Electronic medical record-integrated pharmacogenomics and related clinical decision support concepts.

Clin Pharmacol Ther. 2017 Apr 08;:

Authors: Caraballo PJ, Bielinski SJ, St Sauver JL, Weinshilboum RM

PMID: 28390138 [PubMed - as supplied by publisher]

Exploring functions of long noncoding RNAs across multiple cancers through co-expression network.

Sci Rep. 2017 Apr 07;7(1):754

Authors: Li S, Li B, Zheng Y, Li M, Shi L, Pu X

Abstract
In contrast to protein-coding genes, long-noncoding RNAs (lncRNAs) are much less well understood, despite increasing evidence indicating a wide range of their biological functions, and possible roles in various cancers. Based on public RNA-seq datasets of four solid cancer types, we here utilize Weighted Correlation Network Analysis (WGCNA) to propose a strategy for exploring the functions of lncRNAs altered in more than two cancer types, which we call onco-lncRNAs. Results indicate that cancer-expressed lncRNAs show high tissue specificity and are weakly expressed, more so than protein-coding genes. Most of the 236 onco-lncRNAs we identified have not been reported to have associations with cancers before. Our analysis exploits co-expression network to reveal that onco-lncRNAs likely play key roles in the multistep development of human cancers, covering a wide range of functions in genome stability maintenance, signaling, cell adhesion and motility, morphogenesis, cell cycle, immune and inflammatory response. These observations contribute to a more comprehensive understanding of cancer-associated lncRNAs, while demonstrating a novel and efficient strategy for subsequent functional studies of lncRNAs.

PMID: 28389669 [PubMed - in process]

Identification of IGF-1-enhanced cytokine expressions targeted by miR-181d in glioblastomas via an integrative miRNA/mRNA regulatory network analysis.

Sci Rep. 2017 Apr 07;7(1):732

Authors: Ho KH, Chen PH, Hsi E, Shih CM, Chang WC, Cheng CH, Lin CW, Chen KC

Abstract
The insulin-like growth factor (IGF)-1 signaling is relevant in regulating cell growth and cytokine secretions by glioblastomas. MicroRNAs determine the cell fate in glioblastomas. However, relationships between IGF-1 signaling and miRNAs in glioblastoma pathogenesis are still unclear. Our aim was to validate the IGF-1-mediated mRNA/miRNA regulatory network in glioblastomas. Using in silico analyses of mRNA array and RNA sequencing data from The Cancer Genome Atlas (TCGA), we identified 32 core enrichment genes that were highly associated with IGF-1-promoted cytokine-cytokine receptor interactions. To investigate the IGF-1-downregulated miRNA signature, microarray-based approaches with IGF-1-treated U87-MG cells and array data in TCGA were used. Four miRNAs, including microRNA (miR)-9-5p, miR-9-3p, miR-181d, and miR-130b, exhibited an inverse correlation with IGF-1 levels. The miR-181d, that targeted the most IGF-1-related cytokine genes, was significantly reduced in IGF-1-treated glioma cells. Statistical models incorporating both high-IGF-1 and low-miR-181d statuses better predicted poor patient survival, and can be used as an independent prognostic factor in glioblastomas. The C-C chemokine receptor type 1 (CCR1) and interleukin (IL)-1b demonstrated inverse correlations with miR-181d levels and associations with patient survival. miR-181d significantly attenuated IGF-1-upregulated CCR1 and IL-1b gene expressions. These findings demonstrate a distinct role for IGF-1 signaling in glioma progression via miR-181d/cytokine networks.

PMID: 28389653 [PubMed - in process]

Intuitive pharmacogenetic dosing of risperidone according to CYP2D6 phenotype extrapolated from genotype in a cohort of first episode psychosis patients.

