Tau Isoform-Driven CBD Pathology Transmission in Oligodendrocytes in Humanized Tau Mice

The aggregation of abnormally phosphorylated tau protein in neurons and glia is a neuropathological hallmark of several neurodegenerative disorders, collectively known as tauopathies. They are further subclassified based on the preferential pathological aggregation of three carboxyl-terminal repeat domains (3R) and/or 4R tau. Corticobasal degeneration (CBD) is a rare neurodegenerative disorder classified as a 4R tauopathy. In the present study, we extend analysis of CBD-tau cell-type specific pathology transmission with 3R and 4R tau isoform distinguishable changes. We use a humanized tau (hTau) mouse line, which overexpress all six human tau isoforms in a murine tau knockout background and perform intrastriatal inoculation of control and CBD-tau enriched human brain homogenate. We show that CBD-tau causes hyperphosphorylation of tau at Ser202 predominantly in oligodendrocytes. Next, we demonstrate the spread of tau pathology from striatum to the overlaying corpus callosum and further to the contralateral side. Finally, we demonstrate that the almost exclusive oligodendrocyte-based transmission of hyperphosphorylated tau is reflected in the endogenous 4R tau isoform expression and corresponds to subclassification of CBD as a 4R tauopathy. Additionally, we identify functional changes in oligodendrocytes reflected by myelin basic protein abnormalities upon CBD-tau inoculation. These changes are not observed in murine tau knockout mice lacking both human and murine tau. Our study presents not only in vivo tau isoform–driven region- and cell-specific tau pathology, but also underlines that tau pathology seeding and transmission might be oligodendrocyte-based. These results, which need to be extended to more cases, give new insights into why tauopathies might vary greatly in both histopathological and neuroanatomical patterns

Seasonal variation of aerosol water uptake and its impact on the direct radiative effect at Ny-Ålesund, Svalbard

© Author(s) 2014. This work is distributed under the Creative Commons Attribution 3.0 LicenseIn this study we investigated the impact of water uptake by aerosol particles in ambient atmosphere on their optical properties and their direct radiative effect (ADRE, W m-2) in the Arctic at Ny-Ålesund, Svalbard, during 2008. To achieve this, we combined three models, a hygroscopic growth model, a Mie model and a radiative transfer model, with an extensive set of observational data. We found that the seasonal variation of dry aerosol scattering coefficients showed minimum values during the summer season and the beginning of fall (July-August-September), when small particles (< 100 nm in diameter) dominate the aerosol number size distribution. The maximum scattering by dry particles was observed during the Arctic haze period (March-April-May) when the average size of the particles was larger. Considering the hygroscopic growth of aerosol particles in the ambient atmosphere had a significant impact on the aerosol scattering coefficients: the aerosol scattering coefficients were enhanced by on average a factor of 4.30 ± 2.26 (mean ± standard deviation), with lower values during the haze period (March-April-May) as compared to summer and fall. Hygroscopic growth of aerosol particles was found to cause 1.6 to 3.7 times more negative ADRE at the surface, with the smallest effect during the haze period (March-April-May) and the highest during late summer and beginning of fall (July-August-September).Peer reviewe

Functional pearl: a SQL to C compiler in 500 lines of code

We present the design and implementation of a SQL query processor that outperforms existing database systems and is written in just about 500 lines of Scala code - a convincing case study that high-level functional programming can handily beat C for systems-level programming where the last drop of performance matters. The key enabler is a shift in perspective towards generative programming. The core of the query engine is an interpreter for relational algebra operations, written in Scala. Using the open-source LMS Framework (Lightweight Modular Staging), we turn this interpreter into a query compiler with very low effort. To do so, we capitalize on an old and widely known result from partial evaluation known as Futamura projections, which state that a program that can specialize an interpreter to any given input program is equivalent to a compiler. In this pearl, we discuss LMS programming patterns such as mixed-stage data structures (e.g. data records with static schema and dynamic field components) and techniques to generate low-level C code, including specialized data structures and data loading primitives

The constrained-monad problem

In Haskell, there are many data types that would form monads were it not for the presence of type-class constraints on the operations onthat data type. This is a frustrating problem in practice, because there is a considerable amount of support and infrastructure for monads that these data types cannot use. Using several examples,we show that a monadic computation can be restructured into a normal form such that the standard monad class can be used. The technique is not specific to monads, and we show how it can also be applied to other structures, such as applicative functors. One significant use case for this technique is domain-specific languages,where it is often desirable to compile a deep embedding of a computation to some other language, which requires restricting the types that can appear in that computation

Diesel soot aging in urban plumes within hours under cold dark and humid conditions

Fresh and aged diesel soot particles have different impacts on climate and human health. While fresh diesel soot particles are highly aspherical and non-hygroscopic, aged particles are spherical and hygroscopic. Aging and its effect on water uptake also controls the dispersion of diesel soot in the atmosphere. Understanding the timescales on which diesel soot ages in the atmosphere is thus important, yet knowledge thereof is lacking. We show that under cold, dark and humid conditions the atmospheric transformation from fresh to aged soot occurs on a timescale of less than five hours. Under dry conditions in the laboratory, diesel soot transformation is much less efficient. While photochemistry drives soot aging, our data show it is not always a limiting factor. Field observations together with aerosol process model simulations show that the rapid ambient diesel soot aging in urban plumes is caused by coupled ammonium nitrate formation and water uptake.Peer reviewe

Health care professionals meeting with individuals with Type 2 diabetes and obesity: Balancing coaching and caution

