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Recent Publications

Specifications of Standards in Systems and Synthetic Biology: Status and Developments in 2017.

Specifications of Standards in Systems and Synthetic Biology: Status and Developments in 2017.

J Integr Bioinform. 2018 Mar 29;:

Authors: Schreiber F, Bader GD, Gleeson P, Golebiewski M, Hucka M, Keating SM, Novère NL, Myers C, Nickerson D, Sommer B, Waltemath D

Abstract
Standards are essential to the advancement of Systems and Synthetic Biology. COMBINE provides a formal body and a centralised platform to help develop and disseminate relevant standards and related resources. The regular special issue of the Journal of Integrative Bioinformatics aims to support the exchange, distribution and archiving of these standards by providing unified, easily citable access. This paper provides an overview of existing COMBINE standards and presents developments of the last year.

PMID: 29596055 [PubMed - as supplied by publisher]



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QAPA: a new method for the systematic analysis of alternative polyadenylation from RNA-seq data.

Related Articles

QAPA: a new method for the systematic analysis of alternative polyadenylation from RNA-seq data.

Genome Biol. 2018 Mar 28;19(1):45

Authors: Ha KCH, Blencowe BJ, Morris Q

Abstract
Alternative polyadenylation (APA) affects most mammalian genes. The genome-wide investigation of APA has been hampered by an inability to reliably profile it using conventional RNA-seq. We describe 'Quantification of APA' (QAPA), a method that infers APA from conventional RNA-seq data. QAPA is faster and more sensitive than other methods. Application of QAPA reveals discrete, temporally coordinated APA programs during neurogenesis and that there is little overlap between genes regulated by alternative splicing and those by APA. Modeling of these data uncovers an APA sequence code. QAPA thus enables the discovery and characterization of programs of regulated APA using conventional RNA-seq.

PMID: 29592814 [PubMed - in process]



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Structural basis for the ability of MBD domains to bind methyl-CG and TG sites in DNA.

Structural basis for the ability of MBD domains to bind methyl-CG and TG sites in DNA.

J Biol Chem. 2018 Mar 22;:

Authors: Liu K, Xu C, Lei M, Yang A, Loppnau P, Hughes TR, Min J

Abstract
Cytosine methylation is a well characterized epigenetic mark and occurs at both CG and non-CG sites in DNA. Both methylated CG (mCG)- and mCH (H = A, C, or T)-containing DNAs, especially mCAC-containing DNAs, are recognized by methyl-CpG-binding protein 2 (MeCP2) to regulate gene expression in neuron development. However, the molecular mechanism involved in the binding of methyl-CpG-binding domain (MBD) of MeCP2 to these different DNA motifs is unclear. Here, we systematically characterized the DNA-binding selectivity of the MBDs in MeCP2 and MBD1-4 with isothermal titration calorimetry-based binding assays, mutagenesis studies, and X-ray crystallography. We found that the MBD domains of MeCP2 and MBD1-4<br />bind mCG-containing DNAs independently of the sequence outside the mCG dinucleotide. Moreover, some 1 MBDs bound to both methylated and unmethylated CA dinucleotide-<br />containing DNAs, with a preference for the CAC sequence motif. We also found that MBD domains bind to mCA or nonmethylated CA DNA by recognizing the complementary TG dinucleotide, which is consistent with an overlooked ligand of MeCP2, i.e., the matrix/scaffold attachment regions (MARs/SARs) with a consensus sequence of 5'-GGTGT-3', which was<br />identified in early 1990s. Our results also explain why MeCP2 exhibits similar binding affinity to both mCAand hmCA-containing dsDNAs. In summary, our results suggest that in addition to mCG sites, unmethylated CA or TG sites also serve as DNA-binding sites for MeCP2 and other MBDcontaining proteins. This discovery expands the genome-wide activity of MBD-containing proteins in gene regulation.

PMID: 29567833 [PubMed - as supplied by publisher]



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Antidepressant Use by Class: Association with Major Adverse Cardiac Events in Patients with Coronary Artery Disease.

Antidepressant Use by Class: Association with Major Adverse Cardiac Events in Patients with Coronary Artery Disease.

