Tau Protein Modulates Perineuronal Extracellular Matrix Expression in the TauP301L-acan Mouse Model

Tau mutations promote the formation of tau oligomers and filaments, which are neuropathological signs of several tau-associated dementias. Types of neurons in the CNS are spared of tau pathology and are surrounded by a specialized form of extracellular matrix; called perineuronal nets (PNs). Aggrecan, the major PN proteoglycans, is suggested to mediate PNs neuroprotective function by forming an external shield preventing the internalization of misfolded tau. We recently demonstrated a correlation between aggrecan amount and the expression and phosphorylation of tau in a TauP310L-acan mouse model, generated by crossbreeding heterozygous aggrecan mice with a significant reduction of aggrecan and homozygous TauP301L mice. Neurodegenerative processes have been associated with changes of PN structure and protein signature. In this study, we hypothesized that the structure and protein expression of PNs in this TauP310L-acan mouse is regulated by tau. Immunohistochemical and biochemical analyses demonstrate that protein levels of PN components differ between TauP301LHET-acanWT and TauP301LHET-acanHET mice, accompanied by changes in the expression of protein phosphatase 2 A. In addition, tau can modulate PN components such as brevican. Co-immunoprecipitation experiments revealed a physical connection between PN components and tau. These data demonstrate a complex, mutual interrelation of tau and the proteoglycans of the PN

Age-Related Association of Calcitonin with Parameters of Anthropometry, Bone and Calcium Metabolism during Childhood

Introduction: The thyroid parafollicular hormone calcitonin (CT) shows particularly high blood levels in early childhood, a period of high bone turnover, which decrease with increasing age. Data about the physiological role of CT during infancy, childhood, and adolescence are contradictory or lacking. Objective: We hypothesize that CT demonstrates agerelated correlations with parameters of bone growth and turnover as well as with parameters of calcium homeostasis. Methods: 5,410 measurements of anthropometric data and venous blood samples were collected from 2,636 participants of the LIFE Child study, aged 2 months–18 years. Univariate correlations and multiple regression analysis were performed between serum CT and anthropometric indicators (height standard deviation scores [SDS] and BMI-SDS), markers of calcium (Ca) homeostasis (Ca, parathyroid hormone, 25-OH vitamin D, and phosphate [P]), bone formation (procollagen type 1 N-terminal propeptide [P1NP], osteocalcin), and bone resorption (β-CrossLaps). Results: CT was sinificantly associated with Ca (β = 0.26, p < 0.05) and P1NP/100 (β = 0.005, p < 0.05) in children aged 2 months–1.1 years. These relations were independent of age and sex and could not be confirmed in children aged 1.1–8 years. Independent of age, sex, puberty, P, and height SDS CT showed a significant positive relation to Ca (β = 0.26; p < 0.001) in children aged 8–18 years. Conclusions: Our findings suggest a unique association between CT and Ca in periods of rapid bone growth and point to a possible involvement of CT in promoting bone formation during the first year of lif

Finding the best clearing approach - Towards 3D wide-scale multimodal imaging of aged human brain tissue

The accessibility of new wide-scale multimodal imaging techniques led to numerous clearing techniques emerging over the last decade. However, clearing mesoscopic-sized blocks of aged human brain tissue remains an extremely challenging task. Homogenizing refractive indices and reducing light absorption and scattering are the foundation of tissue clearing. Due to its dense and highly myelinated nature, especially in white matter, the human brain poses particular challenges to clearing techniques. Here, we present a comparative study of seven tissue clearing approaches and their impact on aged human brain tissue blocks (> 5 mm). The goal was to identify the most practical and efficient method in regards to macroscopic transparency, brief clearing time, compatibility with immunohistochemical processing and wide-scale multimodal microscopic imaging. We successfully cleared 26 × 26 × 5 mm3-sized human brain samples with two hydrophilic and two hydrophobic clearing techniques. Optical properties as well as light and antibody penetration depths highly vary between these methods. In addition to finding the best clearing approach, we compared three microscopic imaging setups (the Zeiss Laser Scanning Microscope (LSM) 880 , the Miltenyi Biotec Ultramicroscope ll (UM ll) and the 3i Marianas LightSheet microscope) regarding optimal imaging of large-scale tissue samples. We demonstrate that combining the CLARITY technique (Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging compatible Tissue hYdrogel) with the Zeiss LSM 880 and combining the iDISCO technique (immunolabeling-enabled three-dimensional imaging of solvent-cleared organs) with the Miltenyi Biotec UM ll are the most practical and efficient approaches to sufficiently clear aged human brain tissue and generate 3D microscopic images. Our results point out challenges that arise from seven clearing and three imaging techniques applied to non-standardized tissue samples such as aged human brain tissue

The provenance of the Devonian Old Red Sandstone of the Dingle Peninsula, SW Ireland; the earliest record of Laurentian and peri-Gondwanan sediment mixing in Ireland

