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1.  Correlations in the population structure of music, genes and language 
We present, to our knowledge, the first quantitative evidence that music and genes may have coevolved by demonstrating significant correlations between traditional group-level folk songs and mitochondrial DNA variation among nine indigenous populations of Taiwan. These correlations were of comparable magnitude to those between language and genes for the same populations, although music and language were not significantly correlated with one another. An examination of population structure for genetics showed stronger parallels to music than to language. Overall, the results suggest that music might have a sufficient time-depth to retrace ancient population movements and, additionally, that it might be capturing different aspects of population history than language. Music may therefore have the potential to serve as a novel marker of human migrations to complement genes, language and other markers.
doi:10.1098/rspb.2013.2072
PMCID: PMC3843827  PMID: 24225453
music; genes; language; population structure; coevolution; Taiwan
2.  Circadian Variation of the Human Metabolome Captured by Real-Time Breath Analysis 
PLoS ONE  2014;9(12):e114422.
Circadian clocks play a significant role in the correct timing of physiological metabolism, and clock disruption might lead to pathological changes of metabolism. One interesting method to assess the current state of metabolism is metabolomics. Metabolomics tries to capture the entirety of small molecules, i.e. the building blocks of metabolism, in a given matrix, such as blood, saliva or urine. Using mass spectrometric approaches we and others have shown that a significant portion of the human metabolome in saliva and blood exhibits circadian modulation; independent of food intake or sleep/wake rhythms. Recent advances in mass spectrometry techniques have introduced completely non-invasive breathprinting; a method to instantaneously assess small metabolites in human breath. In this proof-of-principle study, we extend these findings about the impact of circadian clocks on metabolomics to exhaled breath. As previously established, our method allows for real-time analysis of a rich matrix during frequent non-invasive sampling. We sampled the breath of three healthy, non-smoking human volunteers in hourly intervals for 24 hours during total sleep deprivation, and found 111 features in the breath of all individuals, 36–49% of which showed significant circadian variation in at least one individual. Our data suggest that real-time mass spectrometric "breathprinting" has high potential to become a useful tool to understand circadian metabolism, and develop new biomarkers to easily and in real-time assess circadian clock phase and function in experimental and clinical settings.
doi:10.1371/journal.pone.0114422
PMCID: PMC4278702  PMID: 25545545
3.  Discovery, design and synthesis of a selective S1P3 receptor allosteric agonist 
Potent and selective S1P3 receptor (S1P3-R) agonists may represent important proof-of-principle tools used to clarify the receptor biological function and assess the therapeutic potential of the S1P3-R in cardiovascular, inflammatory and pulmonary diseases. N,N-Dicyclohexyl-5-propylisoxazole-3-carboxamide was identified by a high-throughput screening of MLSMR library as a promising S1P3-R agonist. Rational chemical modifications of the hit allowed the identification of N,N-dicyclohexyl-5-cyclopropylisoxazole-3-carboxamide, a S1P3-R agonist endowed with submicromolar activity and exquisite selectivity over the remaining S1P1,2,4,5-R family members. A combination of ligand competition, site-directed mutagenesis and molecular modeling studies showed that the N,N-dicyclohexyl-5-cyclopropylisoxazole-3-carboxamide is an allosteric agonist and binds to the S1P3-R in a manner that does not disrupt the S1P3-R–S1P binding. The lead molecule herein disclosed constitutes a valuable pharmacological tool to explore the molecular basis of the receptor function, and provides the bases for further rational design of more potent and drug-like S1P3-R allosteric agonists.
doi:10.1016/j.bmcl.2013.09.075
PMCID: PMC3963471  PMID: 24135724
S1P3 receptor; Allosteric agonist; Cardiovascular functions
4.  Draft Genome Sequence of Pseudoalteromonas sp. Strain ND6B, an Oil-Degrading Isolate from Eastern Mediterranean Sea Water Collected at a Depth of 1,210 Meters 
Genome Announcements  2014;2(6):e01212-14.
