Tauopathies are clinically, morphologically and biochemically heterogeneous neurodegenerative diseases characterized by the deposition of abnormal tau protein in the brain. The neuropathological ...phenotypes are distinguished based on the involvement of different anatomical areas, cell types and presence of distinct isoforms of tau in the pathological deposits. The nomenclature of primary tauopathies overlaps with the modern classification of frontotemporal lobar degeneration. Neuropathological phenotypes comprise Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age‐related tauopathy, formerly called also as neurofibrillary tangle‐only dementia, and a recently characterized entity called globular glial tauopathy. Mutations in the gene encoding the microtubule‐associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17. In addition, further neurodegenerative conditions with diverse aetiologies may be associated with tau pathologies. Thus, the spectrum of tau pathologies and tauopathy entities expands beyond the traditionally discussed disease forms. Detailed multidisciplinary studies are still required to understand their significance.
Neurodegenerative diseases (NDDs) are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also in peripheral ...organs. These proteins and their biochemical modifications can be potentially targeted for therapy or used as biomarkers. Despite a plethora of modifications demonstrated for different neurodegeneration-related proteins, such as amyloid-β, prion protein, tau, α-synuclein, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma protein (FUS), molecular classification of NDDs relies on detailed morphological evaluation of protein deposits, their distribution in the brain, and their correlation to clinical symptoms together with specific genetic alterations. A further facet of the neuropathology-based classification is the fact that many protein deposits show a hierarchical involvement of brain regions. This has been shown for Alzheimer and Parkinson disease and some forms of tauopathies and TDP-43 proteinopathies. The present paper aims to summarize current molecular classification of NDDs, focusing on the most relevant biochemical and morphological aspects. Since the combination of proteinopathies is frequent, definition of novel clusters of patients with NDDs needs to be considered in the era of precision medicine. Optimally, neuropathological categorizing of NDDs should be translated into in vivo detectable biomarkers to support better prediction of prognosis and stratification of patients for therapy trials.
Astrocytes contribute to the pathogenesis of neurodegenerative proteinopathies as influencing neuronal degeneration or neuroprotection, and also act as potential mediators of the propagation or ...elimination of disease-associated proteins. Protein astrogliopathies can be observed in different forms of neurodegenerative conditions. Morphological characterization of astrogliopathy is used only for the classification of tauopathies. Currently, at least six types of astrocytic tau pathologies are distinguished. Astrocytic plaques (AP), tufted astrocytes (TAs), ramified astrocytes (RA), and globular astroglial inclusions are seen predominantly in primary tauopathies, while thorn-shaped astrocytes (TSA) and granular/fuzzy astrocytes (GFA) are evaluated in aging-related tau astrogliopathy (ARTAG). ARTAG can be seen in the white and gray matter and subpial, subependymal, and perivascular locations. Some of these overlap with the features of tau pathology seen in Chronic traumatic encephalopathy (CTE). Furthermore, gray matter ARTAG shares features with primary tauopathy-related astrocytic tau pathology. Sequential distribution patterns have been described for tau astrogliopathies. Importantly, astrocytic tau pathology in primary tauopathies can be observed in brain areas without neuronal tau deposition. The various morphologies of tau astrogliopathy might reflect a role in the propagation of pathological tau protein, an early response to a yet unidentified neurodegeneration-inducing event, or, particularly for ARTAG, a response to a repeated or prolonged pathogenic process such as blood-brain barrier dysfunction or local mechanical impact. The concept of tau astrogliopathies and ARTAG facilitated communication among research disciplines and triggered the investigation of the significance of astrocytic lesions in neurodegenerative conditions.
Unlike the electroweak sector of the standard model of particle physics, quantum chromodynamics (QCD) is surprisingly symmetric under time reversal. As there is no obvious reason for QCD being so ...symmetric, this phenomenon poses a theoretical problem, often referred to as the strong CP problem. The most attractive solution for this requires the existence of a new particle, the axion-a promising dark-matter candidate. Here we determine the axion mass using lattice QCD, assuming that these particles are the dominant component of dark matter. The key quantities of the calculation are the equation of state of the Universe and the temperature dependence of the topological susceptibility of QCD, a quantity that is notoriously difficult to calculate, especially in the most relevant high-temperature region (up to several gigaelectronvolts). But by splitting the vacuum into different sectors and re-defining the fermionic determinants, its controlled calculation becomes feasible. Thus, our twofold prediction helps most cosmological calculations to describe the evolution of the early Universe by using the equation of state, and may be decisive for guiding experiments looking for dark-matter axions. In the next couple of years, it should be possible to confirm or rule out post-inflation axions experimentally, depending on whether the axion mass is found to be as predicted here. Alternatively, in a pre-inflation scenario, our calculation determines the universal axionic angle that corresponds to the initial condition of our Universe.
According to current guidelines, pulmonary arterial hypertension (PAH) is diagnosed when mean pulmonary arterial pressure (Ppa) exceeds 25 mmHg at rest or 30 mmHg during exercise. Issues that remain ...unclear are the classification of Ppa values <25 mmHg and whether Ppa >30 mmHg during exercise is always pathological. We performed a comprehensive literature review and analysed all accessible data obtained by right heart catheter studies from healthy individuals to determine normal Ppa at rest and during exercise. Data on 1,187 individuals from 47 studies in 13 countries were included. Data were stratified for sex, age, geographical origin, body position and exercise level. Ppa at rest was 14.0+/-3.3 mmHg and this value was independent of sex and ethnicity. Resting Ppa was slightly influenced by posture (supine 14.0+/-3.3 mmHg, upright 13.6+/-3.1 mmHg) and age (<30 yrs: 12.8+/- 3.1 mmHg; 30-50 yrs: 12.9+/-3.0 mmHg; > or = 50 yrs: 14.7+/-4.0 mmHg). Ppa during exercise was dependent on exercise level and age. During mild exercise, Ppa was 19.4+/-4.8 mmHg in subjects aged <50 yrs compared with 29.4+/-8.4 mmHg in subjects > or = 50 yrs (p<0.001). In conclusion, while Ppa at rest is virtually independent of age and rarely exceeds 20 mmHg, exercise Ppa is age-related and frequently exceeds 30 mmHg, especially in elderly individuals, which makes it difficult to define normal Ppa values during exercise.
