Identification of cancer driver modules or pathways is a key step in understanding cancer pathogenesis and exploring patient-specific treatments. Numerous studies have shown that some genes with low mutation frequency are also important for the cancer progression, while previous research have focused on identifying high-frequency mutation genes. In this study, we propose a new framework with a new metric to identify driver modules with low-frequency mutation genes, called iCDModule. Inspired by the gravity model, we integrate the coverage and mutual exclusivity in mutation information, define a new metric between gene pairs, called mutation impact distance, to help identifying potential driver genes sets, including those have extremely low mutation rates but play an important role in functional networks. A genetic network is constructed by combining the defined mutation impact distance and then the driver module identification problem is formalized as the maximum clique solution problem, and an improved ant colony optimization algorithm is used to solve it. iCDModule is applied to TCGA breast cancer, glioblastoma, ovarian cancer to test performance. Experiments show that it can accurately identify known cancer driver modules and pathways, and also detect driver modules containing low-frequency mutation genes. iCDModule is significantly better than other existing methods in identifying driver modules.
INTRODUCTION Design and construction of an extensively modified yeast genome is a direct means to interrogate the integrity, comprehensiveness, and accuracy of the knowledge amassed by the yeast community to date. The international synthetic yeast genome project (Sc2.0) aims to build an entirely designer, synthetic Saccharomyces cerevisiae genome. The synthetic genome is designed to increase genome stability and genetic flexibility while maintaining cell fitness near that of the wild type. A major challenge for a genome synthesis lies in identifying and eliminating fitness-reducing sequence variants referred to as “bugs.” RATIONALE Debugging is imperative for successfully building a fit strain encoding a synthetic genome. However, it is time-consuming and laborious to replace wild-type genes and measure strain fitness systematically. The Sc2.0 PCRTag system, which specifies recoded sequences within open reading frames (ORFs), is designed to distinguish synthetic from wild-type DNA in a simple polymerase chain reaction (PCR) assay. This system provides an opportunity to efficiently map bugs to the related genes by using a pooling strategy and subsequently correct them. Further, as we identify bugs in designer sequences, we will identify gaps in our knowledge and gain a deeper understanding of genome biology, allowing refinement of future design strategies. RESULTS We chemically synthesized yeast chromosome X, synX, designed to be 707,459 base pairs. A high-throughput mapping strategy called pooled PCRTag mapping (PoPM) was developed to identify unexpected bugs during chromosome assembly. With this method, the genotypes of pools of colonies with normal or defective fitness are assessed by PCRTag analysis. The PoPM method exploits the patchwork structure of synthetic and wild-type sequences observed in the majority of putative synthetic DNA integrants or meiotic progeny derived from synthetic/wild-type strain backcross. PCRTag analysis with both synthetic and wild-type specific primers, carried out with genomic DNA extracted from the two pools of clones (normal fitness versus a specific growth defect), can be used to identify regions of synthetic DNA missing from the normal fitness pool and, analogously, sections of wild-type DNA absent from the specific growth-defect pool. In this way, the defect can be efficiently mapped to a very small overlapping region, and subsequent systematic analysis of designed changes in that region can be used to identify the bug. Several bugs were identified and corrected, including a growth defect mapping to a specific synonymously recoded PCRTag sequence in the essential FIP1 ORF and the effect of introducing a loxPsym site that unexpectedly altered the the promoter function of a nearby gene, ATP2. In addition, meiotic crossover was employed to repair the massive duplications and rearrangements in the synthetic chromosome. The debugged synX strain exhibited high fitness under a variety of conditions tested and in competitive growth with the wild-type strain. CONCLUSION Synthetic yeast chromosome X was chemically synthesized from scratch, a rigorous, incremental step toward complete synthesis of the whole yeast genome. Thousands of designer modifications in synX revealed extensive flexibility of the yeast genome. We developed an efficient mapping method, PoPM, to identify bugs during genome synthesis, generalizable to any watermarked synthetic chromosome, and several details of yeast biology were uncovered by debugging. Considering the numerous gene-associated PCRTags available in the synthetic chromosomes, PoPM may represent a powerful tool to map interesting phenotypes of mutated synthetic strains or even mutated wild-type strains to the relevant genes. It may also be useful to study yeast genetic interactions when an unexpected phenotype is generated by alterations in two or more genes, substantially expanding understanding of yeast genomic and cellular functions. The PoPM method is also likely to be useful for mapping phenotype(s) resulting from the genome SCRaMbLE system. Characterization of synX and debugging by pooled PCRTag mapping. ( Top ) Design overview of synthetic chromosome X. ( Bottom ) Flow diagram of pooled PCRTag mapping (PoPM).
