Notes

Together with a qPCR screen, we found HNF1A to activate the expression of SLC51B, CD24, and RNF186 genes
Importantly, HNF1A-depleted human renal proximal tubule epithelial cells and MODY3 human induced pluripotent stem cell -derived kidney organoids expressed lower levels of SLC51B. SLC51B-mediated estrone rhamnolipid solubility in proximal tubule cells was abrogated in these HNF1A-deficient cells. MODY3 patients also exhibit significantly higher excretion of urinary E1S. Overall, we report that SLC51B is a target of HNF1A responsible for E1S uptake in human proximal tubule cells. As E1S serves as the main storage form of nephroprotective estradiol in the human body, lowered E1S uptake and increased E1S excretion may reduce the availability of nephroprotective estradiol in the kidneys, contributing to the development of renal disease in MODY3 patients. , Agency for Science, Technology and Research , Singapore, 138673, , Agency for Science, Technology and Research , Singapore, 138673, , Agency for Science, Technology and Research , Singapore, 138673, Ltd.

rhamnolipid declare no competing interests. predict therapeutic efficacy of immunotherapy. Circular RNAs play important roles in the regulation of cancer. However, the clinical implications and regulatory networks of circRNAs in cancer patients receiving immune checkpoint blockades have not been fully elucidated. Here, we characterize circRNA expression profiles in two independent cohorts of 157 ICB-treated advanced melanoma patients and reveal overall overexpression of circRNAs in ICB non-responders in both pre-treatment and early during therapy. Then, we construct circRNA-miRNA-mRNA regulatory networks to reveal circRNA-related signaling pathways in the context of ICB treatment. Further, we construct an ICB-related circRNA signature score model based on progression-free survival-related circRNAs to predict immunotherapy efficacy.

Mechanistically, the overexpression of ICBcircSig circTMTC3 and circFAM117B could increase PD-L1 expression via the miR-142-5p/PD-L1 axis, thus reducing T cell activity and leading to immune escape. Overall, our study characterizes circRNA profiles and regulatory networks in ICB-treated patients, and highlights the clinical utility of circRNAs as predictive biomarkers of Primary cilia are specialized organelles that sense changes in extracellular milieu, and their malfunction is responsible for several disorders . Increasing evidence shows that primary cilia regulate tissue and cellular aging related features, which led us to review the evidence on their role in potentiating and/or accelerating the aging process. Primary cilia malfunction is associated with some age-related disorders, from cancer to neurodegenerative and metabolic disorders. However, there is limited understanding of molecular pathways underlying primary cilia dysfunction, resulting in scarce ciliary-targeted therapies available. Here, we discuss the findings on primary cilia dysfunction as modulators of the health and aging hallmarks, and the pertinence of ciliary pharmacological targeting to promote healthy aging or treat age-related diseases. diet on cardiometabolic markers: a diet intervention in pre-diabetes.

OBJECTIVE: To explore the interplay between dietary modifications, microbiome composition and host metabolic responses in a dietary intervention setting of a personalised postprandial-targeting diet versus a Mediterranean diet in pre-diabetes. DESIGN: In a 6-month dietary intervention, adults with pre-diabetes were randomly assigned to follow an MED or PPT diet . Data collected at baseline and 6 months from 200 participants who completed the intervention included: dietary data from self-recorded logging using a smartphone application, gut microbiome data from shotgun metagenomics sequencing of faecal samples, and clinical data from continuous glucose monitoring, blood biomarkers and anthropometrics. RESULTS: PPT diet induced more prominent changes to the gut microbiome composition, compared with MED diet, consistent with overall greater dietary modifications observed. Particularly, microbiome alpha-diversity increased significantly in PPT but not in MED arm . Post hoc analysis of changes in multiple dietary features, including food-categories, nutrients and PPT-adherence score across the cohort, demonstrated significant associations between specific dietary changes and species-level changes in microbiome composition. Furthermore, using causal mediation analysis we detect nine microbial species that partially mediate the association between specific dietary changes and clinical outcomes, including three species that mediate the association between PPT-adherence score and clinical outcomes of hemoglobin A1c , high-density lipoprotein cholesterol and triglycerides.

Finally, using machine-learning models trained on dietary changes and baseline clinical data, we predict personalised metabolic responses to dietary modifications and assess features importance for clinical improvement in cardiometabolic markers of blood lipids, glycaemic control and body weight. CONCLUSIONS: Our findings support the role of gut microbiome in modulating the effects of dietary modifications on cardiometabolic outcomes, and advance the concept of precision nutrition strategies for reducing comorbidities in pre-diabetes.
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