Shared rare genetic variants in multiplex autism families suggest a social memory gene under selection.

Autism spectrum disorder (ASD) affects up to 1 in 59 children, and is one of the most common neurodevelopmental disorders. Recent genomic studies have highlighted the role of rare variants in ASD. This study aimed to identify genes affected by rare variants shared by siblings with ASD and validate the function of a candidate gene FRRS1L.

Design Optimization of Lattice Structures under Compression: Study of Unit Cell Types and Cell Arrangements.

Additive manufacturing enables innovative structural design for industrial applications, which allows the fabrication of lattice structures with enhanced mechanical properties, including a high strength-to-relative-density ratio. However, to commercialize lattice structures, it is necessary to define the designability of lattice geometries and characterize the associated mechanical responses, including the compressive strength. The objective of this study was to provide an optimized design process for lattice structures and develop a lattice structure characterization database that can be used to differentiate unit cell topologies and guide the unit cell selection for compression-dominated structures.

Chloride Diffusion by Build Orientation of Cementitious Material-Based Binder Jetting 3D Printing Mortar.

Binder jetting 3D printing (BJ3DP) is used to create geometrical and topology-optimized building structures via architectural geometric design owing to its high degree of freedom in geometry implementation. However, building structures require high mechanical and durability performance. Because of the recent trend of using 3D printing concrete as a structural component in reinforcing bars, its durability with respect to chloride penetration needs to be reviewed.

Functional fine-mapping of noncoding risk variants in amyotrophic lateral sclerosis utilizing convolutional neural network.

Recent large-scale genome-wide association studies have identified common genetic variations that may contribute to the risk of amyotrophic lateral sclerosis (ALS). However, pinpointing the risk variants in noncoding regions and underlying biological mechanisms remains a major challenge. Here, we constructed a convolutional neural network model with a large-scale GWAS meta-analysis dataset to unravel functional noncoding variants associated with ALS based on their epigenetic features.

Computational inference of cancer-specific vulnerabilities in clinical samples.

Background: Systematic in vitro loss-of-function screens provide valuable resources that can facilitate the discovery of drugs targeting cancer vulnerabilities.

Results: We develop a deep learning-based method to predict tumor-specific vulnerabilities in patient samples by leveraging a wealth of in vitro screening data. Acquired dependencies of tumors are inferred in cases in which one allele is disrupted by inactivating mutations or in association with oncogenic mutations.

Convolutional neural network model to predict causal risk factors that share complex regulatory features.

Major progress in disease genetics has been made through genome-wide association studies (GWASs). One of the key tasks for post-GWAS analyses is to identify causal noncoding variants with regulatory function. Here, on the basis of >2000 functional features, we developed a convolutional neural network framework for combinatorial, nonlinear modeling of complex patterns shared by risk variants scattered among multiple associated loci.

Impact of platelet reactivity on long-term prognosis in Korean patients receiving percutaneous coronary intervention.

Both high and low platelet responses to clopidogrel are highly associated with mortality. A therapeutic window for platelet reactivity was recently determined to be an important factor for improving clinical outcomes after percutaneous coronary intervention (PCI). We evaluated the impact of the antiplatelet activity of clopidogrel on long-term clinical outcomes in Korean patients receiving PCI.

Serine metabolism in the brain regulates starvation-induced sleep suppression in .

Sleep and metabolism are physiologically and behaviorally intertwined; however, the molecular basis for their interaction remains poorly understood. Here, we identified a serine metabolic pathway as a key mediator for starvation-induced sleep suppression. Transcriptome analyses revealed that enzymes involved in serine biosynthesis were induced upon starvation in brains.

Selection on the regulation of sympathetic nervous activity in humans and chimpanzees.

Adrenergic α2C receptor (ADRA2C) is an inhibitory modulator of the sympathetic nervous system. Knockout mice for this gene show physiological and behavioural alterations that are associated with the fight-or-flight response. There is evidence of positive selection on the regulation of this gene during chicken domestication.

Predicting the recurrence of noncoding regulatory mutations in cancer.

Background: One of the greatest challenges in cancer genomics is to distinguish driver mutations from passenger mutations. Whereas recurrence is a hallmark of driver mutations, it is difficult to observe recurring noncoding mutations owing to a limited amount of whole-genome sequenced samples. Hence, it is required to develop a method to predict potentially recurrent mutations.

A conserved quality-control pathway that mediates degradation of unassembled ribosomal proteins.

Overproduced yeast ribosomal protein (RP) Rpl26 fails to assemble into ribosomes and is degraded in the nucleus/nucleolus by a ubiquitin-proteasome system quality control pathway comprising the E2 enzymes Ubc4/Ubc5 and the ubiquitin ligase Tom1. tom1 cells show reduced ubiquitination of multiple RPs, exceptional accumulation of detergent-insoluble proteins including multiple RPs, and hypersensitivity to imbalances in production of RPs and rRNA, indicative of a profound perturbation to proteostasis. Tom1 directly ubiquitinates unassembled RPs primarily via residues that are concealed in mature ribosomes.

Selected heterozygosity at cis-regulatory sequences increases the expression homogeneity of a cell population in humans.

Background: Examples of heterozygote advantage in humans are scarce and limited to protein-coding sequences. Here, we attempt a genome-wide functional inference of advantageous heterozygosity at cis-regulatory regions.

Results: The single-nucleotide polymorphisms bearing the signatures of balancing selection are enriched in active cis-regulatory regions of immune cells and epithelial cells, the latter of which provide barrier function and innate immunity.

