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1. Testing and controlling for horizontal pleiotropy with probabilistic Mendelian randomization in transcriptome-wide association studies

   https://doi.org/10.1038/s41467-020-17668-6  

   Yuan, Zhongshang; Zhu, Huanhuan; Zeng, Ping; Yang, Sheng; Sun, Shiquan; Yang, Can; Liu, Jin; Zhou, Xiang (July 2020, Nature Communications)

   Abstract Integrating results from genome-wide association studies (GWASs) and gene expression studies through transcriptome-wide association study (TWAS) has the potential to shed light on the causal molecular mechanisms underlying disease etiology. Here, we present a probabilistic Mendelian randomization (MR) method, PMR-Egger, for TWAS applications. PMR-Egger relies on a MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and is scalable to hundreds of thousands of individuals. In simulations, PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust under various types of model misspecifications, is more powerful than existing TWAS/MR approaches, and can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank. 

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2. Polycentricity in the Yangtze River Delta Urban Agglomeration (YRDUA): More Cohesion or More Disparities?

   https://doi.org/10.3390/su11113106  

   Chen, Wen; Yenneti, Komali; Wei, Yehua Dennis; Yuan, Feng; Wu, Jiawei; Gao, Jinlong (June 2019, Sustainability)

   Urban spatial structure is a critical component of urban planning and development, and among the different urban spatial structure strategies, ‘polycentric mega-city region (PMR)’ has recently received great research and public policy interest in China. However, there is a lack of systematic understanding on the spatiality of PMR from a pluralistic perspective. This study aims to fill this gap by investigating the spatiality of PMR in the Yangtze River Delta Urban Agglomeration (YRDUA) using city-level data on gross domestic product (GDP), population share, and urban income growth for the period 2000–2013. The results reveal that economically, the YRDUA is experiencing greater polycentricity, but in terms of social welfare, the region manifests growing monocentricity. We further find that the triple transition framework (marketization, urbanization, and decentralization) can greatly explain the observed patterns. Although the economic goals are accomplished with better spatial linkages and early economic development policies, inequality in spatial distribution of public services and the continuing legacy of central planning remain barriers for the YRDUA to emerge as a successful PMR. The results of this research offer meaningful insights on the impact of polycentric policies in the YRDUA and support policymakers in the implementation of appropriate urban spatial development strategies. 

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3. Racial Disparities in Methylation of NRF1, FTO, and LEPR Gene in Childhood Obesity

   https://doi.org/10.3390/genes13112030  

   Patel, Priyadarshni; Selvaraju, Vaithinathan; Babu, Jeganathan Ramesh; Wang, Xu; Geetha, Thangiah (November 2022, Genes)

   Childhood obesity has affected the health of millions of children around the world despite vigorous efforts by health experts. The obesity epidemic in the United States has disproportionately afflicted certain racial and ethnic minority groups. African American children are more likely than other children to have obesity-related risk factors such as hyperlipidemia, diabetes, cardiovascular disease, and coronavirus disease (COVID-19). For the reduction in obesity-related health inequalities to be successful, it is essential to identify the variables affecting various groups. A notable advancement in epigenetic biology has been made over the past decade. Epigenetic changes like DNA methylation impact on many genes associated with obesity. Here, we evaluated the DNA methylation levels of the genes NRF1, FTO, and LEPR from the saliva of children using real-time quantitative PCR-based multiplex MethyLight technology. ALU was used as a reference gene, and the Percent of Methylated Reference (PMR) was calculated for each sample. European American children showed a significant increase in PMR of NRF1 and FTO in overweight/obese participants compared to normal weight, but not in African American children. After adjusting for maternal education and annual family income by regression analysis, the PMR of NRF1 and FTO was significantly associated with BMI z-score only in European American children. While for the gene LEPR, African American children had higher methylation in normal weight participants as compared to overweight/obese and no methylation difference in European American children. The PMR of LEPR was significantly negative associated with the obesity measures only in African American children. These findings contribute to a race-specific link between NRF1, FTO, and LEPR gene methylation and childhood obesity. 