Eur Neuropsychopharmacol. 2017 Apr 04;:

Authors: Mas S, Gassó P, Torra M, Bioque M, Lobo A, González-Pinto A, Olmeda MS, Corripio I, Vieta E, Castro-Fornieles J, Rodriguez-Jimenez R, Bobes J, Usall J, Llerena A, Saiz-Ruiz J, Bernardo M, Lafuente A, PEPs Group

Abstract
Risperidone (R) is the most prescribed antipsychotic drug for patients with a first episode of psychosis (FEP). In a naturalistic cohort of chronic psychiatric inpatients, we demonstrated that clinicians adjust R dosage by CYP2D6 activity, despite being blinded to the genotype, which we described as an "intuitive pharmacogenetic" process. The aim of the present study is to replicate our previous findings of intuitive pharmacogenetic in a cohort of FEP patients using CYP2D6 phenotype extrapolated from genotypes. 70 FEP patients, under baseline treatment with R monotherapy were genotyped using the iPLEX® ADME PGx multiplex panel and TaqMan® Genotyping and Copy Number Assays. Plasma concentrations of R and its metabolite, 9-hydroxyrisperidone (9-OH), were determined. The predictive properties of those variables associated with R dosage were tested using a multiple linear regression model as well as regression trees. Significant differences in the mean daily dosage of R among CYP2D6 phenotypes were observed (Kruskal-Wallis test p=0.02): PM (4.00±2.3mg/mL), IM (4.56±2.44), EM (6.22±4.0mg/day) and UM (10.20±4.91mg/day). However, non-significant differences were observed in the R/9-OH ratio or in the Concentration/Dose ratio. Regression tree provided better estimations of R dosage than the multiple linear regression model (MAE=0.958 and R(2)=0.871). We confirm the "intuitive pharmacogenetic" dosing of R according to the CYP2D6 phenotype in a FEP cohort. The results presented provides a rationale for the clinical use of CYP2D6 genotyping in personalized medicine.

PMID: 28389049 [PubMed - as supplied by publisher]

Enhanced Chemosensory Sensitivity in Idiopathic Rhinitis Patients and its Reversal by Nasal Capsaicin Treatment.

J Allergy Clin Immunol. 2017 Apr 04;:

Authors: Van Gerven L, Alpizar YA, Steelant B, Callebaut I, Kortekaas Krohn I, Wouters M, Vermeulen F, Boeckxstaens G, Talavera K, Hellings PW

Abstract
We show electrophysiological evidence for an increased chemical sensitivity in idiopathic rhinitis patients compared to healthy controls. This abnormality is decreased after capsaicin treatment, along with a reduction of symptoms.

PMID: 28389389 [PubMed - as supplied by publisher]

Vanishing Lung Syndrome in a Cystic Fibrosis Patient.

Arch Bronconeumol. 2017 Apr 04;:

Authors: Fila L, Suchanek V, Marel M

PMID: 28389031 [PubMed - as supplied by publisher]

Familial Early-Onset Paget's Disease of Bone Associated with a Novel hnRNPA2B1 Mutation.

Calcif Tissue Int. 2017 Apr 07;:

Authors: Qi X, Pang Q, Wang J, Zhao Z, Wang O, Xu L, Mao J, Jiang Y, Li M, Xing X, Yu W, Asan, Xia W

Abstract
Paget disease of bone (PDB) is a common metabolic bone disease characterized by increased bone resorption and disorganized bone formation which affect single or multiple sites of bones. Although the exact cause of PDB is still controversial, genetic factors are considered to play an important role in PDB. Several genes involved in the differentiation or function of osteoclast were shown to be associated with PDB or related syndrome such as SQSTM1, TNFRSF11A, TNFRSF11B, and ZNF687. Multisystem proteinopathy (MSP), a newly proposed syndrome including inclusion body myopathy (IBM), PDB, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), is mainly caused by mutation in VCP gene. In 2013, a new casual gene for MSP was identified as hnRNPA2B1 gene. This may partly account for the inherited PDB traits which is however negative for mutation in already known causative PDB genes. We investigated a Chinese family with multiple affected individuals with PDB, but none of the members showed symptoms of IBM, FTD, or ALS. Three patients were evaluated clinically, biochemically, and radiographically. To screen for the responsible mutation, whole-exome sequencing was conducted in the proband, another patient, as well as a normal individual from the family. This revealed a novel heterozygous missense mutation of hnRNPA2B1 gene (c.929C>T, p. P310L) in the two patients which was then verified in all affected individuals. We describe here a novel missense mutation in hnRNPA2B1 gene in a large pedigree affected with PDB with members who do not present other manifestations of multisystem proteinopathy, such as IBM, FTD, and ALS.

