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We have derived comprehensive statistics of geomagnetic activity for assessing the occurrence of geomagnetically induced currents (GIC) in the Norwegian high-voltage power grid. The statistical study is based on geomagnetic recordings in 1994–2011 from which the geoelectric field can be modelled and applied to a DC description of the power grid to estimate GIC. The largest GIC up to a few 100 A in the Norwegian grid occur most likely in its southern parts. This follows primarily from the structure of the grid favouring large GIC in the south. The magnetic field has its most rapid variations on the average in the north, but during extreme geomagnetic storms they reach comparable values in the south too. The ground conductivity has also smaller values in the south, which further increases the electric field there. Additionally to results in 1994–2011, we performed a preliminary estimation of a once per 100 year event for geoelectric field by extrapolating the statistics. We found that the largest geoelectric field value would be twice the maximum in 1994–2011. Such value was actually reached on 13–14 July 1982.

We analyse geomagnetic recordings at four subauroral and midlatitude Russian observatories in 1850–1862. The data consist of spot readings made once in hour of the north and east components of the magnetic field. We use the hourly change of the horizontal field vector as the measure of activity. We compare these values to data from modern observatories at corresponding magnetic latitudes (Nurmijärvi, Finland, magnetic latitude ~57 N; Tartu, Estonia, ~54.5 N; Dourbes, Belgium, ~46 N) by reducing their data to the 1-h format. The largest variations at the Russian observatories occurred during the Carrington storm in September 1859 and they reached about 1000 nT/h, which was the instrumental off-scale limit. When the time stamp for the spot readings happens to be optimal, the top variation in the Nurmijärvi data is about 3700 nT/h (July 1982), and at Tartu the maximum is about 1600 nT/h (November 2004). At a midlatitude site Nertchinsk in Russia (magnetic latitude ~45 N), the variation during the Carrington storm was at the off-scale limit, and exceeded the value observed at Dourbes during the Halloween storm in October 2003. At Nertchinsk, the Carrington event was at least four times larger than any other storm in 1850–1862. Despite the limitations of the old recordings and in using only hourly spot readings, the Carrington storm was definitely a very large event at midlatitudes. At higher latitudes, it remains somewhat unclear whether it exceeds the largest modern storms, especially the one in July 1982.

Fluorophore-coupled bile acids (BA) represent an important tool for intravital analysis of BA flux in animal models of cholestatic diseases. However, addition of a fluorophore to a BA may alter transport properties. We developed and validated a 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole-coupled taurocholic acid (3β-NBD-TCA) as a probe for intravital analysis of BA homeostasis. We compared transport of 3β-NBD-TCA to [3H]-TCA in HEK293 cells stably expressing the mouse hepatic or renal BA carriers mNtcp or mAsbt, respectively. We also studied distribution kinetics intravitally in livers and kidneys of anesthetized wildtype and mOatp1a/1b cluster knockout mice (OatpKO) with and without administration of the Ntcp inhibitor Myrcludex B and the ASBT inhibitor AS0369. In vitro, 3β-NBD-TCA and [3H]-TCA showed comparable concentration- and time-dependent transport via mNtcp and mAsbt as well as similar inhibition kinetics for Myrcludex B and AS0369. Intravital analysis in the livers of wildtype and OatpKO mice revealed contribution of both mNtcp and mOatp1a/1b in the 3β-NBD-TCA uptake from the sinusoidal blood into hepatocytes. Combined deletion of mOatp1a/1b and inhibition of mNtcp by Myrcludex B blocked the uptake of 3β-NBD-TCA from sinusoidal blood into hepatocytes. This led to an increase of 3β-NBD-TCA signal in the systemic circulation including renal capillaries, followed by strong enrichment in a subpopulation of proximal renal tubular epithelial cells (TEC). The enrichment of 3β-NBD-TCA in TEC was strongly reduced by the systemic ASBT inhibitor AS0369. NBD-coupled TCA has similar transport kinetics as [3H]-TCA and can be used as a tool to study hepatorenal BA transport. See also the graphical abstract(Fig. 1)., Competing Interests: Nothing to disclose., (Copyright © 2024 Ghallab et al.)

