Mitochondrial abnormalities and low grade inflammation are present in the skeletal muscle of a minority of patients with amyotrophic lateral sclerosis; an observational myopathology study

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a primary progressive neurodegenerative disease characterised by neuronal loss of lower motor neurons (in the spinal cord and brainstem) and/or upper motor neurons (in the motor cortex) and subsequent denervation atrophy of skeletal muscle. AIM A comprehensive examination of muscle pathology from a cohort of clinically confirmed ALS patients, including an investigation of inflammation, complement activation, and deposition of abnormal proteins in order to compare them with findings from an age-matched, control group. MATERIAL AND METHODS 31 muscle biopsies from clinically confirmed ALS patients and 20 normal controls underwent a comprehensive protocol of histochemical and immunohistochemical stains, including HLA-ABC, C5b-9, p62, and TDP-43. RESULTS Neurogenic changes were confirmed in 30/31 ALS cases. In one case, no neurogenic changes could be detected. Muscle fibre necrosis was seen in 5/31 cases and chronic mononuclear inflammatory cell infiltration in 5/31 (2 of them overlapped with those showing muscle necrosis). In four biopsies there was an increase in the proportion of cytochrome oxidase (COX) negative fibres (2-3%). p62 faintly stained cytoplasmic bodies in eight cases and none were immunoreactive to TDP-43. CONCLUSION This large series of muscle biopsies from patients with ALS demonstrates neurogenic atrophy is a nearly uniform finding and that mild mitochondrial abnormalities and low-grade inflammation can be seen and do not rule out the diagnosis of ALS. These findings could lend support to the notion that ALS is a complex and heterogeneous disorder

Role of mitochondrial raft-like microdomains in the regulation of cell apoptosis

Lipid rafts are envisaged as lateral assemblies of specific lipids and proteins that dissociate and associate rapidly and form functional clusters in cell membranes. These structural platforms are not confined to the plasma membrane; indeed lipid microdomains are similarly formed at subcellular organelles, which include endoplasmic reticulum, Golgi and mitochondria, named raft-like microdomains. In addition, some components of raft-like microdomains are present within ER-mitochondria associated membranes. This review is focused on the role of mitochondrial raft-like microdomains in the regulation of cell apoptosis, since these microdomains may represent preferential sites where key reactions take place, regulating mitochondria hyperpolarization, fission-associated changes, megapore formation and release of apoptogenic factors. These structural platforms appear to modulate cytoplasmic pathways switching cell fate towards cell survival or death. Main insights on this issue derive from some pathological conditions in which alterations of microdomains structure or function can lead to severe alterations of cell activity and life span. In the light of the role played by raft-like microdomains to integrate apoptotic signals and in regulating mitochondrial dynamics, it is conceivable that these membrane structures may play a role in the mitochondrial alterations observed in some of the most common human neurodegenerative diseases, such as Amyotrophic lateral sclerosis, Huntington's chorea and prion-related diseases. These findings introduce an additional task for identifying new molecular target(s) of pharmacological agents in these pathologies

Distant agricultural landscapes

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. The final publication is available at Springer via http://dx.doi.org/10.1007/s11625-014-0278-0This paper examines the relationship between the development of the dominant industrial food system and its associated global economic drivers and the environmental sustainability of agricultural landscapes. It makes the case that the growth of the global industrial food system has encouraged increasingly complex forms of “distance” that separate food both geographically and mentally from the landscapes on which it was produced. This separation between food and its originating landscape poses challenges for the ability of more localized agricultural sustainability initiatives to address some of the broader problems in the global food system. In particular, distance enables certain powerful actors to externalize ecological and social costs, which in turn makes it difficult to link specific global actors to particular biophysical and social impacts felt on local agricultural landscapes. Feedback mechanisms that normally would provide pressure for improved agricultural sustainability are weak because there is a lack of clarity regarding responsibility for outcomes. The paper provides a brief illustration of these dynamics with a closer look at increased financialization in the food system. It shows that new forms of distancing are encouraged by the growing significance of financial markets in global agrifood value chains. This dynamic has a substantial impact on food system outcomes and ultimately complicates efforts to scale up small-scale local agricultural models that are more sustainable.The Trudeau Foundation || Social Sciences and Humanities Research Council of Canad

Climate change and freshwater zooplankton: what does it boil down to?

