Local cholesterol metabolism orchestrates remyelination

Cholesterol is an essential component of all cell membranes and particularly enriched in myelin membranes. Myelin membranes are a major target of immune attacks in the chronic neurological disorder multiple sclerosis (MS). During demye- linating insults, cholesterol is released from damaged myelin, increasing local levels of this unique lipid and impeding tissue regeneration. Here, we summarize the current knowledge of cholesterol-dependent processes during demyelination and remyelination, emphasizing cell type-specific responses. We discuss cellular lipid/ cholesterol metabolism during early and late disease phases and highlight the con- cept of lipid-based pharmacological interventions. We propose that knowledge of the interplay between cell type-specific cholesterol handling, inflammation, and blood–brain barrier (BBB) integrity will unravel disease processes and facilitate development of strategies for therapies to promote remyelination

Inducible targeting of CNS astrocytes in Aldh1/1-CreERT2 BAC transgenic mice

Background: Studying astrocytes in higher brain functions has been hampered by the lack of genetic tools for the efficient expression of inducible Cre recombinase throughout the CNS, including the neocortex. Methods: Therefore, we generated BAC transgenic mice, in which CreERT2 is expressed under control of the Aldh1l1 regulatory region. Results: When crossbred to Cre reporter mice, adult Aldh1l1-CreERT2 mice show efficient gene targeting in astrocytes. No such Cre-mediated recombination was detectable in CNS neurons, oligodendrocytes, and microglia. As expected, Aldh1l1-CreERT2 expression was evident in several peripheral organs, including liver and kidney. Conclusions: Taken together, Aldh1l1-CreERT2 mice are a useful tool for studying astrocytes in neurovascular coupling, brain metabolism, synaptic plasticity and other aspects of neuron-glia interactions

Dietary cholesterol promotes repair of demyelinated lesions in the adult brain

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability. Cholesterol is rate-limiting for myelin biogenesis in the developing CNS; however, whether cholesterol insufficiency contributes to remyelination failure in MS, is unclear. Here, we show the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination. In the cuprizone model, acute disease reduces serum cholesterol levels that can be restored by dietary cholesterol. Concomitant with blood-brain barrier impairment, supplemented cholesterol directly supports oligodendrocyte precursor proliferation and differentiation, and restores the balance of growth factors, creating a permissive environment for repair. This leads to attenuated axon damage, enhanced remyelination and improved motor learning. Remarkably, in experimental autoimmune encephalomyelitis, cholesterol supplementation does not exacerbate disease expression. These findings emphasize the safety of dietary cholesterol in inflammatory diseases and point to a previously unrecognized role of cholesterol in promoting repair after demyelinating episodes

Rapidly progressive dementia with thalamic degeneration and peculiar cortical prion protein immunoreactivity, but absence of proteinase K resistant PrP: a new disease entity?

BACKGROUND: Human prion diseases are a group of rare fatal neurodegenerative conditions with well-developed clinical and neuropathological diagnostic criteria. Recent observations have expanded the spectrum of prion diseases beyond the classically recognized forms. RESULTS: In the present study we report six patients with a novel, apparently sporadic disease characterised by thalamic degeneration and rapidly progressive dementia (duration of illness 2-12 months; age at death: 55-81 years). Light and electron microscopic immunostaining for the prion protein (PrP) revealed a peculiar intraneuritic distribution in neocortical regions. Proteinase K resistant PrP (PrPres) was undetectable by Western blotting in frontal cortex from the three cases with frozen tissue, even after enrichment for PrPres by centrifugation or by phosphotungstic acid precipitation. Conformation-dependent immunoassay analysis using a range of PK digestion conditions (and no PK digestion) produced only very limited evidence of meaningful D-N (denatured/native) values, indicative of the presence of disease-associated PrP (PrPSc) in these cases, when the results were compared with appropriate negative control groups. CONCLUSIONS: Our observation expands the spectrum of conditions associated with rapidly progressive dementia and may have implications for the understanding of the pathogenesis of prion diseases

Theory and simulation of quantum photovoltaic devices based on the non-equilibrium Green's function formalism

This article reviews the application of the non-equilibrium Green's function formalism to the simulation of novel photovoltaic devices utilizing quantum confinement effects in low dimensional absorber structures. It covers well-known aspects of the fundamental NEGF theory for a system of interacting electrons, photons and phonons with relevance for the simulation of optoelectronic devices and introduces at the same time new approaches to the theoretical description of the elementary processes of photovoltaic device operation, such as photogeneration via coherent excitonic absorption, phonon-mediated indirect optical transitions or non-radiative recombination via defect states. While the description of the theoretical framework is kept as general as possible, two specific prototypical quantum photovoltaic devices, a single quantum well photodiode and a silicon-oxide based superlattice absorber, are used to illustrated the kind of unique insight that numerical simulations based on the theory are able to provide.Comment: 20 pages, 10 figures; invited review pape