Here, we report the draft genome of Pseudoalteromonas sp. strain ND6B, which is able to grow with crude oil as a carbon source. Strain ND6B was isolated from eastern Mediterranean Sea deep water at a depth of 1,210 m. The genome of strain ND6B provides insight into the oil-degrading ability of the Pseudoalteromonas species.
doi:10.1128/genomeA.01212-14
PMCID: PMC4246160  PMID: 25428968
5.  Draft Genome Sequence of Thalassotalea sp. Strain ND16A Isolated from Eastern Mediterranean Sea Water Collected from a Depth of 1,055 Meters 
Genome Announcements  2014;2(6):e01231-14.
Thalassotalea sp. strain ND16A belongs to the family Colwelliaceae and was isolated from eastern Mediterranean Sea water at a depth of 1,055 m. Members of Colwelliaceae are ubiquitous marine heterotrophs. Here, we report the draft genome sequence of Thalassotalea sp. strain ND16A, a member of the newly described genus Thalassotalea.
doi:10.1128/genomeA.01231-14
PMCID: PMC4246168  PMID: 25428976
6.  Comparative In Vitro Toxicity Profile of Electronic and Tobacco Cigarettes, Smokeless Tobacco and Nicotine Replacement Therapy Products: E-Liquids, Extracts and Collected Aerosols 
The use of electronic cigarettes (e-cigs) continues to increase worldwide in parallel with accumulating information on their potential toxicity and safety. In this study, an in vitro battery of established assays was used to examine the cytotoxicity, mutagenicity, genotoxicity and inflammatory responses of certain commercial e-cigs and compared to tobacco burning cigarettes, smokeless tobacco (SLT) products and a nicotine replacement therapy (NRT) product. The toxicity evaluation was performed on e-liquids and pad-collected aerosols of e-cigs, pad-collected smoke condensates of tobacco cigarettes and extracts of SLT and NRT products. In all assays, exposures with e-cig liquids and collected aerosols, at the doses tested, showed no significant activity when compared to tobacco burning cigarettes. Results for the e-cigs, with and without nicotine in two evaluated flavor variants, were very similar in all assays, indicating that the presence of nicotine and flavors, at the levels tested, did not induce any cytotoxic, genotoxic or inflammatory effects. The present findings indicate that neither the e-cig liquids and collected aerosols, nor the extracts of the SLT and NRT products produce any meaningful toxic effects in four widely-applied in vitro test systems, in which the conventional cigarette smoke preparations, at comparable exposures, are markedly cytotoxic and genotoxic.
doi:10.3390/ijerph111111325
PMCID: PMC4245615  PMID: 25361047
e-cigarette; snus; snuff; e-liquid; aerosol; cytotoxicity; mutagenicity; inflammation; condensate; in vitro
7.  The Neural Basis of Mark Making: A Functional MRI Study of Drawing 
PLoS ONE  2014;9(10):e108628.
Compared to most other forms of visually-guided motor activity, drawing is unique in that it “leaves a trail behind” in the form of the emanating image. We took advantage of an MRI-compatible drawing tablet in order to examine both the motor production and perceptual emanation of images. Subjects participated in a series of mark making tasks in which they were cued to draw geometric patterns on the tablet's surface. The critical comparison was between when visual feedback was displayed (image generation) versus when it was not (no image generation). This contrast revealed an occipito-parietal stream involved in motion-based perception of the emerging image, including areas V5/MT+, LO, V3A, and the posterior part of the intraparietal sulcus. Interestingly, when subjects passively viewed animations of visual patterns emerging on the projected surface, all of the sensorimotor network involved in drawing was strongly activated, with the exception of the primary motor cortex. These results argue that the origin of the human capacity to draw and write involves not only motor skills for tool use but also motor-sensory links between drawing movements and the visual images that emanate from them in real time.
doi:10.1371/journal.pone.0108628
PMCID: PMC4182721  PMID: 25271440
8.  Insights into acetate toxicity in Zymomonas mobilis 8b using different substrates 
Biotechnology for Biofuels  2014;7(1):140.