Psychother Psychosom. 2018 Mar 13;87(2):85-94

Authors: Grace SL, Medina-Inojosa JR, Thomas RJ, Krause H, Vickers-Douglas KS, Palmer BA, Lopez-Jimenez F

Abstract
BACKGROUND: To assess use of antidepressants by class in relation to cardiology practice recommendations, and the association of antidepressant use with the occurrence of major adverse cardiovascular events (MACE) including death.
METHODS: This is a historical cohort study of all patients who completed cardiac rehabilitation (CR) between 2002 and 2012 in a major CR center. Participants completed the Patient Health Questionnaire (PHQ-9) at the start and end of the program. A linkage system enabled ascertainment of antidepressant use and MACE through 2014.
RESULTS: There were 1,694 CR participants, 1,266 (74.7%) of whom completed the PHQ-9 after the program. Depressive symptoms decreased significantly from pre- (4.98 ± 5.20) to postprogram (3.57 ± 4.43) (p < 0.001). Overall, 433 (34.2%) participants were on antidepressants, most often selective serotonin reuptake inhibitors (SSRI; n = 299; 23.6%). The proportion of days covered was approximately 70% for all 4 major antidepressant classes; discontinuation rates ranged from 37.3% for tricyclics to 53.2% for serotonin-norepinephrine reuptake inhibitors (SNRI). Antidepressant use was significantly associated with lower depressive symptoms after CR (before, 7.33 ± 5.94 vs. after, 4.69 ± 4.87; p < 0.001). After a median follow-up of 4.7 years, 264 (20.9%) participants had a MACE. After propensity matching based on pre-CR depressive symptoms among other variables, participants taking tricyclics had significantly more MACE than those not taking tricyclics (HR = 2.46; 95% CI 1.37-4.42), as well as those taking atypicals versus not (HR = 1.59; 95% CI 1.05-2.41) and those on SSRI (HR = 1.45; 95% CI 1.07-1.97). There was no increased risk with use of SNRI (HR = 0.89; 95% CI 0.43-1.82).
CONCLUSION: The use of antidepressants was associated with lower depression, but the use of all antidepressants except SNRI was associated with more adverse events.

PMID: 29533962 [PubMed - as supplied by publisher]



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Reply to Comment on "Adult skin-derived precursor Schwann cell grafts form growths in the injured spinal cord of Fischer rats".

Reply to Comment on "Adult skin-derived precursor Schwann cell grafts form growths in the injured spinal cord of Fischer rats".

Biomed Mater. 2018 Mar 13;:

Authors: May Z, Fuehrman T, Shoichet MS, Tetzlaff W, Biernaskie J, Fouad K

Abstract
letter of response.

PMID: 29532786 [PubMed - as supplied by publisher]



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Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity.

Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity.

Cell. 2018 Mar 05;:

Authors: Kayatekin C, Amasino A, Gaglia G, Flannick J, Bonner JM, Fanning S, Narayan P, Barrasa MI, Pincus D, Landgraf D, Nelson J, Hesse WR, Costanzo M, AMP T2D-GENES Consortium, Myers CL, Boone C, Florez JC, Lindquist S

Abstract
Aggregates of human islet amyloid polypeptide (IAPP) in the pancreas of patients with type 2 diabetes (T2D) are thought to contribute to β cell dysfunction and death. To understand how IAPP harms cells and how this might be overcome, we created a yeast model of IAPP toxicity. Ste24, an evolutionarily conserved protease that was recently reported to degrade peptides stuck within the translocon between the cytoplasm and the endoplasmic reticulum, was the strongest suppressor of IAPP toxicity. By testing variants of the human homolog, ZMPSTE24, with varying activity levels, the rescue of IAPP toxicity proved to be directly proportional to the declogging efficiency. Clinically relevant ZMPSTE24 variants identified in the largest database of exomes sequences derived from T2D patients were characterized using the yeast model, revealing 14 partial loss-of-function variants, which were enriched among diabetes patients over 2-fold. Thus, clogging of the translocon by IAPP oligomers may contribute to β cell failure.

PMID: 29526462 [PubMed - as supplied by publisher]



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Convenience versus Biological Significance: Are PMA-Differentiated THP-1 Cells a Reliable Substitute for Blood-Derived Macrophages When Studying in Vitro Polarization?

Convenience versus Biological Significance: Are PMA-Differentiated THP-1 Cells a Reliable Substitute for Blood-Derived Macrophages When Studying in Vitro Polarization?

