Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Etude des rôles respectifs des facteurs de transcription HNF-4a et HNF-4g dans l'épithélium intestinal

Les deux formes du facteur de transcription HNF-4, HNF-4a et HNF-4g, sont exprimées dans l épithélium intestinal. La première est exprimée sur l ensemble de l axe crypto-villositaire, tandis que l expression de la seconde est restreinte à la villosité, suggérant que ces deux formes d HNF-4 exercent des effets différents dans cet épithélium. L objectif de ma thèse a été de déterminer les rôles respectifs de ces deux récepteurs nucléaires dans l épithélium intestinal. Dans un modèle murin d invalidation du gène hnf-4a, inductible et spécifique de l intestin, j ai pu mettre en évidence son rôle suppresseur de tumeurs : après injection d Azoxyméthane, un carcinogène induisant spécifiquement des tumeurs dans l épithélium colique, les souris invalidées pour HNF-4a ont été les seules à développer des tumeurs colorectales 3 mois après les injections. Concernant HNF-4g, j ai montré que son invalidation entraîne une augmentation de la tolérance au glucose et une hyperinsulinémie en réponse à un apport de glucose oral. Lorsque l apport se fait par voie intra-péritonéale, la glycémie et l insulinémie restent normales, indiquant le rôle primordial de l intestin dans les effets observés. Chez ces souris, le nombre de cellules entéroendocrines de type L et les taux plasmatiques de GLP-1 sont augmentés. Cette augmentation de la sécrétion de GLP-1, entéropeptide à effet incrétine, explique l augmentation de l insulinémie. Aucun de ces effets n est observé chez les souris invalidées pour HNF-4a. HNF-4a et HNF-4g exercent donc des rôles différents au niveau de l épithélium intestinal. L équilibre de la balance entre leur expression respective doit être finement contrôlé pour le maintien de l homéostasie de l épithélium intestinal, du lignage entéroendocrine et de l homéostasie glucidiqueTwo different forms of the transcription factor HNF-4, HNF-4a and HNF-4g, are expressed in the intestinal epithelium. HNF-4a is expressed along the crypt to villus axis and HNF-4g expression is restricted to the villus, suggesting that these two forms exert different effects in this epithelium. The aim of my work was to determine the specific roles of these two nuclear receptors in the intestinal epithelium. In a mouse model of inducible and intestine-specific invalidation of hnf-4a gene, I demonstrated that HNF-4a plays a role of tumor suppressor: after injection of Azoxymethane, a colonic tumor inducer, only HNF-4a invalidated mice developed tumors in the colon, 3 months after injections. Concerning HNF-4g, I showed that its invalidation was responsible for an increase of glucose tolerance and hyperinsulinemia in response to an oral glucose challenge. When glucose was delivered intra peritonealy, glycemia and insulinemia remained normal, highlighting the major role of intestine in the observed effects. In these mice, the number of type Lenteroendocrine cells, and GLP-1 plasma levels were increased. This augmentation of GLP-1 secretion, which has an incretin effect, explains the hyperinsulinemia. None of these effects was observed in HNF-4a invalidated mice. HNF-4a and HNF-4g have different effects in the intestinal epithelium. Equilibrium in the balance between the respective expressions of these two forms must be finely regulated for the maintenance of intestinal epithelium homeostasis, enteroendocrine lineage and glucose homeostasis.PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Integrative multi‐omics analysis of intestinal organoid differentiation

International audienceIntestinal organoids accurately recapitulate epithelial homeostasis in vivo, thereby representing a powerful in vitro system to investigate lineage specification and cellular differentiation. Here, we applied a multi-omics framework on stem cell-enriched and stem cell-depleted mouse intestinal organoids to obtain a holistic view of the molecular mechanisms that drive differential gene expression during adult intestinal stem cell differentiation. Our data revealed a global rewiring of the transcriptome and proteome between intestinal stem cells and enterocytes, with the majority of dynamic protein expression being transcription-driven. Integrating absolute mRNA and protein copy numbers revealed post-transcrip-tional regulation of gene expression. Probing the epigenetic landscape identified a large number of cell-type-specific regulatory elements, which revealed Hnf4g as a major driver of enterocyte differentiation. In summary, by applying an integrative systems biology approach, we uncovered multiple layers of gene expression regulation, which contribute to lineage specification and plasticity of the mouse small intestinal epithelium

Regulation of PPARα by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity.