Background
Lignocellulosic biomass is a promising renewable feedstock for biofuel production. Acetate is one of the major inhibitors liberated from hemicelluloses during hydrolysis. An understanding of the toxic effects of acetate on the fermentation microorganism and the efficient utilization of mixed sugars of glucose and xylose in the presence of hydrolysate inhibitors is crucial for economic biofuel production.
Results
A new microarray was designed including both coding sequences and intergenic regions to investigate the acetate stress responses of Zymomonas mobilis 8b when using single carbon sources of glucose or xylose, or mixed sugars of both glucose and xylose. With the supplementation of exogenous acetate, 8b can utilize all the glucose with a similar ethanol yield, although the growth, final biomass, and ethanol production rate were reduced. However, xylose utilization was inhibited in both media containing xylose or a mixed sugar of glucose and xylose, although the performance of 8b was better in mixed sugar than xylose-only media. The presence of acetate caused genes related to biosynthesis, the flagellar system, and glycolysis to be downregulated, and genes related to stress responses and energy metabolism to be upregulated. Unexpectedly, xylose seems to pose more stress on 8b, recruiting more genes for xylose utilization, than does acetate. Several gene candidates based on transcriptome results were selected for genetic manipulation, and a TonB-dependent receptor knockout mutant was confirmed to have a slight advantage regarding acetate tolerance.
Conclusions
Our results indicate Z. mobilis utilized a different mechanism for xylose utilization, with an even more severe impact on Z. mobilis than that caused by acetate treatment. Our study also suggests redox imbalance caused by stressful conditions may trigger a metabolic reaction leading to the accumulation of toxic intermediates such as xylitol, but Z. mobilis manages its carbon and energy metabolism through the control of individual reactions to mitigate the stressful conditions. We have thus provided extensive transcriptomic datasets and gained insights into the molecular responses of Z. mobilis to the inhibitor acetate when grown in different sugar sources, which will facilitate future metabolic modeling studies and strain improvement efforts for better xylose utilization and acetate tolerance.
Electronic supplementary material
The online version of this article (doi:10.1186/s13068-014-0140-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13068-014-0140-8
PMCID: PMC4189746  PMID: 25298783
9.  Complete Genome Sequence of Pelosinus sp. Strain UFO1 Assembled Using Single-Molecule Real-Time DNA Sequencing Technology 
Genome Announcements  2014;2(5):e00881-14.
Pelosinus species can reduce metals such as Fe(III), U(VI), and Cr(VI) and have been isolated from diverse geographical regions. Five draft genome sequences have been published. We report the complete genome sequence for Pelosinus sp. strain UFO1 using only PacBio DNA sequence data and without manual finishing.
doi:10.1128/genomeA.00881-14
PMCID: PMC4155594  PMID: 25189589
10.  A Sphingosine 1-phosphate receptor 2 selective allosteric agonist 
Bioorganic & medicinal chemistry  2013;21(17):5373-5382.
Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-κB-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other S1P receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound.
doi:10.1016/j.bmc.2013.06.012
PMCID: PMC3786410  PMID: 23849205
11.  Transcriptomic analysis of Clostridium thermocellum Populus hydrolysate-tolerant mutant strain shows increased cellular efficiency in response to Populus hydrolysate compared to the wild type strain 
BMC Microbiology  2014;14:215.
Background
The thermophilic, anaerobic bacterium, Clostridium thermocellum is a model organism for consolidated processing due to its efficient fermentation of cellulose. Constituents of dilute acid pretreatment hydrolysate are known to inhibit C. thermocellum and other microorganisms. To evaluate the biological impact of this type of hydrolysate, a transcriptomic analysis of growth in hydrolysate-containing medium was conducted on 17.5% v/v Populus hydrolysate-tolerant mutant (PM) and wild type (WT) strains of C. thermocellum.
