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ND3, ND1 and 39kDa subunits are more exposed in the de-active form of bovine mitochondrial complex I
(2014)
An intriguing feature of mitochondrial complex I from several species is the so-called A/D transition, whereby the idle enzyme spontaneously converts from the active (A) form to the de-active (D) form. The A/D transition plays an important role in tissue response to the lack of oxygen and hypoxic deactivation of the enzyme is one of the key regulatory events that occur in mitochondria during ischaemia. We demonstrate for the first time that the A/D conformational change of complex I does not affect the macromolecular organisation of supercomplexes in vitro as revealed by two types of native electrophoresis. Cysteine 39 of the mitochondrially-encoded ND3 subunit is known to become exposed upon de-activation. Here we show that even if complex I is a constituent of the I+III2+IV (S1) supercomplex, cysteine 39 is accessible for chemical modification in only the D-form. Using lysine-specific fluorescent labelling and a DIGE-like approach we further identified two new subunits involved in structural rearrangements during the A/D transition: ND1 (MT-ND1) and 39kDa (NDUFA9). These results clearly show that structural rearrangements during de-activation of complex I include several subunits located at the junction between hydrophilic and hydrophobic domains, in the region of the quinone binding site. De-activation of mitochondrial complex I results in concerted structural rearrangement of membrane subunits which leads to the disruption of the sealed quinone chamber required for catalytic turnover.
SAFE Professor Michalis Haliassos was a member of the National Council for Research and Technology (ESET) established by the Government of Greece for the period 2010-2013. The council, consisting of eleven scientists from a range of disciplines, has now published their communiqué "National Strategic Framework for Research and Innovation 2014 -2020".
To promote the advancement of research, technology and innovation in Greece, the strategic plan proposed by the authors seeks to identify areas of existing research strength and excellence that can be further advanced to become engines for progress and growth in Greece, as well as flaws inherent to the present system. The authors stress the need to address current constraints to growth, which include the declining education system; the confusion and weaknesses of R&D governance and management; the discontinuities and inefficiencies of resource allocation and investment; the lack of adaptation to clearly-defined national priorities; and the inadequate opportunities and funding for high-quality research and development to flourish. They stress the need for prioritisation and efficient allocation; stability of the policy frame; predictability of planning; provision of opportunity; recognition of excellence; and responsiveness to current and future needs.
Cytochrome P450 (CYP) epoxygenases generate bioactive lipid epoxides which can be further metabolized to supposedly less active diols by the soluble epoxide hydrolase (sEH). As the role of epoxides and diols in angiogenesis is unclear, we compared retinal vasculature development in wild-type and sEH−/− mice. Deletion of the sEH significantly delayed angiogenesis, tip cell, and filopodia formation, a phenomenon associated with activation of the Notch signaling pathway. In the retina, sEH was localized in Müller glia cells, and Müller cell–specific sEH deletion reproduced the sEH−/− retinal phenotype. Lipid profiling revealed that sEH deletion decreased retinal and Müller cell levels of 19,20–dihydroxydocosapentaenoic acid (DHDP), a diol of docosahexenoic acid (DHA). 19,20-DHDP suppressed endothelial Notch signaling in vitro via inhibition of the γ-secretase and the redistribution of presenilin 1 from lipid rafts. Moreover, 19,20-DHDP, but not the parent epoxide, was able to rescue the defective angiogenesis in sEH−/− mice as well as in animals lacking the Fbxw7 ubiquitin ligase, which demonstrate strong basal activity of the Notch signaling cascade. These studies demonstrate that retinal angiogenesis is regulated by a novel form of neuroretina–vascular interaction involving the sEH-dependent generation of a diol of DHA in Müller cells.
