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    Additional file 1 of Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid ÎČ aggregates in vivo in a mouse model of Alzheimer’s disease

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    Additional file 1: Fig. S1. Validation of AAV.hSyn.mt-roGFP in vitro. a. Mitochondrial co-transfection verified proper targeting of mt-roGFP to mitochondria. N2a cells (top) and primary cortical neurons (bottom) were co-transfected with mt-roGFP (green) and mRuby-Mito-7 (red) and subjected to confocal microscopy imaging. Scale bar represents 10 ÎŒm. b. Double immunolabelling of mt-roGFP (green) and mRuby-ER5 (red, targeting endoplasmic reticulum, ER) in N2a cells shows lack of colocalization and supports the mitochondrial localization of mt-roGFP. Scale bar represents 10 ÎŒm. c. In vitro imaging of cellular oxidative stress with mt-roGFP. Primary cortical neurons were exposed to either the oxidant DTDP or the reducing agent DTT. Images at 800 nm (red), 900 nm (green) and merged are shown. d. The relative changes in ratio 800/900 were represented by histograms of ratio 800/900 frequency distribution in control conditions (grey) and 20 min after exposure to DTT 1 mM (blue) and DTDP 100 ÎŒM (red) (Control, n = 143 cells; DTT 1 mM, n = 125; DTDP 100 ÎŒM, n = 109 cells). Fig. S2. Validation of pAAV.hSyn.mt-roGFP ex vivo. AAV.hSyn.mt-roGFP targets neuronal mitochondria in vivo. a. Colocalization of AAV.hSyn.mt-roGFP (green), NeuN (red) and GS (glutamine synthetase, magenta) in the mouse cortex shown by immunohistochemistry. Note that AAV.hSyn.mt-roGFP only colocalizes with the neuronal marker NeuN. Scale bar represents 10 ÎŒm. b. Colocalization of AAV.hSyn.mt-roGFP (green), HSP60 (mitochondrial marker, red) and NeuN (magenta) in the cortex shown by immunohistochemistry. Scale bar represents 10 ÎŒm. c. Inset. Colocalization of AAV.hSyn.mt-roGFP (green) and HSP60 (red) in cortex shown by immunohistochemistry (top). Scale bar 5 ÎŒm. Graph shows intensity profile of the ROI across the cell. Green line represents the fluorescence intensity of AAV.hSyn.mt-roGFP and red line represents the fluorescence intensity of HSP60. Fig. S3. Original images excited at 800nm and 900nm of Fig. 1b. Fig. S4. Original images excited at 800nm and 900nm of Fig. 2b. Fig. S5. Mitochondrial oxidative stress in male and female mice. Mitochondrial oxidative stress (Ratio 800/900) in neurons was compared between non-Tg and APP/PS1 Tg mice at 10 months of age within males (a) or females (b). Note that only for males the difference is significantly different (a. Males: average per field of view: non-Tg: 0.95 ± 0.026, n = 31 z-stacks; APP/PS1: 1.17 ± 0.046, n = 41 z-stacks from 5 and 9 mice respectively, ***p = 0.0001; Average per mouse: non-Tg: 0.95 ± 0.037, n = 5 mice; APP/PS1: 1.19 ± 0.073, n = 9 mice, *p=0.0190. b. Females: average per field of view: non-Tg: 1.038 ± 0.038, n = 38 z-stacks; APP/PS1: 1.17 ± 0.043, n = 19 z-stacks from 6 and 3 mice respectively; Average per mouse: non-Tg: 1.02 ± 0.08, n = 6 mice; APP/PS1: 1.19 ± 0.067, n = 3 mice). Error bars represent mean ± SEM. Fig. S6. The overall mitochondrial redox levels are not elevated in AD transgenic mouse neurons before AÎČ plaque deposition. a. In vivo images of neurites and cell bodies expressing pAAV.hSyn.mt-roGFP in mitochondria in non-Tg (top) and APP/PS1 Tg mice (bottom) in young mice. Scale bar represents 10 ÎŒm. b, c. Scatter dot plot represents overall mitochondrial oxidative stress (Ratio 800/900) in non-Tg and APP/PS1 Tg mice at 3 months of age, before plaque deposition, in mitochondria in neurons (b, average per field of view, non-Tg: 0.83 ± 0.024, n = 18 z-stacks from 3 mice (3 male); APP/PS1: 0.87 ± 0.024, n = 42 z-stacks from 6 mice (3 male, 3 female); c. average per mouse, non-Tg: 0.82 ± 0.039, n = 3 mice (3 male); APP/PS1: 0.87 ± 0.034, n = 6 mice (3 male, 3 female)). Error bars represent mean ± SEM. Blue dots denote male and pink dots denote female. d. Histogram of mitochondrial oxidative stress frequency distribution (indicated by Ratio 800/900) in the young non-Tg and APP/PS1 Tg mice. e. Representative high resolution pseudocolor images of somas (top) and neurites (bottom) expressing AAV.hSyn.mt-roGFP in mitochondria in vivo in young non-Tg (left) and APP/PS1 Tg mice (right). Scale bar represents 15 or 10 ÎŒm. f. Comparison of mitochondrial oxidative stress (Ratio 800/900) within somas or neurites in 3-month-old non-Tg and APP/PS1 Tg mice. APP/PS1 Tg mice showed higher oxidative stress levels in mitochondria in neurites. Error bars represent mean ± SEM. (somas: 0.79 ± 0.023, n = 9 z-stacks from 3 non-Tg mice (3 male), and 0.75 ± 0.026, n = 10 z-stacks from 3 APP/PS1 Tg mice (1 male, 2 females); neurites: 0.82 ± 0.040, n = 9 z-stacks from 3 non-Tg mice (3 male), and 0.92 ± 0.030, n = 10 z-stacks from 3 APP/PS1 Tg mice (1 males, 4 females); *p = 0.0467). g. Comparison of mitochondrial oxidative stress (Ratio 800/900) in the different cell compartments (somas and neurites) in 3-month-old (old) non-Tg and APP/PS1 Tg mice. Neurites showed significantly higher oxidative stress levels in mitochondria in the APP/PS1 Tg mouse when compared to the somas. Error bars represent mean ± SEM. (Young non-Tg: 0.79 ± 0.023 for somas and 0.82 ± 0.040 for neurites, n = 9 z-stacks from 3 mice (3 male); Young APP/PS1: 0.75 ± 0.026 for somas and 0.92 ± 0.030 for neurites, n = 10 z-stacks from 3 mice (1 male, 2 female), ***p = 0.0003). Blue dots denote male and pink dots denote female. Fig. S7. Original images excited at 800nm and 900nm of Fig. 3b. Fig. S8. Original images excited at 800nm and 900nm of Fig. 4a. Fig. S9. Original images excited at 800nm and 900nm of Fig. 5a. Fig. S10. SS31 reduces AÎČ-associated dystrophic neurite number but not amyloid burden in the AD transgenic mouse. a.  Representative images of the global amount of amyloid in the cortex of SS31 and SS20 treated APP/PS1 mice at 10 mo of age after AÎČ immunostaining. Scale bar represents 100 ÎŒm.  b. Scatter dot plots represent the quantification of amyloid load in the cortex after anti-AÎČ immunostaining or ThioS labeling. The number of dense-core plaques detected by ThioS (top) and the overall load of AÎČ (bottom) was comparable among SS31 and SS20 APP/PS1 treated mice. n = 7 mice per condition. Histograms represent the dense core plaque (top) and diffuse amyloid deposit (bottom) size in both conditions. c. Representative images of neuritic dystrophies (arrow heads, neurofilaments in green) around amyloid plaques (blue) in APP/PS1 mouse after either SS31 or SS20 treatment. Scale bar 20 ÎŒm. d. Scatter dot plot represents the quantification of the number of dystrophic neurites observed per plaque, n = 362 plaques from 4 SS31 APP/PS1 treated mice and n = 295 plaques from 4 SS31 APP/PS1 treated mice, **p < 0.05. e. Scatter dot plot represents the percentage of plaques showing dystrophic neurites, n = 4 – 5 areas per 4 mouse per condition, *p = 0.022

