Lipoprotein(a) [Lp(a)] is underutilized in short-term atherosclerotic cardiovascular disease (ASCVD) risk prediction. This study investigates Lp(a) contribution to short-term ASCVD event prediction us Show more
Lipoprotein(a) [Lp(a)] is underutilized in short-term atherosclerotic cardiovascular disease (ASCVD) risk prediction. This study investigates Lp(a) contribution to short-term ASCVD event prediction using contemporary real-world data and machine learning (ML). A cohort of 731,983 individuals from a claims database was used to investigate the association of Lp(a) with incident ASCVD and all-cause mortality using Cox proportional hazards models. Novel ML models were developed to predict incident ASCVD events at 1, 2, and 3 years after Lp(a) testing. The models were validated in an independent cohort of 53,930 patients. An increase of 50 nmol/L in Lp(a) was independently associated with incident ASCVD events (HR: 1.072; 95% CI: 1.059-1.084) and all-cause mortality (HR: 1.041; 95% CI: 1.015-1.068) after adjustment for age, sex, and race/ethnicity. Novel ML models featuring Lp(a) predicted incident ASCVD events at 1, 2, and 3 years with robust discrimination (C-statistic: 0.83-0.84) in both the derivation and validation cohorts. Modest underestimation of risk was observed in the validation cohort for the 1-year model (calibration slope 1.25). Lp(a) contributed more to 1-year ASCVD prediction than smoking, diabetes, and other lipid parameters. Inclusion of Lp(a) in the 1-year model led to an integrated discrimination improvement of 0.03 and an optimal net reclassification improvement of 10% at a risk threshold of 26%. Lp(a) is a significant predictor of short-term ASCVD risk. Assessing Lp(a) and imminent ASCVD risk may assist in identifying patients who may benefit from escalation of preventative therapies. Show less
In budding yeast, the essential functions of Hsp70 chaperones Ssa1-4 are regulated through expression level, isoform specificity, and cochaperone activity. Suggesting a novel regulatory paradigm, we f Show more
In budding yeast, the essential functions of Hsp70 chaperones Ssa1-4 are regulated through expression level, isoform specificity, and cochaperone activity. Suggesting a novel regulatory paradigm, we find that phosphorylation of Ssa1 T36 within a cyclin-dependent kinase (CDK) consensus site conserved among Hsp70 proteins alters cochaperone and client interactions. T36 phosphorylation triggers displacement of Ydj1, allowing Ssa1 to bind the G1 cyclin Cln3 and promote its degradation. The stress CDK Pho85 phosphorylates T36 upon nitrogen starvation or pheromone stimulation, destabilizing Cln3 to delay onset of S phase. In turn, the mitotic CDK Cdk1 phosphorylates T36 to block Cln3 accumulation in G2/M. Suggesting broad conservation from yeast to human, CDK-dependent phosphorylation of Hsc70 T38 similarly regulates Cyclin D1 binding and stability. These results establish an active role for Hsp70 chaperones as signal transducers mediating growth control of G1 cyclin abundance and activity. Show less