The mechanisms underlying the remarkable capacity of the liver to regenerate are still not completely understood. Particularly, the cross-talk between cytokines and cellular components of the process is of utmost importance because they represent potential avenues for diagnostics and therapeutics. WNT1-inducible-signaling pathway protein 1 (WISP1) is a cytokine member of the CCN family, a family of proteins that play many different roles in liver pathophysiology. WISP1 also belongs to the earliest and strongest upregulated genes in mouse livers after CCl 4 intoxication and has recently been shown to be secreted by tumor cells and to bind to type 1 collagen to cause its linearization in vitro and in tumor tissue in vivo. We show that WISP1 expression is strongly induced by TGFβ, a critical cytokine in wound healing processes. Additionally, secretion of WISP1 protein by hepatic stellate is increased in cells upon TGFβ stimulation (~seven-fold increase). Furthermore, WISP1 facilitates the migration of mouse hepatic stellate cells through collagen in vitro. However, in WISP1 knockout mice, no difference in stellate cell accumulation in damaged liver tissue and no influence on fibrosis was obtained, probably because the knockout of WISP1 was compensated by other factors in vivo.

Rationale: Liver cirrhosis is known to affect drug pharmacokinetics, but the functional assessment of the underlying pathophysiological alterations in drug metabolism is difficult. Methods: Cirrhosis in mice was induced by repeated treatment with carbon tetrachloride for 12 months. A cocktail of six drugs was administered, and parent compounds as well as phase I and II metabolites were quantified in blood, bile, and urine in a time-dependent manner. Pharmacokinetics were modeled in relation to the altered expression of metabolizing enzymes. In discrepancy with computational predictions, a strong increase of glucuronides in blood was observed in cirrhotic mice compared to vehicle controls. Results: The deviation between experimental findings and computational simulations observed by analyzing different hypotheses could be explained by increased sinusoidal export and corresponded to increased expression of export carriers ( Abcc3 and Abcc4 ). Formation of phase I metabolites and clearance of the parent compounds were surprisingly robust in cirrhosis, although the phase I enzymes critical for the metabolism of the administered drugs in healthy mice, Cyp1a2 and Cyp2c29 , were downregulated in cirrhotic livers. RNA-sequencing revealed the upregulation of numerous other phase I metabolizing enzymes which may compensate for the lost CYP isoenzymes. Comparison of genome-wide data of cirrhotic mouse and human liver tissue revealed similar features of expression changes, including increased sinusoidal export and reduced uptake carriers. Conclusion: Liver cirrhosis leads to increased blood concentrations of glucuronides because of increased export from hepatocytes into the sinusoidal blood. Although individual metabolic pathways are massively altered in cirrhosis, the overall clearance of the parent compounds was relatively robust due to compensatory mechanisms., Competing Interests: Author J-FS was employed by the company Bayer AG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fendt, Ghallab, Myllys, Hofmann, Hassan, Hobloss, González, Brackhagen, Marchan, Edlund, Seddek, Abdelmageed, Blank, Schlender, Holland, Hengstler and Kuepfer.)

Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disease in Western countries. It is becoming increasingly evident that peripheral organ-centered inflammatory diseases, including liver diseases, are linked with brain dysfunctions. Therefore, this study aims to unravel the effect of MASLD on brain histology, cognitive functions, and neurotransmitters. For this purpose, mice fed for 48 weeks on standard (SD) or Western diet (WD) were evaluated by behavioral tests, followed by sacrifice and analysis of the liver-brain axis including histopathology, immunohistochemistry, and biochemical analyses. Histological analysis of the liver showed features of Metabolic Dysfunction-Associated Steatohepatitis (MASH) in the WD-fed mice including lipid droplet accumulation, inflammation, and fibrosis. This was accompanied by an elevation of transaminase and alkaline phosphatase activities, increase in inflammatory cytokine and bile acid concentrations, as well as altered amino acid concentrations in the blood. Interestingly, compromised blood capillary morphology coupled with astrogliosis and microgliosis were observed in brain hippocampus of the WD mice, indicating neuroinflammation or a disrupted neurovascular unit. Moreover, attention was impaired in WD-fed mice along with the observations of impaired motor activity and balance, enhanced anxiety, and stereotyped head-twitch response (HTR) behaviors. Analysis of neurotransmitters and modulators including dopamine, serotonin, GABA, glutamate, and acetylcholine showed region-specific dysregulation in the brain of the WD-fed mice. In conclusion, the induction of MASH in mice is accompanied by the alteration of cellular morphology and neurotransmitter expression in the brain, associated with compromised cognitive functions.