    Supplemental Material - Aortic Stiffness Can be Predicted From Different eGFR Formulas With Long Follow-Up in the Malmö Diet Cancer Study

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    Supplemental Material for Aortic Stiffness Can be Predicted From Different eGFR Formulas With Long Follow-Up in the Malmö Diet Cancer Study by Anders Christensson, MD, PhD, Simon Lundgren, MD, Madeleine Johansson, MD, PhD, Peter M. Nilsson, MD, PhD, Gunnar Engström, PhD, and Agne Laucyte-Cibulskiene, MD, PhD in Angiology.</p

    The Comet Interceptor Mission

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    Here we describe the novel, multi-point Comet Interceptor mission. It is dedicated to the exploration of a little-processed long-period comet, possibly entering the inner Solar System for the first time, or to encounter an interstellar object originating at another star. The objectives of the mission are to address the following questions: What are the surface composition, shape, morphology, and structure of the target object? What is the composition of the gas and dust in the coma, its connection to the nucleus, and the nature of its interaction with the solar wind? The mission was proposed to the European Space Agency in 2018, and formally adopted by the agency in June 2022, for launch in 2029 together with the Ariel mission. Comet Interceptor will take advantage of the opportunity presented by ESA’s F-Class call for fast, flexible, low-cost missions to which it was proposed. The call required a launch to a halo orbit around the Sun-Earth L2 point. The mission can take advantage of this placement to wait for the discovery of a suitable comet reachable with its minimum ΔV capability of 600 ms−1. Comet Interceptor will be unique in encountering and studying, at a nominal closest approach distance of 1000 km, a comet that represents a near-pristine sample of material from the formation of the Solar System. It will also add a capability that no previous cometary mission has had, which is to deploy two sub-probes – B1, provided by the Japanese space agency, JAXA, and B2 – that will follow different trajectories through the coma. While the main probe passes at a nominal 1000 km distance, probes B1 and B2 will follow different chords through the coma at distances of 850 km and 400 km, respectively. The result will be unique, simultaneous, spatially resolved information of the 3-dimensional properties of the target comet and its interaction with the space environment. We present the mission’s science background leading to these objectives, as well as an overview of the scientific instruments, mission design, and schedule