PMID: 28389692 [PubMed - as supplied by publisher]

Large Scale Analysis of Variation in the Insulin-like Growth Factor Family in Humans Reveals Rare Disease Links and Common Polymorphisms.

J Biol Chem. 2017 Apr 07;:

Authors: Rotwein P

Abstract
The insulin-like growth factors IGF1 and IGF2 are closely related proteins that are essential for normal growth and development in humans and other species and play critical roles in many physiological and patho-physiological processes. IGF actions are mediated by trans-membrane receptors and modulated by IGF binding proteins. The importance of IGF actions in human physiology is strengthened by the rarity of inactivating mutations in their genes, and by the devastating impact caused by such mutations on normal development and somatic growth. Large-scale genome sequencing has the potential to provide new insights into human variation and disease susceptibility. Toward this end the availability of DNA sequence data from 60,706 people through the Exome Aggregation Consortium has prompted the analyses presented here. Results reveal a broad range of potential missense and other alterations in the coding regions of every IGF family gene but the vast majority of predicted changes were uncommon. The total number of different alleles detected per gene in the population varied over an ~15-fold range, from 57 for IGF1 to 872 for IGF2R, although when corrected for protein length, the rate ranged from 0.22 to 0.59 changes/codon among the 11 genes evaluated. Previously characterized disease-causing mutations in IGF2, IGF1R, IGF2R, or IGFALS all were found in the general population, but with allele frequencies of < 1:30,000. A few new highly prevalent amino acid polymorphisms also were identified. Collectively, these data provide a wealth of opportunities to understand the intricacies of IGF signaling and action in both physiological and pathological contexts.

PMID: 28389567 [PubMed - as supplied by publisher]

A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension.

BMC Pulm Med. 2017 Apr 07;17(1):57

Authors: Higasa K, Ogawa A, Terao C, Shimizu M, Kosugi S, Yamada R, Date H, Matsubara H, Matsuda F

Abstract
BACKGROUND: Pulmonary arterial hypertension (PAH) is a severe lung disease with only few effective treatments available. Familial cases of PAH are usually recognized as an autosomal dominant disease, but incomplete penetrance of the disease makes it difficult to identify pathogenic variants in accordance with a Mendelian pattern of inheritance.
METHODS: To elucidate the complex genetic basis of PAH, we obtained whole exome- or genome-sequencing data of 17 subjects from 9 families with heritable PAH and applied gene-based association analysis with 9 index patients and 300 PAH-free controls.
RESULTS: A burden of rare variants in BMPR2 significantly contributed to the risk of the disease (p = 6.0 × 10(-8)). Eight of nine families carried four previously reported single nucleotide variants and four novel insertion/deletion variants in the gene. One of the novel variants was a large 6.5 kilobase-deletion. In the remaining one family, the patient carried a pathogenic variant in a member of potassium channels, KCNK3, which was the first replicative finding of channelopathy in an Asian population.
CONCLUSIONS: The variety of rare pathogenic variants suggests that gene-based association analysis using genome-wide sequencing data from increased number of samples is essential to tracing the genetic heterogeneity and developing an appropriate panel for genetic testing.

PMID: 28388887 [PubMed - in process]

Class-paired Fuzzy SubNETs: A paired variant of the rank-based network analysis family for feature selection based on protein complexes.

