Explore the vast range of titles available.

ObjectiveReceptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD.DesignRIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or Ripk3-deficient (Ripk3 −/−) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks.ResultsRIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, Ripk3 deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in Ripk3 −/− mice. Furthermore, Ripk3 deficiency hampered tumourigenesis. Intriguingly, Ripk3 −/− mice displayed increased body weight gain, while lipidomics showed that deletion of Ripk3 shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor γ (PPARγ) was increased in Ripk3 −/− mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPARγ in controlling fat deposition and fibrosis.ConclusionHepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease where liver biopsy remains the gold standard for diagnosis. Here we aimed to evaluate the role of circulating adiponectin, leptin, and insulin-like growth factor 1 (IGF-1) levels as non-invasive NAFLD biomarkers and assess their correlation with the metabolome. Materials and Methods: Leptin, adiponectin, and IGF-1 serum levels were measured by ELISA in two independent cohorts of biopsy-proven obese NAFLD patients and healthy-liver controls (discovery: 38 NAFLD, 13 controls; validation: 194 NAFLD, 31 controls) and correlated with clinical data, histology, genetic parameters, and serum metabolomics. Results: In both cohorts, leptin increased in NAFLD vs. controls (discovery: AUROC 0.88; validation: AUROC 0.83; p < 0.0001). The leptin levels were similar between obese and non-obese healthy controls, suggesting that obesity is not a confounding factor. In the discovery cohort, adiponectin was lower in non-alcoholic steatohepatitis (NASH) vs. non-alcoholic fatty liver (AUROC 0.87; p < 0.0001). For the validation cohort, significance was attained for homozygous for PNPLA3 allele c.444C (AUROC 0.63; p < 0.05). Combining adiponectin with specific serum lipids improved the assay performance (AUROC 0.80; p < 0.0001). For the validation cohort, IGF-1 was lower with advanced fibrosis (AUROC 0.67, p < 0.05), but combination with international normalized ratio (INR) and ferritin increased the assay performance (AUROC 0.81; p < 0.01). Conclusion: Serum leptin discriminates NAFLD, and adiponectin combined with specific lipids stratifies NASH. IGF-1, INR, and ferritin distinguish advanced fibrosis.

Background: Radical gastrectomy remains the main treatment for gastric cancer, despite its high mortality. A clinical predictive model of 90-day mortality (90DM) risk after gastric cancer surgery based on the Spanish EURECCA registry database was developed using a matching learning algorithm. We performed an external validation of this model based on data from an international multicenter cohort of patients. Methods: A cohort of patients from the European GASTRODATA database was selected. Demographic, clinical, and treatment variables in the original and validation cohorts were compared. The performance of the model was evaluated using the area under the curve (AUC) for a random forest model. Results: The validation cohort included 2546 patients from 24 European hospitals. The advanced clinical T- and N-category, neoadjuvant therapy, open procedures, total gastrectomy rates, and mean volume of the centers were significantly higher in the validation cohort. The 90DM rate was also higher in the validation cohort (5.6%) vs. the original cohort (3.7%). The AUC in the validation model was 0.716. Conclusion: The externally validated model for predicting the 90DM risk in gastric cancer patients undergoing gastrectomy with curative intent continues to be as useful as the original model in clinical practice.

Global warming could threaten over 400 species with temperature‐dependent sex determination (TSD) worldwide, including all species of sea turtle. During embryonic development, rising temperatures might lead to the overproduction of one sex and, in turn, could bias populations’ sex ratios to an extent that threatens their persistence. If climate change predictions are correct, and biased sex ratios reduce population viability, species with TSD may go rapidly extinct unless adaptive mechanisms, whether behavioural, physiological or molecular, exist to buffer these temperature‐driven effects. Here, we summarize the discovery of the TSD phenomenon and its still elusive evolutionary significance. We then review the molecular pathways underpinning TSD in model species, along with the hormonal mechanisms that interact with temperatures to determine an individual's sex. To illustrate evolutionary mechanisms that can affect sex determination, we focus on sea turtle biology, discussing both the adaptive potential of this threatened TSD taxon, and the risks associated with conservation mismanagement.