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4. The seminal odorant binding protein Obp56g is required for mating plug formation and male fertility in Drosophila melanogaster

   https://doi.org/10.7554/eLife.86409  

   Brown, Nora C; Gordon, Benjamin; McDonough-Goldstein, Caitlin E; Misra, Snigdha; Findlay, Geoffrey D; Clark, Andrew G; Wolfner, Mariana Federica (December 2023, eLife)

   In Drosophila melanogaster and other insects, the seminal fluid proteins (SFPs) and male sex pheromones that enter the female with sperm during mating are essential for fertility and induce profound post-mating effects on female physiology. The SFPs in D. melanogaster and other taxa include several members of the large gene family known as odorant binding proteins (Obps). Work in Drosophila has shown that some Obp genes are highly expressed in the antennae and can mediate behavioral responses to odorants, potentially by binding and carrying these molecules to odorant receptors. These observations have led to the hypothesis that the seminal Obps might act as molecular carriers for pheromones or other compounds important for male fertility, though functional evidence in any species is lacking. Here, we used functional genetics to test the role of the seven seminal Obps in D. melanogaster fertility and the post-mating response (PMR). We found that Obp56g is required for male fertility and the induction of the PMR, whereas the other six genes are dispensable. We found males lacking Obp56g fail to form a mating plug in the mated female’s reproductive tract, leading to ejaculate loss and reduced sperm storage, likely due to its expression in the male ejaculatory bulb. We also examined the evolutionary history of these seminal Obp genes, as several studies have documented rapid evolution and turnover of SFP genes across taxa. We found extensive lability in gene copy number and evidence of positive selection acting on two genes, Obp22a and Obp51a. Comparative RNAseq data from the male reproductive tract of multipleDrosophilaspecies revealed that Obp56g shows high male reproductive tract expression in a subset of taxa, though conserved head expression across the phylogeny. Together, these functional and expression data suggest that Obp56g may have been co-opted for a reproductive function over evolutionary time. 

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5. Phenotypic, metabolic, and biogenesis properties of human stem cell-derived cerebellar spheroids

   https://doi.org/10.1038/s41598-022-16970-1  

   Hua, Timothy; Liu, Chang; Kiran, Sonia; Gray, Kelly; Jung, Sunghoon; Meckes, Jr., David G.; Li, Yan; Sang, Qing-Xiang Amy (July 2022, Scientific Reports)

   Abstract Human cerebellum consists of high density and complexity of neurons. Thus, it is challenging to differentiate cerebellar-like organoids with similar cellular markers and function to the human brain. Our previous study showed that the combination of retinoic acid (RA), Wingless/integrated (Wnt) activator, and Sonic Hedgehog (SHH) activator promotes cerebellar differentiation from human induced pluripotent stem cells (hiPSCs). This study examined phenotypic, metabolic, and biogenesis in early cerebellar development. Cerebellum spheroids were differentiated from human iPSK3 cells. During day 7–14, RA and Wnt activator CHIR99021 were used and SHH activator purmorphamine (PMR) was added later to promote ventralization. Gene expression for early cerebellar layer markers, metabolism, and extracellular vesicle (EV) biogenesis were characterized. Zinc-induced neurotoxicity was investigated as a proof-of-concept of neurotoxicity study. Flow cytometry results showed that there was no significant difference in NEPH3, PTF1A, OLIG2, and MATH1 protein expression between RCP (RA-CHIR-PMR) versus the control condition. However, the expression of cerebellar genes for the molecular layer (BHLE22), the granule cell layer (GABRB2,PAX6,TMEM266,KCNIP4), the Bergmann glial cells (QK1,DAO), and the Purkinje cell layer (ARHGEF33,KIT,MX1,MYH10,PPP1R17,SCGN) was significantly higher in the RCP condition than the control. The shift in metabolic pathways toward glycolysis was observed for RCP condition. The EV biogenesis marker expression was retained. Mild zinc-induced neurotoxicity may exist when zinc exposure exceeds 1.0 µM. RCP treatment can promote specific cerebellar-like differentiation from hiPSCs indicated by gene expression of early cerebellar markers and regionally enriched genes. The higher cerebellar marker expression is accompanied by the elevated glycolysis with the retained EV biogenesis. This study should advance the understanding of biomarkers during early cerebellar development for cerebellum organoid engineering and neurotoxicity study. 

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