Anti-inflammatory treatment induced regenerative oligodendrogenesis in parkinsonian mice

Introduction: The adult mammalian brain retains niches for neural stem cells (NSCs), which can generate glial and neuronal components of the brain tissue. However, it is barely established how chronic neuroinflammation, as it occurs in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, affects adult neurogenesis and, therefore, modulates the brain’s potential for self-regeneration. Methods: Neural stem cell culture techniques, intraventricular tumor necrosis factor (TNF)-a infusion and the 6-hydroxydopamine mouse model were used to investigate the influence of neuroinflammation on adult neurogenesis in the Parkinson’s disease background. Microscopic methods and behavioral tests were used to analyze samples. Results: Here, we demonstrate that differences in the chronicity of TNF-a application to cultured NSCs result in opposed effects on their proliferation. However, chronic TNF-a treatment, mimicking Parkinson’s disease associated neuroinflammation, shows detrimental effects on neural progenitor cell activity. Inversely, pharmacological inhibition of neuroinflammation in a 6-hydroxydopamine mouse model led to increased neural progenitor cell proliferation in the subventricular zone and neuroblast migration into the lesioned striatum. Four months after surgery, we measured improved Parkinson’s disease-associated behavior, which was correlated with long-term antiinflammatory treatment. But surprisingly, instead of newly generated striatal neurons, oligodendrogenesis in the striatum of treated mice was enhanced. Conclusions: We conclude that anti-inflammatory treatment, in a 6-hydroxydopamine mouse model for Parkinson’s disease, leads to activation of adult neural stem cells. These adult neural stem cells generate striatal oligodendrocytes. The higher numbers of newborn oligodendrocytes possibly contribute to axonal stability and function in this mouse model of Parkinson’s disease and thereby attenuate dysfunctions of basalganglian motorcontrol

Guidelines for Fluorescent Guided Biallelic HDR Targeting Selection With PiggyBac System Removal for Gene Editing

The development of new and easy-to-use nucleases, such as CRISPR/Cas9, made tools for gene editing widely accessible to the scientific community. Cas9-based gene editing protocols are robust for creating knock-out models, but the generation of single nucleotide transitions or transversions remains challenging. This is mainly due to the low frequency of homology directed repair, which leads to the screening of a high number of clones to identify positive events. Moreover, lack of simultaneous biallelic modifications, frequently results in second-allele indels. For example, while one allele might undergo homology directed repair, the second can undergo non-homologous end joining repair. Here we present a step-wise protocol for biallelic gene editing. It uses two donors carrying a combination of fluorescent reporters alongside homology arms directed to the same genomic region for biallelic targeting. These homology arms carry the desired composite of modifications to be introduced (homozygous or heterozygous changes). Plus, the backbone of the plasmid carries a third fluorescent reporter for negative selection (to discard random integration events). Fluorescent selection of non-random biallelic targeted clones can be performed by microscopy guided picking or cell sorting (FACS). The positive selection module (PSM), carrying the fluorescence reporter and an antibiotic resistance, is flanked by inverted terminal repeats (ITR) that are recognized by transposase. Upon purification of the clones correctly modified, transfection of the excision-only transposase allows the removal of the PSM resulting in the integration of only the desired modifications

Bone tissue and the nervous system: what do they have in common?

Degenerative diseases affecting bone tissues and the brain represent important problems with high socio-economic impact. Certain bone diseases, such as osteoporosis, are considered risk factors for the progression of neurological disorders. Often, patients with neurodegenerative diseases have bone fractures or reduced mobility linked to osteoarthritis. The bone is a dynamic tissue involved not only in movement but also in the maintenance of mineral metabolism. Bone is also associated with the generation of both hematopoietic stem cells (HSCs), and thus the generation of the immune system, and mesenchymal stem cells (MSCs). Bone marrow is a lymphoid organ and contains MSCs and HSCs, both of which are involved in brain health via the production of cytokines with endocrine functions. Hence, it seems clear that bone is involved in the regulation of the neuronal system and vice versa. This review summarizes the recent knowledge on the interactions between the nervous system and bone and highlights the importance of the interaction between nerve and bone cells. In addition, experimental models that study the interaction between nerve and skeletal cells are discussed, and innovative models are suggested to better evaluate the molecular interactions between these two cell types

Fluvial and permafrost history of the lower Lena River, north‐eastern Siberia, over late Quaternary time

