Global health and national borders : the ethics of foreign aid in a time of financial crisis

Background: The governments and citizens of the developed nations are increasingly called upon to contribute financially to health initiatives outside their borders. Although international development assistance for health has grown rapidly over the last two decades, austerity measures related to the 2008 and 2011 global financial crises may impact negatively on aid expenditures. The competition between national priorities and foreign aid commitments raises important ethical questions for donor nations. This paper aims to foster individual reflection and public debate on donor responsibilities for global health. Methods: We undertook a critical review of contemporary accounts of justice. We selected theories that: (i) articulate important and widely held moral intuitions; (ii) have had extensive impact on debates about global justice; (iii) represent diverse approaches to moral reasoning; and (iv) present distinct stances on the normative importance of national borders. Due to space limitations we limit the discussion to four frameworks. Results: Consequentialist, relational, human rights, and social contract approaches were considered. Responsibilities to provide international assistance were seen as significant by all four theories and place limits on the scope of acceptable national autonomy. Among the range of potential aid foci, interventions for health enjoyed consistent prominence. The four theories concur that there are important ethical responsibilities to support initiatives to improve the health of the worst off worldwide, but offer different rationales for intervention and suggest different implicit limits on responsibilities. Conclusions: Despite significant theoretical disagreements, four influential accounts of justice offer important reasons to support many current initiatives to promote global health. Ethical argumentation can complement pragmatic reasons to support global health interventions and provide an important foundation to strengthen collective action

Global Health and National Borders

ABSTRACT: BACKGROUND: The governments and citizens of the developed nations are increasingly called upon to contribute financially to health initiatives outside their borders. Although international development assistance for health has grown rapidly over the last two decades, austerity measures related to the 2008 and 2011 global financial crises may impact negatively on aid expenditures. The competition between national priorities and foreign aid commitments raises important ethical questions for donor nations. This paper aims to foster individual reflection and public debate on donor responsibilities for global health. METHODS: We undertook a critical review of contemporary accounts of justice. We selected theories that: (i) articulate important and widely held moral intuitions; (ii) have had extensive impact on debates about global justice; (iii) represent diverse approaches to moral reasoning; and (iv) present distinct stances on the normative importance of national borders. Due to space limitations we limit the discussion to four frameworks. RESULTS: Consequentialist, relational, human rights, and social contract approaches were considered. Responsibilities to provide international assistance were seen as significant by all four theories and place limits on the scope of acceptable national autonomy. Among the range of potential aid foci, interventions for health enjoyed consistent prominence. The four theories concur that there are important ethical responsibilities to support initiatives to improve the health of the worst off worldwide, but offer different rationales for intervention and suggest different implicit limits on responsibilities. CONCLUSIONS: Despite significant theoretical disagreements, four influential accounts of justice offer important reasons to support many current initiatives to promote global health. Ethical argumentation can complement pragmatic reasons to support global health interventions and provide an important foundation to strengthen collective action

Outer mitochondrial membrane localization of apoptosis-inducing factor: mechanistic implications for release

Poly(ADP-ribose) polymerase-1-dependent cell death (known as parthanatos) plays a pivotal role in many clinically important events including ischaemia/reperfusion injury and glutamate excitotoxicity. A recent study by us has shown that uncleaved AIF (apoptosis-inducing factor), but not calpain-hydrolysed truncated-AIF, was rapidly released from the mitochondria during parthanatos, implicating a second pool of AIF that might be present in brain mitochondria contributing to the rapid release. In the present study, a novel AIF pool is revealed in brain mitochondria by multiple biochemical analyses. Approx. 30% of AIF loosely associates with the outer mitochondrial membrane on the cytosolic side, in addition to its main localization in the mitochondrial intermembrane space attached to the inner membrane. Immunogold electron microscopic analysis of mouse brain further supports AIF association with the outer, as well as the inner, mitochondrial membrane in vivo. In line with these observations, approx. 20% of uncleaved AIF rapidly translocates to the nucleus and functionally causes neuronal death upon NMDA (N-methyl-d-aspartate) treatment. In the present study we show for the first time a second pool of AIF in brain mitochondria and demonstrate that this pool does not require cleavage and that it contributes to the rapid release of AIF. Moreover, these results suggest that this outer mitochondrial pool of AIF is sufficient to cause cell death during parthanatos. Interfering with the release of this outer mitochondrial pool of AIF during cell injury paradigms that use parthanatos hold particular promise for novel therapies to treat neurological disorders