Ribosomal proteins produced in excess are degraded by the ubiquitin-proteasome system.

Ribosome assembly is an essential process that consumes prodigious quantities of cellular resources. Ribosomal proteins cannot be overproduced in Saccharomyces cerevisiae because the excess proteins are rapidly degraded. However, the responsible quality control (QC) mechanisms remain poorly characterized.

Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases.

Genome-wide association studies have proven the highly polygenic architecture of complex diseases or traits; therefore, single-locus-based methods are usually unable to detect all involved loci, especially when individual loci exert small effects. Moreover, the majority of associated single-nucleotide polymorphisms resides in non-coding regions, making it difficult to understand their phenotypic contribution. In this work, we studied epistatic interactions associated with three common diseases using Korea Association Resource (KARE) data: type 2 diabetes mellitus (DM), hypertension (HT), and coronary artery disease (CAD).

Proteome-wide remodeling of protein location and function by stress.

Protein location and function can change dynamically depending on many factors, including environmental stress, disease state, age, developmental stage, and cell type. Here, we describe an integrative computational framework, called the conditional function predictor (CoFP; http://nbm.ajou.

Patterns of gene expression associated with Pten deficiency in the developing inner ear.

In inner ear development, phosphatase and tensin homolog (PTEN) is necessary for neuronal maintenance, such as neuronal survival and accurate nerve innervations of hair cells. We previously reported that Pten conditional knockout (cKO) mice exhibited disorganized fasciculus with neuronal apoptosis in spiral ganglion neurons (SGNs). To better understand the genes and signaling networks related to auditory neuron maintenance, we compared the profiles of differentially expressed genes (DEGs) using microarray analysis of the inner ear in E14.

A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma.

The molecular mechanisms underlying angioimmunoblastic T cell lymphoma (AITL), a common type of mature T cell lymphoma of poor prognosis, are largely unknown. Here we report a frequent somatic mutation in RHOA (encoding p.Gly17Val) using exome and transcriptome sequencing of samples from individuals with AITL.

Genome-wide bimolecular fluorescence complementation analysis of SUMO interactome in yeast.

The definition of protein-protein interactions (PPIs) in the natural cellular context is essential for properly understanding various biological processes. So far, however, most large-scale PPI analyses have not been performed in the natural cellular context. Here, we describe the construction of a Saccharomyces cerevisiae fusion library in which each endogenous gene is C-terminally tagged with the N-terminal fragment of Venus (VN) for a genome-wide bimolecular fluorescence complementation assay, a powerful technique for identifying PPIs in living cells.

Nsi1 plays a significant role in the silencing of ribosomal DNA in Saccharomyces cerevisiae.

In eukaryotic cells, ribosomal DNA (rDNA) forms the basis of the nucleolus. In Saccharomyces cerevisiae, 100-200 copies of a 9.1-kb rDNA repeat exist as a tandem array on chromosome XII.

Rewiring of genetic networks in response to DNA damage.

Although cellular behaviors are dynamic, the networks that govern these behaviors have been mapped primarily as static snapshots. Using an approach called differential epistasis mapping, we have discovered widespread changes in genetic interaction among yeast kinases, phosphatases, and transcription factors as the cell responds to DNA damage. Differential interactions uncover many gene functions that go undetected in static conditions.

In vivo quantification of protein-protein interactions in Saccharomyces cerevisiae using bimolecular fluorescence complementation assay.

Most of the biological processes are carried out and regulated by dynamic networks of protein-protein interactions. In this study, we demonstrate the feasibility of the bimolecular fluorescence complementation (BiFC) assay for in vivo quantitative analysis of protein-protein interactions in Saccharomyces cerevisiae. We show that the BiFC assay can be used to quantify not only the amount but also the cell-to-cell variation of protein-protein interactions in S.

Potent modulation of P-glycoprotein activity by naturally occurring phenylbutenoids from Zingiber cassumunar.

Five phenylbutenoid derivatives from the rhizomes of Zingiber cassumunar Roxb. (Zingiberaceae) were evaluated for their P-glycoprotein (P-gp) inhibitory effects in a P-gp over-expressing multidrug resistant (MDR) human breast cancer cell line, MCF-7/ADR. As a result, a phenylbutenoid dimer, (+/-)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene (1), exhibited highly potent P-gp inhibitory activity, decreasing the IC(50) value of daunomycin (DNM) to 4.

Protein networks markedly improve prediction of subcellular localization in multiple eukaryotic species.

The function of a protein is intimately tied to its subcellular localization. Although localizations have been measured for many yeast proteins through systematic GFP fusions, similar studies in other branches of life are still forthcoming. In the interim, various machine-learning methods have been proposed to predict localization using physical characteristics of a protein, such as amino acid content, hydrophobicity, side-chain mass and domain composition.

Epigenetic deregulation of the human Oct4 promoter in mouse cells.

To examine whether the epigenetic status of the human Oct4 promoter is similarly regulated in mouse cells, we engineered a human bacterial artificial chromosome to express green fluorescent protein under the control of the hOct4 promoter and stably integrated it into mouse embryonic stem cells (mESCs), NIH3T3, and 293T cells. The hOct4 promoter is unmethylated in mESCs and it undergoes methylation during retinoic acid-induced differentiation. However, the hOct4 promoter is demethylated in NIH3T3 cells even though it is fully methylated in 293T cells.