Recently, major advances in the climate–zooplankton interface have been made some of which appeared to receive much attention in a broader audience of ecologists as well. In contrast to the marine realm, however, we still lack a more holistic summary of recent knowledge in freshwater. We discuss climate change-related variation in physical and biological attributes of lakes and running waters, high-order ecological functions, and subsequent alteration in zooplankton abundance, phenology, distribution, body size, community structure, life history parameters, and behavior by focusing on community level responses. The adequacy of large-scale climatic indices in ecology has received considerable support and provided a framework for the interpretation of community and species level responses in freshwater zooplankton. Modeling perspectives deserve particular consideration, since this promising stream of ecology is of particular applicability in climate change research owing to the inherently predictive nature of this field. In the future, ecologists should expand their research on species beyond daphnids, should address questions as to how different intrinsic and extrinsic drivers interact, should move beyond correlative approaches toward more mechanistic explanations, and last but not least, should facilitate transfer of biological data both across space and time

Amyotrophic Lateral Sclerosis Is Associated with Hypolipidemia at the Presymptomatic Stage in Mice

OBJECTIVE: To demonstrate that hypolipidemia is a typical feature of the mouse model of amyotrophic lateral sclerosis (ALS) and to assess the association between hypolipidemia and disease stage, dietary intake, and sex. METHODS: We compared daily dietary intake, body weight, and serumlipid and glucose levels in ALS mice and wild-type controls at different stages of the disease. FINDINGS: Total cholesterol low-density lipoprotein (LDL) and LDL/high-density lipoprotein (HDL) ratio were significantly lower in ALS mice compared with controls. Subgroup analysis revealed that the incidence of hypolipidemia was significantly greater in male, but not female, ALS mice compared with control mice and that hypolipidemia was present at the presymptomatic stage of the disease. This hypolipidemia can be found without a decrease in the serum levels of other energy sources, such as glucose, in the presymptomatic stage. CONCLUSIONS: Hypolipidemia is present at the presymptomatic stage of the ALS mouse model in the absence of malnutrition, significant neuromuscular degeneration or regeneration, and respiratory difficulty. Our findings suggest that hypolipidemia might be associated with the pathomechanism of ALS and/or lipid-specific metabolism rather than simply an epiphenomenon of neuromuscular degeneration or energy imbalance

Modulation of Astrocytic Mitochondrial Function by Dichloroacetate Improves Survival and Motor Performance in Inherited Amyotrophic Lateral Sclerosis

Mitochondrial dysfunction is one of the pathogenic mechanisms that lead to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). Astrocytes expressing the ALS-linked SOD1G93A mutation display a decreased mitochondrial respiratory capacity associated to phenotypic changes that cause them to induce motor neuron death. Astrocyte-mediated toxicity can be prevented by mitochondria-targeted antioxidants, indicating a critical role of mitochondria in the neurotoxic phenotype. However, it is presently unknown whether drugs currently used to stimulate mitochondrial metabolism can also modulate ALS progression. Here, we tested the disease-modifying effect of dichloroacetate (DCA), an orphan drug that improves the functional status of mitochondria through the stimulation of the pyruvate dehydrogenase complex activity (PDH). Applied to astrocyte cultures isolated from rats expressing the SOD1G93A mutation, DCA reduced phosphorylation of PDH and improved mitochondrial coupling as expressed by the respiratory control ratio (RCR). Notably, DCA completely prevented the toxicity of SOD1G93A astrocytes to motor neurons in coculture conditions. Chronic administration of DCA (500 mg/L) in the drinking water of mice expressing the SOD1G93A mutation increased survival by 2 weeks compared to untreated mice. Systemic DCA also normalized the reduced RCR value measured in lumbar spinal cord tissue of diseased SOD1G93A mice. A remarkable effect of DCA was the improvement of grip strength performance at the end stage of the disease, which correlated with a recovery of the neuromuscular junction area in extensor digitorum longus muscles. Systemic DCA also decreased astrocyte reactivity and prevented motor neuron loss in SOD1G93A mice. Taken together, our results indicate that improvement of the mitochondrial redox status by DCA leads to a disease-modifying effect, further supporting the therapeutic potential of mitochondria-targeted drugs in ALS

Genetic Biomarkers for ALS Disease in Transgenic SOD1G93A Mice

The pathophysiological mechanisms of both familial and sporadic Amyotrophic Lateral Sclerosis (ALS) are unknown, although growing evidence suggests that skeletal muscle tissue is a primary target of ALS toxicity. Skeletal muscle biopsies were performed on transgenic SOD1G93A mice, a mouse model of ALS, to determine genetic biomarkers of disease longevity. Mice were anesthetized with isoflurane, and three biopsy samples were obtained per animal at the three main stages of the disease. Transcriptional expression levels of seventeen genes, Ankrd1, Calm1, Col19a1, Fbxo32, Gsr, Impa1, Mef2c, Mt2, Myf5, Myod1, Myog, Nnt, Nogo A, Pax7, Rrad, Sln and Snx10, were tested in each muscle biopsy sample. Total RNA was extracted using TRIzol Reagent according to the manufacturer's protocol, and variations in gene expression were assayed by real-time PCR for all of the samples. The Pearson correlation coefficient was used to determine the linear correlation between transcriptional expression levels throughout disease progression and longevity. Consistent with the results obtained from total skeletal muscle of transgenic SOD1G93A mice and 74-day-old denervated mice, five genes (Mef2c, Gsr, Col19a1, Calm1 and Snx10) could be considered potential genetic biomarkers of longevity in transgenic SOD1G93A mice. These results are important because they may lead to the exploration of previously unexamined tissues in the search for new disease biomarkers and even to the application of these findings in human studies

