RIPK1 protects from TNF-α-mediated liver damage during hepatitis

Cell death of hepatocytes is a prominent characteristic in the pathogenesis of liver disease, while hepatolysis is a starting point of inflammation in hepatitis and loss of hepatic function. However, the precise molecular mechanisms of hepatocyte cell death, the role of the cytokines of hepatic microenvironment and the involvement of intracellular kinases, remain unclear. Tumor necrosis factor alpha (TNF-alpha) is a key cytokine involved in cell death or survival pathways and the role of RIPK1 has been associated to the TNF-alpha-dependent signaling pathway. We took advantage of two different deficient mouse lines, the RIPK1 kinase dead knock-in mice (Ripk1K45A) and the conditional knockout mice lacking RIPK1 only in liver parenchymal cells (Ripk1LPC-KO), to characterize the role of RIPK1 and TNF-alpha in hepatitis induced by concanavalin A (ConA). Our results show that RIPK1 is dispensable for liver homeostasis under steady-state conditions but in contrast, RIPK1 kinase activity contributes to caspase-independent cell death induction following ConA injection and RIPK1 also serves as a scaffold, protecting hepatocytes from massive apoptotic cell death in this model. In the Ripk1LPC-KO mice challenged with ConA, TNF-alpha triggers apoptosis, responsible for the observed severe hepatitis. Mechanism potentially involves both TNF-independent canonical NF-kappa B activation, as well as TNF-dependent, but canonical NF-kappa B-independent mechanisms. In conclusion, our results suggest that RIPK1 kinase activity is a pertinent therapeutic target to protect liver against excessive cell death in liver diseases

Long term highly saturated fat diet does not induce NASH in Wistar rats

BACKGROUND: Understanding of nonalcoholic steatohepatitis (NASH) is hampered by the lack of a suitable model. Our aim was to investigate whether long term high saturated-fat feeding would induce NASH in rats. METHODS: 21 day-old rats fed high fat diets for 14 weeks, with either coconut oil or butter, and were compared with rats feeding a standard diet or a methionine choline-deficient (MCD) diet, a non physiological model of NASH. RESULTS: MCDD fed rats rapidly lost weight and showed NASH features. Rats fed coconut (86% of saturated fatty acid) or butter (51% of saturated fatty acid) had an increased caloric intake (+143% and +30%). At the end of the study period, total lipid ingestion in term of percentage of energy intake was higher in both coconut (45%) and butter (42%) groups than in the standard (7%) diet group. No change in body mass was observed as compared with standard rats at the end of the experiment. However, high fat fed rats were fattier with enlarged white and brown adipose tissue (BAT) depots, but they showed no liver steatosis and no difference in triglyceride content in hepatocytes, as compared with standard rats. Absence of hepatic lipid accumulation with high fat diets was not related to a higher lipid oxidation by isolated hepatocytes (unchanged ketogenesis and oxygen consumption) or hepatic mitochondrial respiration but was rather associated with a rise in BAT uncoupling protein UCP1 (+25–28% vs standard). CONCLUSION: Long term high saturated fat feeding led to increased "peripheral" fat storage and BAT thermogenesis but did not induce hepatic steatosis and NASH

New Genetic Insights into Pearl Millet Diversity As Revealed by Characterization of Early- and Late-Flowering Landraces from Senegal

Pearl millet (Pennisetum glaucum (L.) R. Br.) is a staple food and a drought-tolerant cereal well adapted to Sub-Saharan Africa agro-ecosystems. An important diversity of pearl millet landraces has been widely conserved by farmers and therefore could help copping with climate changes and contribute to future food security. Hence, characterizing its genetic diversity and population structure can contribute to better assist breeding programs for a sustainable agricultural productivity enhancement. Toward this goal, a comprehensive panel of 404 accessions were used that correspond to 12 improved varieties, 306 early flowering and 86 late-flowering cultivated landraces from Senegal. Twelve highly polymorphic SSR markers were used to study diversity and population structure. Two genes, PgMADS11 and PgPHYC, were genotyped to assess their association to flowering phenotypic difference in landraces. Results indicate a large diversity and untapped potential of Senegalese pearl millet germplasm as well as a genetic differentiation between early- and late-flowering landraces. Further, a fine-scale genetic difference of PgPHYC and PgMADS11 (SNP and indel, respectively) and co-variation of their alleles with flowering time were found among landraces. These findings highlight new genetic insights of pearl millet useful to define heterotic populations for breeding, genomic association panel, or crosses for trait-specific mapping

Preemptive treatment in the acute and early subacute phase of uncomplicated type B aortic dissections with poor prognosis factors

ObjectiveDue to its favorable outcome regarding late morbidity and mortality, thoracic endovascular repair (TEVAR) is becoming more popular for uncomplicated type B aortic dissection (TBAD). This study aimed to compare preemptive endovascular treatment and optimal medical treatment (OMT) and OMT alone in patients presenting uncomplicated TBAD with predictors of aortic progression.DesignRetrospective multicenter studyMethodsWe analyzed patients with uncomplicated TBAD and risk factors of progression in two French academic centers. Aortic events [defined as aortic-related (re)intervention or aortic-related death after initial hospitalization], postoperative complications, non-aortic events, and radiologic aortic progression and remodeling were recorded and analyzed. Analysis was performed on an intention-to-treat basis.ResultsBetween 2011 and 2021, preemptive endovascular procedures at the acute and early subacute phase (<30 days) were performed on 24 patients (group 1) and OMT alone on 26 patients (group 2). With a mean follow-up of 38.08 ± 24.53 months, aortic events occurred in 20.83% of patients from group 1 and 61.54% of patients from group 2 (p < .001). No patient presented aortic-related death during follow-up. There were no differences in postoperative events (p = 1.00) and non-aortic events (p = 1.00). OMT patients had significantly more aneurysmal progression of the thoracic aorta (p < .001) and maximal aortic diameter (p < .001). Aortic remodeling was found in 91.67% of patients in group 1 and 42.31% of patients in group 2 (p < .001). A subgroup analysis of patients in group 1 showed that patients treated with preemptive TEVAR and STABILISE had reduced maximum aortic diameters at the 1-year (p = .010) and last follow-up (p = .030) compared to those in patients treated with preemptive TEVAR alone.ConclusionPreemptive treatment of uncomplicated TBAD with risk factors of progression reduces the risk of long-term aortic events. Over 60% of medically treated patients will require intervention during follow-up, with no benefit in terms of postoperative events. Even after surgical treatment, patients in the OMT group had significantly more aneurysmal progression, along with poorer aortic remodeling

Michael Davis : William Blake, a new kind of man, 1977

Piquet Françoise-Marie. Michael Davis : William Blake, a new kind of man, 1977. In: Dix-huitième Siècle, n°11, 1979. L'année 1778. pp. 528-529

W. J. T. Mitchell : Blake's Composite Art > a study of the Illuminated Poetry, 1978

Piquet Françoise-Marie. W. J. T. Mitchell : Blake's Composite Art > a study of the Illuminated Poetry, 1978. In: Dix-huitième Siècle, n°11, 1979. L'année 1778. pp. 529-530