Efficient Prevention of Neurodegenerative Diseases by Depletion of Starvation Response Factor Ataxin-2

Ataxin-2 (ATXN2) homologs exist in all eukaryotic organisms and may have contributed to their origin. Apart from a role in endocytosis, they are known for global effects on mRNA repair and ribosomal translation. Cell size, protein synthesis, and fat and glycogen storage are repressed by ATXN2 via mTORC1 signaling. However, specific liver mitochondrial matrix enzymes and the mitochondrial repair factor PINK1 require ATXN2 abundance. During periods of starvation, ATXN2 is transcriptionally induced and localized to cytosolic stress granules, where nuclear factors dock to compensate RNA pathology. These physiological actions were now revealed to be crucial for human neurodegenerative diseases, given that ATXN2 depletion is surprisingly efficient in preventing motor neuron and cerebellar atrophy, as demonstrated in mouse models, flies, and yeast

Stepwise positional-orientational order and the multicritical-multistructural global phase diagram of the s=3/2 Ising model from renormalization-group theory

The spin-3/2 Ising model, with nearest-neighbor interactions only, is the prototypical system with two different ordering species, with concentrations regulated by a chemical potential. Its global phase diagram, obtained in d=3 by renormalization-group theory in the Migdal-Kadanoff approximation or equivalently as an exact solution of a d=3 hierarchical lattice, with flows subtended by 40 different fixed points, presents a very rich structure containing eight different ordered and disordered phases, with more than 14 different types of phase diagrams in temperature and chemical potential. It exhibits phases with orientational and/or positional order. It also exhibits quintuple phase transition reentrances. Universality of critical exponents is conserved across different renormalization-group flow basins via redundant fixed points. One of the phase diagrams contains a plastic crystal sequence, with positional and orientational ordering encountered consecutively as temperature is lowered. The global phase diagram also contains double critical points, first-order and critical lines between two ordered phases, critical end points, usual and unusual (inverted) bicritical points, tricritical points, multiple tetracritical points, and zero-temperature criticality and bicriticality. The four-state Potts permutation-symmetric subspace is contained in this model

The examination of protective effects of gallic acid against damage of oxidative stress during induced-experimental renal ischemia-reperfusion in experiment

Aim: In this study, probable effects of gallic acid were investigated in experimentally induced renal I/R injury in rats. Material and methods: For this purpose, each group consisted of 7 Sprague dawley male albino rats. Groups were defined as follows; Group I: control group; Group II: I/R group; Group III, IV and V: I/R+Gallic acid (50, 100 and 200 mg.kg(-1) respectively-i.p.). Left kidney was removed by nephrectomy except for Group I. I/R was induced in the other kidney. Gallic acid was given 15 mins before ischemia induction. SOD, CAT and Gpx activities were determined by electrophoresis. MDA, MPO levels were determined spectrophotometrically. Histopathological investigations were also performed in kidney tissues. BUN and Creatinine levels in serum were determined. Results: BUN, Creatinine and MDA levels were statistically significant but MPO level was not statistically significantly increased in Group II. For SOD, CAT, Gpx activities in Group II, an increase was determined with respect to Group I. Histopathological investigations revealed widespread hyperemia in glomerulus, expansion of the structure between tubules and cell disruptions in Group II. In Group V (200 mg.kg-1 gallic acid), in terms of biochemical parameters, in spite of the significant decrease in BUN, Creatinine and MDA levels; a decrease was determined in SOD, CAT and Gpx isoenzyme activities. Group V showed histologically that I/R injury had been prevented to a greater extent and appearances were close to the control. Conclusion: As a result, in terms of our study, evaluations regarding kidney functions and histopathology have shown that gallic acid has protective effects in renal I/R injury (Tab. 2, Fig. 5, Ref. 36). Text in PDF www.elis.sk

Multiagent cooperation for solving global optimization problems: an extendible framework with example cooperation strategies