Myofacial Pain is the most common form of temporomandibular disorders (TMD), affecting principally women in reproductive age. The etiology of TMD is still controversial. Currently a multifactorial theory has received a great support among the scientific community. This theory draws attention to the interaction of psychological, neuromuscular and oral pathogenic factors. Objectives: to describe the possible etiological factors of the Myofacial Pain; and to evaluate the effectiveness of the current treatments for Myofacial Pain. Materials and methods: a narrative review of the etiological factors and epidemiological data of Myofacial Pain introduces this work. Thereafter the author presents five systematic reviews of RCTs which have been published during the last thirteen years (1999-2012) for the use of acupuncture, low level laser therapy, drugs, physiotherapeutical interventions, splint therapy, and psychosocial interventions in the treatment of Myofacial Pain. Moreover, the author reports a systematic review and meta-analysis of all the available literature of two modern approaches for the treatment of Myofacial Pain. A comparison between the “usual treatment” based on splint therapy and psychosocial interventions was conducted. Results: the author did not find sufficient evidence to support therapies based on one single intervention. However, the condition of the patients with myofacial pain could be treated more effectively with combined treatments. After comparing “usual treatment” with psychosocial interventions, the author observed a tendency of the latter to improve psychological outcomes, whereas the first one was slightly more effective to enhance clinical functional outcomes. In general, a high level of heterogeneity was observed among the included studies of the different systematic reviews. The quality of the studies is susceptible to be improved. Clinical implications: the author proposes core outcomes to be implemented within the research on myofacial pain in particular and temporomandibular disorders in general, in order to enable scientifical comparisons between different therapies.
Background: Hypoxia-inducible factor-1α (HIF-1α) and NF-κB play important roles in the inflammatory response after hemorrhagic shock and resuscitation (H/R). Here, the role of myeloid HIF-1α in liver hypoxia, injury, and inflammation after H/R with special regard to NF-κB activation was studied.
Methods: Mice with a conditional HIF-1α knockout (KO) in myeloid cell-line and wild-type (WT) controls were hemorrhaged for 90 min ( mm Hg) and resuscitated. Controls underwent only surgical procedures.
Results: After six hours, H/R enhanced the expression of HIF-1α-induced genes vascular endothelial growth factor (VEGF) and adrenomedullin (ADM). In KO mice, this was not observed. H/R-induced liver injury in HIF-1α KO was comparable to WT. Elevated plasma interleukin-6 (IL-6) levels after H/R were not reduced by HIF-1α KO. Local hepatic hypoxia was not significantly reduced in HIF-1α KO compared to controls after H/R. H/R-induced NF-κB phosphorylation in liver did not significantly differ between WT and KO.
Conclusions: Here, deleting HIF-1α in myeloid cells and thereby in Kupffer cells was not protective after H/R. This data indicates that other factors, such as NF-κB, due to its upregulated phosphorylation in WT and KO mice, contrary to HIF-1α, are rather key modulators of inflammation after H/R in our model.
Myelodysplastic syndromes (MDSs) represent clonal disorders mainly of the elderly that are characterized by ineffective hematopoiesis and an increased risk of transformation into acute myeloid leukemia. The pathogenesis of MDS is thought to evolve from accumulation and selection of specific genetic or epigenetic events. Emerging evidence indicates that MDS is not solely a hematopoietic disease but rather affects the entire bone marrow microenvironment, including bone metabolism. Many of these cells, in particular mesenchymal stem and progenitor cells (MSPCs) and osteoblasts, express a number of adhesion molecules and secreted factors that regulate blood regeneration throughout life by contributing to hematopoietic stem and progenitor cell (HSPC) maintenance, self-renewal and differentiation. Several endocrine factors, such as erythropoietin, parathyroid hormone and estrogens, as well as deranged iron metabolism modulate these processes. Thus, interactions between MSPC and HSPC contribute to the pathogenesis of MDS and associated pathologies. A detailed understanding of these mechanisms may help to define novel targets for diagnosis and possibly therapy. In this review, we will discuss the scientific rationale of "osteohematology" as an emerging research field in MDS and outline clinical implications.