Arctic warming and permafrost thaw visibly expose changes in the landscape of the Lena River delta, the largest Arctic delta. Determining the past and modern river regime of thick deltaic deposits shaping the Lena River mouth in north-eastern Siberia is critical for understanding the history of delta formation and carbon sequestration. Using a 65 m long sediment core from the delta apex a set of sedimentological techniques is applied to aid reconstructing the Lena River history. The analysis includes: (i) grain-size measurements and the determination of the bedload composition; (ii) X-ray fluorescence, X-ray diffractometry, and magnetic susceptibility measurements and heavy mineral analysis for tracking mineral change; (iii) pH, electrical conductivity, ionic concentrations, and the δ18O and δD stable isotope composition from ground ice for reconstructing permafrost formation. In addition; (iv) total and dissolved organic carbon is assessed. Chronology is based on; (vi) radiocarbon dating of organic material (accelerator mass spectrometry and conventional) and is complemented by two infrared – optically stimulated luminescence dates. The record stretches back approximately to Marine Isotope Stage 7. It holds periods from traction, over saltation, to suspension load sedimentation. Minerogenic signals do not indicate provenance change over time. They rather reflect the change from high energy to a lower energy regime after Last Glacial Maximum time parallel to the fining-up grain-size trend. A prominent minimum in the ground ice stable isotope record at early Holocene highlights that a river arm migration and an associated refreeze of the underlying river talik has altered the isotopic composition at that time. Fluvial re-routing might be explained by internal dynamics in the Lena River lowland or due to a tectonic movement, since the study area is placed in a zone of seismic activity. At the southern Laptev Sea margin onshore continental compressional patterns are bordering offshore extensional normal faults

Kohlenstoff-Einlagerung und -Freisetzung in bis zu 200.000 Jahre alten Böden in Nordsibirien.

Auf Bol'shoy Lyakhovsky, die südlichste der Neusibirischen Inseln, wurden fünf Bohrkerne mit einer Gesamtlänge von 52 m gewonnen. Sie erfassen Permafrostböden aus dem Holozän bis zurück ins Prä-Eem (ca. 200 Tausend Jahre vor heute). Die z.Zt. laufenden geowissenschaftlichen Analysen der Kerne beinhalten sedimentologische, geophysikalische, biogeochemische und mikrobiologische Techniken. Hauptziel des Projektes ist es, die aktuelle natürliche Produktion von Treibhausgasen in Permafrostböden zu bewerten, um eine künftige Treibhausgasproduktion in einer wärmer werdenden Arktis besser abzuschätzen. Die heutigen Raten der Treibhausgasproduktion werden dabei mit Signalen des Abbaus organischer Substanz in den zurückliegenden zwei Glazial-Interglazial-Zyklen in Beziehung gesetzt. Diese Studie ist Teil des deutsch-russischen Gemeinschaftsprojektes CARBOPERM, das mehr als 50 Wissenschaftler aus verschiedenen Instituten in Deutschland und Russland verbindet. Das 3-Jahres-Projekt widmet sich dem besseren Verständnis der Bildung, Umwandlung und Freisetzung von organischem Kohlenstoff in nordsibirischen Permafrostlandschaften

TRIM32-dependent transcription in adult neural progenitor cells regulates neuronal differentiation

In the adult mammalian brain, neural stem cells in the subventricular zone continuously generate new neurons for the olfactory bulb. Cell fate commitment in these adult neural stem cells is regulated by cell fate-determining proteins. Here, we show that the cell fate-determinant TRIM32 is upregulated during differentiation of adult neural stem cells into olfactory bulb neurons. We further demonstrate that TRIM32 is necessary for the correct induction of neuronal differentiation in these cells. In the absence of TRIM32, neuroblasts differentiate slower and show gene expression profiles that are characteristic of immature cells. Interestingly, TRIM32 deficiency induces more neural progenitor cell proliferation and less cell death. Both effects accumulate in an overproduction of adult-generated olfactory bulb neurons of TRIM32 knockout mice. These results highlight the function of the cell fate-determinant TRIM32 for a balanced activity of the adult neurogenesis process

Water extracts from Siberian thawing permafrost - from land to ocean

To better understand and quantify fluxes of dissolved elements upon permafrost thaw, water-soluble elements from Siberian permafrost samples covering a wide geographic range were determined by extraction. We measured the pH- and EC-values as well as the total dissolved major and secondary cation concentrations and anion concentrations for 270 water extracts from 12 different sites around the Laptev Sea. Cation concentrations were analyzed using inductively coupled plasma-optical emission spectrometry and anion concentrations by ion chromatography. Hydrogen carbonate concentrations were measured by potentiometric pH-value titration using an automatic titrator. Electrical conductivity and pH values were measured using a WTW MultiLab 540 multi-parameter device. As ground ice melts throughout Siberia with continued climate warming, drainage of the soils in many locations is improving and exposing mineral surfaces that were previously largely inert by their perennially frozen condition and unaffected by active weathering through seasonal wetting and drying cycles. Chemical analyses of water extracts allow an assessment of the potential interactions between mineral surfaces and pore melt water and the characteristics and biogeochemical and ecological consequences of the export of melt water from thawing permafrost. The (hydro-)chemical flux from permafrost sources into the riverine and marine realms is mainly defined by its source signatures and concentrations, which will be addressed in the present study. We compare our values with water data from lakes, rivers and the Arctic Ocean. The influence of terrestrial input from thawing permafrost including ground ice is expected to increase as coastal and river shore erosion as well as other permafrost degradation processes accelerate under Arctic warming and mobilize previously freeze-locked material. The increasing influx of dissolved elements influences transport and deposition processes in aquatic environments as well as nutrient supply, food chains and life cycles with largely understudied consequences for aquatic and coastal ecosystems in the Arctic