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Alexander D Giddey, Elise de Kock, Kehilwe C Nakedi, Shaun Garnett, Andrew J M Nel, Nelson C Soares, Jonathan M Blackburn
In the last 40 years only one new antitubercular drug has been approved, whilst resistance to current drugs, including rifampicin, is spreading. Here, we used the model organism Mycobacterium smegmatis to study mechanisms of phenotypic mycobacterial resistance, employing quantitative mass spectrometry-based proteomics to investigate the temporal effects of sub-lethal concentrations of rifampicin on the mycobacterial proteome at time-points corresponding to early response, onset of bacteriostasis and early recovery...
March 6, 2017: Scientific Reports
Haoyang Zeng, Matthew D Edwards, Yuchun Guo, David K Gifford
We present a novel ensemble-based computational framework, EnsembleExpr, that achieved the best performance in the Fourth Critical Assessment of Genome Interpretation (CAGI4) "eQTL-causal SNPs" challenge for identifying eQTLs and prioritizing their gene expression effects. Expression quantitative trait loci (eQTLs) are genome sequence variants that result in gene expression changes and thus are prime suspects in the search for contributions to the causality of complex traits. When EnsembleExpr is trained on data from massively parallel reporter assays (MPRA) it accurately predicts reporter expression levels from unseen regulatory sequences and identifies sequence variants that exhibit significant changes in reporter expression...
February 21, 2017: Human Mutation
Michael A Beer
We participated in the Critical Assessment of Genome Interpretation eQTL challenge to further test computational models of regulatory variant impact and their association with human disease. Our prediction model is based on a discriminative gapped-kmer SVM (gkm-SVM) trained on genome-wide chromatin accessibility data in the cell type of interest. The comparisons with massively parallel reporter assays (MPRA) in lymphoblasts show that gkm-SVM is among the most accurate prediction models even though all other models used the MPRA data for model training, and gkm-SVM did not...
January 25, 2017: Human Mutation
Brett B Maricque, Joseph D Dougherty, Barak A Cohen
Recent large-scale genomics efforts to characterize the cis-regulatory sequences that orchestrate genome-wide expression patterns have produced impressive catalogues of putative regulatory elements. Most of these sequences have not been functionally tested, and our limited understanding of the non-coding genome prevents us from predicting which sequences are bona fide cis-regulatory elements. Recently, massively parallel reporter assays (MPRAs) have been deployed to measure the activity of putative cis-regulatory sequences in several biological contexts, each with specific advantages and distinct limitations...
October 23, 2016: Nucleic Acids Research
Jason Ernst, Alexandre Melnikov, Xiaolan Zhang, Li Wang, Peter Rogov, Tarjei S Mikkelsen, Manolis Kellis
Massively parallel reporter assays (MPRAs) enable nucleotide-resolution dissection of transcriptional regulatory regions, such as enhancers, but only few regions at a time. Here we present a combined experimental and computational approach, Systematic high-resolution activation and repression profiling with reporter tiling using MPRA (Sharpr-MPRA), that allows high-resolution analysis of thousands of regions simultaneously. Sharpr-MPRA combines dense tiling of overlapping MPRA constructs with a probabilistic graphical model to recognize functional regulatory nucleotides, and to distinguish activating and repressive nucleotides, using their inferred contribution to reporter gene expression...
November 2016: Nature Biotechnology
Ryan N Doan, Byoung-Il Bae, Beatriz Cubelos, Cindy Chang, Amer A Hossain, Samira Al-Saad, Nahit M Mukaddes, Ozgur Oner, Muna Al-Saffar, Soher Balkhy, Generoso G Gascon, Marta Nieto, Christopher A Walsh
Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations-identified by whole-genome and targeted "HAR-ome" sequencing-showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases...
October 6, 2016: Cell
Peicheng Du, Charles D Sohaskey, Lanbo Shi
Mycobacterium tuberculosis can persist for years in the hostile environment of the host in a non-replicating or slowly replicating state. While active disease predominantly results from reactivation of a latent infection, the molecular mechanisms of M. tuberculosis reactivation are still poorly understood. We characterized the physiology and global transcriptomic profiles of M. tuberculosis during reactivation from hypoxia-induced non-replicating persistence. We found that M. tuberculosis reactivation upon reaeration was associated with a lag phase, in which the recovery of cellular physiological and metabolic functions preceded the resumption of cell replication...
2016: Frontiers in Microbiology
Ilias Georgakopoulos-Soares, Naman Jain, Jesse M Gray, Martin Hemberg
MOTIVATION: With the rapid advances in DNA synthesis and sequencing technologies and the continuing decline in the associated costs, high-throughput experiments can be performed to investigate the regulatory role of thousands of oligonucleotide sequences simultaneously. Nevertheless, designing high-throughput reporter assay experiments such as massively parallel reporter assays (MPRAs) and similar methods remains challenging. RESULTS: We introduce MPRAnator, a set of tools that facilitate rapid design of MPRA experiments...
