Why and How Meet n-3 PUFA Dietary Recommendations?

Obesity and the metabolic syndrome are systemic inflammatory diseases reaching epidemic proportions. Contemporary changes in human nutrition occurred characterized by increased consumption of fat and of vegetable oils rich in n-6 polyunsaturated fatty acids (PUFAs) together with decrease in n-3 PUFA-rich foods, resulting in an n-6/n-3 ratio of 10–20/1 in Western diet for a ratio around 1/1 in the diet of our ancestors. The literature provides compelling evidence for the health benefit of n-3 PUFA consumption on inflammation and metabolic syndrome prevention and treatment. Such evidence led to the establishment of comprehensive recommendations. However, we show here that, both in collective catering proposed to children and in hospital diet, it is not straightforward to meet such recommendations. Willingness of governments to institute changes, with accountable decisions on catering, nutritional education, and food processing, is required to face our neglected responsibility in promoting balanced diet and consumption of foods rich in essential nutrients in the general population

Next generation of ALDH substrates and their potential to study maturational lineage biology in stem and progenitor cells

High aldehyde dehydrogenase (ALDH) activity is a feature of stem cells from normal and cancerous tissues and a reliable universal marker used to isolate them. There are numerous ALDH isoforms with preferred substrate specificity variably expressed depending on tissue, cell type, and organelle and cell status. On the other hand, a given substrate may be metabolized by several enzyme isoforms. Currently ALDH activity is evidenced by using Aldefluor, a fluorescent substrate likely to be metabolized by numerous ALDH isoforms. Therefore, isolation techniques based on ALDH activity detection select a heterogeneous population of stem or progenitor cells. Despite active research in the field, the precise role(s) of different ALDH isoforms in stem cells remains enigmatic. Understanding the metabolic role of different ALDH isoform in the control of stem cell phenotype and cell fate during development, tissue homeostasis, or repair, as well as carcinogenesis, should open perspectives to significant discoveries in tissue biology. In this perspective, novel ALDH substrates are being developed. Here we describe how new substrates could be instrumental for better isolation of cell population with stemness potential and for defining hierarchy of cell populations in tissue. Finally, we speculate on other potential applications

Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin resistant high-fat diet fed foz/foz mice

Non-alcoholic fatty liver (steatosis) and steatohepatitis [non-alcoholic steatohepatitis (NASH)] are hepatic complications of the metabolic syndrome. Endoplasmic reticulum (ER) stress is proposed as a crucial disease mechanism in obese and insulin-resistant animals (such as ob/ob mice) with simple steatosis, but its role in NASH remains controversial. We therefore evaluated the role of ER stress as a disease mechanism in foz/foz mice, which develop both the metabolic and histological features that mimic human NASH. We explored ER stress markers in the liver of foz/foz mice in response to a high-fat diet (HFD) at several time points. We then evaluated the effect of treatment with an ER stress inducer tunicamycin, or conversely with the ER protectant tauroursodeoxycholic acid (TUDCA), on the metabolic and hepatic features. foz/foz mice are obese, glucose intolerant and develop NASH characterized by steatosis, inflammation, ballooned hepatocytes and apoptosis from 6 weeks of HFD feeding. This was not associated with activation of the upstream unfolded protein response [phospho-eukaryotic initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α) activity and spliced X-box-binding protein 1 (Xbp1)]. Activation of c-Jun N-terminal kinase (JNK) and up-regulation of activating transcription factor-4 (Atf4) and CCAAT/enhancer-binding protein-homologous protein (Chop) transcripts were however compatible with a ‘pathological’ response to ER stress. We tested this by using intervention experiments. Induction of chronic ER stress failed to worsen obesity, glucose intolerance and NASH pathology in HFD-fed foz/foz mice. In addition, the ER protectant TUDCA, although reducing steatosis, failed to improve glucose intolerance, hepatic inflammation and apoptosis in HFD-fed foz/foz mice. These results show that signals driving hepatic inflammation, apoptosis and insulin resistance are independent of ER stress in obese diabetic mice with steatohepatitis

Defective adaptive thermogenesis contributes to metabolic syndrome and liver steatosis in obese mice