Proteomics. 2017 Apr 08;:

Authors: Goh WW, Wong L

Abstract
Identifying reproducible yet relevant protein features in proteomics data is a major challenge. Analysis at the level of protein complexes can resolve this issue and we have developed a suite of feature-selection methods collectively referred to as Rank-Based Network Analysis (RBNA). RBNAs differ in their individual statistical test setup but are similar in the sense that they deploy rank-defined weights amongst proteins per sample. This procedure is known as gene fuzzy scoring. Currently, no RBNA exists for paired-sample scenarios where both control and test tissues originate from the same source (e.g. same patient). It is expected that paired tests, when used appropriately, are more powerful than approaches intended for unpaired samples. We report that the class-paired RBNA, PPFSNET, dominates in both simulated and real data scenarios. Moreover, for the first time, we explicitly incorporate batch-effect resistance as an additional evaluation criterion for feature-selection approaches. Batch effects are class irrelevant variations arising from different handlers or processing times, and can obfuscate analysis. We demonstrate that PPFSNET and PFSNET, are particularly resistant against batch effects, and only select features strongly correlated with class but not batch. This article is protected by copyright. All rights reserved.

PMID: 28390171 [PubMed - as supplied by publisher]

Taxonomy of the order Mononegavirales: update 2017.

Arch Virol. 2017 Apr 07;:

Authors: Amarasinghe GK, Bào Y, Basler CF, Bavari S, Beer M, Bejerman N, Blasdell KR, Bochnowski A, Briese T, Bukreyev A, Calisher CH, Chandran K, Collins PL, Dietzgen RG, Dolnik O, Dürrwald R, Dye JM, Easton AJ, Ebihara H, Fang Q, Formenty P, Fouchier RA, Ghedin E, Harding RM, Hewson R, Higgins CM, Hong J, Horie M, James AP, Jiāng D, Kobinger GP, Kondo H, Kurath G, Lamb RA, Lee B, Leroy EM, Li M, Maisner A, Mühlberger E, Netesov SV, Nowotny N, Patterson JL, Payne SL, Paweska JT, Pearson MN, Randall RE, Revill PA, Rima BK, Rota P, Rubbenstroth D, Schwemmle M, Smither SJ, Song Q, Stone DM, Takada A, Terregino C, Tesh RB, Tomonaga K, Tordo N, Towner JS, Vasilakis N, Volchkov VE, Wahl-Jensen V, Walker PJ, Wang B, Wang D, Wang F, Wang LF, Werren JH, Whitfield AE, Yan Z, Ye G, Kuhn JH

Abstract
In 2017, the order Mononegavirales was expanded by the inclusion of a total of 69 novel species. Five new rhabdovirus genera and one new nyamivirus genus were established to harbor 41 of these species, whereas the remaining new species were assigned to already established genera. Furthermore, non-Latinized binomial species names replaced all paramyxovirus and pneumovirus species names, thereby accomplishing application of binomial species names throughout the entire order. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).

PMID: 28389807 [PubMed - as supplied by publisher]

Experimental evaluation of host adaptation of Lactobacillus reuteri to different vertebrate species.

Appl Environ Microbiol. 2017 Apr 07;:

Authors: Duar RM, Frese SA, Lin XB, Fernando SC, Burkey TE, Tasseva G, Peterson DA, Blom J, Wenzel CQ, Szymanski CM, Walter J