The Lower Old Red Sandstone in southern Ireland is hosted in the Early Devonian Dingle Basin, which lies immediately south of the Iapetus Suture on the Dingle Peninsula, County Kerry. The basin developed as a post-Caledonian pullapart structure prior to Acadian deformation, which in turn was followed by end-Carboniferous Variscan deformation. Detrital zircon U–Th–Pb geochronology is complemented by mica Ar–Ar and apatite U–Pb geochronology to gain a comprehensive understanding of the provenance of the Lower Devonian Lower Old Red Sandstone of the Dingle Basin and assess contributions of major tectonic components (e.g. Laurentia, Ganderia). Sedimentary rocks in the Lower Old Red Sandstone have similar detrital zircon age distributions, which are dominated by c. 1.2 Ga zircons as well as late Neoproterozoic grains. This indicates a dominant contribution of detritus of Laurentian affinity as well as contributions from westerly and southerly derived Ganderian detritus. Caledonian uplift of the area north of the Iapetus Suture would have facilitated a large contribution of (peri-)Laurentian material. The Upper Old Red Sandstone on the Dingle Peninsula has a distinctly different detrital zircon character including few late Neoproterozoic zircons and abundant zircons of c. 1.05 Ga age, indicating sediment derivation only from Laurentia and no recycling from the Lower Old Red Sandstone

Gute Praxis Datenlinkage (GPD) : Good Practice Data Linkage

Das personenbezogene Verknüpfen verschiedener Datenquellen (Datenlinkage) für Forschungszwecke findet in den letzten Jahren in Deutschland zunehmend Anwendung. Jedoch fehlen hierfür konsentierte methodische Standards. Ziel dieses Beitrages ist es, solche Standards für Forschungsvorhaben zu definieren. Eine weitere Intention ist es, dem Lesenden eine Checkliste zur Bewertung geplanter Forschungsvorhaben und Artikel bereitzustellen. Zu diesem Zweck hat eine aus Mitgliedern verschiedener Fachgesellschaften zusammengesetzte Expertengruppe seit 2016 insgesamt 7 Leitlinien mit 27 konkreten Empfehlungen erstellt. Die Gute Praxis Datenlinkage beinhaltet die folgenden Leitlinien: (1) Forschungsziele, Fragestellung, Datenquellen und Ressourcen, (2) Dateninfrastruktur und Datenfluss, (3) Datenschutz, (4) Ethik, (5) Schlüsselvariablen und Linkageverfahren, (6) Datenprüfung/Qualitätssicherung sowie (7) Langfristige Datennutzung für noch festzulegende Fragestellungen. Jede Leitlinie wird ausführlich diskutiert. Zukünftige Aktualisierungen werden wissenschaftliche und datenschutzrechtliche Entwicklungen berücksichtigen

Multidimensional Characterization and Differentiation of Neurons in the Anteroventral Cochlear Nucleus

Multiple parallel auditory pathways ascend from the cochlear nucleus. It is generally accepted that the origin of these pathways are distinct groups of neurons differing in their anatomical and physiological properties. In extracellular in vivo recordings these neurons are typically classified on the basis of their peri-stimulus time histogram. In the present study we reconsider the question of classification of neurons in the anteroventral cochlear nucleus (AVCN) by taking a wider range of response properties into account. The study aims at a better understanding of the AVCN's functional organization and its significance as the source of different ascending auditory pathways. The analyses were based on 223 neurons recorded in the AVCN of the Mongolian gerbil. The range of analysed parameters encompassed spontaneous activity, frequency coding, sound level coding, as well as temporal coding. In order to categorize the unit sample without any presumptions as to the relevance of certain response parameters, hierarchical cluster analysis and additional principal component analysis were employed which both allow a classification on the basis of a multitude of parameters simultaneously. Even with the presently considered wider range of parameters, high number of neurons and more advanced analytical methods, no clear boundaries emerged which would separate the neurons based on their physiology. At the current resolution of the analysis, we therefore conclude that the AVCN units more likely constitute a multi-dimensional continuum with different physiological characteristics manifested at different poles. However, more complex stimuli could be useful to uncover physiological differences in future studies

Tau Protein Modulates Perineuronal Extracellular Matrix Expression in the TauP301L-acan Mouse Model

Tau mutations promote the formation of tau oligomers and filaments, which are neuropathological signs of several tau-associated dementias. Types of neurons in the CNS are spared of tau pathology and are surrounded by a specialized form of extracellular matrix; called perineuronal nets (PNs). Aggrecan, the major PN proteoglycans, is suggested to mediate PNs neuroprotective function by forming an external shield preventing the internalization of misfolded tau. We recently demonstrated a correlation between aggrecan amount and the expression and phosphorylation of tau in a TauP310L-acan mouse model, generated by crossbreeding heterozygous aggrecan mice with a significant reduction of aggrecan and homozygous TauP301L mice. Neurodegenerative processes have been associated with changes of PN structure and protein signature. In this study, we hypothesized that the structure and protein expression of PNs in this TauP310L-acan mouse is regulated by tau. Immunohistochemical and biochemical analyses demonstrate that protein levels of PN components differ between TauP301LHET-acanWT and TauP301LHET-acanHET mice, accompanied by changes in the expression of protein phosphatase 2 A. In addition, tau can modulate PN components such as brevican. Co-immunoprecipitation experiments revealed a physical connection between PN components and tau. These data demonstrate a complex, mutual interrelation of tau and the proteoglycans of the PN