Hereditary early-onset Parkinsonism : the role of the FBXO7 protein

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, which affects ~1-2% of the population above the age of 60 years old. We identified pathogenic mutations in the FBXO7 gene in two families with early-onset, progressive parkinsonism and pyramidal tract dysfunctions. This finding provided the conclusive evidence that FBXO7 is the disease-causing gene in this newly-identified autosomal recessive form, which we termed PARK15. Very little was known about the two protein isoforms, which are predicted to be encoded by FBXO7, and nothing was known about their expression in the human brain. Here, we demonstrated the expression of these proteins in normal human cells and the consequences of mutations in cells derived from PARK15 patients. In parallel with the above-mentioned in vitro experiments, we also generated the first in vivo model of PARK15 by transient, morpholino-mediated knockdown of the homologous gene Fbxo7 in zebrafish. This model displayed both pathologic and behavioural hallmarks of human parkinsonism (dopaminergic neuronal loss and dopamine-dependent bradykinesia), representing therefore a valid tool for investigating the mechanisms of selective dopaminergic neuronal death. Moreover, the expression of FBXO7 proteins in the brain of normal human subjects and of PD patients was investigated. We observed widespread neuronal FBXO7 immunoreactivity throughout the brain regions, of note, the FBXO7 immunoreactivity was also detected in the Lewy bodies and Lewy neuritis, suggesting a role for FBXO7 proteins in the pathogenesis of Lewy-body pathology in the common (non-Mendelian) forms of synucleinopathies

Dopaminergic Neuronal Loss and Dopamine-Dependent Locomotor Defects in Fbxo7-Deficient Zebrafish

Recessive mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, a Mendelian form of early-onset, levodopa-responsive parkinsonism with severe loss of nigrostriatal dopaminergic neurons. However, the function of the protein encoded by FBXO7, and the pathogenesis of PARK15 remain unknown. No animal models of this disease exist. Here, we report the generation of a vertebrate model of PARK15 in zebrafish. We first show that the zebrafish Fbxo7 homolog protein (zFbxo7) is expressed abundantly in the normal zebrafish brain. Next, we used two zFbxo7-specific morpholinos (targeting protein translation and mRNA splicing, respectively), to knock down the zFbxo7 expression. The injection of either of these zFbxo7-specific morpholinos in the fish embryos induced a marked decrease in the zFbxo7 protein expression, and a range of developmental defects. Furthermore, whole-mount in situ mRNA hybridization showed abnormal patterning and significant decrease in the number of diencephalic tyrosine hydroxylase-expressing neurons, corresponding to the human nigrostriatal or ventral tegmental dopaminergic neurons. Of note, the number of the dopamine transporter-expressing neurons was much more severely depleted, suggesting dopaminergic dysfunctions earlier and larger than those due to neuronal loss. Last, the zFbxo7 morphants displayed severe locomotor disturbances (bradykinesia), which were dramatically improved by the dopaminergic agonist apomorphine. The severity of these morphological and behavioral abnormalities correlated with the severity of zFbxo7 protein deficiency. Moreover, the effects of the co-injection of zFbxo7- and p53-specific morpholinos were similar to those obtained with zFbxo7-specific morpholinos alone, supporting further the contention that the observed phenotypes were specifically due to the knock down of zFbxo7. In conclusion, this novel vertebrate model reproduces pathologic and behavioral hallmarks of human parkinsonism (dopaminergic neuronal loss and dopamine-dependent bradykinesia), representing therefore a valid tool for investigating the mechanisms of selective dopaminergic neuronal death, and screening for modifier genes and therapeutic compounds

Использование барий-стронциевого карбонатита при изготовлении сварочных флюсов на основе техногенных отходов металлургического производства

