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1.  Glycan-Foraging Systems Reveal the Adaptation of Capnocytophaga canimorsus to the Dog Mouth 
mBio  2015;6(2):e02507-14.
Capnocytophaga canimorsus is known to form two kinds of cells on blood agar plates (coccoid and bacillary), evoking phase variation. When grown in coculture with animal cells these bacteria appeared only as bacilli, but in the presence of vancomycin they were round, indicating that coccoid shapes likely result from weakening of the peptidoglycan layer. Polysaccharide utilization locus 5 (PUL5) and sialidase mutant bacteria, unable to retrieve glycans from glycoproteins, grew less than wild-type bacteria and also appeared polymorphic unless GlcNAc was added, suggesting that C. canimorsus is unable to synthesize GlcNAc, an essential component of peptidoglycan. Accordingly, a genome analysis was conducted and revealed that C. canimorsus strain 5 lacks the GlmM and GlmU enzymes, which convert glucosamine into GlcNAc. Expression of the Escherichia coli GlmM together with the acetyltransferase domain of GlmU allowed PUL5 mutant bacteria to grow normally, indicating that C. canimorsus is a natural auxotroph that relies on GlcNAc harvested from the host N-glycoproteins for peptidoglycan synthesis. Mucin, a heavily O-glycosylated protein abundant in saliva, also rescued growth and the shape of PUL5 mutant bacteria. Utilization of mucin was found to depend on Muc, a Sus-like system encoded by PUL9. Contrary to all known PUL-encoded systems, Muc cleaves peptide bonds of mucin rather than glycosidic linkages. Thus, C. canimorsus has adapted to build its peptidoglycan from the glycan-rich dog’s mouth glycoproteins.
Capnocytophaga canimorsus is a bacterium that lives as a commensal in the dog mouth and causes severe infections in humans. In vitro, it forms two kinds of cells (coccoid and bacillary), evoking phase variation. Here, we show that cell rounding likely results from weakening of the peptidoglycan layer due to a shortage of N-acetylglucosamine (GlcNAc). C. canimorsus cannot synthesize GlcNAc because of the lack of key enzymes. In its niche, the dog mouth, C. canimorsus retrieves GlcNAc by foraging glycans from salivary mucin and N-linked glycoproteins through two different apparatuses, Muc and Gpd, both of which are related to the Bacteroides starch utilization system. The Muc system is peculiar in the sense that the enzyme of the complex is a protease and not a glycosylhydrolase, as it cleaves peptide bonds in order to capture glycan chains. This study provides a molecular genetic demonstration for the complex adaptation of C. canimorsus to its ecological niche, the oral cavity of dogs.
PMCID: PMC4358021  PMID: 25736888
2.  Near-infrared (NIR) perfusion angiography in minimally invasive colorectal surgery 
Surgical Endoscopy  2014;28(7):2221-2226.
Anastomotic leakage is a devastating complication of colorectal surgery. However, there is no technology indicative of in situ perfusion of a laparoscopic colorectal anastomosis.
We detail the use of near-infrared (NIR) laparoscopy (PinPoint System, NOVADAQ, Canada) in association with fluorophore [indocyanine green (ICG), 2.5 mg/ml] injection in 30 consecutive patients who underwent elective minimally invasive colorectal resection using the simultaneous appearance of the cecum or distal ileum as positive control.
The median (range) age of the patients was 64 (40–81) years with a median (range) BMI of 26.7 (20–35.5) kg/m2. Twenty-four patients had left-sided resections (including six low anterior resections) and six had right-sided resections. Of the total, 25 operations were cancer resections and five were for benign disease [either diverticular strictures (n = 3) or Crohn’s disease (n = 2)]. A high-quality intraoperative ICG angiogram was achieved in 29/30 patients. After ICG injection, median (range) time to perfusion fluorescence was 35 (15–45) s. Median (range) added time for the technique was 5 (3–9) min. Anastomotic perfusion was documented as satisfactory in every successful case and encouraged avoidance of defunctioning stomas in three patients with low anastomoses. There were no postoperative anastomotic leaks.
