Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development.

BACKGROUND & AIMS Fatty liver disease, including non-alcoholic fatty liver (NAFLD) and steatohepatitis (NASH), has been associated with increased intestinal barrier permeability and translocation of bacteria or bacterial products into the blood circulation. In this study, we aimed to unravel the role of both intestinal barrier integrity and microbiota in NAFLD/NASH development. METHODS C57BL/6J mice were fed with high-fat diet (HFD) or methionine-choline-deficient diet for 1 week or longer to recapitulate aspects of NASH (steatosis, inflammation, insulin resistance). Genetic and pharmacological strategies were then used to modulate intestinal barrier integrity. RESULTS We show that disruption of the intestinal epithelial barrier and gut vascular barrier (GVB) are early events in NASH pathogenesis. Mice fed HFD for only 1 week undergo a diet-induced dysbiosis that drives GVB damage and bacterial translocation into the liver. Fecal microbiota transplantation from HFD-fed mice into specific pathogen-free recipients induces GVB damage and epididymal adipose tissue enlargement. GVB disruption depends on interference with the WNT/β-catenin signaling pathway, as shown by genetic intervention driving β-catenin activation only in endothelial cells, preventing GVB disruption and NASH development. The bile acid analogue and farnesoid X receptor agonist obeticholic acid (OCA) drives β-catenin activation in endothelial cells. Accordingly, pharmacologic intervention with OCA protects against GVB disruption, both as a preventive and therapeutic agent. Importantly, we found upregulation of the GVB leakage marker in the colon of patients with NASH. CONCLUSIONS We have identified a new player in NASH development, the GVB, whose damage leads to bacteria or bacterial product translocation into the blood circulation. Treatment aimed at restoring β-catenin activation in endothelial cells, such as administration of OCA, protects against GVB damage and NASH development. LAY SUMMARY The incidence of fatty liver disease is reaching epidemic levels in the USA, with more than 30% of adults having NAFLD (non-alcoholic fatty liver disease), which can progress to more severe non-alcoholic steatohepatitis (NASH). Herein, we show that disruption of the intestinal epithelial barrier and gut vascular barrier are early events in the development of NASH. We show that the drug obeticholic acid protects against barrier disruption and thereby prevents the development of NASH, providing further evidence for its use in the prevention or treatment of NASH

Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study

Background Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by elevated plasma levels of LDL-cholesterol that confers an increased risk of premature atherosclerotic cardiovascular disease. Early identification and treatment of FH patients can improve prognosis and reduce the burden of cardiovascular mortality. Aim of this study was to perform the mutational analysis of FH patients identified through a collaboration of 20 Lipid Clinics in Italy (LIPIGEN Study). Methods We recruited 1592 individuals with a clinical diagnosis of definite or probable FH according to the Dutch Lipid Clinic Network criteria. We performed a parallel sequencing of the major candidate genes for monogenic hypercholesterolemia (LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1). Results A total of 213 variants were detected in 1076 subjects. About 90% of them had a pathogenic or likely pathogenic variants. More than 94% of patients carried pathogenic variants in LDLR gene, 27 of which were novel. Pathogenic variants in APOB and PCSK9 were exceedingly rare. We found 4 true homozygotes and 5 putative compound heterozygotes for pathogenic variants in LDLR gene, as well as 5 double heterozygotes for LDLR/APOB pathogenic variants. Two patients were homozygous for pathogenic variants in LDLRAP1 gene resulting in autosomal recessive hypercholesterolemia. One patient was found to be heterozygous for the ApoE variant p.(Leu167del), known to confer an FH phenotype. Conclusions This study shows the molecular characteristics of the FH patients identified in Italy over the last two years. Full phenotypic characterization of these patients and cascade screening of family members is now in progress

Familial hypercholesterolemia: The Italian Atherosclerosis Society Network (LIPIGEN)

BACKGROUND AND AIMS: Primary dyslipidemias are a heterogeneous group of disorders characterized by abnormal levels of circulating lipoproteins. Among them, familial hypercholesterolemia is the most common lipid disorder that predisposes for premature cardiovascular disease. We set up an Italian nationwide network aimed at facilitating the clinical and genetic diagnosis of genetic dyslipidemias named LIPIGEN (LIpid TransPort Disorders Italian GEnetic Network). METHODS: Observational, multicenter, retrospective and prospective study involving about 40 Italian clinical centers. Genetic testing of the appropriate candidate genes at one of six molecular diagnostic laboratories serving as nationwide DNA diagnostic centers. RESULTS AND CONCLUSIONS: From 2012 to October 2016, available biochemical and clinical information of 3480 subjects with familial hypercholesterolemia identified according to the Dutch Lipid Clinic Network (DLCN) score were included in the database and genetic analysis was performed in 97.8% of subjects, with a mutation detection rate of 92.0% in patients with DLCN score 656. The establishment of the LIPIGEN network will have important effects on clinical management and it will improve the overall identification and treatment of primary dyslipidemias in Italy