Exploratory factor analysis of graphical features for link prediction in social networks

Social Networks attract much attention due to their ability to replicate social interactions at scale. Link prediction, or the assessment of which unconnected nodes are likely to connect in the future, is an interesting but non-trivial research area. Three approaches exist to deal with the link prediction problem: feature-based models, Bayesian probabilistic models, probabilistic relational models. In feature-based methods, graphical features are extracted and used for classification. Usually, these features are subdivided into three feature groups based on their formula. Some formulas are extracted based on neighborhood graph traverse. Accordingly, there exists three groups of features, neighborhood features, path-based features, node-based features. In this paper, we attempt to validate the underlying structure of topological features used in feature-based link prediction. The results of our analysis indicate differing results from the prevailing grouping of these features, which indicates that current literatures\u27 classification of feature groups should be redefined. Thus, the contribution of this work is exploring the factor loading of graphical features in link prediction in social networks. To the best of our knowledge, there is no prior studies had addressed it

Active surveillance of Q fever in human and animal population of Cyprus

BACKGROUND: A long-term active surveillance of Q fever was conducted in Cyprus organized in two phases. METHODS: Following serological tests and identification of seropositive humans and animals for C. burnetii in two villages (VIL1 and VIL2), all seronegative individuals were followed up for one year on a monthly basis by trained physicians to detect possible seroconversion for Q fever. In the second phase of the study, active surveillance for one year was conducted in the entire Cyprus. Physicians were following specific case definition criteria for Q fever. Standardized questionnaires, a geographical information system on a regional level, Immunofluorescence Assay (IFA) examinations and shell vial technique were used. RESULTS: Eighty-one seronegative humans and 239 seronegative animals from both villages participated in the first phase surveillance period of Q fever. Despite the small number of confirmed clinical cases (2 humans and 1 goat), a significant percentage of new seropositives for C. burnetii (44.4% of human participants and 13.8% of animals) was detected at the end of the year. During the second phase of surveillance, 82 humans, 100 goats, and 76 sheep were considered suspected cases of Q fever. However, only 9 human, 8 goat, and 4 sheep cases were serologically confirmed, while C. burnetii was isolated from three human and two animal samples. The human incidence rate was estimated at 1.2 per 100,000 population per year. CONCLUSION: A small number of confirmed clinical cases of Q fever were observed despite the high seroprevalence for C. burnetii in human and animal population of Cyprus. Most of the cases in the local population of Cyprus appear to be subclinical. Moreover further studies should investigate the role of ticks in the epidemiology of Q fever and their relation to human seropositivity

Intraspecies Transmission of BASE Induces Clinical Dullness and Amyotrophic Changes

The disease phenotype of bovine spongiform encephalopathy (BSE) and the molecular/ biological properties of its prion strain, including the host range and the characteristics of BSE-related disorders, have been extensively studied since its discovery in 1986. In recent years, systematic testing of the brains of cattle coming to slaughter resulted in the identification of at least two atypical forms of BSE. These emerging disorders are characterized by novel conformers of the bovine pathological prion protein (PrPTSE), named high-type (BSE-H) and low-type (BSE-L). We recently reported two Italian atypical cases with a PrPTSE type identical to BSE-L, pathologically characterized by PrP amyloid plaques and known as bovine amyloidotic spongiform encephalopathy (BASE). Several lines of evidence suggest that BASE is highly virulent and easily transmissible to a wide host range. Experimental transmission to transgenic mice overexpressing bovine PrP (Tgbov XV) suggested that BASE is caused by a prion strain distinct from the BSE isolate. In the present study, we experimentally infected Friesian and Alpine brown cattle with Italian BSE and BASE isolates via the intracerebral route. BASE-infected cattle developed amyotrophic changes accompanied by mental dullness. The molecular and neuropathological profiles, including PrP deposition pattern, closely matched those observed in the original cases. This study provides clear evidence of BASE as a distinct prion isolate and discloses a novel disease phenotype in cattle