Managerial power in the German model: the case of Bertelsmann and the antecedents of neoliberalism

Our article extends the research on authoritarian neoliberalism to Germany, through a history of the Bertelsmann media corporation – sponsor and namesake of Germany’s most influential neoliberal think-tank. Our article makes three conceptual moves. Firstly, we argue that conceptualizing German neoliberalism in terms of an ‘ordoliberal paradigm’ is of limited use in explaining the rise and fall of Germany’s distinctive socio-economic model (Modell Deutschland). Instead, we locate the origins of authoritarian tendencies in the corporate power exercised by managers rather than in the power of state-backed markets imagined by ordoliberals. Secondly, we focus on the managerial innovations of Bertelsmann as a key actor enmeshed with Modell Deutschland. We show that the adaptation of business management practices of an endogenous ‘Cologne School’ empowered Bertelsmann’s postwar managers to overcome existential crises and financial constraints despite being excluded from Germany’s corporate support network. Thirdly, we argue that their further development in the 1970s also enabled Bertelsmann to curtail and circumvent the forms of labour representation associated with Modell Deutschland. Inspired by cybernetic management theories that it used to limit and control rather than revive market competition among its workforce, Bertelsmann began to act and think outside the postwar settlement between capital and labour before the settlement’s hotly-debated demise since the 1990s

Correlation of immune phenotype with IDH mutation in diffuse glioma.

Tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) are targets of immune checkpoint inhibitors. Forty-three World Health Organization (WHO) grade II/III gliomas (39 IDH-mutant [mut], 4 IDH-wildtype [wt]) and 14 IDH-mut glioblastomas (GBM) were analyzed for TIL (CD3+; PD1+) infiltration and PD-L1 expression. Results were compared with the data of a previously published series of 117 IDH-wt glioblastomas. PD-L1 gene expression levels were evaluated in 677 diffuse gliomas grades II-IV from The Cancer Genome Atlas (TCGA) database. TIL and PD-L1 expression were observed in approximately half of WHO grade II/III gliomas. IDH-wt status was associated with significantly higher TIL infiltration and PD-L1 expression among all (grades II-IV) cases (n = 174, P < 0.001) and within the cohort of glioblastomas (n = 131, P < 0.001). In low-grade glioma (LGG) and glioblastoma cohorts of TCGA, significantly higher PD-L1 gene expression levels were evident in IDH-wt compared with IDH-mut samples (LGG: N = 516; P = 1.933e-11, GBM: N = 161; P < 0.009). Lower PD-L1 gene expression was associated with increased promoter methylation (Spearman correlation coefficient -0.36; P < 0.01) in the LGG cohort of TCGA. IDH-mut gliomas had higher PD-L1 gene promoter methylation levels than IDH-wt gliomas (P < 0.01). The immunological tumor microenvironment of diffuse gliomas differs in association with IDH mutation status. IDH-wt gliomas display a more prominent TIL infiltration and higher PD-L1 expression than IDH-mut cases. Mechanistically this may be at least in part due to differential PD-L1 gene promoter methylation levels. Our findings may be relevant for immune modulatory treatment strategies in glioma patients

Прогнозирование гидравлического разрыва пласта низкопроницаемых коллекторов на основе математического моделирования на месторождении Х

Объектом исследования является месторождение нефти с низкой проницаемостью, на котором был проведен гидроразрыв пласта с целью увеличения добычи нефти. Цель работы – разработать имитационную модель гидроразрыва с использованием вариационного подхода к гидроразрыву в качестве механической модели, что позволяет использовать единую расчетную область для представления как трещины, так и коллектора, и устраняет необходимость явной идентификации трещины. и направления распространения. В процессе исследования была рассмотрена группа сложных математических моделей деформации.The object of the study is an oil field with low permeability, where hydraulic fracturing was carried out in order to increase oil production. The aim of the work is to develop a simulation model of hydraulic fracturing using a variational approach to hydraulic fracturing as a mechanical model, which allows using a single computational domain to represent both the fracture and the reservoir, and eliminates the need for explicit fracture identification. and directions of distribution. In the course of the study, a group of complex mathematical models of deformation and fluid flow was considered

Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport

Abstract Background: Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood-brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery. Methods: Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis. Results: Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightness re-establishes directly after termination of anesthesia, providing a defined window for drug delivery. In a therapeutic glioblastoma trial in mice, simultaneous exposure to isoflurane and cytotoxic agent improves efficacy of chemotherapy. Conclusions: Combination therapy, involving isoflurane-mediated BBB permeation with drug administration has far-reaching therapeutic implications for CNS malignancies