Results
In two levels of Populus hydrolysate medium (0% and 10% v/v), the PM showed both gene specific increases and decreases of gene expression compared to the wild-type strain. The PM had increased expression of genes in energy production and conversion, and amino acid transport and metabolism in both standard and 10% v/v Populus hydrolysate media. In particular, expression of the histidine metabolism increased up to 100 fold. In contrast, the PM decreased gene expression in cell division and sporulation (standard medium only), cell defense mechanisms, cell envelope, cell motility, and cellulosome in both media. The PM downregulated inorganic ion transport and metabolism in standard medium but upregulated it in the hydrolysate media when compared to the WT. The WT differentially expressed 1072 genes in response to the hydrolysate medium which included increased transcription of cell defense mechanisms, cell motility, and cellulosome, and decreased expression in cell envelope, amino acid transport and metabolism, inorganic ion transport and metabolism, and lipid metabolism, while the PM only differentially expressed 92 genes. The PM tolerates up to 17.5% v/v Populus hydrolysate and growth in it elicited 489 genes with differential expression, which included increased expression in energy production and conversion, cellulosome production, and inorganic ion transport and metabolism and decreased expression in transcription and cell defense mechanisms.
Conclusion
These results suggest the mechanisms of tolerance for the Populus hydrolysate-tolerant mutant strain of C. thermocellum are based on increased cellular efficiency caused apparently by downregulation of non-critical genes and increasing the expression of genes in energy production and conversion rather than tolerance to specific hydrolysate components. The wild type, conversely, responds to hydrolysate media by down-regulating growth genes and up-regulating stress response genes.
doi:10.1186/s12866-014-0215-5
PMCID: PMC4236516  PMID: 25128475
Clostridium thermocellum; Populus hydrolysate; Inhibitor tolerance; Gene expression; Transcriptomic; RNA-seq; Consolidated bioprocessing
12.  Integrated Metagenomics and Metatranscriptomics Analyses of Root-Associated Soil from Transgenic Switchgrass 
Genome Announcements  2014;2(4):e00777-14.
The benefits of using transgenic switchgrass with decreased levels of caffeic acid 3-O-methyltransferase (COMT) as biomass feedstock have been clearly demonstrated. However, its effect on the soil microbial community has not been assessed. Here we report metagenomic and metatranscriptomic analyses of root-associated soil from COMT switchgrass compared with nontransgenic counterparts.
doi:10.1128/genomeA.00777-14
PMCID: PMC4132618  PMID: 25125642
13.  Improved Draft Genome Sequence of Clostridium pasteurianum Strain ATCC 6013 (DSM 525) Using a Hybrid Next-Generation Sequencing Approach 
Genome Announcements  2014;2(4):e00790-14.
We present an improved draft genome sequence for Clostridium pasteurianum strain ATCC 6013 (DSM 525), the type strain of the species and an important solventogenic bacterium with industrial potential. Availability of a near-complete genome sequence will enable strain engineering of this promising bacterium.