В данной работе рассмотрена возможность использования барий-стронциевого карбонатита при изготовлении сварочных флюсов на основе шлака производства силикомарганца, а так же на основе ковшевых электросталеплавильных шлаков, образованных при производстве рельсовых марок стали. В серии опытов в лабораторных условиях изготавливали и исследовали различные составы сварочных флюсов, были определены химические составы наплавленного металла, проведен металлографический анализ.In this paper the possibility of using barium-strontium carbonatite in the manufacture of welding fluxes on the basis of slag from the production of silicomanganese, and based on ladle steelmaking slags formed in the production of rail steel grades. In a series of experiments in the laboratory have produced and investigated different compositions of welding fluxes, were determined the chemical compositions of the weld metal metallographic analysis

Loss of Nuclear Activity of the FBXO7 Protein in Patients with Parkinsonian-Pyramidal Syndrome (PARK15)

Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of brain dopaminergic neurons, the same which are lost in Parkinson's disease. The protein(s) encoded by FBXO7 remain very poorly characterized. Here, we show that two protein isoforms are expressed from the FBXO7 gene in normal human cells. The isoform 1 is more abundant, particularly in primary skin fibroblasts. Both isoforms are undetectable in cell lines from the PARK15 patient of an Italian family; the isoform 1 is undetectable and the isoform 2 is severely decreased in the patients from a Dutch PARK15 family. In human cell lines and mouse primary neurons, the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization. An intact N-terminus is needed for the nuclear FBXO7 localization, as N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization. Furthermore, the N-terminus of wild type FBXO7 (but not of mutant FBXO7) is able to confer nuclear localization to profilin (a cytoplasmic protein). Our data also suggest that overexpressed mutant FBXO7 proteins (T22M, R378G and R498X) have decreased stability compared to their wild type counterpart. In human brain, FBXO7 immunoreactivity was highest in the nuclei of neurons throughout the cerebral cortex, intermediate in the globus pallidum and the substantia nigra, and lowest in the hippocampus and cerebellum. In conclusion, the common cellular abnormality found in the PARK15 patients from the Dutch and Italian families is the depletion of the FBXO7 isoform 1, which normally localizes in the cell nucleus. The activity of FBXO7 in the nucleus appears therefore crucial for the maintenance of brain neurons and the pathogenesis of PARK15

Robust Multi-Label Classification with Enhanced Global and Local Label Correlation

Data representation is of significant importance in minimizing multi-label ambiguity. While most researchers intensively investigate label correlation, the research on enhancing model robustness is preliminary. Low-quality data is one of the main reasons that model robustness degrades. Aiming at the cases with noisy features and missing labels, we develop a novel method called robust global and local label correlation (RGLC). In this model, subspace learning reconstructs intrinsic latent features immune from feature noise. The manifold learning ensures that outputs obtained by matrix factorization are similar in the low-rank latent label if the latent features are similar. We examine the co-occurrence of global and local label correlation with the constructed latent features and the latent labels. Extensive experiments demonstrate that the classification performance with integrated information is statistically superior over a collection of state-of-the-art approaches across numerous domains. Additionally, the proposed model shows promising performance on multi-label when noisy features and missing labels occur, demonstrating the robustness of multi-label classification

Robust Multi-Label Classification with Enhanced Global and Local Label Correlation

Data representation is of significant importance in minimizing multi-label ambiguity. While most researchers intensively investigate label correlation, the research on enhancing model robustness is preliminary. Low-quality data is one of the main reasons that model robustness degrades. Aiming at the cases with noisy features and missing labels, we develop a novel method called robust global and local label correlation (RGLC). In this model, subspace learning reconstructs intrinsic latent features immune from feature noise. The manifold learning ensures that outputs obtained by matrix factorization are similar in the low-rank latent label if the latent features are similar. We examine the co-occurrence of global and local label correlation with the constructed latent features and the latent labels. Extensive experiments demonstrate that the classification performance with integrated information is statistically superior over a collection of state-of-the-art approaches across numerous domains. Additionally, the proposed model shows promising performance on multi-label when noisy features and missing labels occur, demonstrating the robustness of multi-label classification

Intuitionistic Fuzzy-Based Three-Way Label Enhancement for Multi-Label Classification