Perfusion angiography of colorectal anastomosis at the time of their laparoscopic construction is feasible and readily achievable with minimal added intraoperative time. Further work is required to determine optimum sensitivity and threshold levels for assessment of perfusion sufficiency, in particular with regard to anastomotic viability.
Electronic supplementary material
The online version of this article (doi:10.1007/s00464-014-3432-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4065377  PMID: 24566744
Laparoscopy; Colorectal resection; Anastomotic leak; Near infrared (NIR) laparoscopy; Indocyanine green (ICG); Perfusion
3.  Best Practices for Scientific Computing 
PLoS Biology  2014;12(1):e1001745.
We describe a set of best practices for scientific software development, based on research and experience, that will improve scientists' productivity and the reliability of their software.
PMCID: PMC3886731  PMID: 24415924
4.  Bootstrap Aggregating of Alternating Decision Trees to Detect Sets of SNPs that Associate with Disease 
Genetic epidemiology  2012;36(2):99-106.
Complex genetic disorders are a result of a combination of genetic and non-genetic factors, all potentially interacting. Machine learning methods hold the potential to identify multi-locus and environmental associations thought to drive complex genetic traits. Decision trees, a popular machine learning technique, offer a computationally low complexity algorithm capable of detecting associated sets of SNPs of arbitrary size, including modern genome-wide SNP scans. However, interpretation of the importance of an individual SNP within these trees can present challenges.
We present a new decision tree algorithm denoted as Bagged Alternating Decision Trees (BADTrees) that is based on identifying common structural elements in a bootstrapped set of ADTrees. The algorithm is order nk2, where n is the number of SNPs considered and k is the number of SNPs in the tree constructed. Our simulation study suggests that BADTrees have higher power and lower type I error rates than ADTrees alone and comparable power with lower type I error rates compared to logistic regression. We illustrate the application of these data using simulated data as well as from the Lupus Large Association Study 1 (7822 SNPs in 3548 individuals). Our results suggest that BADTrees holds promise as a low computational order algorithm for detecting complex combinations of SNP and environmental factors associated with disease.
PMCID: PMC3769952  PMID: 22851473
Machine Learning; Genetic Association; Gene-Gene Interaction; Multi-locus Models
5.  Neuroscience and Learning: Implications for Teaching Practice 
Although neuroscience studies have provided us with an increasingly detailed picture of the basis for learning and memory, very little of this information has been applied within the area of teaching practice. We suggest that a better understanding of neuroscience may offer significant advantages for educators. In this context, we have considered recent studies in the neuroscience of learning and memory, with particular emphasis on working and semantic memory, and also suggest that neuroscience research into self-referential networks may improve our understanding of the learning process. Finally, we propose that advances in understanding the neural basis for metacognition may encourage the development of new perspectives that may help us to motivate students to learn about their own learning processes.
PMCID: PMC4089653  PMID: 25157206
neuroscience; education; learning; memory; default network; metacognition
Arthritis and rheumatism  2011;63(7):2049-2057.
PMCID: PMC3128183  PMID: 21437871
7.  Imaging Drug Delivery to Skin with Stimulated Raman Scattering Microscopy 
Molecular pharmaceutics  2011;8(3):969-975.