doi:10.1128/genomeA.00790-14
PMCID: PMC4125779  PMID: 25103768
14.  New Model for Electron Flow for Sulfate Reduction in Desulfovibrio alaskensis G20 
To understand the energy conversion activities of the anaerobic sulfate-reducing bacteria, it is necessary to identify the components involved in electron flow. The importance of the abundant type I tetraheme cytochrome c3 (TpIc3) as an electron carrier during sulfate respiration was questioned by the previous isolation of a null mutation in the gene encoding TpIc3, cycA, in Desulfovibrio alaskensis G20. Whereas respiratory growth of the CycA mutant with lactate and sulfate was little affected, growth with pyruvate and sulfate was significantly impaired. We have explored the phenotype of the CycA mutant through physiological tests and transcriptomic and proteomic analyses. Data reported here show that electrons from pyruvate oxidation do not reach adenylyl sulfate reductase, the enzyme catalyzing the first redox reaction during sulfate reduction, in the absence of either CycA or the type I cytochrome c3:menaquinone oxidoreductase transmembrane complex, QrcABCD. In contrast to the wild type, the CycA and QrcA mutants did not grow with H2 or formate and sulfate as the electron acceptor. Transcriptomic and proteomic analyses of the CycA mutant showed that transcripts and enzymes for the pathway from pyruvate to succinate were strongly decreased in the CycA mutant regardless of the growth mode. Neither the CycA nor the QrcA mutant grew on fumarate alone, consistent with the omics results and a redox regulation of gene expression. We conclude that TpIc3 and the Qrc complex are D. alaskensis components essential for the transfer of electrons released in the periplasm to reach the cytoplasmic adenylyl sulfate reductase and present a model that may explain the CycA phenotype through confurcation of electrons.
doi:10.1128/AEM.02963-13
PMCID: PMC3911205  PMID: 24242254
15.  Chronopharmacology: New Insights and Therapeutic Implications 
Annual review of pharmacology and toxicology  2013;54:10.1146/annurev-pharmtox-011613-135923.
1 Abstract
Most facets of mammalian physiology and behavior vary according to time-of-day thanks to an endogenous “circadian” clock. Therefore, it is not surprising that many aspects of pharmacology and toxicology also oscillate according to the same 24-hour clocks. Daily oscillations in abundance of proteins necessary for either drug absorption or metabolism result in circadian pharmacokinetics; and oscillations in the physiological systems targeted by these drugs result in circadian pharmacodynamics. These clocks are present in most cells of the body, but organized in hierarchical fashion. Interestingly, some aspects of physiology and behavior are controlled directly via a “master clock” in the suprachiasmatic nuclei of the hypothalamus, while others are controlled by “slave” oscillators in separate brain regions or body tissues. Recent research shows that these clocks can respond to different cues, and thereby show different phase relationships. Therefore, full prediction of chronopharmacology in pathological contexts will likely require a systems biology approach considering “chrono-interactions” among different clock-regulated systems.
doi:10.1146/annurev-pharmtox-011613-135923
PMCID: PMC3885389  PMID: 24160700
circadian rhythms; drug metabolism; chronotherapy; cancer; peripheral oscillators; systems biology
16.  Draft Genome Sequence of the Lignin-Degrading Burkholderia sp. Strain LIG30, Isolated from Wet Tropical Forest Soil 
Genome Announcements  2014;2(3):e00637-14.
Burkholderia species are common soil Betaproteobacteria capable of degrading recalcitrant aromatic compounds and xenobiotics. Burkholderia sp. strain LIG30 was isolated from wet tropical forest soil and is capable of utilizing lignin as a sole carbon source. Here we report the draft genome sequence of Burkholderia sp. strain LIG30.
doi:10.1128/genomeA.00637-14
PMCID: PMC4064042  PMID: 24948777
17.  Evaluation and validation of de novo and hybrid assembly techniques to derive high-quality genome sequences 
Bioinformatics  2014;30(19):2709-2716.
Motivation: To assess the potential of different types of sequence data combined with de novo and hybrid assembly approaches to improve existing draft genome sequences.
Results: Illumina, 454 and PacBio sequencing technologies were used to generate de novo and hybrid genome assemblies for four different bacteria, which were assessed for quality using summary statistics (e.g. number of contigs, N50) and in silico evaluation tools. Differences in predictions of multiple copies of rDNA operons for each respective bacterium were evaluated by PCR and Sanger sequencing, and then the validated results were applied as an additional criterion to rank assemblies. In general, assemblies using longer PacBio reads were better able to resolve repetitive regions. In this study, the combination of Illumina and PacBio sequence data assembled through the ALLPATHS-LG algorithm gave the best summary statistics and most accurate rDNA operon number predictions. This study will aid others looking to improve existing draft genome assemblies.