Feeding ecology is an essential component of an organism's life, but foraging comes with risks and energetic costs. Species in which populations exhibit more than one feeding strategy, such as sea turtles, are good systems for investigating how feeding ecology impacts life‐history traits, reproduction and carried over effects across generations. Here, we investigated how the feeding ecology of loggerhead sea turtles (Caretta caretta) nesting at the Cabo Verde archipelago correlates with reproductive outputs and offspring quality. We determined the feeding ecology of female turtles before and during the breeding season from stable isotope analysis of carbon and nitrogen and correlated isotopic ratio with female and offspring traits. We found that female turtles feeding at higher trophic positions produced larger clutches. We also found that females with higher δ13C values, typical of productive foraging areas, had greater fat reserves, were less likely to be infected by leech parasites and produced heavier offspring. The offspring of infected mothers with higher δ13C values performed best in crawling and self‐righting trials than those of non‐infected mothers with higher δ13C values. This study shows adult female loggerheads that exploit productive areas build capital reserves that impact their reproductive success and multiple proxies for offspring quality. Overall, our findings provide valuable insights into the complex interplay between feeding ecology and reproductive success, and reveal the transgenerational carry‐over effects of both feeding ecology and health on offspring quality in sea turtles. The feeding ecology of loggerhead sea turtles plays a crucial role in shaping their reproductive outcomes and offspring quality. Through stable isotope analysis, we observed that females feeding at higher trophic positions produced larger clutches. Those with less depleted δ13C values, indicative of productive foraging areas, exhibited greater fat reserves, lower susceptibility to leech parasites and produced heavier offspring, suggesting that not all foraging habitats are equal and can significantly influence the fitness of sea turtle populations.

Long-term monitoring of host-parasite interactions is important for understanding the consequences of infection on host fitness and population dynamics. In an eight-year survey of the loggerhead sea turtle ( Caretta caretta ) population nesting in Cabo Verde, we determined the spatiotemporal variation of Ozobranchus margoi , a sanguivorous leech best known as a vector for sea turtle fibropapilloma virus. We quantified O. margoi association with turtles’ δ 15 N and δ 13 C stable isotopes to identify where infection occurs. We then measured the influence of infection on reproduction and offspring fitness. We found that parasite prevalence has increased from 10% of the population in 2010, to 33% in 2017. Stable isotope analysis of host skin samples suggests transmission occurs within the host’s feeding grounds. Interestingly, we found a significant interaction between individual size and infection on the reproductive success of turtles. Specifically, small, infected females produced fewer offspring of poorer condition, while in contrast, large, infected turtles produced greater clutch sizes and larger offspring. We interpret this interaction as evidence, upon infection, for a size-dependent shift in reproductive strategy from bet hedging to terminal investment, altering population dynamics. This link between infection and reproduction underscores the importance of using long-term monitoring to quantify the impact of disease dynamics over time.

Abstract Global warming could drive species with temperature-dependent sex determination to extinction by persistently skewing offspring sex ratios. Evolved mechanisms that buffer these biases are therefore paramount for their persistence. Here, we tested whether maternally-derived sex steroid hormones affect the sex-determination cascade and provide a physiological mechanism to buffer sex ratio bias in the endangered loggerhead sea turtle (Caretta caretta). We quantified estradiol and testosterone in nesting females and their egg yolks at oviposition, before incubating nests in situ at standardised temperatures. Upon hatchling emergence, we developed a new, non-lethal method to establish the sex of individuals. Despite standardised incubation temperatures, sex ratios varied widely among nests, correlating non-linearly with the estradiol:testosterone ratio in egg yolks. Males were produced at an equal ratio, with females produced either side of this optimum. This result provides evidence that maternal hormone transfer forms a physiological mechanism that impacts sex determination in this endangered species. Competing Interest Statement The authors have declared no competing interest.

Feeding ecology is an essential component of an organism’s life, but foraging comes with risks and energetic costs. Species in which populations exhibit more than one feeding strategy, such as sea turtles, are good systems for investigating how feeding ecology impacts life-history traits, reproduction and carried over effects across generations. Here, we investigated how the feeding ecology of loggerhead sea turtles (Caretta caretta) nesting at the Cabo Verde archipelago correlates with reproductive outputs and offspring fitness. We determined the feeding ecology of female turtles before and during the breeding season from stable isotope analysis of carbon and nitrogen, and correlated isotopic ratio with female and hatchling fitness traits. We found that female turtles feeding at higher trophic positions produced larger clutches. We also found that females with less depleted δ13C values, typical of productive foraging areas, had greater fat reserves, were less likely to be infected by leech parasites, and produced heavier offspring. The offspring of infected mothers with less depleted δ13C values performed best in crawling and self-righting trials than those of non-infected mothers with less depleted δ13C values. Overall, our study shows adult female loggerheads that exploit productive areas build capital reserves that impact their reproductive success and offspring fitness. Together, we uphold the suggestion that not all foraging habitats are equal, and can alter the fitness of populations.