We use Direct Coupling Analysis (DCA) to determine epistatic interactions between loci of variability of the SARS-CoV-2 virus, segmenting genomes by month of sampling. We use full-length, high-quality genomes from the GISAID repository up to October 2021, in total over 3,500,000 genomes. We find that DCA terms are more stable over time than correlations, but nevertheless change over time as mutations disappear from the global population or reach fixation. Correlations are enriched for phylogenetic effects, and in particularly statistical dependencies at short genomic distances, while DCA brings out links at longer genomic distance. We discuss the validity of a DCA analysis under these conditions in terms of a transient Quasi-Linkage Equilibrium state. We identify putative epistatic interaction mutations involving loci in Spike.
Aims and Scope: Asia-Pacific Psychiatry is an international psychiatric journal focused on the Asia and Pacific Rim region, and is the official journal of the Pacific Rim College of Psychiatry.Asia-Pacific Psychiatry enables psychiatrists and other mental health professionals in the region to share their research, educational programs and clinical experience with a larger international readership.The journal offers a venue for high quality research for and from the region in the face of minimal international publication availability for authors concerned with the region.This includes findings highlighting the diversity in psychiatric behavior, treatment and outcome related to social, ethnic, cultural, and economic differences of the region.The journal publishes peer-reviewed articles and reviews, as well as clinically and educationally focused papers on regional best practices.Images, videos, a young psychiatrist's corner, meeting reports, a journal club, and contextual commentaries differentiate this journal from existing main stream psychiatry research journals that are focused on other regions, or nationally focused within countries of Asia and the Pacific Rim.
is an important domesticated fungus that has been applied to produce many traditional fermented foods under high osmotic conditions. However, the detailed mechanisms of tolerance to osmotic stress remain largely unknown. Here, we construct a target-deleted strain (Δ
Self‐sustained actuators powered by natural, low‐energy sources based on liquid crystal elastomers (LCEs) are attractive as they offer high safety, abundant energy availability, and practicality in applications. However, achieving stable self‐sustaining motion with low‐energy sources requires high actuation strain rates within a narrow temperature range near ambient conditions—a great challenge as LCEs with low nematic‐to‐isotropic transition temperatures (Tni) generally exhibit reduced actuation strain and strain rates. To address this, we synthesized a carbon nanotube‐doped LCE with a low Tni and reversible Diels‐Alder crosslinks, termed DALCE, and readily (re)fabricated it into specific structures (e.g., twisted‐and‐coiled or bimorph shapes). By leveraging material‐structure synergy, we achieved both low Tni and high actuation strain rates, enabling self‐rolling, self‐breathing and autonomous twisting‐untwisting movements powered by ambient/body temperature or natural sunlight. This low‐energy, self‐sustained actuator design opens new possibilities for LCE‐based biomedical applications and naturally powered automatic devices.
To construct a lentiviral vector for RNA interference (RNAi) of human glycerol kinase (GK) gene to stably down-regulate GK expression in human hepatocytes.The sequence of siRNA for GK interference were cloned into the pSicoR vector. Following packaging in 293T cells, the lentivirus was titrated using fluorescence activated cell sorting. Human hepatocyte L02 cells was infected with the lentivirus and the expression of GK was analyzed using Western blotting.The lentiviral particle pSicoR-GK was successfully packaged with a virus titer reaching 3×10(7) pfu/ml. The expression level of GK protein was down-regulated to 20% of the control level in L02 cells infected with the lentivirus.The lentiviral vector for RNAi of human GK gene has been successfully constructed, which can significantly down-regulate GK expression in human hepatocytes.
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