Recent studies of genomic variation associated with autism have suggested the existence of extreme heterogeneity. Large-scale transcriptomics should complement these results to identify core ...molecular pathways underlying autism. Here we report results from a large-scale RNA sequencing effort, utilizing region-matched autism and control brains to identify neuronal and microglial genes robustly dysregulated in autism cortical brain. Remarkably, we note that a gene expression module corresponding to M2-activation states in microglia is negatively correlated with a differentially expressed neuronal module, implicating dysregulated microglial responses in concert with altered neuronal activity-dependent genes in autism brains. These observations provide pathways and candidate genes that highlight the interplay between innate immunity and neuronal activity in the aetiology of autism.
Genome-wide tests, including genome-wide association studies (GWAS) of germ-line genetic variants, driver tests of cancer somatic mutations, and transcriptome-wide association tests of RNAseq data, ...carry a high multiple testing burden. This burden can be overcome by enrolling larger cohorts or alleviated by using prior biological knowledge to favor some hypotheses over others. Here we compare these two methods in terms of their abilities to boost the power of hypothesis testing.
We provide a quantitative estimate for progress in cohort sizes and present a theoretical analysis of the power of oracular hard priors: priors that select a subset of hypotheses for testing, with an oracular guarantee that all true positives are within the tested subset. This theory demonstrates that for GWAS, strong priors that limit testing to 100-1000 genes provide less power than typical annual 20-40% increases in cohort sizes. Furthermore, non-oracular priors that exclude even a small fraction of true positives from the tested set can perform worse than not using a prior at all.
Our results provide a theoretical explanation for the continued dominance of simple, unbiased univariate hypothesis tests for GWAS: if a statistical question can be answered by larger cohort sizes, it should be answered by larger cohort sizes rather than by more complicated biased methods involving priors. We suggest that priors are better suited for non-statistical aspects of biology, such as pathway structure and causality, that are not yet easily captured by standard hypothesis tests.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Great efforts are being made to develop advanced polygenic risk scores (PRS) to improve the prediction of complex traits and diseases. However, most existing PRS are primarily trained on European ...ancestry populations, limiting their transferability to non-European populations. In this article, we propose a novel method for generating multi-ancestry Polygenic Risk scOres based on enSemble of PEnalized Regression models (PROSPER). PROSPER integrates genome-wide association studies (GWAS) summary statistics from diverse populations to develop ancestry-specific PRS with improved predictive power for minority populations. The method uses a combination of
(lasso) and
(ridge) penalty functions, a parsimonious specification of the penalty parameters across populations, and an ensemble step to combine PRS generated across different penalty parameters. We evaluate the performance of PROSPER and other existing methods on large-scale simulated and real datasets, including those from 23andMe Inc., the Global Lipids Genetics Consortium, and All of Us. Results show that PROSPER can substantially improve multi-ancestry polygenic prediction compared to alternative methods across a wide variety of genetic architectures. In real data analyses, for example, PROSPER increased out-of-sample prediction R
for continuous traits by an average of 70% compared to a state-of-the-art Bayesian method (PRS-CSx) in the African ancestry population. Further, PROSPER is computationally highly scalable for the analysis of large SNP contents and many diverse populations.
Synthetic polymers are employed to create highly defined microenvironments with controlled biochemical and biophysical properties for cell culture and tissue engineering. Chemical modification is ...required to input biological or chemical ligands, which often changes the fundamental structural properties of the material. Here, a simple modular biomaterial design strategy is reported that employs functional cyclodextrin nanobeads threaded onto poly(ethylene glycol) (PEG) polymer necklaces to form multifunctional hydrogels. Nanobeads with desired chemical or biological functionalities can be simply threaded onto the PEG chains to form hydrogels, creating an accessible platform for users. The design and synthesis of these multifunctional hydrogels are described, structure‐property relationships are elucidated, and applications ranging from stem cell culture and differentiation to tissue engineering are demonstrated.
Poly(ethylene glycol) is used to create synthetic hydrogel microenvironments for cells, but the ether backbone lacks sites for functionalization. Here, supramolecular chemistry is applied to create modular hydrogels using α‐cyclodextrins modified with biological and chemical functional groups with independently controlled crosslinking densities designed to direct stem cell functions.
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.
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.
Based on 1 013 652 individuals from four ancestry groups (European, Hispanic, African, and East Asian), we demonstrated the reliability of the ancestry-specific genetic risk score for prostate cancer ...(concordance with the observed risk) and suitability for genetic testing.
Reliability of prostate cancer (PCa) genetic risk score (GRS), that is, the concordance between its estimated risk and observed risk, is required for genetic testing at the individual level. Reliability data are lacking for non-European racial/ethnic populations, which hinders its clinical use and exacerbates racial disparity.
To calibrate PCa ancestry-specific GRS in four racial/ethnic populations.