Mouse models are frequently used to study chronic liver diseases (CLDs). To assess their translational relevance, we quantified the similarity of commonly used mouse models to human CLDs based on transcriptome data. Gene-expression data from 372 patients were compared with data from acute and chronic mouse models consisting of 227 mice, and additionally to nine published gene sets of chronic mouse models. Genes consistently altered in humans and mice were mapped to liver cell types based on single-cell RNA-sequencing data and validated by immunostaining. Considering the top differentially expressed genes, the similarity between humans and mice varied among the mouse models and depended on the period of damage induction. The highest recall (0.4) and precision (0.33) were observed for the model with 12-months damage induction by CCl 4 and by a Western diet, respectively. Genes consistently up-regulated between the chronic CCl 4 model and human CLDs were enriched in inflammatory and developmental processes, and mostly mapped to cholangiocytes, macrophages, and endothelial and mesenchymal cells. Down-regulated genes were enriched in metabolic processes and mapped to hepatocytes. Immunostaining confirmed the regulation of selected genes and their cell type specificity. Genes that were up-regulated in both acute and chronic models showed higher recall and precision with respect to human CLDs than exclusively acute or chronic genes. Conclusion: Similarly regulated genes in human and mouse CLDs were identified. Despite major interspecies differences, mouse models detected 40% of the genes significantly altered in human CLD. The translational relevance of individual genes can be assessed at https://saezlab.shinyapps.io/liverdiseaseatlas/., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of 'rest-and-jump genes' that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30-48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.

Background & Aims: Acute liver failure (ALF) represents an unmet medical need in Western countries. Although the link between intestinal dysbiosis and chronic liver disease is well-established, there is little evidence for a functional role of gut-liver interaction during ALF. Here we hypothesized that intestinal dysbiosis may affect ALF., Methods: To test this hypothesis, we assessed the association of proton pump inhibitor (PPI) or long-term antibiotics (ABx) intake, which have both been linked to intestinal dysbiosis, and occurrence of ALF in the 500,000 participants of the UK BioBank population-based cohort. For functional studies, male Nlrp6 -/- mice were used as a dysbiotic mouse model and injected with a sublethal dose of acetaminophen (APAP) or lipopolysaccharide (LPS) to induce ALF., Results: Multivariate Cox regression analyses revealed a significantly increased risk (odds ratio, 2.3-3) for developing ALF in UK BioBank participants with PPI or ABx. Similarly, dysbiotic Nlrp6 -/- mice displayed exacerbated APAP- and LPS-induced liver injury, which was linked to significantly reduced gut and liver tissue microbiota diversity and correlated with increased intestinal permeability at baseline. Fecal microbiota transfer (FMT) from Nlrp6 -/- mice into wild-type (WT) mice augmented liver injury on APAP treatment in recipient WT mice, resembling the inflammatory phenotype of Nlrp6 -/- mice. Specifically, FMT skewed monocyte polarization in WT mice toward a Ly6C hi inflammatory phenotype, suggesting a critical function of these cells as sensors of gut-derived signals orchestrating the inflammatory response., Conclusions: Our data show an important yet unknown function of intestinal microbiota during ALF. Intestinal dysbiosis was transferrable to healthy WT mice via FMT and aggravated liver injury. Our study highlights intestinal microbiota as a targetable risk factor for ALF., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Little is known about how liver fibrosis influences lobular zonation. To address this question, we used three mouse models of liver fibrosis, repeated CCl 4 administration for 2, 6 and 12 months to induce pericentral damage, as well as bile duct ligation (21 days) and mdr2 - / - mice to study periportal fibrosis. Analyses were performed by RNA-sequencing, immunostaining of zonated proteins and image analysis. RNA-sequencing demonstrated a significant enrichment of pericentral genes among genes downregulated by CCl 4 ; vice versa, periportal genes were enriched among the upregulated genes. Immunostaining showed an almost complete loss of pericentral proteins, such as cytochrome P450 enzymes and glutamine synthetase, while periportal proteins, such as arginase 1 and CPS1 became expressed also in pericentral hepatocytes. This pattern of fibrosis-associated 'periportalization' was consistently observed in all three mouse models and led to complete resistance to hepatotoxic doses of acetaminophen (200 mg/kg). Characterization of the expression response identified the inflammatory pathways TGFβ, NFκB, TNFα, and transcription factors NFKb1, Stat1, Hif1a, Trp53, and Atf1 among those activated, while estrogen-associated pathways, Hnf4a and Hnf1a, were decreased. In conclusion, liver fibrosis leads to strong alterations of lobular zonation, where the pericentral region adopts periportal features. Beside adverse consequences, periportalization supports adaptation to repeated doses of hepatotoxic compounds., Competing Interests: the authors declare no conflicts of interest.