Abstract
The species Lactobacillus reuteri has diversified into host-specific lineages implying a long term association with different vertebrates. Strains from rodent lineages show specific adaptations to mice, but the processes underlying the evolution of L. reuteri in other hosts remain unknown. We administered three standardized inocula composed of strains from different host-confined lineages to mice, pigs, chickens and humans. The ecological performance of each strain in the gastrointestinal tract of each host was determined by typing random colonies recovered from fecal samples collected over five consecutive days post-administration. Results revealed that rodent strains were predominant in mice, confirming previous findings of host adaptation. In chickens, poultry strains of the lineage-VI (poultry-VI) and human isolates from the same lineage (human-VI) were recovered at the highest second highest rate, respectively. Interestingly, human-VI strains were virtually undetected in human feces. These findings together with ancestral state reconstructions indicate poultry-VI and human-VI strains share an evolutionary history with chickens. Genomic analysis revealed that poultry-VI strains possess a large and variable accessory genome, whereas human-VI strains display low genetic diversity and possess genes encoding antibiotic resistance and capsular polysaccharide synthesis which might have allowed temporal colonization of humans. Experiments in pigs and humans did not provide evidence of host-adaptation of L. reuteri to these hosts. Overall, our findings demonstrate host adaptation of L. reuteri to rodents and chickens, supporting a joint evolution of this bacterial species with several vertebrate hosts, although questions remain about its natural history in humans and pigs.IMPORTANCE Gut microbes are often hypothesized to have co-evolved with their vertebrate hosts. However, the evidence is sparse and the evolutionary mechanisms have not been identified. We developed and applied an experimental approach to determine host adaptation of L. reuteri to different hosts. Our findings confirm adaptation to rodents and provide evidence of adaptation to poultry, suggesting that L. reuteri evolved via natural selection in different hosts. By complementing phylogenetic analyses with experimental evidence, this study provides novel information about the mechanisms driving host-microbe co-evolution with vertebrates and serve as a basis to inform the application of L. reuteri as a probiotic for different host species.

PMID: 28389535 [PubMed - as supplied by publisher]

Epigenetic Regulation of KPC1 Ubiquitin Ligase Effects the NF-κB Pathway in Melanoma.

Clin Cancer Res. 2017 Apr 07;:

Authors: Iida Y, Ciechanover A, Marzese DM, Hata K, Bustos M, Ono S, Wang J, Salomon MP, Tran K, Lam S, Hsu SC, Nelson N, Kravtsova-Ivantsiv Y, Mills GB, Davies MA, Hoon DS

Abstract
PURPOSE: Abnormal activation of the NF-κB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-κB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of NF-κB pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma.
EXPERIMENTAL DESIGN: The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue micro-arrays; n=137, JWCI cohort; n=40) and The Cancer Genome Atlas database (TCGA cohort, n=370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-κB, and the epigenetic regulations of KPC1, including DNA methylation and microRNA expression.
RESULTS: We verified that KPC1 suppresses melanoma proliferation by processing NF-κB1 p105 into p50, thereby modulating NF-κB-target gene expression. Concordantly, KPC1 expression was down-regulated in AJCC stage IV melanoma compared to early stages (stage I/II p=0.013, stage III p=0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma (n=137, Hazard Ratio 1.810, p=0.006). Furthermore, our data showed that high miR-155-5p expression, which is controlled by DNA methylation at its promoter region (TCGA; Pearson's r -0.455, p<0.001), is significantly associated with KPC1 down-regulation (JWCI; p=0.028, TCGA; p=0.003).
CONCLUSIONS: This study revealed novel epigenetic regulation of KPC1 associated with NF-κB pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets.

PMID: 28389511 [PubMed - as supplied by publisher]

Kinetically accessible yield (KAY) for redirection of metabolism to produce exo-metabolites.