Faith conversion experiences are first of all personal before being universal. While biblical history records relatively few conversion encounters as dramatic and as explosive as Saint Paul's on the road to Damascus, it is not rare for individuals in the throes of a religious conversion to fall prey to intensely agonizing confusion. That is what happened to Martin Jumbam when he marched for peace in his country alongside the charismatic and irrepressible Emeritus Archbishop of Douala in Cameroon, Christian Cardinal Tumi. He joined the prelate as a secular journalist but went back home more than ever conscious of his state as a fallen Christian, the first step in his journey of faith. Since then, all his writing, be it secular or religious, now bears the fruits of that encounter, characterized by intense empathy for the human person. This book recounts the myriad ways Jumbam's encounters with Christian Cardinal Tumi have activated, nourished and inspired his faith.
We study self- and cross-excitation of shocks in the Eurozone sovereign CDS market. We adopt a multivariate setting with credit default intensities driven by mutually exciting jump processes, to capture the salient features observed in the data, in particular, the clustering of high default probabilities both in time (over days) and in space (across countries). The feedback between jump events and the intensity of these jumps is the key element of the model. We derive closed-form formulae for CDS prices, and estimate the model by matching theoretical prices to their empirical counterparts. We find evidence of self-excitation and asymmetric cross-excitation. Using impulse-response analysis, we assess the impact of shocks and a potential policy intervention not just on a single country under scrutiny but also, through the effect on cross-excitation risk which generates systemic sovereign risk, on other interconnected countries.
Families are central to the social and emotional development of youth, and most families engage in musical activities together, such as listening to music or talking about their favorite songs. However, empirical evidence of the positive effects of musical family rituals on social cohesion and emotional well-being is scarce. Furthermore, the role of culture in the shaping of musical family rituals and their psychological benefits has been neglected entirely. This paper investigates musical rituals in families and in peer groups (as an important secondary socialization context) in two traditional/collectivistic and two secular/individualistic cultures, and across two developmental stages (adolescence vs. young adulthood). Based on cross-sectional data from 760 young people in Kenya, the Philippines, New Zealand, and Germany, our study revealed that across cultures music listening in families and in peer groups contributes to family and peer cohesion, respectively. Furthermore, the direct contribution of music in peer groups on well-being appears across cultural contexts, whereas musical family rituals affect emotional well-being in more traditional/collectivistic contexts. Developmental analyses show that musical family rituals are consistently and strongly related to family cohesion across developmental stages, whereas musical rituals in peer groups appear more dependent on the developmental stage (in interaction with culture). Contributing to developmental as well as cross-cultural psychology, this research elucidated musical rituals and their positive effects on the emotional and social development of young people across cultures. The implications for future research and family interventions are discussed.
In 1989 the triumphant discourse on the 'end of history' brought the death of socialism and the expansion of liberal democracy. The proclamation of the end of history could also be read literally, as the death of 'history' as a discipline with a homogenized narrative. It is in the same year that Pierra Nora wrote a groundbreaking article, which disentangled the fundamental opposition between history and memory, and at the end assumed the standpoint of memory. The article departs from the diagnosis of post-Yugoslav contemporary accounts of Yugoslav and partisan events. The critique of nationalist and Yugonostalgic discourses discloses shared assumptions that are based on the 'romantic' temporality of Nation and on history as a closed process. In the main part of the article the author works on the special, multiple temporality of partisan poetry that emerged during the WWII partisan struggle. The special temporality hinges on the productive and tensed relationship between the 'not yet existing' - the position of the new society free of foreign occupation, but also in a radically transformed society - and the contemporary struggle within war, which is also marked by the fear that the rupture of the struggle might not be remembered rightly, if at all. The memory of the present struggle remains to be the task to be realized not only for poets, but for everyone participating in the struggle. This is where the revolutionary temporality of the unfinished process comes to its fore, relating poetry to struggle, but again producing a form of poetry in the struggle.