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bstract
We study the physical mechanism of how an external magnetic field influences the QCD quark condensate. Two competing mechanisms are identified, both relying on the interaction between the ...magnetic field and the low quark modes. While the coupling to valence quarks enhances the condensate, the interaction with sea quarks suppresses it in the transition region. The latter “sea effect” acts by ordering the Polyakov loop and, thereby, reduces the number of small Dirac eigenmodes and the condensate. It is most effective around the transition temperature, where the Polyakov loop effective potential is flat and a small correction to it by the magnetic field can have a significant effect. Around the critical temperature, the sea suppression overwhelms the valence enhancement, resulting in a net suppression of the condensate, named inverse magnetic catalysis. We support this physical picture by lattice simulations including continuum extrapolated results on the Polyakov loop as a function of temperature and magnetic field. We argue that taking into account the increase in the Polyakov loop and its interaction with the low-lying modes is essential to obtain the full physical picture, and should be incorporated in effective models for the description of QCD in magnetic fields in the transition region.
We propose a new way of understanding how chiral symmetry is realized in the high temperature phase of QCD. Based on the finding that a simple free instanton gas precisely describes the details of ...the lowest part of the spectrum of the lattice overlap Dirac operator, we propose an instanton-based random matrix model of QCD with dynamical quarks. Simulations of this model reveal that even for small quark mass the Dirac spectral density has a singularity at the origin, caused by a dilute gas of free instantons. Even though the interaction, mediated by light dynamical quarks, creates small instanton-anti-instanton molecules, those do not influence the singular part of the spectrum, and this singular part is shown to dominate Banks-Casher type sums in the chiral limit. By generalizing the Banks-Casher formula for the singular spectrum, we show that in the chiral limit the chiral condensate vanishes if there are at least two massless flavors. Our model also indicates a possible way of resolving a long-standing debate, as it suggests that for two massless quark flavors the U(1)_{A} symmetry is likely to remain broken up to arbitrarily high finite temperatures.
Iron accumulation in the brain is a common feature of many neurodegenerative diseases. Its involvement spans across the main proteinopathies involving tau, amyloid-beta, alpha-synuclein, and TDP-43. ...Accumulating evidence supports the contribution of iron in disease pathologies, but the delineation of its pathogenic role is yet challenged by the complex involvement of iron in multiple neurotoxicity mechanisms and evidence supporting a reciprocal influence between accumulation of iron and protein pathology. Here, we review the major proteinopathy-specific observations supporting four distinct hypotheses: (1) iron deposition is a consequence of protein pathology; (2) iron promotes protein pathology; (3) iron protects from or hinders protein pathology; and (4) deposition of iron and protein pathology contribute parallelly to pathogenesis. Iron is an essential element for physiological brain function, requiring a fine balance of its levels. Understanding of disease-related iron accumulation at a more intricate and systemic level is critical for advancements in iron chelation therapies.
This paper presents a novel approach for active structures driven by soft dielectric electro-active polymers (EAPs), which can perform contractive displacements at external tensile load. The active ...structure is composed of an array of equal segments, where the dielectric films are arranged in a pile-up configuration. The proposed active structure has the capability of exhibiting uniaxial contractive deformations, while being exposed to external tensile forces. The serial arrangement of active segments has one contracting degree of freedom in the thickness direction of the dielectric EAP film layers.
Due to the envisaged tension force transmission capability, special attention is paid to the electrode design which is of paramount importance with regard to functionality of the actuator. A compliant electrode system with anisotropic deformation properties is presented based on nano scale carbon powder. In experiments, the free deformation as well as the contractive motion under external tensile loading of several actuator configurations with different setups is characterized. These involve the study of various sizes and numbers of stacked film layers as well as different electrode designs.
miR-146a and miR-155 are key regulators of the innate immune response. We hypothesized that an inflammation-mediated dysregulation of these miRNAs may occur in patients with Down syndrome (DS) and ...Alzheimer's disease (AD).
The miRNA expression patterns were investigated by in situ hybridization in developing hippocampus from controls, patients with DS and in adults with AD pathology (DS and sporadic AD; sAD). Quantitative real-time PCR was employed to evaluate the miRNA levels in the hippocampus of sAD and in mouse models of DS and AD. Both miRNAs were expressed in prenatal human hippocampus. In DS we detected increased miR-146a expression in reactive astrocytes. Increased expression of miR-146a was found in the hippocampus of sAD and negatively correlated with its target IRAK-1. APP/PS1 mice showed a significant increase in the expression of both miRNAs at 11-13 months of age as compared to WT and mice at 3 months. A negative correlation between miR-146a levels and its target TRAF6 was observed in both Ts65Dn and APP/PS1 mice.
These findings suggest a possible involvement of miR-146a and miR-155 in brain development and neurodegeneration. In particular, we provide evidence of a dysregulation of these two immunomodulatory miRNAs in AD with a potential therapeutical implication, deserving further investigation.
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