Search for: All records

The genetic basis of complex traits involves the function of many genes with small effects as well as complex gene-gene and gene-environment interactions. As one of the major players in complex diseases, the role of gene-environment interactions has been increasingly recognized. Motivated by epidemiology studies to evaluate the joint effect of environmental mixtures, we developed a functional varying-index coefficient model (FVICM) to assess the combined effect of environmental mixtures and their interactions with genes, under a longitudinal design with quantitative traits. Built upon the previous work, we extend the FVICM model to accommodate binary longitudinal traits through the development of a generalized functional varying-index coefficient model (gFVICM). This model examines how the genetic effects on a disease trait are nonlinearly influenced by a combination of environmental factors. We derive an estimation procedure for the varying-index coefficient functions using quadratic inference functions combined with penalized splines. A hypothesis testing procedure is proposed to evaluate the significance of the nonparametric index functions. Extensive Monte Carlo simulations are conducted to evaluate the performance of the method under finite samples. The utility of the method is further demonstrated through a case study with a pain sensitivity dataset. SNPs were found to have their effects on blood pressure nonlinearly influenced by a combination of environmental factors. 

Human complex diseases are affected by both genetic and environmental factors. When multiple environmental risk factors are present, the interaction effect between a gene and the environmental mixture can be larger than the addition of individual interactions, resulting in the so-called synergistic gene–environment (GxE) interactions. Existing literature has shown the power of synergistic gene-environment interaction analysis with cross-sectional traits. In this work, we propose a functional varying index coefficient model for longitudinal traits together with multiple longitudinal environmental risk factors and assess how the genetic effects on a longitudinal disease trait are nonlinearly modified by a mixture of environmental influences. We derive an estimation procedure for the nonparametric functional varying index coefficients under the quadratic inference function and penalized spline framework. We evaluate some theoretical properties such as estimation consistency and asymptotic normality of the estimates. We further propose a hypothesis testing procedure to assess the significance of the synergistic GxE effect. The performance of the estimation and testing procedure is evaluated through Monte Carlo simulation studies. Finally, the utility of the method is illustrated by a real dataset from a pain sensitivity study in which SNP effects are nonlinearly modulated by a mixture of drug dosages and other environmental variables to affect patients’ blood pressure and heart rate. 

Novelty and appropriateness are two fundamental components of creativity. However, the way in which novelty and appropriateness are separated at behavioral and neural levels remains poorly understood. In the present study, we aim to distinguish behavioral and neural bases of novelty and appropriateness of creative idea generation. In alignment with two established theories of creative thinking, which respectively, emphasize semantic association and executive control, behavioral results indicate that novelty relies more on associative abilities, while appropriateness relies more on executive functions. Next, employing a connectome predictive modeling (CPM) approach in resting-state fMRI data, we define two functional network-based models—dominated by interactions within the default network and by interactions within the limbic network—that respectively, predict novelty and appropriateness (i.e., cross-brain prediction). Furthermore, the generalizability and specificity of the two functional connectivity patterns are verified in additional resting-state fMRI and task fMRI. Finally, the two functional connectivity patterns, respectively mediate the relationship between semantic association/executive control and novelty/appropriateness. These findings provide global and predictive distinctions between novelty and appropriateness in creative idea generation. 

During Hedgehog (Hh) signal transduction in development and disease, the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO) communicates with GLI transcription factors by binding the protein kinase A catalytic subunit (PKA-C) and physically blocking its enzymatic activity. Here, we show that GPCR kinase 2 (GRK2) orchestrates this process during endogenous mouse and zebrafish Hh pathway activation in the primary cilium. Upon SMO activation, GRK2 rapidly relocalizes from the ciliary base to the shaft, triggering SMO phosphorylation and PKA-C interaction. Reconstitution studies reveal that GRK2 phosphorylation enables active SMO to bind PKA-C directly. Lastly, the SMO-GRK2-PKA pathway underlies Hh signal transduction in a range of cellular and in vivo models. Thus, GRK2 phosphorylation of ciliary SMO and the ensuing PKA-C binding and inactivation are critical initiating events for the intracellular steps in Hh signaling. More broadly, our study suggests an expanded role for GRKs in enabling direct GPCR interactions with diverse intracellular effectors. 

Antibiotic resistance is of crucial interest to both human and animal medicine. It has been recognized that increased environmental monitoring of antibiotic resistance is needed. Metagenomic DNA sequencing is becoming an attractive method to profile antibiotic resistance genes (ARGs), including a special focus on pathogens. A number of computational pipelines are available and under development to support environmental ARG monitoring; the pipeline we present here is promising for general adoption for the purpose of harmonized global monitoring. Specifically, ARGem is a user-friendly pipeline that provides full-service analysis, from the initial DNA short reads to the final visualization of results. The capture of extensive metadata is also facilitated to support comparability across projects and broader monitoring goals. The ARGem pipeline offers efficient analysis of a modest number of samples along with affordable computational components, though the throughput could be increased through cloud resources, based on the user’s configuration. The pipeline components were carefully assessed and selected to satisfy tradeoffs, balancing efficiency and flexibility. It was essential to provide a step to perform short read assembly in a reasonable time frame to ensure accurate annotation of identified ARGs. Comprehensive ARG and mobile genetic element databases are included in ARGem for annotation support. ARGem further includes an expandable set of analysis tools that include statistical and network analysis and supports various useful visualization techniques, including Cytoscape visualization of co-occurrence and correlation networks. The performance and flexibility of the ARGem pipeline is demonstrated with analysis of aquatic metagenomes. The pipeline is freely available athttps://github.com/xlxlxlx/ARGem. 

Abstract Hedgehog (Hh) signaling relies on the primary cilium, a cell surface organelle that serves as a signaling hub for the cell. Using proximity labeling and quantitative proteomics, we identify Numb as a ciliary protein that positively regulates Hh signaling. Numb localizes to the ciliary pocket and acts as an endocytic adaptor to incorporate Ptch1 into clathrin-coated vesicles, thereby promoting Ptch1 exit from the cilium, a key step in Hh signaling activation. Numb loss impedes Sonic hedgehog (Shh)-induced Ptch1 exit from the cilium, resulting in reduced Hh signaling. Numb loss in spinal neural progenitors reduces Shh-induced differentiation into cell fates reliant on high Hh activity. Genetic ablation of Numb in the developing cerebellum impairs the proliferation of granule cell precursors, a Hh-dependent process, resulting in reduced cerebellar size. This study highlights Numb as a regulator of ciliary Ptch1 levels during Hh signal activation and demonstrates the key role of ciliary pocket-mediated endocytosis in cell signaling.