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Mutational robustness

Milad Yousefi, Moslem Yousefi, Ricardo Poley Martins Ferreira, Joong Hoon Kim, Flavio S Fogliatto
Long length of stay and overcrowding in emergency departments (EDs) are two common problems in the healthcare industry. To decrease the average length of stay (ALOS) and tackle overcrowding, numerous resources, including the number of doctors, nurses and receptionists need to be adjusted, while a number of constraints are to be considered at the same time. In this study, an efficient method based on agent-based simulation, machine learning and the genetic algorithm (GA) is presented to determine optimum resource allocation in emergency departments...
October 17, 2017: Artificial Intelligence in Medicine
Zahra Erami, Bassem D Khalil, Gilbert Salloum, Yanhua Yao, Jaclyn LoPiccolo, Aliaksei Shymanets, Bernd Nürnberg, Anne R Bresnick, Jonathan M Backer
Phosphoinositide 3-kinases (PI 3-kinases) are regulated by a diverse range of upstream activators, including receptor tyrosine kinases (RTKs), G-protein-coupled receptors (GPCRs), and small GTPases from the Ras, Rho and Rab families. For the Class IA PI 3-kinase PI3Kβ, two mechanisms for GPCR-mediated regulation have been described: direct binding of Gβγ subunits to the C2-helical domain linker of p110β, and Dock180/Elmo1-mediated activation of Rac1, which binds to the Ras-Binding Domain of p110β. We now show that the integration of these dual pathways is unexpectedly complex...
October 18, 2017: Biochemical Journal
Thomas LaBar, Christoph Adami
Most mutations are deleterious and cause a reduction in population fitness known as the mutational load. In small populations, weakened selection against slightly-deleterious mutations results in an additional fitness reduction. Many studies have established that populations can evolve a reduced mutational load by evolving mutational robustness, but it is uncertain whether small populations can evolve a reduced susceptibility to drift-related fitness declines. Here, using mathematical modeling and digital experimental evolution, we show that small populations do evolve a reduced vulnerability to drift, or 'drift robustness'...
October 18, 2017: Nature Communications
Amin Aalipour, Jonathan C Dudley, Seung-Min Park, Surya Murty, Jacob J Chabon, Evan A Boyle, Maximilian Diehn, Sanjiv S Gambhir
BACKGROUND: Cell-free DNA (cfDNA) diagnostics are emerging as a new paradigm of disease monitoring and therapy management. The clinical utility of these diagnostics is relatively limited by a low signal-to-noise ratio, such as with low allele frequency (AF) mutations in cancer. While enriching for rare alleles to increase their AF before sample analysis is one strategy that can greatly improve detection capability, current methods are limited in their generalizability, ease of use, and applicability to point mutations...
October 16, 2017: Clinical Chemistry
José G Grajales-Reyes, Aurian García-González, José C María-Ríos, Gary E Grajales-Reyes, Manuel Delgado-Vélez, Carlos A Báez-Pagán, Orestes Quesada, Christopher M Gómez, José A Lasalde-Dominicci
Muscle nicotinic acetylcholine receptor (nAChR) mutations can lead to altered channel kinetics and neuromuscular junction degeneration, a neurodegenerative disorder collectively known as slow-channel congenital myasthenic syndrome (SCCMS). A multivariate analysis using running wheels was used to generate activity profiles for a variety of SCCMS models, uncovering unique locomotor patterns for the different nAChR mutants. Particularly, the αL251T and ɛL269F mutations exhibit decreased event distance, duration, and velocity over a period of 24 hours...
October 13, 2017: Journal of Neuromuscular Diseases
Zuxu Yao, Ronald Moy, Talisha Allen, Burkhard Jansen
INTRODUCTION: A number of diagnoses in clinical dermatology are currently histopathologically confirmed and this image recognition-based confirmation generally requires surgical biopsies. The increasing ability of molecular pathology to corroborate or correct a clinical diagnosis based on objective gene expression, mutation analysis, or molecular microbiome data is on the horizon and would be further supported by a tool or procedure to collect samples non-invasively. This study characterizes such a tool in form of a 'bladeless' adhesive patch-based skin biopsy device...
October 1, 2017: Journal of Drugs in Dermatology: JDD
Chenqiang Jia, Cong Huai, Jiaqi Ding, Lingna Hu, Bo Su, Hongyan Chen, Daru Lu
The detection of mutant DNA is critical for precision medicine, but low-frequency DNA mutation is very hard to be determined. CRISPR/Cas9 is a robust tool for in vivo gene editing, and shows the potential for precise in vitro DNA cleavage. Here we developed a DNA mutation detection system based on CRISPR/Cas9 that can detect gene mutation efficiently even in a low-frequency condition. The system of CRISPR/Cas9 cleavage in vitro showed a high accuracy similar to traditional T7 endonuclease I (T7E1) assay in estimating mutant DNA proportion in the condition of normal frequency...