Front Pharmacol. 2018;9:71

Authors: Tedesco S, De Majo F, Kim J, Trenti A, Trevisi L, Fadini GP, Bolego C, Zandstra PW, Cignarella A, Vitiello L

Abstract
Human peripheral-blood monocytes are used as an established in vitro system for generating macrophages. For several reasons, monocytic cell lines such as THP-1 have been considered as a possible alternative. In view of their distinct developmental origins and phenotypic attributes, we set out to assess the extent to which human monocyte-derived macrophages (MDMs) and phorbol-12-myristate-13-acetate (PMA)-differentiated THP-1 cells were overlapping across a variety of responses to activating stimuli. Resting (M0) macrophages were polarized toward M1 or M2 phenotypes by 48-h incubation with LPS (1 μg/ml) and IFN-γ (10 ng/ml) or with IL-4 (20 ng/ml) and IL-13 (5 ng/ml), respectively. At the end of stimulation, MDMs displayed more pronounced changes in marker gene expression than THP-1. Upon assaying an array of 41 cytokines, chemokines and growth factors in conditioned media (CM) using the Luminex technology, secretion of 29 out of the 41 proteins was affected by polarized activation. While in 12 of them THP-1 and MDM showed comparable trends, for the remaining 17 proteins their responses to activating stimuli did markedly differ. Quantitative comparison for selected analytes confirmed this pattern. In terms of phenotypic activation markers, measured by flow cytometry, M1 response was similar but the established MDM M2 marker CD163 was undetectable in THP-1 cells. In a beads-based assay, MDM activation did not induce significant changes, whereas M2 activation of THP-1 decreased phagocytic activity compared to M0 and M1. In further biological activity tests, both MDM and THP-1 CM failed to affect proliferation of mouse myogenic progenitors, whereas they both reduced adipogenic differentiation of mouse fibro-adipogenic progenitor cells (M2 to a lesser extent than M1 and M0). Finally, migration of human umbilical vein endothelial cells was enhanced by CM irrespective of cell type and activation state except for M0 CM from MDMs. In summary, PMA-differentiated THP-1 macrophages did not entirely reproduce the response spectrum of primary MDMs to activating stimuli. We suggest that THP-1 be regarded as a simplified model of human macrophages when investigating relatively straightforward biological processes, such as polarization and its functional implications, but not as an alternative source in more comprehensive immunopharmacology and drug screening programs.

PMID: 29520230 [PubMed]



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Highly multiplexed and quantitative cell-surface protein profiling using genetically barcoded antibodies.

Highly multiplexed and quantitative cell-surface protein profiling using genetically barcoded antibodies.

Proc Natl Acad Sci U S A. 2018 Feb 23;:

Authors: Pollock SB, Hu A, Mou Y, Martinko AJ, Julien O, Hornsby M, Ploder L, Adams JJ, Geng H, Müschen M, Sidhu SS, Moffat J, Wells JA

Abstract
Human cells express thousands of different surface proteins that can be used for cell classification, or to distinguish healthy and disease conditions. A method capable of profiling a substantial fraction of the surface proteome simultaneously and inexpensively would enable more accurate and complete classification of cell states. We present a highly multiplexed and quantitative surface proteomic method using genetically barcoded antibodies called phage-antibody next-generation sequencing (PhaNGS). Using 144 preselected antibodies displayed on filamentous phage (Fab-phage) against 44 receptor targets, we assess changes in B cell surface proteins after the development of drug resistance in a patient with acute lymphoblastic leukemia (ALL) and in adaptation to oncogene expression in a Myc-inducible Burkitt lymphoma model. We further show PhaNGS can be applied at the single-cell level. Our results reveal that a common set of proteins including FLT3, NCR3LG1, and ROR1 dominate the response to similar oncogenic perturbations in B cells. Linking high-affinity, selective, genetically encoded binders to NGS enables direct and highly multiplexed protein detection, comparable to RNA-sequencing for mRNA. PhaNGS has the potential to profile a substantial fraction of the surface proteome simultaneously and inexpensively to enable more accurate and complete classification of cell states.

PMID: 29476010 [PubMed - as supplied by publisher]



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Whole transcriptome analysis reveals differential gene expression profile reflecting macrophage polarization in response to influenza A H5N1 virus infection.

Whole transcriptome analysis reveals differential gene expression profile reflecting macrophage polarization in response to influenza A H5N1 virus infection.