Among genetic susceptibility loci associated with late-onset Alzheimer disease (LOAD), genetic polymorphisms identified in genes encoding lipid carriers led to the hypothesis that a disruption of lipid metabolism could promote disease progression. We previously reported that amyloid precursor protein (APP) involved in Alzheimer disease (AD) physiopathology impairs lipid synthesis needed for cortical networks' activity and that activation of peroxisome proliferator-activated receptor α (PPARα), a metabolic regulator involved in lipid metabolism, improves synaptic plasticity in an AD mouse model. These observations led us to investigate a possible correlation between PPARα function and full-length APP expression. Here, we report that PPARα expression and activation were inversely related to APP expression both in LOAD brains and in early-onset AD cases with a duplication of the APP gene, but not in control human brains. Moreover, human APP expression decreased PPARA expression and its related target genes in transgenic mice and in cultured cortical cells, while opposite results were observed in APP-silenced cortical networks. In cultured neurons, APP-mediated decrease or increase in synaptic activity was corrected by a PPARα-specific agonist and antagonist, respectively. APP-mediated control of synaptic activity was abolished following PPARα deficiency, indicating a key function of PPARα in this process

Sex-regulated gene dosage effect of PPARα on synaptic plasticity.

Mechanisms driving cognitive improvements following nuclear receptor activation are poorly understood. The peroxisome proliferator-activated nuclear receptor alpha (PPARα) forms heterodimers with the nuclear retinoid X receptor (RXR). We report that PPARα mediates the improvement of hippocampal synaptic plasticity upon RXR activation in a transgenic mouse model with cognitive deficits. This improvement results from an increase in GluA1 subunit expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, eliciting an AMPA response at the excitatory synapses. Associated with a two times higher PPARα expression in males than in females, we show that male, but not female, PPARα null mutants display impaired hippocampal long-term potentiation. Moreover, PPARα knockdown in the hippocampus of cognition-impaired mice compromises the beneficial effects of RXR activation on synaptic plasticity only in males. Furthermore, selective PPARα activation with pemafibrate improves synaptic plasticity in male cognition-impaired mice, but not in females. We conclude that striking sex differences in hippocampal synaptic plasticity are observed in mice, related to differences in PPARα expression levels.info:eu-repo/semantics/publishe

Gender specific improvement of synaptic function by activation of RXR nuclear receptor is mediated by PPAR alpha.

info:eu-repo/semantics/nonPublishe

NR2F2 controls malignant squamous cell carcinoma state by promoting stemness and invasion and repressing differentiation

The nongenetic mechanisms required to sustain malignant tumor state are poorly understood. During the transition from benign tumors to malignant carcinoma, tumor cells need to repress differentiation and acquire invasive features. Using transcriptional profiling of cancer stem cells from benign tumors and malignant skin squamous cell carcinoma (SCC), we identified the nuclear receptor NR2F2 as uniquely expressed in malignant SCC. Using genetic gain of function and loss of function in vivo, we show that NR2F2 is essential for promoting the malignant tumor state by controlling tumor stemness and maintenance in mouse and human SCC. We demonstrate that NR2F2 promotes tumor cell proliferation, epithelial-mesenchymal transition and invasive features, while repressing tumor differentiation and immune cell infiltration by regulating a common transcriptional program in mouse and human SCCs. Altogether, we identify NR2F2 as a key regulator of malignant cancer stem cell functions that promotes tumor renewal and restricts differentiation to sustain a malignant tumor state.info:eu-repo/semantics/publishe

Gender specific improvement of synaptic function by activation of RXR nuclear receptor is mediated by PPARalpha

OBJECTIVES: Nuclear receptors (NRs) are ligand-dependent transcription factors regulating gene expression. Among NRs, peroxisome proliferator-activated receptor (PPAR) forms permissive obligate heterodimers with retinoid X receptor (RXR). NRs activation with specific agonists leads to brain function improvement in mouse models of neurodegenerative diseases. However, the link between NRs activation and cognitive improvement is missing. Here, we analyzed how RXR activation improves synaptic plasticity and neuronal function and identified PPARalpha as a crucial player. METHODS: LTP was measured in the hippocampus of PPARalpha null mice and in a mouse model of Alzheimer’s disease (5xFAD) treated with the RXR agonist bexarotene or with pemafibrate, a selective PPARα activator. PPARalpha expression was acutely decreased in the hippocampus of 5xFAD mice by using an AAV-ShPpara. Glutamatergic responses were measured by calcium imaging in rat primary cortical cultures. NMDA and AMPA receptors subunits expression were assessed by RT-qPCR and western blotting. RESULTS: Upon RXR activation, the PPARalpha-dependent upregulation of the GluA1 subunitcontaining AMPA receptors mediates LTP improvement in 5xFAD mice and AMPA-responses in cortical cells. PPARalpha deficiency severely impaired LTP and GluA1 expression in male but not in female PPARalpha null mice. PPARalpha-knockdown in the hippocampus of 5xFAD mice compromises the beneficial effects of RXR activation on synaptic plasticity only in males. PPARalpha activation with pemafibrate improves synaptic plasticity in male 5xFAD mice, but not in females. CONCLUSIONS: PPARalpha plays a central role in hippocampal synaptic plasticity by driving the expression of GluA1 subunit of AMPARs in a gender specific manner