January 1, 2017: Bioinformatics
Jacob C Ulirsch, Satish K Nandakumar, Li Wang, Felix C Giani, Xiaolan Zhang, Peter Rogov, Alexandre Melnikov, Patrick McDonel, Ron Do, Tarjei S Mikkelsen, Vijay G Sankaran
Genome-wide association studies (GWAS) have successfully identified thousands of associations between common genetic variants and human disease phenotypes, but the majority of these variants are non-coding, often requiring genetic fine-mapping, epigenomic profiling, and individual reporter assays to delineate potential causal variants. We employ a massively parallel reporter assay (MPRA) to simultaneously screen 2,756 variants in strong linkage disequilibrium with 75 sentinel variants associated with red blood cell traits...
June 2, 2016: Cell
Ryan Tewhey, Dylan Kotliar, Daniel S Park, Brandon Liu, Sarah Winnicki, Steven K Reilly, Kristian G Andersen, Tarjei S Mikkelsen, Eric S Lander, Stephen F Schaffner, Pardis C Sabeti
Although studies have identified hundreds of loci associated with human traits and diseases, pinpointing causal alleles remains difficult, particularly for non-coding variants. To address this challenge, we adapted the massively parallel reporter assay (MPRA) to identify variants that directly modulate gene expression. We applied it to 32,373 variants from 3,642 cis-expression quantitative trait loci and control regions. Detection by MPRA was strongly correlated with measures of regulatory function. We demonstrate MPRA's capabilities for pinpointing causal alleles, using it to identify 842 variants showing differential expression between alleles, including 53 well-annotated variants associated with diseases and traits...
June 2, 2016: Cell
Leonardo M R Ferreira, Torsten B Meissner, Tarjei S Mikkelsen, William Mallard, Charles W O'Donnell, Tamara Tilburgs, Hannah A B Gomes, Raymond Camahort, Richard I Sherwood, David K Gifford, John L Rinn, Chad A Cowan, Jack L Strominger
HLA-G, a nonclassical HLA molecule uniquely expressed in the placenta, is a central component of fetus-induced immune tolerance during pregnancy. The tissue-specific expression of HLA-G, however, remains poorly understood. Here, systematic interrogation of the HLA-G locus using massively parallel reporter assay (MPRA) uncovered a previously unidentified cis-regulatory element 12 kb upstream of HLA-G with enhancer activity, Enhancer L Strikingly, clustered regularly-interspaced short palindromic repeats (CRISPR)/Cas9-mediated deletion of this enhancer resulted in ablation of HLA-G expression in JEG3 cells and in primary human trophoblasts isolated from placenta...
May 10, 2016: Proceedings of the National Academy of Sciences of the United States of America
Aditi Sharma, Tige Rustad, Gaurang Mahajan, Arun Kumar, Kanury V S Rao, Sharmistha Banerjee, David R Sherman, Shekhar C Mande
The 60 kDa heat shock proteins, also known as Cpn60s (GroELs) are components of the essential protein folding machinery of the cell, but are also dominant antigens in many infectious diseases. Although generally essential for cellular survival, in some organisms such as Mycobacterium tuberculosis, one or more paralogous Cpn60s are known to be dispensable. In M. tuberculosis, Cpn60.2 (GroEL2) is essential for cell survival, but the biological role of the non-essential Cpn60.1 (GroEL1) is still elusive. To understand the relevance of Cpn60...
March 2016: Tuberculosis
Xiaogang Wang, Wen Chen, Shengtao Mei, Xudong Chen
We propose an algorithm for jointly designing two phase-only masks (POMs) that allow for the encryption and noise-free retrieval of triple images. The images required for optical retrieval are first stored in quick-response (QR) codes for noise-free retrieval and flexible readout. Two sparse POMs are respectively calculated from two different images used as references for authentication based on modified Gerchberg-Saxton algorithm (GSA) and pixel extraction, and are then used as support constraints in a modified double-phase retrieval algorithm (MPRA), together with the above-mentioned QR codes...
2015: Scientific Reports
Samaneh Saedi, Masoud Youssefi, Hadi Safdari, Saman Soleimanpour, Parviz Marouzi, Kiarash Ghazvini
Advances in DNA sequencing have greatly enhanced the molecular epidemiology studies. In order to assess evolutionary and phylogenetic relation of Mycobacterium tuberculosis isolates several gene targets were evaluated. In this study, appropriate fragments of 5 highly variable genes (rpsL, mprA, lipR, katG, and fgd1 genes) were sequenced. The sequence data were analyzed with neighbor-joining method using mega and Geneious software. The phylogenetic trees analyzes revealed that the discriminatory power of lipR is much stronger than that observed in the other genes...
