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We show that for smooth and proper varieties over local fields with no non-trivial vector fields, good reduction descends over purely inseparable extensions. We use this to extend the Neron-Ogg-Shafarevich criterion for K3 surfaces to the equicharacteristic $p>0$ case., 15 pages, comments welcome!

Legend for Supplementary Figures S1-S8.

Supplementary Tables S1-S2. Primer sequences used for qRT-PCR (S1); Primary and secondary antibodies used for Western blot analysis (S2).

Supplementary Materials and Methods. Description of additional methods and procedures used in the study. Also includes Supplementary Reference.

Supplementary Figures S1-S8. Deletion of NEMO and TNF-R1 in NEMOΔhepa and TNF-R1-/- livers (S1); No changes in proliferation despite the up-regulation of cell cycle regulators in p21-deficient NEMOΔhepa livers (S2); Reduced CD45 expression in NEMOΔhepa/p21-/- livers (S3); Increased inflammation in LPS treated animals (S4); TNF-R1 deletion rescues the hypersensitivity of NEMOΔhepa/p21-/- mice against LPS (S5); Development of severe cholestasis is dependent on p21 expression (S6); Enhanced liver injury due to loss of p21 expression in 52 week-old animals (S7); Presence of adenomas in livers of 26 week old animals (S8).

Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC., This work was supported by the MINECO Retos SAF2016-78711, SAF2017-87919-R, PID2020-117827RB-IOO, PID2020-117941RB-IOO, PID2020-117116RB-I00, EXOHEP-CM S2017/BMD-3727, NanoLiver-CM Y2018/NMT-4949, AMMF 2018/117, COST Action CA17112 and UCM-25/2019, La Caixa Foundation Program HR17-00601; Asociación Española Contra el Cáncer (AECC PROYE20084REGU); the German Research Foundation (SFB1382 Project ID 403224013/A02). FJC and YAN are Ramón y Cajal Researchers RYC-2014-15242 and RYC-2015-17438, respectively. FJC is a Gilead Liver Research Scholar. The research group belongs to the validated Research Groups Ref. 970935 “Liver Pathophysiology”, 920631 “Lymphocyte immunobiology”, 920361 “Inmunogenética e inmunología de las mucosas” and IBL-6 (imas12-associated). FG and KZ are Chinese Scholarship Council (CSC) fellows. O.E.-V is supported by Beca FPI associated to MINECO SAR2017-87919R and R.B.-U by programa de Financiación de Universidad Complutense de Madrid—Banco Santander, CT63/19. DMM contract is supported by CIBEREHD. DMM, MRG, AR, JA and RG receive support from the Andalusian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018) and from the Instituto de Salud Carlos III (PI16/01842, PI19/01404; PI19/00589). TB is supported by the German Research Foundation (SFB1382 Project ID 403224013/B07).

Cancers 13(22), 5680 (2021). doi:10.3390/cancers13225680 special issue: "Special issue "Cell cycle proteins as promising targets in cancer therapy" / special issue editor: Arun K. Rishi, guest editor", Published by MDPI, Basel

Objectives: Lately, many countries have restricted or even banned transfat, and palm oil has become a preferred replacement for food manufacturers. Whether palm oil is potentially an unhealthy food mainly due to its high content of saturated Palmitic Acid (PA) is a matter of debate. The aim of this study was to test whether qualitative aspects of diet such as levels of PA and the fat source are risk factors for Metabolic Syndrome (MS) and Metabolic Associated Fatty Liver Disease (MAFLD). Methods: C57BL/6 male mice were fed for 14 weeks with three types of Western diet (WD): 1. LP-WD—low concentration of PA (main fat source—corn and soybean oils), 2. HP-WD—high concentration of PA (main fat source—palm oil), 3. HP-Trans-WD—high concentration of PA (mainly transfat). Results: All types of WD caused weight gain, adipocyte enlargement, hepatomegaly, lipid metabolism alterations, and steatohepatitis. Feeding with HP diets led to more prominent obesity, hypercholesterolemia, stronger hepatic injury, and fibrosis. Only the feeding with HP-Trans-WD resulted in glucose intolerance and elevation of serum transaminases. Brief withdrawal of WDs reversed MS and signs of MAFLD. However, mild hepatic inflammation was still detectable in HP groups. Conclusions: HP and HP-Trans-WD play a crucial role in the genesis of MS and MAFLD.