PCa ancestry-specific GRSs, calculated from published risk-associated single-nucleotide polymorphisms in corresponding racial/ethnic populations, were evaluated in men who participated in 23andMe, Inc. genetic testing and consented for research, including 888 086 of European (EUR), 81 109 of Hispanic (HIS), 30 472 of African (AFR), and 13 985 of East Asian (EAS) ancestry, as classified by 23andMe's ancestry composition algorithm.
The concordance between the observed and estimated PCa risks at ten ancestry-specific GRS deciles was measured primarily by using the calibration slope (β), where 1 represents a perfect calibration. Platt scaling was used to correct the systematic bias of GRS.
A linear trend of an increased observed PCa prevalence in men with higher ancestry-specific GRS deciles was found in each racial population (all p-trend < 0.001). A calibration analysis revealed a systematic bias of GRS; β was considerably lower than 1 (0.73, 0.64, 0.66, and 0.75 in EUR, HIS, AFR, and EAS ancestries, respectively). This bias was reduced after the Platt scaling correction: β for scaled GRS in the testing dataset (40% of individuals) approximated 1 for all groups (0.95, 1.05, 1.02, and 1.01 in EUR, HIS, AFR, and EAS populations, respectively). The generalizability of the Platt correction needs to be validated in independent cohorts.
A systematic bias of ancestry-specific GRS in the direction of an overestimated risk for men in the highest decile was found in EUR and non-EUR populations. GRS is well calibrated after correction and is appropriate for genetic testing at the individual level for personalized PCa screening.
A corrected genetic risk score is more reliable (supported by the observed prostate cancer PCa risk) and appropriate for genetic testing for personalized PCa screening.
A novel, highly efficient heterogeneous palladium‐catalyzed carbonylative cyclization of aryl iodides and benzyl acetylenes has been developed under an atmospheric pressure of CO. The reaction ...proceeds smoothly in a bioderived solvent 2‐methyltetrahydrofuran (2‐MeTHF) at 50 °C using an MCM‐41‐anchored bidentate phosphine palladium complex Pd(OAc)2‐MCM‐41‐P,P as catalyst with DiPEA as base, delivering a wide variety of 3‐alkylidenefuran‐2‐ones in good to excellent yields. The Pd(OAc)2‐MCM‐41‐P,P complex can be easily recovered by a simple centrifugation and recycled more than ten times without any remarkable loss of catalytic activity. The present method not only avoids the use of toxic solvents such as benzene, toluene and THF, but also addresses the key problem of expensive palladium catalyst recovery and recycle, thus preventing palladium contamination in the final product.
A general, efficient and practical method for the synthesis of 3‐alkylidenefuran‐2‐ones has been developed from readily accessible aryl iodides and benzyl acetylenes via a recyclable palladium‐catalyzed carbonylative coupling reaction in a green solvent 2‐MeTHF. The reaction proceeds smoothly under a CO atmosphere and mild conditions, yielding a wide range of furanones in good to excellent yields.
An efficient heterogeneous copper(I)-catalyzed cross-coupling of aryl iodides and pinacolborane has been developed. The reaction proceeds smoothly in THF at room temperature by using 10 mol% of ...MCM-41-anchored NHC-copper(I) complex MCM-41-NHC-CuI as catalyst and sodium hydride as base and provides a general and practical route for the synthesis of a wide variety of arylboronates in good to high yields. This heterogenized copper(I) catalyst can be facilely prepared via a simple two-step procedure starting from easily accessible and inexpensive reagents, and exhibits a higher catalytic activity than CuI and can be recycled more than ten times without any significant loss of its catalytic activity.
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Background: MUTYH-associated polyposis (MAP) is an autosomal recessive condition that accounts for about 0.3-0.7% of all colorectal cancer (CRC) cases. The two most common variants ...among people of Northern European descent are MUTYH Y179C (rs34612342) and G396D (rs36053993), with a carrier frequency of 1-2%. However, understanding the frequency of these variants in other populations can better inform population health approaches for CRC screening and prevention. This study assessed the frequency of these two variants in a generally unselected group of genotyped individuals who have used direct-to-consumer (DTC) genetic testing (23andMe, Inc. Sunnyvale, CA). Methods: Study participants were genotyped on Illumina genotyping arrays, which included the Y179C and G396D variants. Eligible subjects were 23andMe customers who were at least 18 years of age and who consented to participate in research. IRB approval was obtained from Ethical and Independent Review Services. Results: Out of the 3,617,279 eligible participants included in this study, the overall allele frequencies of Y179C and G396D were 0.18% and 0.51%, respectively. People of European descent had the highest frequencies (0.22% and 0.59%), while people of Ashkenazi Jewish, East Asian, and South Asian descent had the lowest frequencies ( < 0.015% for both variants). The allele frequencies for people of Hispanic/Latino descent were 0.15% and 0.51%. Conclusions: This is the first description of an unselected cohort of individuals with MUTYH Y179C and G396D variants identified through DTC genetic testing. While these two variants were most common among people of European descent, they were also observed at relatively high frequency among people of Hispanic/Latino descent. These results may help guide CRC screening and prevention strategies in different ethnicities.
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