Availability and implementation: All assembly tools except CLC Genomics Workbench are freely available under GNU General Public License.
Contact: brownsd@ornl.gov
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu391
PMCID: PMC4173024  PMID: 24930142
18.  Emergence in the central nervous system 
Cognitive Neurodynamics  2012;7(3):173-195.
“Emergence” is an idea that has received much attention in consciousness literature, but it is difficult to find characterizations of that concept which are both specific and useful. I will precisely define and characterize a type of epistemic (“weak”) emergence and show that it is a property of some neural circuits throughout the CNS, on micro-, meso- and macroscopic levels. I will argue that possession of this property can result in profoundly altered neural dynamics on multiple levels in cortex and other systems. I will first describe emergent neural entities (ENEs) abstractly. I will then show how ENEs function specifically and concretely, and demonstrate some implications of this type of emergence for the CNS.
doi:10.1007/s11571-012-9229-6
PMCID: PMC3654151  PMID: 24427200
Emergence; Internal viewpoint; Recurrence; Recursive; Gamma; Theta; Microcircuit; Mesoscopic; Mushroom body
19.  Exploring the Frontier of Electronic Health Record Surveillance: The Case of Post-Operative Complications 
Medical care  2013;51(6):509-516.
Background
The aim of this study was to build electronic algorithms using a combination of structured data and natural language processing (NLP) of text notes for potential safety surveillance of nine post-operative complications.
Methods
Post-operative complications from six medical centers in the Southeastern United States were obtained from the Veterans Affairs Surgical Quality Improvement Program (VASQIP) registry. Development and test datasets were constructed using stratification by facility and date of procedure for patients with and without complication. Algorithms were developed from VASQIP outcome definitions using NLP coded concepts, regular expressions, and structured data. The VASQIP nurse reviewer served as the reference standard for evaluating sensitivity and specificity. The algorithms were designed in the development and evaluated in the test dataset.
Results
Sensitivity and specificity in the test set were 85% and 92% for acute renal failure, 80% and 93% for sepsis, 56% and 94% for deep vein thrombosis, 80% and 97% for pulmonary embolism, 88% and 89% for acute myocardial infarction, 88% and 92% for cardiac arrest, 80% and 90% for pneumonia, 95% and 80% for urinary tract infection, and 80% and 93% for wound infection, respectively. A third of the complications occurred outside of the hospital setting.
Conclusions
Computer algorithms on data extracted from the electronic health record produced respectable sensitivity and specificity across a large sample of patients seen in six different medical centers. This study demonstrates the utility of combining natural language processing with structured data for mining the information contained within the electronic health record.
doi:10.1097/MLR.0b013e31828d1210
PMCID: PMC3658153  PMID: 23673394
surgical complications; adverse events; patient safety; electronic surveillance; natural language processing; text mining
20.  Elucidation of Zymomonas mobilis physiology and stress responses by quantitative proteomics and transcriptomics 
Zymomonas mobilis is an excellent ethanologenic bacterium. Biomass pretreatment and saccharification provides access to simple sugars, but also produces inhibitors such as acetate and furfural. Our previous work has identified and confirmed the genetic change of a 1.5-kb deletion in the sodium acetate tolerant Z. mobilis mutant (AcR) leading to constitutively elevated expression of a sodium proton antiporter encoding gene nhaA, which contributes to the sodium acetate tolerance of AcR mutant. In this study, we further investigated the responses of AcR and wild-type ZM4 to sodium acetate stress in minimum media using both transcriptomics and a metabolic labeling approach for quantitative proteomics the first time. Proteomic measurements at two time points identified about eight hundreds proteins, or about half of the predicted proteome. Extracellular metabolite analysis indicated AcR overcame the acetate stress quicker than ZM4 with a concomitant earlier ethanol production in AcR mutant, although the final ethanol yields and cell densities were similar between two strains. Transcriptomic samples were analyzed for four time points and revealed that the response of Z. mobilis to sodium acetate stress is dynamic, complex, and involved about one-fifth of the total predicted genes from all different functional categories. The modest correlations between proteomic and transcriptomic data may suggest the involvement of posttranscriptional control. In addition, the transcriptomic data of forty-four microarrays from four experiments for ZM4 and AcR under different conditions were combined to identify strain-specific, media-responsive, growth phase-dependent, and treatment-responsive gene expression profiles. Together this study indicates that minimal medium has the most dramatic effect on gene expression compared to rich medium followed by growth phase, inhibitor, and strain background. Genes involved in protein biosynthesis, glycolysis and fermentation as well as ATP synthesis and stress response play key roles in Z. mobilis metabolism with consistently strong expression levels under different conditions.
