration of transport and land-use policy will be key to rising to this challenge.
Car sharing and car clubs can also potentially reduce CO
2 emissions, although the aggregate reduction in congestion and emissions has not been measured with an adequate degree of precision in the literature.
Teleworking and teleshopping can potentially reduce congestion and also CO
2 emissions. However, the evidence for this reduction is rather mixed, as it is unclear whether these measures lead to overall reductions in road transport.
Eco-driving campaigns aim to inform and educate drivers in order to induce them to drive in a fuel-efficient and thus environmentally friendly way. There seems to be some consensus in the literature that eco-driving could lead to reductions in CO
2 emissions of around 10 per cent.
Information and education policies have often been advocated as instruments which may affect
behavioural change. We find in this paper that these types of measures are necessary, but not sufficient for behavioural change.
Advertising and marketing may go a long way in changing peoples’ behaviour. In California, for example,
Kahn (2007) finds the “Prius” effect: the Toyota Prius is preferred by consumers relative to other similarly green vehicles, probably due to extensive marketing and celebrity endorsements.
Family life changes are also found to trigger changes in behaviour (
Goodwin, 1989, 2008). People whose lives are being changed by some important development (birth of a child, retirement, etc) tend to respond more to changes in the relative attractiveness of different transport modes. Advertising campaigns promoting a modal shift towards public transport, for instance, may thus be more successful if targeted at people in the process of important life transitions.
Research and Development is crucial for developing sustainable and low-carbon transport for the future, and it is essential that governments provide incentives to undertake R&D, so that new low-carbon technologies in the transport sector can be demonstrated and applied at a large scale.
Finally, we consider the issue of
policy combination and integration. There is evidence that the combination and integration of policies can lead to positive side-effects and synergies. Policy integration is crucial in order to rise to the challenges we face in moving towards a sustainable mobility model. We conclude that classical economic policies may be successfully combined with a number of policy measures discussed in this paper in order to achieve sustainability in transport.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The respiratory chain has been proposed as an attractive target for the development of new therapies to tackle human fungal pathogens. This arises from the presence of fungal-specific electron ...transport chain components and links between respiration and the control of virulence traits in several pathogenic species. However, as the physiological roles of mitochondria remain largely undetermined with respect to pathogenesis, its value as a potential new drug target remains to be determined. The use of respiration inhibitors as fungicides is well developed but has been hampered by the emergence of rapid resistance to current inhibitors. In addition, recent data suggest that adaptation of the human fungal pathogen,
Candida albicans
, to respiration inhibitors can enhance virulence traits such as yeast-to-hypha transition and cell wall organisation. We conclude that although respiration holds promise as a target for the development of new therapies to treat human fungal infections, we require a more detailed understanding of the role that mitochondria play in stress adaption and virulence.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Atg6 (beclin 1 in mammals) is a core component of the Vps34 complex that is required for autophagy. Beclin 1 (Becn1) functions as a tumor suppressor, and Becn1(+/-) tumors in mice possess elevated ...cell stress and p62 levels, altered NF-κB signaling and genome instability. The tumor suppressor function of Becn1 has been attributed to its role in autophagy, and the potential functions of Atg6/Becn1 in other vesicle trafficking pathways for tumor development have not been considered. Here, we generate Atg6 mutant Drosophila and demonstrate that Atg6 is essential for autophagy, endocytosis and protein secretion. By contrast, the core autophagy gene Atg1 is required for autophagy and protein secretion, but it is not required for endocytosis. Unlike null mutants of other core autophagy genes, all Atg6 mutant animals possess blood cell masses. Atg6 mutants have enlarged lymph glands (the hematopoietic organ in Drosophila), possess elevated blood cell numbers, and the formation of melanotic blood cell masses in these mutants is not suppressed by mutations in either p62 or NFκB genes. Thus, like mammals, altered Atg6 function in flies causes hematopoietic abnormalities and lethality, and our data indicate that this is due to defects in multiple membrane trafficking processes.
L-Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and plays important roles in a wide variety of brain functions, but it is also a key player in the ...pathogenesis of many neurological disorders. The control of glutamate concentrations is critical to the normal functioning of the central nervous system, and in this review we discuss how glutamate transporters regulate glutamate concentrations to maintain dynamic signaling mechanisms between neurons. In 2004, the crystal structure of a prokaryotic homolog of the mammalian glutamate transporter family of proteins was crystallized and its structure determined. This has paved the way for a better understanding of the structural basis for glutamate transporter function. In this review we provide a broad perspective of this field of research, but focus primarily on the more recent studies with a particular emphasis on how our understanding of the structure of glutamate transporters has generated new insights.
The mitochondrial respiratory chain, also known as the electron transport chain (ETC), is crucial to life, and energy production in the form of ATP is the main mitochondrial function. Three ...proton-translocating enzymes of the ETC, namely complexes I, III and IV, generate proton motive force, which in turn drives ATP synthase (complex V). The atomic structures and basic mechanisms of most respiratory complexes have previously been established, with the exception of complex I, the largest complex in the ETC. Recently, the crystal structure of the entire complex I was solved using a bacterial enzyme. The structure provided novel insights into the core architecture of the complex, the electron transfer and proton translocation pathways, as well as the mechanism that couples these two processes.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
•NRT1/PTR proteins transport a wide variety of substrates.•Members of this family should be named NPF (NRT1/PTR Family).•Phylogenetic studies of 31 fully sequenced plant genomes identify eight ...subfamilies.
Members of the plant NITRATE TRANSPORTER 1/PEPTIDE TRANSPORTER (NRT1/PTR) family display protein sequence homology with the SLC15/PepT/PTR/POT family of peptide transporters in animals. In comparison to their animal and bacterial counterparts, these plant proteins transport a wide variety of substrates: nitrate, peptides, amino acids, dicarboxylates, glucosinolates, IAA, and ABA. The phylogenetic relationship of the members of the NRT1/PTR family in 31 fully sequenced plant genomes allowed the identification of unambiguous clades, defining eight subfamilies. The phylogenetic tree was used to determine a unified nomenclature of this family named NPF, for NRT1/PTR FAMILY. We propose that the members should be named accordingly: NPFX.Y, where X denotes the subfamily and Y the individual member within the species.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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