Journal of cellular and molecular medicine : JCMM 25(4), 1982-1999 (2021). doi:10.1111/jcmm.16015, Published by Wiley-Blackwell, Hoboken, NJ

Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol‐associated and metabolic‐associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol‐associated liver disease plus metabolic‐associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA‐sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets., DUAL model perfectly mimics all histological, metabolic and transcriptomic gene signatures of human advanced steatohepatitis, and thus serve as a preclinical tool for the development of therapeutic targets.

International journal of molecular sciences 21(9), 3267 (2020). doi:10.3390/ijms21093267 special issue: "Special Issue "Pathophysiology of Liver Fibrosis and Its Therapies" / Special Issue Editor: Dr. Pavel Strnad, Guest Editor", Published by Molecular Diversity Preservation International, Basel

Background & Aims Caspase 8 (CASP8) is the apical initiator caspase in death receptor-mediated apoptosis. Strong evidence for a link between death receptor signaling pathways and cholestasis has recently emerged. Herein, we investigated the role of CASP8-dependent and independent pathways during experimental cholestasis. Methods Liver injury was characterized in a cohort of human sera (n = 28) and biopsies from patients with stage IV primary biliary cholangitis. In parallel, mice with either specific deletion of Casp8 in liver parenchymal cells (Casp8Δhepa) or hepatocytes (Casp8Δhep), and mice with constitutive Ripk3 (Ripk3−/−) deletion, were subjected to surgical ligation of the common bile duct (BDL) from 2 to 28 days. Floxed (Casp8fl/fl) and Ripk3+/+ mice were used as controls. Moreover, the pan-caspase inhibitor IDN-7314 was used, and cell death mechanisms were studied in primary isolated hepatocytes. Results Overexpression of activated caspase 3, CASP8 and RIPK3 was characteristic of liver explants from patients with primary biliary cholangitis. Twenty-eight days after BDL, Casp8Δhepa mice showed decreased necrotic foci, serum aminotransferase levels and apoptosis along with diminished compensatory proliferation and ductular reaction. These results correlated with a decreased inflammatory profile and ameliorated liver fibrogenesis. A similar phenotype was observed in Ripk3−/− mice. IDN-7314 treatment decreased CASP8 levels but failed to prevent BDL-induced cholestasis, independently of CASP8 in hepatocytes. Conclusion These findings show that intervention against CASP8 in liver parenchymal cells – specifically in cholangiocytes – might be a beneficial option for treating obstructive cholestasis, while broad pan-caspase inhibition might trigger undesirable side effects. Lay summary Loss of caspase 8 – a protein involved in programmed cell death – in liver parenchymal cells protects against experimental cholestasis. Therefore, specific pharmacological intervention against caspase 8 might be a valid alternative for the treatment of obstructive cholestasis in the clinic, whereas broad pan-caspase inhibiting drugs might trigger undesirable side effects.

Opposing activities of Notch and Wnt signaling regulate mucosal barrier homeostasis and differentiation of intestinal epithelial cells. Specifically, Wnt activity is essential for differentiation of secretory cells including Wnt3-producing Paneth cells, whereas Notch signaling strongly promotes generation of absorptive cells. Loss of caspase-8 in intestinal epithelium (casp8∆int) is associated with fulminant epithelial necroptosis, severe Paneth cell death, secondary intestinal inflammation, and an increase in Notch activity. Here, we found that pharmacological Notch inhibition with dibenzazepine (DBZ) is able to essentially rescue the loss of Paneth cells, deescalate the inflammatory phenotype, and reduce intestinal permeability in casp8∆int mice. The secretory cell metaplasia in DBZ-treated casp8∆int animals is proliferative, indicating for Notch activities partially insensitive to gamma-secretase inhibition in a casp8∆int background. Our data suggest that casp8 acts in the intestinal Notch network.

Let $K$ be the field of fractions of a local Henselian DVR with perfect residue field. Assuming potential semi-stable reduction, we show that an unramified Galois-action on second $\ell$-adic cohomology of a K3 surface over $K$ implies that the surface has good reduction after a finite and unramified extension. We give examples where this unramified extension is really needed. Moreover, we give applications to good reduction after tame extensions and Kuga-Satake Abelian varieties. On our way, we settle existence and termination of certain semi-stable flops in mixed characteristic, and study group actions and their quotients on models of varieties., Comment: 40 pages, final version