doi:10.3389/fmicb.2014.00246
PMCID: PMC4033097  PMID: 24904559
Zymomonas mobilis; microarray; proteomics and metabolomics; acetate; pretreatment inhibitor; stress responses; quantitative proteomics; systems biology
21.  Comparison of single-molecule sequencing and hybrid approaches for finishing the genome of Clostridium autoethanogenum and analysis of CRISPR systems in industrial relevant Clostridia 
Background
Clostridium autoethanogenum strain JA1-1 (DSM 10061) is an acetogen capable of fermenting CO, CO2 and H2 (e.g. from syngas or waste gases) into biofuel ethanol and commodity chemicals such as 2,3-butanediol. A draft genome sequence consisting of 100 contigs has been published.
Results
A closed, high-quality genome sequence for C. autoethanogenum DSM10061 was generated using only the latest single-molecule DNA sequencing technology and without the need for manual finishing. It is assigned to the most complex genome classification based upon genome features such as repeats, prophage, nine copies of the rRNA gene operons. It has a low G + C content of 31.1%. Illumina, 454, Illumina/454 hybrid assemblies were generated and then compared to the draft and PacBio assemblies using summary statistics, CGAL, QUAST and REAPR bioinformatics tools and comparative genomic approaches. Assemblies based upon shorter read DNA technologies were confounded by the large number repeats and their size, which in the case of the rRNA gene operons were ~5 kb. CRISPR (Clustered Regularly Interspaced Short Paloindromic Repeats) systems among biotechnologically relevant Clostridia were classified and related to plasmid content and prophages. Potential associations between plasmid content and CRISPR systems may have implications for historical industrial scale Acetone-Butanol-Ethanol (ABE) fermentation failures and future large scale bacterial fermentations. While C. autoethanogenum contains an active CRISPR system, no such system is present in the closely related Clostridium ljungdahlii DSM 13528. A common prophage inserted into the Arg-tRNA shared between the strains suggests a common ancestor. However, C. ljungdahlii contains several additional putative prophages and it has more than double the amount of prophage DNA compared to C. autoethanogenum. Other differences include important metabolic genes for central metabolism (as an additional hydrogenase and the absence of a phophoenolpyruvate synthase) and substrate utilization pathway (mannose and aromatics utilization) that might explain phenotypic differences between C. autoethanogenum and C. ljungdahlii.
Conclusions
Single molecule sequencing will be increasingly used to produce finished microbial genomes. The complete genome will facilitate comparative genomics and functional genomics and support future comparisons between Clostridia and studies that examine the evolution of plasmids, bacteriophage and CRISPR systems.
doi:10.1186/1754-6834-7-40
PMCID: PMC4022347  PMID: 24655715
22.  Draft Genome Sequence of Rhodococcus rhodochrous Strain ATCC 21198 
Genome Announcements  2014;2(1):e00054-14.