Metab Eng. 2017 Apr 04;:

Authors: Lafontaine Rivera JG, Theisen MK, Chen PW, Liao JC

Abstract
The product formation yield (product formed per unit substrate consumed) is often the most important performance indicator in metabolic engineering. Until now, the actual yield cannot be predicted, but it can be bounded by its maximum theoretical value. The maximum theoretical yield is calculated by considering the stoichiometry of the pathways and cofactor regeneration involved. Here we found that in many cases, dynamic stability becomes an issue when excessive pathway flux is drawn to a product. This constraint reduces the yield and renders the maximal theoretical yield too loose to be predictive. We propose a more realistic quantity, defined as the kinetically accessible yield (KAY) to predict the maximum accessible yield for a given flux alteration. KAY is either determined by the point of instability, beyond which steady states become unstable and disappear, or a local maximum before becoming unstable. Thus, KAY is the maximum flux that can be redirected for a given metabolic engineering strategy without losing stability. Strictly speaking, calculation of KAY requires complete kinetic information. With limited or no kinetic information, an Ensemble Modeling strategy can be used to determine a range of likely values for KAY, including an average prediction. We first apply the KAY concept with a toy model to demonstrate the principle of kinetic limitations on yield. We then used a full-scale E. coli model (193 reactions, 153 metabolites) and this approach was successful in E. coli for predicting production of isobutanol: the calculated KAY values are consistent with experimental data for three genotypes previously published.

PMID: 28389394 [PubMed - as supplied by publisher]

An engineering paradigm in the biomedical sciences: Knowledge as epistemic tool.

Prog Biophys Mol Biol. 2017 Apr 04;:

Authors: Boon M

Abstract
In order to deal with the complexity of biological systems and attempts to generate applicable results, current biomedical sciences are adopting concepts and methods from the engineering sciences. Philosophers of science have interpreted this as the emergence of an engineering paradigm, in particular in systems biology and synthetic biology. This article aims at the articulation of the supposed engineering paradigm by contrast with the physics paradigm that supported the rise of biochemistry and molecular biology. This articulation starts from Kuhn's notion of a disciplinary matrix, which indicates what constitutes a paradigm. It is argued that the core of the physics paradigm is its metaphysical and ontological presuppositions, whereas the core of the engineering paradigm is the epistemic aim of producing useful knowledge for solving problems external to the scientific practice. Therefore, the two paradigms involve distinct notions of knowledge. Whereas the physics paradigm entails a representational notion of knowledge, the engineering paradigm involves the notion of 'knowledge as epistemic tool'.

PMID: 28389261 [PubMed - as supplied by publisher]

Shape of my heart: cell-cell adhesion and cytoskeletal dynamics during Drosophila cardiac morphogenesis.

Exp Cell Res. 2017 Apr 04;:

Authors: McFaul CM, Fernandez-Gonzalez R

Abstract
The fruit fly Drosophila melanogaster has recently emerged as an excellent system to investigate the genetics of cardiovascular development and disease. Drosophila provides an inexpensive and genetically-tractable in vivo system with a large number of conserved features. In addition, the Drosophila embryo is transparent, and thus amenable to time-lapse fluorescence microscopy, as well as biophysical and pharmacological manipulations. One of the conserved aspects of heart development from Drosophila to humans is the initial assembly of a tube. Here, we review the cellular behaviours and molecular dynamics important for the initial steps of heart morphogenesis in Drosophila, with particular emphasis on the cell-cell adhesion and cytoskeletal networks that cardiac precursors use to move, coordinate their migration, interact with other tissues and eventually sculpt a beating heart.

PMID: 28389210 [PubMed - as supplied by publisher]

A Tunable Diffusion-Consumption Mechanism of Cytokine Propagation Enables Plasticity in Cell-to-Cell Communication in the Immune System.

Immunity. 2017 Mar 28;:

Authors: Oyler-Yaniv A, Oyler-Yaniv J, Whitlock BM, Liu Z, Germain RN, Huse M, Altan-Bonnet G, Krichevsky O

Abstract
Immune cells communicate by exchanging cytokines to achieve a context-appropriate response, but the distances over which such communication happens are not known. Here, we used theoretical considerations and experimental models of immune responses in vitro and in vivo to quantify the spatial extent of cytokine communications in dense tissues. We established that competition between cytokine diffusion and consumption generated spatial niches of high cytokine concentrations with sharp boundaries. The size of these self-assembled niches scaled with the density of cytokine-consuming cells, a parameter that gets tuned during immune responses. In vivo, we measured interactions on length scales of 80-120 μm, which resulted in a high degree of cell-to-cell variance in cytokine exposure. Such heterogeneous distributions of cytokines were a source of non-genetic cell-to-cell variability that is often overlooked in single-cell studies. Our findings thus provide a basis for understanding variability in the patterning of immune responses by diffusible factors.