Abstract Fatty liver diseases are complications of the metabolic syndrome associated with obesity, insulin resistance and low grade inflammation. Our aim was to uncover mechanisms contributing to hepatic complications in this setting. We used foz/foz mice prone to obesity, insulin resistance and progressive fibrosing non-alcoholic steatohepatitis (NASH). Foz/foz mice are hyperphagic but wild-type (WT)-matched calorie intake failed to protect against obesity, adipose inflammation and glucose intolerance. Obese foz/foz mice had similar physical activity level but reduced energy expenditure. Thermogenic adaptation to high-fat diet (HFD) or to cold exposure was severely impaired in foz/foz mice compared with HFD-fed WT littermates due to lower sympathetic tone in their brown adipose tissue (BAT). Intermittent cold exposure (ICE) restored BAT function and thereby improved glucose tolerance, decreased fat mass and liver steatosis. We conclude that failure of BAT adaptation drives the metabolic complications of obesity in foz/foz mice, including development of liver steatosis. Induction of endogenous BAT function had a significant therapeutic impact on obesity, glucose tolerance and liver complications and is a potential new avenue for therapy of non-alcoholic fatty liver disease (NAFLD)

DUX4c Is Up-Regulated in FSHD. It Induces the MYF5 Protein and Human Myoblast Proliferation

Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contractions of the D4Z4 repeat array in 4q35. We have previously identified a double homeobox gene (DUX4) within each D4Z4 unit that encodes a transcription factor expressed in FSHD but not control myoblasts. DUX4 and its target genes contribute to the global dysregulation of gene expression observed in FSHD. We have now characterized the homologous DUX4c gene mapped 42 kb centromeric of the D4Z4 repeat array. It encodes a 47-kDa protein with a double homeodomain identical to DUX4 but divergent in the carboxyl-terminal region. DUX4c was detected in primary myoblast extracts by Western blot with a specific antiserum, and was induced upon differentiation. The protein was increased about 2-fold in FSHD versus control myotubes but reached 2-10-fold induction in FSHD muscle biopsies. We have shown by Western blot and by a DNA-binding assay that DUX4c over-expression induced the MYF5 myogenic regulator and its DNA-binding activity. DUX4c might stabilize the MYF5 protein as we detected their interaction by co-immunoprecipitation. In keeping with the known role of Myf5 in myoblast accumulation during mouse muscle regeneration DUX4c over-expression activated proliferation of human primary myoblasts and inhibited their differentiation. Altogether, these results suggested that DUX4c could be involved in muscle regeneration and that changes in its expression could contribute to the FSHD pathology

CropPol: a dynamic, open and global database on crop pollination

Seventy five percent of the world's food crops benefit from insect pollination. Hence, there has been increased interest in how global change drivers impact this critical ecosystem service. Because standardized data on crop pollination are rarely available, we are limited in our capacity to understand the variation in pollination benefits to crop yield, as well as to anticipate changes in this service, develop predictions, and inform management actions. Here, we present CropPol, a dynamic, open and global database on crop pollination. It contains measurements recorded from 202 crop studies, covering 3,394 field observations, 2,552 yield measurements (i.e. berry weight, number of fruits and kg per hectare, among others), and 47,752 insect records from 48 commercial crops distributed around the globe. CropPol comprises 32 of the 87 leading global crops and commodities that are pollinator dependent. Malus domestica is the most represented crop (32 studies), followed by Brassica napus (22 studies), Vaccinium corymbosum (13 studies), and Citrullus lanatus (12 studies). The most abundant pollinator guilds recorded are honey bees (34.22% counts), bumblebees (19.19%), flies other than Syrphidae and Bombyliidae (13.18%), other wild bees (13.13%), beetles (10.97%), Syrphidae (4.87%), and Bombyliidae (0.05%). Locations comprise 34 countries distributed among Europe (76 studies), Northern America (60), Latin America and the Caribbean (29), Asia (20), Oceania (10), and Africa (7). Sampling spans three decades and is concentrated on 2001-05 (21 studies), 2006-10 (40), 2011-15 (88), and 2016-20 (50). This is the most comprehensive open global data set on measurements of crop flower visitors, crop pollinators and pollination to date, and we encourage researchers to add more datasets to this database in the future. This data set is released for non-commercial use only. Credits should be given to this paper (i.e., proper citation), and the products generated with this database should be shared under the same license terms (CC BY-NC-SA). This article is protected by copyright. All rights reserved