    Electrochromic Displays Screen Printed on Transparent Nanocellulose‐Based Substrates

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    Manufacturing of electronic devices via printing techniques is often considered to be an environmentally friendly approach, partially due to the efficient utilization of materials. Traditionally, printed electronic components (e.g., sensors, transistors, and displays) are relying on flexible substrates based on plastic materials; this is especially true in electronic display applications where, most of the times, a transparent carrier is required in order to enable presentation of the display content. However, plastic‐based substrates are often ruled out in end user scenarios striving toward sustainability. Paper substrates based on ordinary cellulose fibers can potentially replace plastic substrates, but the opaqueness limits the range of applications where they can be used. Herein, electrochromic displays that are manufactured, via screen printing, directly on state‐of‐the‐art fully transparent substrates based on nanocellulose are presented. Several different nanocellulose‐based substrates, based on either nanofibrillated or nanocrystalline cellulose, are manufactured and evaluated as substrates for the manufacturing of electrochromic displays, and the optical and electrical switching performances of the resulting display devices are reported and compared. The reported devices do not require the use of metals and/or transparent conductive oxides, thereby providing a sustainable all‐printed electrochromic display technology

    Endogenous incretin levels and risk of first incident cancer: a prospective cohort study

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    Concerns have been raised regarding a potentially increased risk of cancer associated with treatment with glucagon-like peptide-1 (GLP-1) receptor agonists. Here, we explored whether fasting and oral glucose tolerance test post-challenge glucose-dependent insulinotropic peptide (GIP) and GLP-1 levels were associated with incident first cancer. Within the cardiovascular re-examination arm of the population-based Malmö Diet Cancer study (n = 3734), 685 participants with a previous cancer diagnosis were excluded, resulting in 3049 participants (mean age 72.2 ± 5.6 years, 59.5% women), of whom 485 were diagnosed with incident first cancer (median follow-up time 9.9 years). Multivariable Cox-regression and competing risk regression (death as competing risk) were used to explore associations between incretin levels and incident first cancer. Higher levels of fasting GLP-1 (462 incident first cancer cases/2417 controls) showed lower risk of incident first cancer in competing risk regression (sub-hazard ratio 0.90; 95% confidence interval 0.82–0.99; p = 0.022). No association was seen for fasting GIP, post-challenge GIP, or post-challenge GLP-1 and incident first cancer. In this prospective study, none of the fasting and post-challenge levels of GIP and GLP-1 were associated with higher risk of incident first cancer; by contrast, higher levels of fasting GLP-1 were associated with lower risk of incident first cancer

    Sustainable hypertension care – How can it be achieved?

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    PrP<sup>Sc</sup> selectively binds 6-O-sulfated HS in cerebellar samples from Gerstmann-StraĂŒssler-Scheinker (GSS)-affected patients.

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    Mass spectrometry analysis of HS bound to PrPSc and brain lysate from the same sample (the former published [46]). Quantification shows (A), unsulfated (NAc and NH2) and sulfated (NS, 2S, 6S) HS, (B), individual HS disaccharides, and (C), the average sulfation per disaccharide of HS. N = 3 cerebellar samples. Note: other disaccharides were not significantly different (S4 Table). *PPPP2: glucosamine (GlcNH2); NS: N-sulfated glucosamine (GlcNS); 2S: 2-O-sulfated glucuronic or iduronic acids (2-O-S); 6S: 6-O-sulfated glucosamine (6-O-S). (TIF)</p

    Neuronal Ndst1 depletion accelerates prion protein clearance and slows neurodegeneration in prion infection.

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    Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a abundant extracellular matrix component. HS facilitates fibril formation in vitro, yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for accelerating prion conversion in vitro. Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase / N-sulfotransferase) from neurons or astrocytes, we investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, affecting mice infected with extracellular, plaque-forming, but not membrane bound, prions. Live PET imaging revealed rapid clearance of recombinant prion protein monomers into the CSF of neuronal Ndst1- deficient mice, neuronal, further suggesting that HS sulfate groups hinder transit of extracellular prion protein monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme to target to facilitate aggregate clearance

    Connecting the multiple dimensions of global soil fungal diversity

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    How the multiple facets of soil fungal diversity vary worldwide remains virtually unknown, hindering the management of this essential species-rich group. By sequencing high-resolution DNA markers in over 4000 topsoil samples from natural and human-altered ecosystems across all continents, we illustrate the distributions and drivers of different levels of taxonomic and phylogenetic diversity of fungi and their ecological groups. We show the impact of precipitation and temperature interactions on local fungal species richness (alpha diversity) across different climates. Our findings reveal how temperature drives fungal compositional turnover (beta diversity) and phylogenetic diversity, linking them with regional species richness (gamma diversity). We integrate fungi into the principles of global biodiversity distribution and present detailed maps for biodiversity conservation and modeling of global ecological processes
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