October 11, 2017: Gene
Dylan J Meyer, Craig Gatto, Pablo Artigas
Primary aldosteronism, a condition in which too much aldosterone is produced and that leads to hypertension, is often initiated by an aldosterone-producing adenoma within the zona glomerulosa of the adrenal cortex. Somatic mutations of ATP1A1, encoding the Na/K pump α1 subunit, have been found in these adenomas. It has been proposed that a passive inward current transported by several of these mutant pumps is a "gain-of-function" activity that produces membrane depolarization and concomitant increases in aldosterone production...
October 13, 2017: Journal of General Physiology
Sabrina Jutz, Annika Hennig, Wolfgang Paster, Ömer Asrak, Dejana Dijanovic, Florian Kellner, Winfried F Pickl, Johannes B Huppa, Judith Leitner, Peter Steinberger
Blockade of the T cell coinhibitory molecules CTLA-4 and PD-1 has clinical utility to strengthen T cell responses. In addition to these immune checkpoints an ever-growing number of molecules has been implicated in generating coinhibitory signals in T cells. However, investigating coinhibitory molecules in primary human cells is complicated by the restricted expression and promiscuity of both coinhibitory receptors and their ligands. Here we have evaluated the potential of fluorescence-based transcriptional reporters based on the human Jurkat T cell line in conjunction with engineered T cell stimulator cell lines for investigating coinhibitory pathways...
September 12, 2017: Oncotarget
Pengfei Ma, Yujie Fu, Mei-Chun Cai, Ying Yan, Ying Jing, Shengzhe Zhang, Minjiang Chen, Jie Wu, Ying Shen, Liang Zhu, Hong-Zhuan Chen, Wei-Qiang Gao, Mengzhao Wang, Zhenyu Gu, Trever G Bivona, Xiaojing Zhao, Guanglei Zhuang
Recent genomic analyses have revealed substantial tumor heterogeneity across various cancers. However, it remains unclear whether and how genomic heterogeneity is constrained during tumor evolution. Here, we sequence a unique cohort of multiple synchronous lung cancers (MSLCs) to determine the relative diversity and uniformity of genetic drivers upon identical germline and environmental background. We find that each multicentric primary tumor harbors distinct oncogenic alterations, including novel mutations that are experimentally demonstrated to be functional and therapeutically targetable...
October 10, 2017: Nature Communications
Yusuke Nomura, Kaori Yamazaki, Ryo Amano, Kenta Takada, Takashi Nagata, Naohiro Kobayashi, Yoichiro Tanaka, Junichi Fukunaga, Masato Katahira, Tomoko Kozu, Yoshikazu Nakamura, Yuji Haishima, Hidetaka Torigoe, Taiichi Sakamoto
To develop a high-affinity aptamer against AML1 Runt domain, two aptamers were conjugated based on their structural information. The newly designed aptamer Apt14 was generated by the conjugation of two RNA aptamers (Apt1 and Apt4) obtained by SELEX against AML1 Runt domain, resulting in improvement in its binding performance. The residues of AML1 Runt domain in contact with Apt14 were predicted in silico and confirmed by mutation and NMR analyses. It was suggested that the conjugated internal loop renders additional contacts and is responsible for the enhancement in the binding affinity...
July 14, 2017: Journal of Biochemistry
Yajie Liu, Dong Liu, Wei Yang, Xia-Ling Wu, Luhua Lai, Wen-Bin Zhang
Genetically encoded covalent peptide tagging technology, such as the SpyTag-SpyCatcher reaction, has emerged as a unique way to do chemistry with proteins. Herein, we report the reactivity engineering of SpyTag-SpyCatcher mutant pairs and show that distinct reactivity can be encrypted for the same reaction based on protein sequences of high similarity. Valuable features, including high selectivity, inverse temperature dependence and (nearly) orthogonal reactivity, could be achieved based on as few as three mutations...
September 1, 2017: Chemical Science
Yung-Jong Shiah, Hsu-Liang Hsieh, Huai-Ju Chen, Dean I Radin
OBJECTIVE: A previous experiment suggested that consumption of intentionally treated tea influenced subjective mood under double-blind, controlled conditions. To investigate that effect objectively, again under double-blind, controlled conditions, we studied whether Arabidopsis thaliana seeds hydrated with intentionally treated vs. untreated water would show differences in hypocotyl length, anthocyanin, and chlorophyll. DESIGN: Three Buddhist monks focused their intention on commercially bottled water with the goal of improving the growth of seeds; bottled water from the same source served as an untreated control...