Early diagnosis and better rhythm management to improve outcomes in patients with atrial fibrillation: the 8th AFNET/EHRA consensus conference

Aims Despite marked progress in the management of atrial fibrillation (AF), detecting AF remains difficult and AF-related complications cause unacceptable morbidity and mortality even on optimal current therapy.Methods and results This document summarizes the key outcomes of the 8th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). Eighty-three international experts met in Hamburg for 2 days in October 2021. Results of the interdisciplinary, hybrid discussions in breakout groups and the plenary based on recently published and unpublished observations are summarized in this consensus paper to support improved care for patients with AF by guiding prevention, individualized management, and research strategies. The main outcomes are (i) new evidence supports a simple, scalable, and pragmatic population-based AF screening pathway; (ii) rhythm management is evolving from therapy aimed at improving symptoms to an integrated domain in the prevention of AF-related outcomes, especially in patients with recently diagnosed AF; (iii) improved characterization of atrial cardiomyopathy may help to identify patients in need for therapy; (iv) standardized assessment of cognitive function in patients with AF could lead to improvement in patient outcomes; and (v) artificial intelligence (AI) can support all of the above aims, but requires advanced interdisciplinary knowledge and collaboration as well as a better medico-legal framework.Conclusions Implementation of new evidence-based approaches to AF screening and rhythm management can improve outcomes in patients with AF. Additional benefits are possible with further efforts to identify and target atrial cardiomyopathy and cognitive impairment, which can be facilitated by AI.</p

Critical assessment of protein intrinsic disorder prediction

Abstract: Intrinsically disordered proteins, defying the traditional protein structure–function paradigm, are a challenge to study experimentally. Because a large part of our knowledge rests on computational predictions, it is crucial that their accuracy is high. The Critical Assessment of protein Intrinsic Disorder prediction (CAID) experiment was established as a community-based blind test to determine the state of the art in prediction of intrinsically disordered regions and the subset of residues involved in binding. A total of 43 methods were evaluated on a dataset of 646 proteins from DisProt. The best methods use deep learning techniques and notably outperform physicochemical methods. The top disorder predictor has Fmax = 0.483 on the full dataset and Fmax = 0.792 following filtering out of bona fide structured regions. Disordered binding regions remain hard to predict, with Fmax = 0.231. Interestingly, computing times among methods can vary by up to four orders of magnitude

Liver Regeneration: Different Sub-Populations of Parenchymal Cells at Play Choreographed by an Injury-Specific Microenvironment

Liver regeneration is crucial for the maintenance of liver functional mass during homeostasis and diseases. In a disease context-dependent manner, liver regeneration is contributed to by hepatocytes or progenitor cells. As long as they are replicatively competent, hepatocytes are the main cell type responsible for supporting liver size homeostasisand regeneration. The concept that all hepatocytes within the lobule have the same proliferative capacity but are differentially recruited according to the localization of the wound, or whether a yet to be defined sub-population of hepatocytes supports regeneration is still debated. In a chronically or severely injured liver, hepatocytes may enter a state of replicative senescence. In such conditions, small biliary cells activate and expand, a process called ductular reaction (DR). Work in the last few decades has demonstrated that DR cells can differentiate into hepatocytes and thereby contribute to parenchymal reconstitution. In this study we will review the molecular mechanisms supporting these two processes to determine potential targets that would be amenable for therapeutic manipulation to enhance liver regeneration

Host Factors in Dysregulation of the Gut Barrier Function during Alcohol-Associated Liver Disease.

Chronic alcohol consumption and alcohol-associated liver disease (ALD) represent a major public health problem worldwide. Only a minority of patients with an alcohol-use disorder (AUD) develop severe forms of liver disease (e.g., steatohepatitis and fibrosis) and finally progress to the more advanced stages of ALD, such as severe alcohol-associated hepatitis and decompensated cirrhosis. Emerging evidence suggests that gut barrier dysfunction is multifactorial, implicating microbiota changes, alterations in the intestinal epithelium, and immune dysfunction. This failing gut barrier ultimately allows microbial antigens, microbes, and metabolites to translocate to the liver and into systemic circulation. Subsequent activation of immune and inflammatory responses contributes to liver disease progression. Here we review the literature about the disturbance of the different host defense mechanisms linked to gut barrier dysfunction, increased microbial translocation, and impairment of liver and systemic inflammatory responses in the different stages of ALD