Earthquakes, religion, and transition to self-government in Italian cities

This article presents a unique historical experiment to explore the dynamics of institutional change in the Middle Ages. We have assembled a novel data set, where information on political institutions for northern central Italian cities between 1000 and 1300 is matched with detailed information on the earthquakes that occurred in the area and period of interest. Exploiting the panel structure of the data, we document that the occurrence of an earthquake retarded institutional transition from autocratic regimes to self-government (the commune) in cities where the political and the religious leaders were the same person (episcopal see cities), but not in cities where political and religious powers were distinct (non–episcopal see cities). Such differential effect holds for destructive seismic episodes and for events that were felt by the population but did not cause any material damage to persons or objects. Ancillary results show that seismic events provoked a positive and statistically significant differential effect on the construction and further ornamentation of religious buildings between episcopal and non–episcopal see cities. Our findings are consistent with the idea that earthquakes, interpreted in the Middle Ages as manifestation of the will and outrage of God, represented a shock to people’s religious beliefs and, as a consequence, enhanced the ability of political-religious leaders to restore social order after a crisis relative to the emerging communal institutions

Wealth accumulation and institutional capture. the rise of the Medici and the fall of the Florentine republic

We study mechanisms and consequences of an institutional capture using novel hand-collected data from the Florentine Republic. In the 14th-15th centuries, political offices were assigned in Florence by a system combining elections and lottery, which ensured for several decades a substantial alternation of power. During the 1420s, after a fiscal crisis, the Medici family became the first lender of the Republic, obtained a leading position in the city, and captured the o ce allocation mechanism, while leaving the political institutions formally unchanged. Employing individual level information on wealth, political participation, and party a affiliation, we first document how the Medici manipulated o ce assignment and we show that, under their regime, participation into politics became a source of individual wealth accumulation. By using complementary data sources on voluntary loans to the Republic, we then provide several pieces of evidence that explain our findings in terms of rent extraction. Finally, we illustrate that individuals at the top of the wealth distribution gained from the institutional capture at the expenses of other citizens

Online Florentine Catasto of 1457

The “Florentine Catasto of 1457” was digitized by Marianna Belloc (Sapienza Università di Roma), Francesco Drago (Università di Catania), Mattia Fochesato (Università Bocconi), and Roberto Galbiati (CNRS-SciencesPo). The original documents can be accessed at “Archivio di Stato di Firenze, Viale della Giovine Italia 6, 50122 Firenze, IT” and are included in the archival fund “Catasto del 1457 - Portate dei Cittadini”, Volumes 785-832. Information on Cosimo de Medici and his family (that is missing in the original documents) was taken from de Roover, R. (1963: p.26), “The Rise and Decline of the Medici Bank 1397-1494”, Cambridge (Mass): Harvard University Press

Multigenerational transmission of wealth. Florence 1403-1480

By using hand-collected data on households’ wealth assessments, we study multigenerational mobility in Florence during the late Middle Ages. We find that Florentine society was quite mobile but also that multigenerational mobility was lower than implied by two generations estimates. We reconcile these findings by showing their consistency with a model where wealth transmission is governed by an unobserved latent factor. We also show that, given our estimates, this model is compatible with the long-run persistence found by previous studies. Finally, we find that participation in marriage networks and in politics correlates with persistence of the economic status across generations.By using hand-collected data on households' wealth assessments, we study multigenerational mobility in Florence during the late Middle Ages. We find that Florentine society was more mobile than one would expect but also that multigenerational mobility was lower than implied by two generations estimates. We reconcile these findings by showing their consistency with a model where wealth transmission is governed by an unobserved latent factor. We also show that, given our estimates, this model is compatible with the long-run persistence obtained by previous studies. Finally, we find that participation in marriage networks and in politics correlates with persistence of the economic status across generations

The importance of being (slightly) modified: The role of rRNA editing on gene expression control and its connections with cancer

In human ribosomal RNAs, over 200 residues are modified by specific, RNA-driven enzymatic complexes or stand-alone, RNA-independent enzymes. In most cases, modification sites are placed in specific positions within important functional areas of the ribosome. Some evidence indicates that the altered control in ribosomal RNA modifications may affect ribosomal function during mRNA translation. Here we provide an overview of the connections linking ribosomal RNA modifications to ribosome function, and suggest how aberrant modifications may affect the control of the expression of key cancer genes, thus contributing to tumor development. In addition, the future perspectives in this field are discussed

Cross-country correlation analysis for research on COVID-19

Italy has been hit particularly badly by the COVID-19 pandemic and has one of the highest case fatality rates. High levels of intergenerational interaction in the country have been identified as a potential contributor to this. This column cautions against drawing policy implications from simple cross-country correlation analysis. It argues instead that sound empirical analysis using detailed and harmonised microdata at the European level should be conducted to analyse the effectiveness of policy interventions