Rhodococcus rhodochrous is a Gram-positive red-pigmented bacterium commonly found in the soil. The draft genome sequence for R. rhodochrous strain ATCC 21198 is presented here to provide genetic data for a better understanding of its lipid-accumulating capabilities.
doi:10.1128/genomeA.00054-14
PMCID: PMC3924371  PMID: 24526639
23.  Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A2 
Lipoprotein-associated phospholipase A2 (Lp-PLA2 or PLA2G7) binds to low-density lipoprotein (LDL) particles, where it is thought to hydrolyze oxidatively truncated phospholipids. Lp-PLA2 has also been implicated as a pro-tumorigenic enzyme in human prostate cancer. Several inhibitors of Lp-PLA2 have been described, including darapladib, which is currently in phase 3 clinical development for the treatment of atherosclerosis. The selectivity that darapladib and other Lp-PLA2 inhibitors display across the larger serine hydrolase family has not, however, been reported. Here, we describe the use of both general and tailored activity-based probes for profiling Lp-PLA2 and inhibitors of this enzyme in native biological systems. We show that both darapladib and a novel class of structurally distinct carbamate inhibitors inactivate Lp-PLA2 in mouse tissues and human cell lines with high selectivity. Our findings thus identify both inhibitors and chemoproteomic probes that are suitable for investigating Lp-PLA2 function in biological systems.
doi:10.1016/j.bmcl.2012.11.061
PMCID: PMC3549684  PMID: 23260346
Phospholipase; Inhibitor; Screening; Proteomics
24.  SAR analysis of novel non-peptidic NPBWR1 (GPR7) antagonists 
In this Letter we report on the advances in our NPBWR1 antagonist program aimed at optimizing the 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule previously obtained from a high-throughput screening (HTS)-derived hit. Synthesis and structure–activity relationships (SAR) studies around the 3,5-dimethylphenyl and 4-methoxyphenyl regions resulted in the identification of a novel series of non-peptidic submicromolar NPBWR1 antagonists based on a 5-chloro-4-(4-alkoxyphenoxy)-2-(benzyl)pyridazin-3(2H)-one chemotype. Amongst them, 5-chloro-2-(9H-fluoren-9-yl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one 9h (CYM50769) inhibited NPW activation of NPBWR1 with a submicromolar IC50, and displayed high selectivity against a broad array of off-targets with pharmaceutical relevance. Our medicinal chemistry study provides innovative non-peptidic selective NPBWR1 antagonists that may enable to clarify the biological role and therapeutic utility of the target receptor in the regulation of feeding behavior, pain, stress, and neuroendocrine function.
doi:10.1016/j.bmcl.2012.12.030
PMCID: PMC3621982  PMID: 23287738
NPBWR1 (GPR7) antagonists; Anorexia; Analgesia; Stress
25.  The neural basis of audiomotor entrainment: an ALE meta-analysis 
Synchronization of body movement to an acoustic rhythm is a major form of entrainment, such as occurs in dance. This is exemplified in experimental studies of finger tapping. Entrainment to a beat is contrasted with movement that is internally driven and is therefore self-paced. In order to examine brain areas important for entrainment to an acoustic beat, we meta-analyzed the functional neuroimaging literature on finger tapping (43 studies) using activation likelihood estimation (ALE) meta-analysis with a focus on the contrast between externally-paced and self-paced tapping. The results demonstrated a dissociation between two subcortical systems involved in timing, namely the cerebellum and the basal ganglia. Externally-paced tapping highlighted the importance of the spinocerebellum, most especially the vermis, which was not activated at all by self-paced tapping. In contrast, the basal ganglia, including the putamen and globus pallidus, were active during both types of tapping, but preferentially during self-paced tapping. These results suggest a central role for the spinocerebellum in audiomotor entrainment. We conclude with a theoretical discussion about the various forms of entrainment in humans and other animals.
doi:10.3389/fnhum.2014.00776
PMCID: PMC4179708  PMID: 25324765
entrainment; acoustic; finger tapping; cerebellum; basal ganglia; ALE; timing; meter

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