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Polygenic risk scores (PRSs) increasingly predict complex traits; however, suboptimal performance in non-European populations raise concerns about clinical applications and health inequities. We developed CT-SLEB, a powerful and scalable method to calculate PRSs, using ancestry-specific genome-wide association study summary statistics from multiancestry training samples, integrating clumping and thresholding, empirical Bayes and superlearning. We evaluated CT-SLEB and nine alternative methods with large-scale simulated genome-wide association studies (~19 million common variants) and datasets from 23andMe, Inc., the Global Lipids Genetics Consortium, All of Us and UK Biobank, involving 5.1 million individuals of diverse ancestry, with 1.18 million individuals from four non-European populations across 13 complex traits. Results demonstrated that CT-SLEB significantly improves PRS performance in non-European populations compared with simple alternatives, with comparable or superior performance to a recent, computationally intensive method. Moreover, our simulation studies offered insights into sample size requirements and SNP density effects on multiancestry risk prediction.

Electrospun fibers based on aliphatic polyesters, such as poly(ε-caprolactone) (PCL), have been widely used in regenerative medicine and drug delivery applications due to their biocompatibility, low cost and ease of fabrication. However, these aliphatic polyester fibers are hydrophobic in nature, resulting in poor wettability, and they lack functional groups for decorating the scaffold with chemical and biological cues. Current strategies employed to overcome these challenges include coating and blending the fibers with bioactive components or chemically modifying the fibers with plasma treatment and reactants. In the present study, we report on designing multifunctional electrospun nanofibers based on the inclusion complex of PCL-α-cyclodextrin (PCL-α-CD), which provides both structural support and multiple functionalities for further conjugation of bioactive components. This strategy is independent of any chemical modification of the PCL main chain, and electrospinning of PCL-α-CD is as easy as electrospinning PCL. Here, we describe synthesis of the PCL-α-CD electrospun nanofibers, elucidate composition and structure, and demonstrate the utility of functional groups on the fibers by conjugating a fluorescent small molecule and a polymeric-nanobead to the nanofibers. Furthermore, we demonstrate the application of PCL-α-CD nanofibers for promoting osteogenic differentiation of human adipose-derived stem cells (hADSCs), which induced a higher level of expression of osteogenic markers and enhanced production of extracellular matrix (ECM) proteins or molecules compared with control PCL fibers.

Smooth muscle cells (SMC) make up most of the vascular system. In advanced atherosclerotic plaques, dying SMCs undergo a complex death mode. In the present study, we examined the activation of autophagy in SMCs overloaded with excess free cholesterol (FC) and investigated the possible role which autophagy plays during the FC-induced cell death. After incubation with excess FC, a robust expression of autophagic vacuoles (AV) was detected using both fluorescence microscopy and transmission electron microscopy (TEM). The results revealed that FC induced a time-dependent upregulation of microtubule-associated protein-1 light chain 3-II (LC3-II). Inhibition of autophagy by 3-methyladenine (3-MA) enhanced both cell apoptosis and necrosis, while on the contrary, rapamycin inhibited cell death following cholesterol application. Furthermore, the impact of the colocalization of fragmented mitochondria with AVs was observed after cholesterol treatment. Our results also revealed that the modulation of autophagy directly influenced the cellular organellar stress. In conclusion, our findings demonstrated that excess FC induced the activation of autophagy in SMCs as a cellular defense mechanism, possibly through the degradation of dysfunctional organelles such as mitochondria and endoplasmic reticulum.

Smooth muscle cells (SMC) make up most of the vascular system. In advanced atherosclerotic plaques, dying SMCs undergo a complex death mode. In the present study, we examined the activation of autophagy in SMCs overloaded with excess free cholesterol (FC) and investigated the possible role which autophagy plays during the FC-induced cell death. After incubation with excess FC, a robust expression of autophagic vacuoles (AV) was detected using both fluorescence microscopy and transmission electron microscopy (TEM). The results revealed that FC induced a time-dependent upregulation of microtubule-associated protein-1 light chain 3-II (LC3-II). Inhibition of autophagy by 3-methyladenine (3-MA) enhanced both cell apoptosis and necrosis, while on the contrary, rapamycin inhibited cell death following cholesterol application. Furthermore, the impact of the colocalization of fragmented mitochondria with AVs was observed after cholesterol treatment. Our results also revealed that the modulation of autophagy directly influenced the cellular organellar stress. In conclusion, our findings demonstrated that excess FC induced the activation of autophagy in SMCs as a cellular defense mechanism, possibly through the degradation of dysfunctional organelles such as mitochondria and endoplasmic reticulum.

Introduction:Pharmacogenetic testing holds great potential for supporting clinical decision making and optimizing medication outcomes. CYP2C19 and SLCO1B1 are two examples of cardiovascular pharmacogenes with the evidence supporting implementation in clinical practice. However, the clinical uptake of pharmacogenetic testing has been slow. Recent FDA authorization for a direct-to-consumer (DTC) pharmacogenetic test will improve access to pharmacogenetic testing. This study aims to characterize the frequency of four variants CYP2C19 (*2, *3, and *17) and SLCO1B1 (*5) in a generally unselected group of genotyped individuals who have used DTC genetic testing (23andMe, Inc. Mountain View, CA).Methods:Participants were genotyped between 2013 and 2019 using Illumina genotyping arrays that included the CYP2C19*2 (c.681G>A, rs4244285), *3 (c.636G>A, rs4986893), and *17 (c.-806C>T, rs12248560), and SLCO1B1*5 (c.521T>C, rs4149056) variants. Eligible subjects were 23andMe U.S. customers who were > 18 years of age and consented to participate in research. IRB approval was obtained from Ethical & Independent Review Services.Results:More than 80% of genotyped individuals consented to participate in this study. Out of approximately 3.5 million eligible participants included in this analysis, the overall variant frequencies of CYP2C19 *2, *3, and *17 were 15.4%, 0.3%, and 20.2%, respectively. The overall variant frequency of SLCO1B1*5 was 15.0%. Frequencies of actionable phenotypes (translation of variant/diplotypes to predicted phenotypes) and stratification of variant frequencies by ethnicity are underway and will be presented.Conclusions:Approximately 70% of genotyped participants had at least one potentially clinically relevant variant in CYP2C19 or SLCO1B1. Nearly 60% of genotyped participants had at least one of the three tested CYP2C19 variants and 28% had the SLCO1B1 variant. These findings suggest that preemptive DTC pharmacogenetic testing can be used to disseminate potentially clinically useful information to a large number of consumers and facilitate conversations with their healthcare providers about implications for their current and future therapies.