Dynamic and redundant regulation of LRRK2 and LRRK1 expression

<p>Abstract</p> <p>Background</p> <p>Mutations within the <it>leucine-rich repeat kinase 2 </it>(<it>LRRK2</it>) gene account for a significant proportion of autosomal-dominant and some late-onset sporadic Parkinson's disease. Elucidation of LRRK2 protein function in health and disease provides an opportunity for deciphering molecular pathways important in neurodegeneration. In mammals, LRRK1 and LRRK2 protein comprise a unique family encoding a GTPase domain that controls intrinsic kinase activity. The expression profiles of the murine LRRK proteins have not been fully described and insufficiently characterized antibodies have produced conflicting results in the literature.</p> <p>Results</p> <p>Herein, we comprehensively evaluate twenty-one commercially available antibodies to the LRRK2 protein using mouse <it>LRRK2 </it>and human <it>LRRK2 </it>expression vectors, wild-type and <it>LRRK2</it>-null mouse brain lysates and human brain lysates. Eleven antibodies detect over-expressed human LRRK2 while four antibodies detect endogenous human LRRK2. In contrast, two antibodies recognize over-expressed mouse LRRK2 and one antibody detected endogenous mouse LRRK2. LRRK2 protein resides in both soluble and detergent soluble protein fractions. <it>LRRK2 </it>and the related <it>LRRK1 </it>genes encode low levels of expressed mRNA species corresponding to low levels of protein both during development and in adulthood with largely redundant expression profiles.</p> <p>Conclusion</p> <p>Despite previously published results, commercially available antibodies generally fail to recognize endogenous mouse LRRK2 protein; however, several antibodies retain the ability to detect over-expressed mouse LRRK2 protein. Over half of the commercially available antibodies tested detect over-expressed human LRRK2 protein and some have sufficient specificity to detect endogenous LRRK2 in human brain. The mammalian LRRK proteins are developmentally regulated in several tissues and coordinated expression suggest possible redundancy in the function between <it>LRRK1 </it>and <it>LRRK2</it>.</p

Functional interaction of Parkinson's disease-associated LRRK2 with members of the dynamin GTPase superfamily

Mutations in LRRK2 cause autosomal dominant Parkinson's disease (PD). LRRK2 encodes a multi-domain protein containing GTPase and kinase domains, and putative protein-protein interaction domains. Familial PD mutations alter the GTPase and kinase activity of LRRK2 in vitro. LRRK2 is suggested to regulate a number of cellular pathways although the underlying mechanisms are poorly understood. To explore such mechanisms, it has proved informative to identify LRRK2-interacting proteins, some of which serve as LRRK2 kinase substrates. Here, we identify common interactions of LRRK2 with members of the dynamin GTPase superfamily. LRRK2 interacts with dynamin 1-3 that mediate membrane scission in clathrin-mediated endocytosis and with dynamin-related proteins that mediate mitochondrial fission (Drp1) and fusion (mitofusins and OPA1). LRRK2 partially co-localizes with endosomal dynamin-1 or with mitofusins and OPA1 at mitochondrial membranes. The subcellular distribution and oligomeric complexes of dynamin GTPases are not altered by modulating LRRK2 in mouse brain, whereas mature OPA1 levels are reduced in G2019S PD brains. LRRK2 enhances mitofusin-1 GTP binding, whereas dynamin-1 and OPA1 serve as modest substrates of LRRK2-mediated phosphorylation in vitro. While dynamin GTPase orthologs are not required for LRRK2-induced toxicity in yeast, LRRK2 functionally interacts with dynamin-1 and mitofusin-1 in cultured neurons. LRRK2 attenuates neurite shortening induced by dynamin-1 by reducing its levels, whereas LRRK2 rescues impaired neurite outgrowth induced by mitofusin-1 potentially by reversing excessive mitochondrial fusion. Our study elucidates novel functional interactions of LRRK2 with dynamin-superfamily GTPases that implicate LRRK2 in the regulation of membrane dynamics important for endocytosis and mitochondrial morpholog

Neurodegenerative phenotypes in an A53T α-synuclein transgenic mouse model are independent of LRRK2