Various types of DNA viruses are known to elicit the formation of a large nuclear viral replication compartment and marginalization of the cell chromatin. We used three-dimensional soft x-ray tomography, confocal and electron microscopy, combined with numerical modelling of capsid diffusion to analyse the molecular organization of chromatin in herpes simplex virus 1 infection and its effect on the transport of progeny viral capsids to the nuclear envelope. Our data showed that the formation of the viral replication compartment at late infection resulted in the enrichment of heterochromatin in the nuclear periphery accompanied by the compaction of chromatin. Random walk modelling of herpes simplex virus 1-sized particles in a three-dimensional soft x-ray tomography reconstruction of an infected cell nucleus demonstrated that the peripheral, compacted chromatin restricts viral capsid diffusion, but due to interchromatin channels capsids are able to reach the nuclear envelope, the site of their nuclear egress.

The realization that nuclear distribution of DNA, RNA, and proteins differs between cell types and developmental stages suggests that nuclear organization serves regulatory functions. Understanding the logic of nuclear architecture and how it contributes to differentiation and cell fate commitment remains challenging. Here, we use soft X-ray tomography (SXT) to image chromatin organization, distribution, and biophysical properties during neurogenesis in vivo. Our analyses reveal that chromatin with similar biophysical properties forms an elaborate connected network throughout the entire nucleus. Although this interconnectivity is present in every developmental stage, differentiation proceeds with concomitant increase in chromatin compaction and re-distribution of condensed chromatin toward the nuclear core. HP1β, but not nucleosome spacing or phasing, regulates chromatin rearrangements because it governs both the compaction of chromatin and its interactions with the nuclear envelope. Our experiments introduce SXT as a powerful imaging technology for nuclear architecture., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Lytic infection with herpes simplex virus type 1 (HSV-1) induces profound modification of the cell nucleus including formation of a viral replication compartment and chromatin marginalization into the nuclear periphery. We used three-dimensional soft X-ray tomography, combined with cryogenic fluorescence, confocal and electron microscopy, to analyse the transformation of peripheral chromatin during HSV-1 infection. Our data showed an increased presence of low-density gaps in the marginalized chromatin at late infection. Advanced data analysis indicated the formation of virus-nucleocapsid-sized (or wider) channels extending through the compacted chromatin of the host. Importantly, confocal and electron microscopy analysis showed that these gaps frequently contained viral nucleocapsids. These results demonstrated that HSV-1 infection induces the formation of channels penetrating the compacted layer of cellular chromatin and allowing for the passage of progeny viruses to the nuclear envelope, their site of nuclear egress.

We report here a multipurpose dynamic-interface-based segmentation tool, suitable for segmenting planar, cylindrical, and spherical surfaces in 3D. The method is fast enough to be used conveniently even for large images. Its implementation is straightforward and can be easily realized in many environments. Its memory consumption is low, and the set of parameters is small and easy to understand. The method is based on the Edwards-Wilkinson equation, which is traditionally used to model the equilibrium fluctuations of a propagating interface under the influence of temporally and spatially varying noise. We report here an adaptation of this equation into multidimensional image segmentation, and its efficient discretization.

Gene positioning and regulation of nuclear architecture are thought to influence gene expression. Here, we show that, in mouse olfactory neurons, silent olfactory receptor (OR) genes from different chromosomes converge in a small number of heterochromatic foci. These foci are OR exclusive and form in a cell-type-specific and differentiation-dependent manner. The aggregation of OR genes is developmentally synchronous with the downregulation of lamin b receptor (LBR) and can be reversed by ectopic expression of LBR in mature olfactory neurons. LBR-induced reorganization of nuclear architecture and disruption of OR aggregates perturbs the singularity of OR transcription and disrupts the targeting specificity of the olfactory neurons. Our observations propose spatial sequestering of heterochromatinized OR family members as a basis of monogenic and monoallelic gene expression., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The opportunistic pathogen Candida albicans can undergo phenotypic switching between a benign, unicellular phenotype and an invasive, multicellular form that causes candidiasis. Increasingly, strains of Candida are becoming resistant to antifungal drugs, making the treatment of candidiasis difficult, especially in immunocompromised or critically ill patients. Consequently, there is a pressing need to develop new drugs that circumvent fungal drug-resistance mechanisms. In this work we used soft X-ray tomography to image the subcellular changes that occur as a consequence of both phenotypic switching and of treating C. albicans with antifungal peptoids, a class of candidate therapeutics unaffected by drug resistance mechanisms. Peptoid treatment suppressed formation of the pathogenic hyphal phenotype and resulted in striking changes in cell and organelle morphology, most dramatically in the nucleus and nucleolus, and in the number, size, and location of lipidic bodies. In particular, peptoid treatment was seen to cause the inclusion of lipidic bodies into the nucleus.