The burden of diabetes and obesity is increasing worldwide, indicating a need to find the best standard for diabetes care. The aim of this study was to generate a theory grounded in empirical data derived from a deeper understanding of health care professionals’ main concerns when they consult with individuals with diabetes and obesity and how they handle these concerns. Tape-recorded interviews were conducted with seven groups and three individual members of a diabetes team in an area of western Sweden. The grounded theory (GT) method was used to analyse the transcribed interviews. A core category, labelled Balancing coaching and caution and three categories (Coaching and supporting, Ambivalence and uncertainty, and Adjusting intentions) emerged. The core category and the three categories formed a substantive theory that explained and illuminated how health care professionals manage their main concern; their ambition to give professional individualised care; and find the right strategy for each individual with diabetes and obesity. The theory generated by this study can improve our understanding of how a lack of workable strategies limits caregivers’ abilities to reach their goals. It also helps identify the factors that contribute to the complexity of meetings between caregivers and individuals with diabetes

Transfer Functions for Protein Signal Transduction: Application to a Model of Striatal Neural Plasticity

We present a novel formulation for biochemical reaction networks in the context of signal transduction. The model consists of input-output transfer functions, which are derived from differential equations, using stable equilibria. We select a set of 'source' species, which receive input signals. Signals are transmitted to all other species in the system (the 'target' species) with a specific delay and transmission strength. The delay is computed as the maximal reaction time until a stable equilibrium for the target species is reached, in the context of all other reactions in the system. The transmission strength is the concentration change of the target species. The computed input-output transfer functions can be stored in a matrix, fitted with parameters, and recalled to build discrete dynamical models. By separating reaction time and concentration we can greatly simplify the model, circumventing typical problems of complex dynamical systems. The transfer function transformation can be applied to mass-action kinetic models of signal transduction. The paper shows that this approach yields significant insight, while remaining an executable dynamical model for signal transduction. In particular we can deconstruct the complex system into local transfer functions between individual species. As an example, we examine modularity and signal integration using a published model of striatal neural plasticity. The modules that emerge correspond to a known biological distinction between calcium-dependent and cAMP-dependent pathways. We also found that overall interconnectedness depends on the magnitude of input, with high connectivity at low input and less connectivity at moderate to high input. This general result, which directly follows from the properties of individual transfer functions, contradicts notions of ubiquitous complexity by showing input-dependent signal transmission inactivation.Comment: 13 pages, 5 tables, 15 figure

Basic Science in Movement Disorders: Fueling the Engine of Translation into Clinical Practice

\ua9 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Basic Science is crucial for the advancement of clinical care for Movement Disorders. Here, we provide brief updates on how basic science is important for understanding disease mechanisms, disease prevention, disease diagnosis, development of novel therapies and to establish the basis for personalized medicine. We conclude the viewpoint by a call to action to further improve interactions between clinician and basic scientists. \ua9 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Estimate of pre-thermal quench non-thermal electron density profile during Ar pellet shutdowns of low-density target plasmas in DIII-D

The radial density profile of pre-thermal quench (pre-TQ) early-time non-thermal (hot) electrons is estimated by combining electron cyclotron emission and soft x-ray data during the rapid shutdown of low-density (ne≲1019m−3) DIII-D target plasmas with cryogenic argon pellet injection. This technique is mostly limited in these experiments to the pre-TQ phase and quickly loses validity during the TQ. Two different cases are studied: a high (10 keV) temperature target and a low (4 keV) temperature target. The results indicate that early-time, low-energy (∼10 keV) hot electrons form ahead of the argon pellet as it enters the plasma, affecting the pellet ablation rate; it is hypothesized that this may be caused by rapid cross field transport of argon ions ahead of the pellet or by rapid cross field transport of hot electrons. Fokker-Planck modeling of the two shots suggests that the hot electron current is quite significant during the pre-TQ phase (up to 50% of the total current). Comparison between modeled pre-TQ hot electron current and post-TQ hot electron current inferred from avalanche theory suggests that hot electron current increases during the high-temperature target TQ but decreases during the low-temperature target TQ. The uncertainties in this estimate are large; however, if true, this suggests that TQ radial loss of hot electron current could be larger than previously estimated in DIII-D

LMS-Verify: abstraction without regret for verified systems programming

Performance critical software is almost always developed in C, as programmers do not trust high-level languages to deliver the same reliable performance. This is bad because low-level code in unsafe languages attracts security vulnerabilities and because development is far less productive, with PL advances mostly lost on programmers operating under tight performance constraints. High-level languages provide memory safety out of the box, but they are deemed too slow and unpredictable for serious system software. Recent years have seen a surge in staging and generative programming: the key idea is to use high-level languages and their abstraction power as glorified macro systems to compose code fragments in first-order, potentially domain-specific, intermediate languages, from which fast C can be emitted. But what about security? Since the end result is still C code, the safety guarantees of the high-level host language are lost. In this paper, we extend this generative approach to emit ACSL specifications along with C code. We demonstrate that staging achieves ``abstraction without regret'' for verification: we show how high-level programming models, in particular higher-order composable contracts from dynamic languages, can be used at generation time to compose and generate first-order specifications that can be statically checked by existing tools. We also show how type classes can automatically attach invariants to data types, reducing the need for repetitive manual annotations. We evaluate our system on several case studies that varyingly exercise verification of memory safety, overflow safety, and functional correctness. We feature an HTTP parser that is (1) fast (2) high-level: implemented using staged parser combinators (3) secure: with verified memory safety. This result is significant, as input parsing is a key attack vector, and vulnerabilities related to HTTP parsing have been documented in all widely-used web servers.</jats:p