August 30, 2017: Explore: the Journal of Science and Healing
Mathieu Quinodoz, Beryl Royer-Bertrand, Katarina Cisarova, Silvio Alessandro Di Gioia, Andrea Superti-Furga, Carlo Rivolta
In contrast to recessive conditions with biallelic inheritance, identification of dominant (monoallelic) mutations for Mendelian disorders is more difficult, because of the abundance of benign heterozygous variants that act as massive background noise (typically, in a 400:1 excess ratio). To reduce this overflow of false positives in next-generation sequencing (NGS) screens, we developed DOMINO, a tool assessing the likelihood for a gene to harbor dominant changes. Unlike commonly-used predictors of pathogenicity, DOMINO takes into consideration features that are the properties of genes, rather than of variants...
October 5, 2017: American Journal of Human Genetics
Marijana Aradjanski, Sukru Anil Dogan, Stephan Lotter, Shuaiyu Wang, Steffen Hermans, Rolf Wibom, Elena Rugarli, Aleksandra Trifunovic
Although mitochondria are ubiquitous, each mitochondrial disease has surprisingly distinctly different pattern of tissue and organ involvement. Congruently, mutations in genes encoding for different mitochondrial tRNA synthetases result in the development of a very flamboyant group of diseases. Mutations in some of these genes, including aspartyl-tRNA synthetase (DARS2), lead to the onset of a white matter disease-leukoencephalopathy with brainstem and spinal cord involvement, and lactate elevation (LBSL) characterized by progressive spastic ataxia and characteristic leukoencephalopathy signature with multiple long-tract involvements...
August 3, 2017: Human Molecular Genetics
Lorna Kelly, Anjna Badhan, Grace C Roberts, Jean Lutamyo Mbisa, Mark Harris
Hepatitis C virus (HCV) genotype (GT) 3 is the second most prevalent of the seven HCV genotypes and exhibits the greatest resistance to the highly potent, direct-acting antivirals (DAAs) that are currently in use. Previously a stable cell line harbouring the S52 GT3 sub-genomic replicon (SGR) was established, but this SGR was unable to robustly replicate transiently. As transient SGRs are a critical tool in the development of DAAs, and in the study of viral resistance, we sought to establish a transient SGR system based on S52...
October 6, 2017: Journal of General Virology
Jonathan D Young, Chunhui Cai, Xinghua Lu
BACKGROUND: One approach to improving the personalized treatment of cancer is to understand the cellular signaling transduction pathways that cause cancer at the level of the individual patient. In this study, we used unsupervised deep learning to learn the hierarchical structure within cancer gene expression data. Deep learning is a group of machine learning algorithms that use multiple layers of hidden units to capture hierarchically related, alternative representations of the input data...
October 3, 2017: BMC Bioinformatics
Kumardeep Chaudhary, Olivier B Poirion, Liangqun Lu, Lana X Garmire
Identifying robust survival subgroups of hepatocellular carcinoma (HCC) will significantly improve patient care. Currently, endeavor of integrating multi-omics data to explicitly predict HCC survival from multiple patient cohorts is lacking. To fill in this gap, we present a deep learning (DL) based model on HCC that robustly differentiates survival subpopulations of patients in six cohorts. We build the DL based, survival-sensitive model on 360 HCC patients' data using RNA-seq, miRNA-seq and methylation data from TCGA, which predicts prognosis as good as an alternative model where genomics and clinical data are both considered...
October 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ephrem Mekonnen, Endashaw Bekele
The human FMO2 (flavin-containing monooxygenase 2) gene has been shown to be involved in innate immunity against microbial infections, including tuberculosis (TB), via the modulation of oxidative stress levels. It has also been found to possess a curious loss-of-function mutation (FMO2*1/FMO2*2) that demonstrates a distinctive differentiation in expression, function and ethno-geographic distribution. However, despite evidences of ethnic-specific genetic associations in the inflammatory profile of TB, no studies were done to investigate whether these patterns of variations correlate with evidences for the involvement of FMO2 in antimicrobial immune responses and ethnic differences in the distribution of FMO2 polymorphisms except for some pharmacogenetic data that suggest a potentially deleterious role for the functional variant (FMO2*1)...
2017: PloS One
Song Yi, Ning-Ning Liu, Limei Hu, Hui Wang, Nidhi Sahni
A complete understanding of human cancer variants requires new methods to systematically and efficiently assess the functional effects of genomic mutations at a large scale. Here, we describe a set of tools to rapidly clone and stratify thousands of cancer mutations at base resolution. This protocol provides a massively parallel pipeline to achieve high stringency and throughput. The approach includes high-throughput generation of mutant clones by Gateway, confirmation of variant identity by barcoding and next-generation sequencing, and stratification of cancer variants by multiplexed interaction profiling...
November 2017: Nature Protocols
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