Initiation and progression of liver fibrosis requires proliferation and activation of resting hepatic stellate cells (HSCs). Cyclin E1 (CcnE1) is the regulatory subunit of the cyclin-dependent kinase 2 (Cdk2) and controls cell cycle re-entry. We have recently shown that genetic inactivation of CcnE1 prevents activation, proliferation, and survival of HSCs and protects from liver fibrogenesis. The aim of the present study was to translate these findings into preclinical applications using an RNA interference (RNAi)-based approach. CcnE1-siRNA (small interfering RNA) efficiently inhibited CcnE1 gene expression in murine and human HSC cell lines and in primary HSCs, resulting in diminished proliferation and increased cell death. In C57BL/6 wild-type (WT) mice, delivery of stabilized siRNA using a liposome-based carrier targeted approximately 95% of HSCs, 70% of hepatocytes, and 40% of CD45+ cells after single injection. Acute CCl4 -mediated liver injury in WT mice induced endogenous CcnE1 expression and proliferation of surviving hepatocytes and nonparenchymal cells, including CD45+ leukocytes. Pretreatment with CcnE1-siRNA reverted CcnE1 induction to baseline levels of healthy mice, which was associated with reduced liver injury, diminished proliferation of hepatocytes and leukocytes, and attenuated overall inflammatory response. For induction of liver fibrosis, WT mice were challenged with CCl4 for 4-6 weeks. Co-treatment with CcnE1-siRNA once a week was sufficient to continuously block CcnE1 expression and cell-cycle activity of hepatocytes and nonparenchymal cells, resulting in significantly ameliorated liver fibrosis and inflammation. Importantly, CcnE1-siRNA also prevented progression of liver fibrosis if applied after onset of chronic liver injury. Conclusion Therapeutic targeting of CcnE1 in vivo using RNAi is feasible and has high antifibrotic activity. (Hepatology 2017;66:1242-1257).

The naive analogue of the N\'eron-Ogg-Shafarevich criterion is false for K3 surfaces, that is, there exist K3 surfaces over Henselian, discretely valued fields $K$, with unramified $\ell$-adic \'etale cohomology groups, but which do not admit good reduction over $K$. Assuming potential semi-stable reduction, we show how to correct this by proving that a K3 surface has good reduction if and only if $H^2_{\mathrm{\acute{e}t}}(X_{\overline{K}},\mathbb{Q}_\ell)$ is unramified, and the associated Galois representation over the residue field coincides with the second cohomology of a certain "canonical reduction" of $X$. We also prove the corresponding results for $p$-adic \'etale cohomology., Comment: 52 pages, completely rewritten with significantly stronger main results

We explore Tate-type conjectures over $p$-adic fields. We study a conjecture of Raskind that predicts the surjectivity of $$ ({\rm NS}(X_{\bar{K}}) \otimes_{\mathbb{Z}}\mathbb{Q}_p)^{G_K} \longrightarrow H^2_{\rm et}(X_{\bar{K}},\mathbb{Q}_p(1))^{G_K} $$ if $X$ is smooth and projective over a $p$-adic field $K$ and has totally degenerate reduction. Sometimes, this is related to $p$-adic uniformisation. For abelian varieties, Raskind's conjecture is equivalent to the question whether $$ {\rm Hom}(A,B)\otimes{\mathbb{Q}}_p \,\to\, {\rm Hom}_{G_K}(V_p(A),V_p(B)) $$ is surjective if $A$ and $B$ are abeloid varieties over $K$. Using $p$-adic Hodge theory and Fontaine's functors, we reformulate both problems into questions about the interplay of $\mathbb{Q}$- versus $\mathbb{Q}_p$-structures inside filtered $(\varphi,N)$-modules. Finally, we disprove all of these conjectures and questions by showing that they can fail for algebraisable abeloid surfaces., Comment: 44 pages, final version

Am Anfang war der Klang. War er ein Summen oder Flustern, kam er vom Rauschen des Stromes, der an dieser Stelle besonders wild dahinschoss, oder vom Echo, das die hohe Steinwand hier besonders laut zuruckwarf? Jedenfalls war es dieser Klang, dem der markante Schieferfelsen bei Rheinkilometer 554 seinen Namen verdankt: »der Berg, wo es summt (rauscht)«1, Loreley. Dieses Wort wiederum klang einst in den Ohren von Clemens Brentano, als ware es ein Frauenname, und dies inspirierte ihn, »auf keine andere Grundlage als den Namen Lurlei«2, eine Figur und eine Geschichte dazu zu erdichten, genau genommen ihrer zwei. »Frau Lureley«, diese »Tochter der Phantasie«3 – Brentanos Phantasie –, hatte schon bald unzahlige Schwestern, Cousinen und Nichten, und so fand der Klang jenes Felsens einen Widerhall, wie er in der deutschen Kulturgeschichte beispiellos ist und der einerseits zeigt, dass nicht jedes Echo wohlklingend ist und andererseits, wie sehr ein Echo das Gesagte manchmal verzerren, wo nicht gar entstellen oder ubertonen kann.