Mutations in the genes encoding LRRK2 and α-synuclein cause autosomal dominant forms of familial Parkinson's disease (PD). Fibrillar forms of α-synuclein are a major component of Lewy bodies, the intracytoplasmic proteinaceous inclusions that are a pathological hallmark of idiopathic and certain familial forms of PD. LRRK2 mutations cause late-onset familial PD with a clinical, neurochemical and, for the most part, neuropathological phenotype that is indistinguishable from idiopathic PD. Importantly, α-synuclein-positive Lewy bodies are the most common pathology identified in the brains of PD subjects harboring LRRK2 mutations. These observations may suggest that LRRK2 functions in a common pathway with α-synuclein to regulate its aggregation. To explore the potential pathophysiological interaction between LRRK2 and α-synuclein in vivo, we modulated LRRK2 expression in a well-established human A53T α-synuclein transgenic mouse model with transgene expression driven by the hindbrain-selective prion protein promoter. Deletion of LRRK2 or overexpression of human G2019S-LRRK2 has minimal impact on the lethal neurodegenerative phenotype that develops in A53T α-synuclein transgenic mice, including premature lethality, pre-symptomatic behavioral deficits and human α-synuclein or glial neuropathology. We also find that endogenous or human LRRK2 and A53T α-synuclein do not interact together to influence the number of nigrostriatal dopaminergic neurons. Taken together, our data suggest that α-synuclein-related pathology, which occurs predominantly in the hindbrain of this A53T α-synuclein mouse model, occurs largely independently from LRRK2 expression. These observations fail to provide support for a pathophysiological interaction of LRRK2 and α-synuclein in vivo, at least within neurons of the mouse hindbrai

Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death

Caspase-independent death mechanisms have been shown to execute apoptosis in many types of neuronal injury. P53 has been identified as a key regulator of neuronal cell death after acute injury such as DNA damage, ischemia, and excitotoxicity. Here, we demonstrate that p53 can induce neuronal cell death via a caspase-mediated process activated by apoptotic activating factor-1 (Apaf1) and via a delayed onset caspase-independent mechanism. In contrast to wild-type cells, Apaf1-deficient neurons exhibit delayed DNA fragmentation and only peripheral chromatin condensation. More importantly, we demonstrate that apoptosis-inducing factor (AIF) is an important factor involved in the regulation of this caspase-independent neuronal cell death. Immunofluorescence studies demonstrate that AIF is released from the mitochondria by a mechanism distinct from that of cytochrome-c in neurons undergoing p53-mediated cell death. The Bcl-2 family regulates this release of AIF and subsequent caspase-independent cell death. In addition, we show that enforced expression of AIF can induce neuronal cell death in a Bax- and caspase-independent manner. Microinjection of neutralizing antibodies against AIF significantly decreased injury-induced neuronal cell death in Apaf1-deficient neurons, indicating its importance in caspase-independent apoptosis. Taken together, our results suggest that AIF may be an important therapeutic target for the treatment of neuronal injury

Cricetid

14 p. : ill. ; 24 cm.Includes bibliographical references (p. 13-14)."Two specimens, a partial right mandibular ramus with M[subscript 1]-M[subscript 3] and an isolated left M[subscript 2], represent a new genus and species of rodent, Nanomys simplicidens. The teeth of this rodent are so lacking in special characters that its phylogenetic position is difficult to interpret, but it seems best referred to the Cricetidae"--P. [1]

The AAA+ ATPase Thorase Regulates AMPA Receptor-Dependent Synaptic Plasticity and Behavior

SummaryThe synaptic insertion or removal of AMPA receptors (AMPAR) plays critical roles in the regulation of synaptic activity reflected in the expression of long-term potentiation (LTP) and long-term depression (LTD). The cellular events underlying this important process in learning and memory are still being revealed. Here we describe and characterize the AAA+ ATPase Thorase, which regulates the expression of surface AMPAR. In an ATPase-dependent manner Thorase mediates the internalization of AMPAR by disassembling the AMPAR-GRIP1 complex. Following genetic deletion of Thorase, the internalization of AMPAR is substantially reduced, leading to increased amplitudes of miniature excitatory postsynaptic currents, enhancement of LTP, and elimination of LTD. These molecular events are expressed as deficits in learning and memory in Thorase null mice. This study identifies an AAA+ ATPase that plays a critical role in regulating the surface expression of AMPAR and thereby regulates synaptic plasticity and learning and memory