This paper proposes the use of multiagent cooperation for solving global optimization problems through the introduction of a new multiagent environment, MANGO. The strength of the environment lays in itsflexible structure based on communicating software agents that attempt to solve a problem cooperatively. This structure allows the execution of a wide range of global optimization algorithms described as a set of interacting operations. At one extreme, MANGO welcomes an individual non-cooperating agent, which is basically the traditional way of solving a global optimization problem. At the other extreme, autonomous agents existing in the environment cooperate as they see fit during run time. We explain the development and communication tools provided in the environment as well as examples of agent realizations and cooperation scenarios. We also show how the multiagent structure is more effective than having a single nonlinear optimization algorithm with randomly selected initial points

Law of denial

Law’s claim of mastery over past political violence is frequently undermined by reversals of that relationship of mastery, so that the violence of the law, and especially its symbolic violence, becomes easily incorporated into longues durées of political violence, rather than mastering them, settling them, or providing closure. Doing justice to the past, therefore, requires a political and theoretical attunement to the ways in which law, in purportedly attempting to address past political violence, inscribes itself into contemporary contexts of violence. While this may be limited to an analysis of how law is an effect of and affects the political, theoretically this attunement can be further refined by means of a critique of dynamics that are internal to law itself and that have to do with how law understands its own historicity, as well as its relationship to history and historiography. This article aims to pursue such a critique, taking as its immediate focus the ECHR case of Perinçek v Switzerland, with occasional forays into debates around the criminalisation of Armenian genocide denialism in France. The Perinçek case concerned Switzerland's criminalisation of the denial of the Armenian genocide, and concluded in 2015 after producing two judgments, first by the Second Chamber, and then by the Grand Chamber of the ECHR. However, although they both found for the applicant, the two benches had very different lines of reasoning, and notably different conceptions regarding the relationship between law and history. I proceed by tracing the shifting status of 'history' and 'historians' in these two judgments, and paying attention to the deferrals, disclaimers and ellipses that structure law's relation to history. This close reading offers the opportunity for a critical reappraisal of the relationship between law, denial and violence: I propose that the symbolic violence of the law operative in memory laws is a product of that which remains unresolved in law's understanding of historicity (including its own), its self-understanding vis-à-vis the task of historiography, and its inability to respond to historical violence without inscribing itself into a history of violence, a process regarding which it remains in denial

Indicators for relational values of nature’s contributions to good quality of life:The IPBES approach for Europe and Central Asia

Relational values are values of desirable relationships between people and nature and among people (through nature). We report on the approach to capture relational values of nature s contributions to people in the regional assessment for Europe and Central Asia of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES). We present a framework considering indicators along four relational value dimensions about people s relationships with nature: security and sovereignty; health; equity and justice; and heritage, social identity and stewardship. The framework has been operationalized for three nature s contributions to people (NCP): regulation of freshwater quality and quantity, food and feed, and physical and psychological experiences derived from nature. We identify ways to empirically assess relational values of nature s contributions to people at regional and continental scales with social-ecological indicators and proxies, ranging from biophysical indicators to indicators that intersect socio-economic with biophysical data. We conclude that many of the identified indicators can be considered as useful proxies of relational values in a quantitative way. The analysis shows that relational values are essential to consider at the science-policy interface as they are an important set of values that people hold about nature and that go beyond instrumental relations. © 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor and Francis Group

Correction: A european spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics (PLoS ONE (2016) 11:9 (e0162866) DOI: 10.1371/journal.pone.0162866)

The thirty-Third author's name is spelled incorrectly. The correct name is: Jadranka Sertić

Human genetics and neuropathology suggest a link between miR-218 and amyotrophic lateral sclerosis pathophysiology

Motor neuron–specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons, miR-218 is down-regulated and its mRNA targets are reciprocally up-regulated (derepressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity in motor neurons may be susceptible to failure in human ALS, suggesting that miR-218 may be a potential therapeutic target in motor neuron disease

A European spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant interpopulation pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective