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1.  Recent Advances in the C–H-Functionalization of the Distal Positions in Pyridines and Quinolines 
Tetrahedron  2015;71(46):8683-8716.
This review summarizes recent developments in the C–H-functionalization of the distal positions of pyridines, quinolines and related azaheterocycles. While the functionalization of the C2 position has been known for a long time and is facilitated by the proximity to N1, regioselective reactions in the distal positions are more difficult to achieve and have only emerged in the last decade. Recent advances in the transition metal-catalyzed distal C–H-functionalization of these synthetically-important azaheterocycles are discussed in detail, with the focus on the scope, site-selectivity and mechanistic aspects of the reactions.
Graphical Abstract
doi:10.1016/j.tet.2015.08.034
PMCID: PMC4666591  PMID: 26640303
C–C Bond formation; Borylation; C–H-Functionalization; N-Heterocycles; Pyridines; Quinolines; Transition metal catalysis; Site-selectivity
2.  Antimicrobial peptide resistance in Neisseria meningitidis 
Biochimica et biophysica acta  2015;1848(11 0 0):3026-3031.
Antimicrobial peptides (AMPs) play an important role as a host defense against microbial pathogens and are key components of the human innate immune response. Neisseria meningitidis frequently colonizes the human nasopharynx as a commensal but also is a worldwide cause of epidemic meningitis and rapidly fatal sepsis. In the human respiratory tract, the only known reservoir of N. meningitidis, meningococci are exposed to human endogenous AMPs. Thus, it is not surprising that meningococci have evolved effective mechanisms to confer intrinsic and high levels of resistance to the action of AMPs. This article reviews the current knowledge about AMP resistance mechanisms employed by N. meningitidis. Two major resistance mechanisms employed by meningococci are the constitutive modification of the lipid A head groups of lipooligosaccharides by phosphoethanolamine and the active efflux pump mediated excretion of AMPs. Other factors influencing AMP resistance, such as the major porin PorB, the pilin biogenesis apparatus, and capsular polysaccharides, have also been identified. Even with an inherently high intrinsic resistance, several AMP resistance determinants can be further induced upon exposure to AMPs. Many well-characterized AMP resistance mechanisms in other Gram-negative bacteria are not found in meningococci. Thus, N. meningitidis utilizes a limited but highly effective set of molecular mechanisms to mediate antimicrobial peptide resistance.
Graphical abstract
doi:10.1016/j.bbamem.2015.05.006
PMCID: PMC4605851  PMID: 26002321
3.  Pleomorphic Structures in Human Blood Are Red Blood Cell-Derived Microparticles, Not Bacteria 
PLoS ONE  2016;11(10):e0163582.
Background
Red blood cell (RBC) transfusions are a common, life-saving therapy for many patients, but they have also been associated with poor clinical outcomes. We identified unusual, pleomorphic structures in human RBC transfusion units by negative-stain electron microscopy that appeared identical to those previously reported to be bacteria in healthy human blood samples. The presence of viable, replicating bacteria in stored blood could explain poor outcomes in transfusion recipients and have major implications for transfusion medicine. Here, we investigated the possibility that these structures were bacteria.
Results
Flow cytometry, miRNA analysis, protein analysis, and additional electron microscopy studies strongly indicated that the pleomorphic structures in the supernatant of stored RBCs were RBC-derived microparticles (RMPs). Bacterial 16S rDNA PCR amplified from these samples were sequenced and was found to be highly similar to species that are known to commonly contaminate laboratory reagents.
Conclusions
These studies suggest that pleomorphic structures identified in human blood are RMPs and not bacteria, and they provide an example in which laboratory contaminants may can mislead investigators.
doi:10.1371/journal.pone.0163582
PMCID: PMC5070825  PMID: 27760197
4.  Metadata-driven Clinical Data Loading into i2b2 for Clinical and Translational Science Institutes 
Clinical and Translational Science Award (CTSA) recipients have a need to create research data marts from their clinical data warehouses, through research data networks and the use of i2b2 and SHRINE technologies. These data marts may have different data requirements and representations, thus necessitating separate extract, transform and load (ETL) processes for populating each mart. Maintaining duplicative procedural logic for each ETL process is onerous. We have created an entirely metadata-driven ETL process that can be customized for different data marts through separate configurations, each stored in an extension of i2b2 ‘s ontology database schema. We extended our previously reported and open source Eureka! Clinical Analytics software with this capability. The same software has created i2b2 data marts for several projects, the largest being the nascent Accrual for Clinical Trials (ACT) network, for which it has loaded over 147 million facts about 1.2 million patients.
PMCID: PMC5001768  PMID: 27570667
5.  Concise Total Synthesis of Trichodermamides A, B and C Enabled by an Efficient Construction of the 1,2-Oxazadecaline Core 
We report herein a facile and efficient method of the construction of the cis-1,2-oxazadecaline system, distinctive of (pre)trichodermamides, aspergillazine A, gliovirin and FA-2097. The formation of the 1,2-oxazadecaline core was accomplished by a 1,2-addition of an αC-lithiated O-silyl ethyl pyruvate oxime to benzoquinone, that is followed by an oxa-Michael ring-closure. The method was successfully applied to the concise total synthesis of trichodermamide A (in gram quantities), trichodermamide B, as well as the first synthesis of trichodermamide C.
doi:10.1021/jacs.5b05205
PMCID: PMC4711935  PMID: 26084356
6.  Experimental and Mechanistic Analysis of the Palladium-Catalyzed Oxidative C8-Selective C–H Homocoupling of Quinoline N-Oxides 
A novel site-selective palladium-catalyzed oxidative C8–H homocoupling reaction of quinoline N-oxides has been developed. The reaction affords substituted 8,8'-biquinolyl N,N'-dioxides that can be readily converted to a variety of functionalized 8,8'-biquinolyls. Mechanistic studies point to the crucial role of the oxidant and a non-innocent behavior of acetic acid as a solvent.
doi:10.1039/c5cc02227d
PMCID: PMC4714569  PMID: 25966913
7.  TFG Promotes Organization of Transitional ER and Efficient Collagen Secretion 
Cell Reports  2016;15(8):1648-1659.
Summary
Collagen is the most abundant protein in the animal kingdom. It is of fundamental importance during development for cell differentiation and tissue morphogenesis as well as in pathological processes such as fibrosis and cancer cell migration. However, our understanding of the mechanisms of procollagen secretion remains limited. Here, we show that TFG organizes transitional ER (tER) and ER exit sites (ERESs) into larger structures. Depletion of TFG results in dispersion of tER elements that remain associated with individual ER-Golgi intermediate compartments (ERGICs) as largely functional ERESs. We show that TFG is not required for the transport and packaging of small soluble cargoes but is necessary for the export of procollagen from the ER. Our work therefore suggests a key relationship between the structure and function of ERESs and a central role for TFG in optimizing COPII assembly for procollagen export.
Graphical Abstract
Highlights
•TFG is required to organize transitional ER into larger structures•Following depletion of TFG, ERESs remain in close apposition to the ERGIC•Mini-ERESs support secretion of small soluble cargo•Large ERESs are required for procollagen secretion
McCaughey et al. show that TFG is required to support the organization of ER exit sites (ERESs) into larger structures. This higher-order organization is required for efficient secretion of procollagen.
doi:10.1016/j.celrep.2016.04.062
PMCID: PMC4885023  PMID: 27184855
8.  Mouse and Human Genetic Analyses Associate Kalirin with Ventral Striatal Activation during Impulsivity and with Alcohol Misuse 
Impulsivity is associated with a spectrum of psychiatric disorders including drug addiction. To investigate genetic associations with impulsivity and initiation of drug taking, we took a two-step approach. First, we identified genes whose expression level in prefrontal cortex, striatum and accumbens were associated with impulsive behavior in the 5-choice serial reaction time task across 10 BXD recombinant inbred (BXD RI) mouse strains and their progenitor C57BL/6J and DBA2/J strains. Behavioral data were correlated with regional gene expression using GeneNetwork (www.genenetwork.org), to identify 44 genes whose probability of association with impulsivity exceeded a false discovery rate of < 0.05. We then interrogated the IMAGEN database of 1423 adolescents for potential associations of SNPs in human homologs of those genes identified in the mouse study, with brain activation during impulsive performance in the Monetary Incentive Delay task, and with novelty seeking scores from the Temperament and Character Inventory, as well as alcohol experience. There was a significant overall association between the human homologs of impulsivity-related genes and percentage of premature responses in the MID task and with fMRI BOLD-response in ventral striatum (VS) during reward anticipation. In contrast, no significant association was found between the polygenic scores and anterior cingulate cortex activation. Univariate association analyses revealed that the G allele (major) of the intronic SNP rs6438839 in the KALRN gene was significantly associated with increased VS activation. Additionally, the A-allele (minor) of KALRN intronic SNP rs4634050, belonging to the same haplotype block, was associated with increased frequency of binge drinking.
doi:10.3389/fgene.2016.00052
PMCID: PMC4823271  PMID: 27092175
impulsivity; binge drinking; adolescent; fMRI; BXD recombinant inbred strains; monetary incentive delay; 5-choice serial reaction time task
9.  Diversity of factor H-binding protein in Neisseria meningitidis carriage isolates 
Vaccine  2011;29(35):6049-6058.
Several meningococcal vaccines under development for prevention of serogroup B disease target the factor H-binding protein (FHbp), an immunogenic lipoprotein expressed on the surface of Neisseria meningitidis. Based upon sequence and phylogenetic analyses, FHbp can be classified into 3 protein variants (1, 2 or 3) or 2 subfamilies (A or B). The potential effect of FHbp-containing vaccines on meningococcal carriage is not known. We determined the diversity of FHbp among a population of carriage isolates obtained from Georgia and Maryland high school students in 1998 and 2006–2007. Analysis of the fHbp gene sequence from 408 carriage isolates identified 30 different FHbp protein sequences. The majority of carriage isolates harbored FHbp proteins belonging to variant 2/subfamily A. Association between FHbp proteins and genetic lineage was observed among the carriage isolates. However, split decomposition analysis, together with tests of linkage disequilibrium and pairwise homoplasy suggest recombination at fHbp contribute to allelic diversity. Of note, the FHbp proteins in serogroup B vaccines under development are either absent or not well represented in this carriage population. The FHbp genetic repertoire observed in carriage isolate populations will be useful in understanding the potential impact of FHbp-containing vaccines on meningococcal carriage.
doi:10.1016/j.vaccine.2011.06.025
PMCID: PMC4762365  PMID: 21704667
Meningococcal vaccine; FHbp; Genetic lineage; Recombination
10.  Assessment of Overlap of Phylogenetic Transmission Clusters and Communities in Simple Sexual Contact Networks: Applications to HIV-1 
PLoS ONE  2016;11(2):e0148459.
Background
Transmission patterns of sexually-transmitted infections (STIs) could relate to the structure of the underlying sexual contact network, whose features are therefore of interest to clinicians. Conventionally, we represent sexual contacts in a population with a graph, that can reveal the existence of communities. Phylogenetic methods help infer the history of an epidemic and incidentally, may help detecting communities. In particular, phylogenetic analyses of HIV-1 epidemics among men who have sex with men (MSM) have revealed the existence of large transmission clusters, possibly resulting from within-community transmissions. Past studies have explored the association between contact networks and phylogenies, including transmission clusters, producing conflicting conclusions about whether network features significantly affect observed transmission history. As far as we know however, none of them thoroughly investigated the role of communities, defined with respect to the network graph, in the observation of clusters.
Methods
The present study investigates, through simulations, community detection from phylogenies. We simulate a large number of epidemics over both unweighted and weighted, undirected random interconnected-islands networks, with islands corresponding to communities. We use weighting to modulate distance between islands. We translate each epidemic into a phylogeny, that lets us partition our samples of infected subjects into transmission clusters, based on several common definitions from the literature. We measure similarity between subjects’ island membership indices and transmission cluster membership indices with the adjusted Rand index.
Results and Conclusion
Analyses reveal modest mean correspondence between communities in graphs and phylogenetic transmission clusters. We conclude that common methods often have limited success in detecting contact network communities from phylogenies. The rarely-fulfilled requirement that network communities correspond to clades in the phylogeny is their main drawback. Understanding the link between transmission clusters and communities in sexual contact networks could help inform policymaking to curb HIV incidence in MSMs.
doi:10.1371/journal.pone.0148459
PMCID: PMC4749335  PMID: 26863322
12.  Palladium-Catalyzed C8-Selective C–H Arylation of Quinoline N-Oxides: Insights into the Electronic, Steric and Solvation Effects on the Site-Selectivity by Mechanistic and DFT Computational Studies 
ACS catalysis  2014;5(1):167-175.
We report herein a palladium-catalyzed C–H arylation of quinoline N-oxides that proceeds with high selectivity in favor of the C8-isomer. This site-selectivity is unusual for palladium, since all of the hitherto described methods of palladium-catalyzed C–H functionalization of quinoline N-oxides are highly C2-selective. The reaction exhibits a broad synthetic scope with respect to quinoline N-oxides and iodoarenes and can be significantly accelerated to sub-hour reaction times under microwave irradiation. The C8-arylation method can be carried out on gram scale and has excellent functional group tolerance. Mechanistic and Density Functional Theory (DFT) computational studies provide evidence for the cyclopalladation pathway and describe key parameters influencing the site-selectivity.
doi:10.1021/cs501813v
PMCID: PMC4286811  PMID: 25580364
13.  Differential Processing of Consonance and Dissonance within the Human Superior Temporal Gyrus 
The auditory cortex is well-known to be critical for music perception, including the perception of consonance and dissonance. Studies on the neural correlates of consonance and dissonance perception have largely employed non-invasive electrophysiological and functional imaging techniques in humans as well as neurophysiological recordings in animals, but the fine-grained spatiotemporal dynamics within the human auditory cortex remain unknown. We recorded electrocorticographic (ECoG) signals directly from the lateral surface of either the left or right temporal lobe of eight patients undergoing neurosurgical treatment as they passively listened to highly consonant and highly dissonant musical chords. We assessed ECoG activity in the high gamma (γhigh, 70–150 Hz) frequency range within the superior temporal gyrus (STG) and observed two types of cortical sites of interest in both hemispheres: one type showed no significant difference in γhigh activity between consonant and dissonant chords, and another type showed increased γhigh responses to dissonant chords between 75 and 200 ms post-stimulus onset. Furthermore, a subset of these sites exhibited additional sensitivity towards different types of dissonant chords, and a positive correlation between changes in γhigh power and the degree of stimulus roughness was observed in both hemispheres. We also observed a distinct spatial organization of cortical sites in the right STG, with dissonant-sensitive sites located anterior to non-sensitive sites. In sum, these findings demonstrate differential processing of consonance and dissonance in bilateral STG with the right hemisphere exhibiting robust and spatially organized sensitivity toward dissonance.
doi:10.3389/fnhum.2016.00154
PMCID: PMC4829599  PMID: 27148011
electrocorticography (ECoG); consonance and dissonance; auditory cortex; high gamma; music perception
14.  Insulin promotes Rip11 accumulation at the plasma membrane by inhibiting a dynamin- and PI3-kinase-dependent, but Akt-independent, internalisation event 
Cellular Signalling  2016;28(1):74-82.
Rip11 is a Rab11 effector protein that has been shown to be important in controlling the trafficking of several intracellular cargoes, including the fatty acid transporter FAT/CD36, V-ATPase and the glucose transporter GLUT4. We have previously demonstrated that Rip11 translocates to the plasma membrane in response to insulin and here we examine the basis of this regulated phenomenon in more detail. We show that Rip11 rapidly recycles between the cell interior and surface, and that the ability of insulin to increase the appearance of Rip11 at the cell surface involves an inhibition of Rip11 internalisation from the plasma membrane. By contrast the hormone has no effect on the rate of Rip11 translocation towards the plasma membrane. The ability of insulin to inhibit Rip11 internalisation requires dynamin and class I PI3-kinases, but is independent of the activation of the protein kinase Akt; characteristics which are very similar to the mechanism by which insulin inhibits GLUT4 endocytosis.
doi:10.1016/j.cellsig.2015.10.014
PMCID: PMC4678287  PMID: 26515129
Insulin; Rip11; Rab; Recycling; Endocytosis
15.  Macrolide Resistance in Streptococcus pneumoniae 
Streptococcus pneumoniae is a common commensal and an opportunistic pathogen. Suspected pneumococcal upper respiratory infections and pneumonia are often treated with macrolide antibiotics. Macrolides are bacteriostatic antibiotics and inhibit protein synthesis by binding to the 50S ribosomal subunit. The widespread use of macrolides is associated with increased macrolide resistance in S. pneumoniae, and the treatment of pneumococcal infections with macrolides may be associated with clinical failures. In S. pneumoniae, macrolide resistance is due to ribosomal dimethylation by an enzyme encoded by erm(B), efflux by a two-component efflux pump encoded by mef (E)/mel(msr(D)) and, less commonly, mutations of the ribosomal target site of macrolides. A wide array of genetic elements have emerged that facilitate macrolide resistance in S. pneumoniae; for example erm(B) is found on Tn917, while the mef (E)/mel operon is carried on the 5.4- or 5.5-kb Mega element. The macrolide resistance determinants, erm(B) and mef (E)/mel, are also found on large composite Tn916-like elements most notably Tn6002, Tn2009, and Tn2010. Introductions of 7-valent and 13-valent pneumococcal conjugate vaccines (PCV-7 and PCV-13) have decreased the incidence of macrolide-resistant invasive pneumococcal disease, but serotype replacement and emergence of macrolide resistance remain an important concern.
doi:10.3389/fcimb.2016.00098
PMCID: PMC5030221  PMID: 27709102
Streptococcus pneumoniae; antibiotic resistance; macrolide resistance; erm(B); mef(A/E)/mel(msr(D)); Mega; pneumococci
16.  Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography 
Epilepsia  2015;56(6):959-967.
Objective
Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video–electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions.
Methods
Ambulatory ECoG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal ECoG activity. ECoG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded.
Results
Eighty-two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0–376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording.
Significance
About one third of the subjects implanted with bilateral MTL electrodes required >1 month of chronic ambulatory ECoG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory ECoG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video-EEG monitoring, and can contribute to treatment decisions.
doi:10.1111/epi.13010
PMCID: PMC4676303  PMID: 25988840
EEG monitoring; Electrocorticography; Ambulatory EEG; Intracranial EEG; Responsive stimulation; Localization
17.  Exaggerated Waiting Impulsivity Associated with Human Binge Drinking, and High Alcohol Consumption in Mice 
Neuropsychopharmacology  2014;39(13):2919-2927.
There are well-established links between impulsivity and alcohol use in humans and animal models; however, whether exaggerated impulsivity is a premorbid risk factor or a consequence of alcohol intake remains unclear. In a first approach, human young (18–25 years) social binge and non-binge drinkers were tested for motor impulsivity and attentional abilities in a human version of the Five-Choice Serial Reaction Time Task (Sx-5CSRTT), modeled on the rodent 5CSRTT. Participants completed four variants of the Sx-5CSRT, in addition to being screened for impulsive traits (BIS-11 questionnaire) and impulsive behavior (by means of the Delay Discounting Questionnaire, Two-Choice Impulsivity Paradigm (TCIP), Stop Signal Reaction Time, and Time Estimation Task). Using a second approach, we compared one of these impulsivity measures, 5CSRTT performance, in two inbred strains of mice known to differ in alcohol intake. Compared with non-bingers (NBD; n=22), binge drinkers (BD, n=22) showed robust impairments in attention and premature responding when evaluated under increased attentional load, in addition to presenting deficits in decision making using the TCIP. The best predictors for high binge drinking score were premature responding in the Sx-5CSRTT, trait impulsivity in the BIS-11, and decision making in the TCIP. Alcohol-naïve C57BL/6J (B6) mice (alcohol preferring) were more impulsive in the 5CSRTT than DBA2/J (D2) mice (alcohol averse); the degree of impulsivity correlated with subsequent alcohol consumption. Homologous measures in animal and human studies indicate increased premature responding in young social BD and in the ethanol-preferring B6 strain of mice.
doi:10.1038/npp.2014.151
PMCID: PMC4229569  PMID: 24947901
18.  Towards Quantitative Spatial Models of Seabed Sediment Composition 
PLoS ONE  2015;10(11):e0142502.
There is a need for fit-for-purpose maps for accurately depicting the types of seabed substrate and habitat and the properties of the seabed for the benefits of research, resource management, conservation and spatial planning. The aim of this study is to determine whether it is possible to predict substrate composition across a large area of seabed using legacy grain-size data and environmental predictors. The study area includes the North Sea up to approximately 58.44°N and the United Kingdom’s parts of the English Channel and the Celtic Seas. The analysis combines outputs from hydrodynamic models as well as optical remote sensing data from satellite platforms and bathymetric variables, which are mainly derived from acoustic remote sensing. We build a statistical regression model to make quantitative predictions of sediment composition (fractions of mud, sand and gravel) using the random forest algorithm. The compositional data is analysed on the additive log-ratio scale. An independent test set indicates that approximately 66% and 71% of the variability of the two log-ratio variables are explained by the predictive models. A EUNIS substrate model, derived from the predicted sediment composition, achieved an overall accuracy of 83% and a kappa coefficient of 0.60. We demonstrate that it is feasible to spatially predict the seabed sediment composition across a large area of continental shelf in a repeatable and validated way. We also highlight the potential for further improvements to the method.
doi:10.1371/journal.pone.0142502
PMCID: PMC4657885  PMID: 26600040
19.  Palladium-Catalyzed C8-Selective C–H Arylation of Quinoline N-Oxides: Insights into the Electronic, Steric, and Solvation Effects on the Site Selectivity by Mechanistic and DFT Computational Studies 
ACS Catalysis  2014;5(1):167-175.
We report herein a palladium-catalyzed C–H arylation of quinoline N-oxides that proceeds with high selectivity in favor of the C8 isomer. This site selectivity is unusual for palladium, since all of the hitherto described methods of palladium-catalyzed C–H functionalization of quinoline N-oxides are highly C2 selective. The reaction exhibits a broad synthetic scope with respect to quinoline N-oxides and iodoarenes and can be significantly accelerated to subhour reaction times under microwave irradiation. The C8-arylation method can be carried out on a gram scale and has excellent functional group tolerance. Mechanistic and density functional theory (DFT) computational studies provide evidence for the cyclopalladation pathway and describe key parameters influencing the site selectivity.
doi:10.1021/cs501813v
PMCID: PMC4286811  PMID: 25580364
C−H activation; quinolines; C−C coupling; palladium; site selectivity; solvent effects
20.  The Gap Procedure: for the identification of phylogenetic clusters in HIV-1 sequence data 
BMC Bioinformatics  2015;16:355.
Background
In the context of infectious disease, sequence clustering can be used to provide important insights into the dynamics of transmission. Cluster analysis is usually performed using a phylogenetic approach whereby clusters are assigned on the basis of sufficiently small genetic distances and high bootstrap support (or posterior probabilities). The computational burden involved in this phylogenetic threshold approach is a major drawback, especially when a large number of sequences are being considered. In addition, this method requires a skilled user to specify the appropriate threshold values which may vary widely depending on the application.
Results
This paper presents the Gap Procedure, a distance-based clustering algorithm for the classification of DNA sequences sampled from individuals infected with the human immunodeficiency virus type 1 (HIV-1). Our heuristic algorithm bypasses the need for phylogenetic reconstruction, thereby supporting the quick analysis of large genetic data sets. Moreover, this fully automated procedure relies on data-driven gaps in sorted pairwise distances to infer clusters, thus no user-specified threshold values are required. The clustering results obtained by the Gap Procedure on both real and simulated data, closely agree with those found using the threshold approach, while only requiring a fraction of the time to complete the analysis.
Conclusions
Apart from the dramatic gains in computational time, the Gap Procedure is highly effective in finding distinct groups of genetically similar sequences and obviates the need for subjective user-specified values. The clusters of genetically similar sequences returned by this procedure can be used to detect patterns in HIV-1 transmission and thereby aid in the prevention, treatment and containment of the disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-015-0791-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12859-015-0791-x
PMCID: PMC4634160  PMID: 26538192
Clustering; Phylogenetics; HIV; Genetic distance estimation
21.  Synthetic and Mechanistic Aspects of the Regioselective Base-Mediated Reaction of Perfluoroalkyl- and Perfluoroarylsilanes with Heterocyclic N-Oxides 
Organic & biomolecular chemistry  2014;12(32):6190-6199.
The scope and mechanistic implications of the direct transformation of heterocyclic N-oxides to 2-trifluoromethyl-, and related perfluoroalkyl- and perfluoroaryl-substituted N-heterocycles has been studied. The reaction is effected by perfluoroalkyl- and perfluorophenyltrimethylsilane in the presence of strong base. In situ displacement of the para-fluoro substituent in the pentafluorophenyl ring and the methoxy group in 8-methoxyquinolines with additional nucleophiles allows for further site-selective refunctionalization of the N-heterocyclic products.
doi:10.1039/c4ob01088d
PMCID: PMC4134925  PMID: 24993899
22.  Ebola Virus Disease: Experience and Decision Making for the First Patients outside of Africa 
PLoS Medicine  2015;12(7):e1001857.
David Stephens and colleagues describe their experience of treating patients with Ebola virus disease at Emory University in the United States.
doi:10.1371/journal.pmed.1001857
PMCID: PMC4517924  PMID: 26218574
23.  The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice 
Psychopharmacology  2015;232(18):3431-3441.
Rationale
Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice.
Objective
We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy.
Methods
Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding.
Results
Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70–75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection.
Conclusions
Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone.
Electronic supplementary material
The online version of this article (doi:10.1007/s00213-015-3995-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s00213-015-3995-x
PMCID: PMC4537503  PMID: 26141191
Naltrexone; Drinking-in-the-dark; Receptor occupancy; Inverse agonist; Mu-opioid receptor
24.  Linear growth faltering in infants is associated with Acidaminococcus sp. and community-level changes in the gut microbiota 
Microbiome  2015;3:24.
Background
Chronic malnutrition, termed stunting, is defined as suboptimal linear growth, affects one third of children in developing countries, and leads to increased mortality and poor developmental outcomes. The causes of childhood stunting are unknown, and strategies to improve growth and related outcomes in children have only had modest impacts. Recent studies have shown that the ecosystem of microbes in the human gut, termed the microbiota, can induce changes in weight. However, the specific changes in the gut microbiota that contribute to growth remain unknown, and no studies have investigated the gut microbiota as a determinant of chronic malnutrition.
Results
We performed secondary analyses of data from two well-characterized twin cohorts of children from Malawi and Bangladesh to identify bacterial genera associated with linear growth. In a case-control analysis, we used the graphical lasso to estimate covariance network models of gut microbial interactions from relative genus abundances and used network analysis methods to select genera associated with stunting severity. In longitudinal analyses, we determined associations between these selected microbes and linear growth using between-within twin regression models to adjust for confounding and introduce temporality. Reduced microbiota diversity and increased covariance network density were associated with stunting severity, while increased relative abundance of Acidaminococcus sp. was associated with future linear growth deficits.
Conclusions
We show that length growth in children is associated with community-wide changes in the gut microbiota and with the abundance of the bacterial genus, Acidaminococcus. Larger cohorts are needed to confirm these findings and to clarify the mechanisms involved.
Electronic supplementary material
The online version of this article (doi:10.1186/s40168-015-0089-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s40168-015-0089-2
PMCID: PMC4477476  PMID: 26106478
Microbiota; Microbiome; Intestinal; Stunting; Growth; Statistical learning; Networks
25.  Straightforward Access to Hexahydropyrrolo[2,3-b]indole Core by a Regioselective C3-Azo Coupling Reaction of Arenediazonium Compounds with Tryptamines 
European journal of organic chemistry  2014;2014(17):3662-3670.
A base-mediated regioselective electrophilic addition of arenediazonium salts at the C3-position of tryptamines followed by cyclization provides an efficient entry to C3-nitrogenated hexahydropyrrolo[2,3-b]indoles (HPIs) that can subsequently be transformed into 3-arylhexahydropyrrolo[2,3-b]indoles and other HPI derivatives. The reaction is the first example of a 1,2-diamination that utilizes easily accessible arenediazonium salts as nitrogenous electrophiles.
doi:10.1002/ejoc.201402088
PMCID: PMC4233011  PMID: 25408620
Diazonium compounds; Electrophilic addition; Hydrazines; Pyrroloindolines; Synthetic methods

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