Multi-label classification deals with the determination of instance-label associations for unseen instances. Although many margin-based approaches are delicately developed, the uncertainty classifications for those with smaller separation margins remain unsolved. The intuitionistic fuzzy set is an effective tool to characterize the concept of uncertainty, yet it has not been examined for multi-label cases. This paper proposed a novel model called intuitionistic fuzzy three-way label enhancement (IFTWLE) for multi-label classification. The IFTWLE combines label enhancement with an intuitionistic fuzzy set under the framework of three-way decisions. For unseen instances, we generated the pseudo-label for label uncertainty evaluation from a logical label-based model. An intuitionistic fuzzy set-based instance selection principle seamlessly bridges logical label learning and numerical label learning. The principle is hierarchically developed. At the label level, membership and non-membership functions are pair-wisely defined to measure the local uncertainty and generate candidate uncertain instances. After upgrading to the instance level, we select instances from the candidates for label enhancement, whereas they remained unchanged for the remaining. To the best of our knowledge, this is the first attempt to combine logical label learning with numerical label learning into a unified framework for minimizing classification uncertainty. Extensive experiments demonstrate that, with the selectively reconstructed label importance, IFTWLE achieves statistically superior over the state-of-the-art multi-label classification algorithms in terms of classification accuracy. The computational complexity of this algorithm is On2mk, where n, m, and k denote the unseen instances count, label count, and average label-specific feature size, respectively

Using Natural Language Techniques to Identify the Hero, Villain, and Victim in News Articles

Deliver a Google Chrome extension that analyzes the entities (individuals, organizations, countries, etc.) contained within a news article and categorizes the most important entities as either being a hero, villain, or victim

Dopaminergic Neuronal Loss and Dopamine-Dependent Locomotor Defects in Fbxo7-Deficient Zebrafish

<div><p>Recessive mutations in the <em>F-box only protein 7</em> gene (<em>FBXO7</em>) cause PARK15, a Mendelian form of early-onset, levodopa-responsive parkinsonism with severe loss of nigrostriatal dopaminergic neurons. However, the function of the protein encoded by <em>FBXO7</em>, and the pathogenesis of PARK15 remain unknown. No animal models of this disease exist. Here, we report the generation of a vertebrate model of PARK15 in zebrafish. We first show that the zebrafish Fbxo7 homolog protein (zFbxo7) is expressed abundantly in the normal zebrafish brain. Next, we used two zFbxo7-specific morpholinos (targeting protein translation and mRNA splicing, respectively), to knock down the zFbxo7 expression. The injection of either of these zFbxo7-specific morpholinos in the fish embryos induced a marked decrease in the zFbxo7 protein expression, and a range of developmental defects. Furthermore, whole-mount <em>in situ</em> mRNA hybridization showed abnormal patterning and significant decrease in the number of diencephalic <em>tyrosine hydroxylase</em>-expressing neurons, corresponding to the human nigrostriatal or ventral tegmental dopaminergic neurons. Of note, the number of the <em>dopamine transporter</em>-expressing neurons was much more severely depleted, suggesting dopaminergic dysfunctions earlier and larger than those due to neuronal loss. Last, the zFbxo7 morphants displayed severe locomotor disturbances (bradykinesia), which were dramatically improved by the dopaminergic agonist apomorphine. The severity of these morphological and behavioral abnormalities correlated with the severity of zFbxo7 protein deficiency. Moreover, the effects of the co-injection of zFbxo7- and p53-specific morpholinos were similar to those obtained with zFbxo7-specific morpholinos alone, supporting further the contention that the observed phenotypes were specifically due to the knock down of zFbxo7. In conclusion, this novel vertebrate model reproduces pathologic and behavioral hallmarks of human parkinsonism (dopaminergic neuronal loss and dopamine-dependent bradykinesia), representing therefore a valid tool for investigating the mechanisms of selective dopaminergic neuronal death, and screening for modifier genes and therapeutic compounds.</p> </div