PMID: 28389069 [PubMed - as supplied by publisher]

Transcriptomic buffering of cryptic genetic variation contributes to meningococcal virulence.

BMC Genomics. 2017 Apr 07;18(1):282

Authors: Ampattu BJ, Hagmann L, Liang C, Dittrich M, Schlüter A, Blom J, Krol E, Goesmann A, Becker A, Dandekar T, Müller T, Schoen C

Abstract
BACKGROUND: Commensal bacteria like Neisseria meningitidis sometimes cause serious disease. However, genomic comparison of hyperinvasive and apathogenic lineages did not reveal unambiguous hints towards indispensable virulence factors. Here, in a systems biological approach we compared gene expression of the invasive strain MC58 and the carriage strain α522 under different ex vivo conditions mimicking commensal and virulence compartments to assess the strain-specific impact of gene regulation on meningococcal virulence.
RESULTS: Despite indistinguishable ex vivo phenotypes, both strains differed in the expression of over 500 genes under infection mimicking conditions. These differences comprised in particular metabolic and information processing genes as well as genes known to be involved in host-damage such as the nitrite reductase and numerous LOS biosynthesis genes. A model based analysis of the transcriptomic differences in human blood suggested ensuing metabolic flux differences in energy, glutamine and cysteine metabolic pathways along with differences in the activation of the stringent response in both strains. In support of the computational findings, experimental analyses revealed differences in cysteine and glutamine auxotrophy in both strains as well as a strain and condition dependent essentiality of the (p)ppGpp synthetase gene relA and of a short non-coding AT-rich repeat element in its promoter region.
CONCLUSIONS: Our data suggest that meningococcal virulence is linked to transcriptional buffering of cryptic genetic variation in metabolic genes including global stress responses. They further highlight the role of regulatory elements for bacterial virulence and the limitations of model strain approaches when studying such genetically diverse species as N. meningitidis.

PMID: 28388876 [PubMed - in process]

Pgltools: a genomic arithmetic tool suite for manipulation of Hi-C peak and other chromatin interaction data.

BMC Bioinformatics. 2017 Apr 07;18(1):207

Authors: Greenwald WW, Li H, Smith EN, Benaglio P, Nariai N, Frazer KA

Abstract
BACKGROUND: Genomic interaction studies use next-generation sequencing (NGS) to examine the interactions between two loci on the genome, with subsequent bioinformatics analyses typically including annotation, intersection, and merging of data from multiple experiments. While many file types and analysis tools exist for storing and manipulating single locus NGS data, there is currently no file standard or analysis tool suite for manipulating and storing paired-genomic-loci: the data type resulting from "genomic interaction" studies. As genomic interaction sequencing data are becoming prevalent, a standard file format and tools for working with these data conveniently and efficiently are needed.
RESULTS: This article details a file standard and novel software tool suite for working with paired-genomic-loci data. We present the paired-genomic-loci (PGL) file standard for genomic-interactions data, and the accompanying analysis tool suite "pgltools": a cross platform, pypy compatible python package available both as an easy-to-use UNIX package, and as a python module, for integration into pipelines of paired-genomic-loci analyses.
CONCLUSIONS: Pgltools is a freely available, open source tool suite for manipulating paired-genomic-loci data. Source code, an in-depth manual, and a tutorial are available publicly at www.github.com/billgreenwald/pgltools , and a python module of the operations can be installed from PyPI via the PyGLtools module.

PMID: 28388874 [PubMed - in process]

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