October 2015: Current Microbiology
Ravindranath Dhulipalla, Shruthi Bade, Appaiah Chowdary Bollepalli, Kishore Kumar Katuri, Narasimha Swamy Devulapalli, Chakrapani Swarna
OBJECTIVE: The aim of the present study was to evaluate the periodontal risk of individuals using periodontal risk assessment (PRA) model and modified PRA model. MATERIALS AND METHODS: A total of 50 patients with chronic periodontitis, age 30-60 years were selected randomly and charting of the periodontal status was performed and those who met the inclusion criteria were enrolled in the study. Parameters recorded were- percentage of sites with bleeding on probing (BOP), number of sites with pocket depths (PD) ≥ 5mm, number of the teeth lost, bone loss (BL)/age ratio, Clinical attachment loss(CAL)/age ratio, diabetic and smoking status, dental status, systemic factors like diabetes were assessed...
February 2015: Journal of Clinical and Diagnostic Research: JCDR
Xinling Hu, Xiaojing Li, Lige Huang, John Chan, Yuling Chen, Haiteng Deng, Kaixia Mi
Tuberculosis (TB) is caused by the ancient pathogen, Mycobacterium tuberculosis, and is one of the most serious infectious diseases in the world. Isoniazid (INH) is an important first-line drug for the treatment of active and latent TB. INH resistance is an increasing problem in the treatment of TB. Phenotypic resistance to INH, however, is poorly understood. In this study, we constructed a strain of Mycobacterium bovis BCG that overexpresses the latency-related universal stress protein (USP), BCG_2013, and designated this strain BCG-2013...
March 6, 2015: Journal of Proteome Research
Guangxiang Cao, Susan T Howard, Peipei Zhang, Xisheng Wang, Xiu-Lan Chen, Buka Samten, Xiuhua Pang
The regulatory mechanisms that control the ESX-1 secretion system, a key player in the pathogenesis of Mycobacterium tuberculosis, have not been fully elucidated. However, factors that regulate the ESX-1 substrate EspA usually affect ESX-1 function. Previous studies showed that espA is directly regulated by the nucleoid-associated protein EspR and the two-component system (TCS) MprAB. The PhoPR TCS also activates espA, but the direct target of PhoP was unknown. In this report, we reveal that EspR is directly regulated by MprA and PhoP-Rv, but not by PhoP-Ra...
March 2015: Microbiology
Alexandre Melnikov, Xiaolan Zhang, Peter Rogov, Li Wang, Tarjei S Mikkelsen
The genetic reporter assay is a well-established and powerful tool for dissecting the relationship between DNA sequences and their gene regulatory activities. The potential throughput of this assay has, however, been limited by the need to individually clone and assay the activity of each sequence on interest using protein fluorescence or enzymatic activity as a proxy for regulatory activity. Advances in high-throughput DNA synthesis and sequencing technologies have recently made it possible to overcome these limitations by multiplexing the construction and interrogation of large libraries of reporter constructs...
2014: Journal of Visualized Experiments: JoVE
Pouya Kheradpour, Jason Ernst, Alexandre Melnikov, Peter Rogov, Li Wang, Xiaolan Zhang, Jessica Alston, Tarjei S Mikkelsen, Manolis Kellis
Genome-wide chromatin annotations have permitted the mapping of putative regulatory elements across multiple human cell types. However, their experimental dissection by directed regulatory motif disruption has remained unfeasible at the genome scale. Here, we use a massively parallel reporter assay (MPRA) to measure the transcriptional levels induced by 145-bp DNA segments centered on evolutionarily conserved regulatory motif instances within enhancer chromatin states. We select five predicted activators (HNF1, HNF4, FOXA, GATA, NFE2L2) and two predicted repressors (GFI1, ZFP161) and measure reporter expression in erythroleukemia (K562) and liver carcinoma (HepG2) cell lines...
May 2013: Genome Research
Da Lü, Huanxin Meng, Li Xu, Ruifang Lu, Li Zhang, Zhibin Chen, Xianghui Feng, Dong Shi, Yu Tian, Xian'e Wang
BACKGROUND: Periodontal risk assessment (PRA) model was designed for risk evaluation of treated patients with periodontal disease. However, its use on generalized aggressive periodontitis (GAgP) had been scarcely reported. This study aims to investigate the association of original PRA/modified PRA (MPRA) and compliance of periodontal maintenance with long-term treatment outcomes of Chinese patients with GAgP. METHODS: Eighty-eight patients from a GAgP cohort, who completed active periodontal treatment (APT) and accepted reevaluation 3 to 11 years (mean of 5...
November 2013: Journal of Periodontology
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