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Background: Evidence from cohort studies indicates a bidirectional relationship between periodontal disease and type 2 diabetes (T2D), but the underlying mechanisms remain unknown. In this study, we aimed to (1) identify saliva, plasma, and multifluid metabolomic signatures associated with periodontal disease and (2) determine if these signatures predict T2D progression and cardiometabolic biomarkers at year 3., Methods and Results: We included participants from the SOALS (San Juan Overweight Adult Longitudinal Study) (n=911). Metabolites from saliva (k=635) and plasma (k=1051) were quantified using liquid chromatography-mass spectrometry. We applied elastic net regression with 10-fold cross-validation to identify baseline metabolomic signatures of periodontal disease. Multivariable Cox proportional hazards regression and linear regression were used to evaluate the association with T2D progression and biomarker concentrations. Metabolomic profiles included highly weighted metabolites related to lysine and pyrimidine metabolism. Periodontal disease or its 3 metabolomic signatures were not associated with T2D progression in 3 years. Prospectively, 1-SD increments in the multifluid and saliva metabolomic signatures were associated with higher low-density lipoprotein (multifluid: 12.9±5.70, P =0.02; saliva: 13.3±5.11, P =0.009). A 1-SD increment in the plasma metabolomic signature was also associated with Homeostatic Model Assessment for Insulin Resistance (2.67±1.14, P =0.02) and triglyceride (0.52±0.18, P =0.002)., Conclusions: Although metabolomic signatures of periodontal disease could not predict T2D progression, they were associated with low-density lipoprotein, triglyceride, and Homeostatic Model Assessment for Insulin Resistance levels at year 3.

Phytoplankton productivity and community structure in the East China Sea (ECS) play an important role in marine ecology and carbon cycle, but both have been changing rapidly in response to recent oceanic and atmospheric circulation changes. However, the lack of long-term records of phytoplankton productivity and community structure variability in the region hinders our understanding of natural forcing mechanisms. Here, we use the phytoplankton biomarker (brassicasterol, dinosterol and alkenones) contents as well as the ratios between these biomarkers in three sediment cores from the ECS shelf to reconstruct the spatiotemporal variations of productivity and community of diatoms, dinoflagellates and coccolithophores during the Holocene, respectively. During 9–7 ka, the ECS shelf was characterized by low phytoplankton productivity with low coccolithophore contribution, caused by the oligotrophic condition mainly owing to the restricted Kuroshio Current (KC) intrusion under low sea-level conditions, thus the lack of nutrient input. Phytoplankton productivity generally increased during 7–4.6 ka, in response to the initial intrusion of the Yellow Sea Warm Current (YSWC, a branch of the KC), bringing nutrient from the subsurface KC to the upper layer of the ECS for phytoplankton growth. Phytoplankton productivity continuously increased during 4.6–1 ka, due to an enhanced circulation system (YSWC and Yellow Sea Coastal Current (YSCC)) driven by strong East Asia Winter Monsoon (EAWM). Significantly, high alkenone contents and coccolithophore contribution in the eastern core F11A was associated with its location closer to the warm and saline YSWC, which was suitable for coccolithophore growth. Beyond diagenetic processes which could partly account for higher biomarker contents near core tops, elevated phytoplankton productivity during the last 1 ka might be induced by more nutrient supply from the intensified circulation system driven by enhanced KC and anthropogenic activities. The latter also resulted in high dinoflagellate proportions in all three cores. These temporal and spatial changes of phytoplankton productivity and community structure in the ECS during the Holocene corresponded to different mechanisms by the air-sea interaction, providing insights into distinguishing natural forcing and anthropogenic influences on marine ecology. • We reconstruct phytoplankton productivity and community structure in the ECS. • Biomarker records reveal increased phytoplankton productivity during the Holocene. • Variations of productivity and community structure relate to air-sea forcing. [ABSTRACT FROM AUTHOR]

• MFN2 was downregulated in human kidney renal clear cell carcinoma (KIRC). • Lower expression of MFN2 was associated with an inferior tumor prognosis in KIRC. • MFN2 expression was significantly associated with immune cell infiltration in KIRC. • MFN2 overexpression inhibited the KIRC cell proliferation and migration abilities. Treatment of advanced kidney renal clear cell carcinoma (KIRC) remains challenging in clinic. The functional role and prognostic significance of MFN2 in KIRC are still unclear. In this study, we first performed a bioinformatic analysis to determine the expression level and prognostic value of MFN2 in KIRC using The Cancer Genome Atlas (TCGA) dataset, and then validated the MFN2 mRNA expression in our cohort of clinical tissue samples and cell lines of KIRC via RT-qPCR. Cox regression model was used to identify the independent prognostic factors. A nomogram was constructed to predict the prognosis of KIRC patients. Gene set enrichment analysis (GSEA) was performed to predict the involved functional pathways of MFN2 co-expressed genes. The association between MFN2 expression level and immune cell infiltration was assessed using the TIMER and the TIDISB databases. In addition, cell proliferation and migration abilities of two KIRC cell lines with MFN2 overexpression were evaluated by MTS and wound healing assays, respectively. Downregulation of MFN2 was observed in KIRC tissues and cell lines compared to the normal controls. Kaplan-Meier curve analysis indicated an inferior survival outcomes in KIRC patients with lower MFN2 expression, uncovering the tumor-suppressive role of MFN2 in KIRC. Cox regression results showed that higher MFN2 expression was one of the independent protective factors in KIRC. Besides, function predictive analysis revealed that MFN2 co-expressed genes were enriched in the biological processes of energy metabolism and autophagy. Moreover, MFN2 expression was observed to be significantly associated with immune cell infiltration and a variety of markers of tumor infiltrating immune cells (TIICs) including multiple immune checkpoints in KIRC tissues. Finally, MFN2 overexpression significantly inhibited cell proliferation and migration abilities of two KIRC cell lines examined. Generally, our data suggested that MFN2 may serve as a potential prognostic biomarker and therapeutic target in KIRC. [ABSTRACT FROM AUTHOR]