BMC Med Genomics. 2018 Feb 23;11(1):20

Authors: Zhang N, Bao YJ, Tong AH, Zuyderduyn S, Bader GD, Malik Peiris JS, Lok S, Lee SM

Abstract
BACKGROUND: Avian influenza A H5N1 virus can cause lethal disease in humans. The virus can trigger severe pneumonia and lead to acute respiratory distress syndrome. Data from clinical, in vitro and in vivo suggest that virus-induced cytokine dysregulation could be a contributory factor to the pathogenesis of human H5N1 disease. However, the precise mechanism of H5N1 infection eliciting the unique host response are still not well understood.
METHODS: To obtain a better understanding of the molecular events at the earliest time points, we used RNA-Seq to quantify and compare the host mRNA and miRNA transcriptomes induced by the highly pathogenic influenza A H5N1 (A/Vietnam/3212/04) or low virulent H1N1 (A/Hong Kong/54/98) viruses in human monocyte-derived macrophages at 1-, 3-, and 6-h post infection.
RESULTS: Our data reveals that two macrophage populations corresponding to M1 (classically activated) and M2 (alternatively activated) macrophage subtypes respond distinctly to H5N1 virus infection when compared to H1N1 virus or mock infection, a distinction that could not be made from previous microarray studies. When this confounding variable is considered in our statistical model, a clear set of dysregulated genes and pathways emerges specifically in H5N1 virus-infected macrophages at 6-h post infection, whilst was not found with H1N1 virus infection. Furthermore, altered expression of genes in these pathways, which have been previously implicated in viral host response, occurs specifically in the M1 subtype. We observe a significant up-regulation of genes in the RIG-I-like receptor signaling pathway. In particular, interferons, and interferon-stimulated genes are broadly affected. The negative regulators of interferon signaling, the suppressors of cytokine signaling, SOCS-1 and SOCS-3, were found to be markedly up-regulated in the initial round of H5N1 virus replication. Elevated levels of these suppressors could lead to the eventual suppression of cellular antiviral genes, contributing to pathophysiology of H5N1 virus infection.
CONCLUSIONS: Our study provides important mechanistic insights into the understanding of H5N1 viral pathogenesis and the multi-faceted host immune responses. The dysregulated genes could be potential candidates as therapeutic targets for treating H5N1 disease.

PMID: 29475453 [PubMed - in process]



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Angiogenic patterning by STEEL, an endothelial-enriched long noncoding RNA.

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Angiogenic patterning by STEEL, an endothelial-enriched long noncoding RNA.

Proc Natl Acad Sci U S A. 2018 Feb 21;:

Authors: Man HSJ, Sukumar AN, Lam GC, Turgeon PJ, Yan MS, Ku KH, Dubinsky MK, Ho JJD, Wang JJ, Das S, Mitchell N, Oettgen P, Sefton MV, Marsden PA

Abstract
Endothelial cell (EC)-enriched protein coding genes, such as endothelial nitric oxide synthase (eNOS), define quintessential EC-specific physiologic functions. It is not clear whether long noncoding RNAs (lncRNAs) also define cardiovascular cell type-specific phenotypes, especially in the vascular endothelium. Here, we report the existence of a set of EC-enriched lncRNAs and define a role for spliced-transcript endothelial-enriched lncRNA (STEEL) in angiogenic potential, macrovascular/microvascular identity, and shear stress responsiveness. STEEL is expressed from the terminus of the HOXD locus and is transcribed antisense to HOXD transcription factors. STEEL RNA increases the number and integrity of de novo perfused microvessels in an in vivo model and augments angiogenesis in vitro. The STEEL RNA is polyadenylated, nuclear enriched, and has microvascular predominance. Functionally, STEEL regulates a number of genes in diverse ECs. Of interest, STEEL up-regulates both eNOS and the transcription factor Kruppel-like factor 2 (KLF2), and is subject to feedback inhibition by both eNOS and shear-augmented KLF2. Mechanistically, STEEL up-regulation of eNOS and KLF2 is transcriptionally mediated, in part, via interaction of chromatin-associated STEEL with the poly-ADP ribosylase, PARP1. For instance, STEEL recruits PARP1 to the KLF2 promoter. This work identifies a role for EC-enriched lncRNAs in the phenotypic adaptation of ECs to both body position and hemodynamic forces and establishes a newer role for lncRNAs in the transcriptional regulation of EC identity.

PMID: 29467285 [PubMed - as supplied by publisher]



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