Efficient drug delivery to the skin is essential for the treatment of major dermatologic diseases, such as eczema, psoriasis and acne. However, many compounds penetrate the skin barrier poorly and require optimized formulations to ensure their bioavailability. Here, stimulated Raman scattering (SRS) microscopy, a recently-developed, label-free chemical imaging tool, is used to acquire high resolution images of multiple chemical components of a topical formulation as it penetrates into mammalian skin. This technique uniquely provides label-free, non-destructive, three-dimensional images with high spatiotemporal resolution. It reveals novel features of (trans)dermal drug delivery in the tissue environment: different rates of drug penetration via hair follicles as compared to the intercellular pathway across the stratum corneum are directly observed, and the precipitation of drug crystals on the skin surface is visualized after the percutaneous penetration of the co-solvent excipient in the formulation. The high speed three-dimensional imaging capability of SRS thus reveals features that cannot be seen with other techniques, providing both kinetic information and mechanistic insight into the (trans)dermal drug delivery process.
PMCID: PMC3109166  PMID: 21548600
Skin; topical drug delivery; stimulated Raman scattering microscopy; skin penetration pathways; dermatopharmacokinetics
8.  The design of a reflectionless arterial prosthesis 
Journal of Biological Physics  2010;37(1):51-60.
We propose a new technique to characterize a reflectionless arterial prosthesis. The corresponding transmission and reflection coefficients are determined from the geometric and the elastic properties of the arterial wall, and the interaction between the latter and the prosthesis are studied accordingly.
PMCID: PMC3006462  PMID: 22210960
Blood waves; Transmission coefficient; Reflection coefficient; Prosthesis
9.  Comparative analysis of methods for detecting interacting loci 
BMC Genomics  2011;12:344.
PMCID: PMC3161015  PMID: 21729295
10.  Quantitative structure-permeation relationship for iontophoretic transport across the skin 
The objective was to relate the efficiency of a charged drug to carry current across the skin during iontophoresis to its structural and/or physicochemical properties. The corollary was the establishment of a predictive relationship useful to predict the feasibility of iontophoretic drug delivery, and for the selection and optimization of drug candidates for this route of administration. A dataset of 16 cations, for which iontophoretic fluxes have been measured under identical conditions, with no competition from exogenous co-ions, was compiled. Maximum transport numbers correlated with ion mobilities and decreased with ionic size, the dependence indicating that the electromigration mechanism of iontophoresis would become negligible for drugs of hydrodynamic radius greater than about 8Å. Validation of the model was demonstrated by successfully predicting the transport numbers of three structurally distinct dipeptides, the iontophoretic data for which had been determined under distinctly different experimental conditions. Finally, for the “training” set of cations, a strong linear dependence between their transport numbers in skin and those in aqueous solution was demonstrated; the former were larger by approximately a factor of 1.4 consistent with skin’s cation permselectivity. In conclusion, this research offers a practical contribution to the development of a predictive structure-transport model of iontophoresis.
PMCID: PMC2082109  PMID: 17707106
iontophoresis; skin; transport number; conductivity; structure-transport relationship
11.  In Vivo Methods for the Assessment of Topical Drug Bioavailability 
Pharmaceutical Research  2007;25(1):87-103.
This paper reviews some current methods for the in vivo assessment of local cutaneous bioavailability in humans after topical drug application. After an introduction discussing the importance of local drug bioavailability assessment and the limitations of model-based predictions, the focus turns to the relevance of experimental studies. The available techniques are then reviewed in detail, with particular emphasis on the tape stripping and microdialysis methodologies. Other less developed techniques, including the skin biopsy, suction blister, follicle removal and confocal Raman spectroscopy techniques are also described.
PMCID: PMC2217624  PMID: 17985216
cutaneous bioavailability; cutaneous drug concentration; dermatopharmacokinetics; microdialysis; tape stripping
12.  WebMOTIFS: automated discovery, filtering and scoring of DNA sequence motifs using multiple programs and Bayesian approaches 
Nucleic Acids Research  2007;35(Web Server issue):W217-W220.
WebMOTIFS provides a web interface that facilitates the discovery and analysis of DNA-sequence motifs. Several studies have shown that the accuracy of motif discovery can be significantly improved by using multiple de novo motif discovery programs and using randomized control calculations to identify the most significant motifs or by using Bayesian approaches. WebMOTIFS makes it easy to apply these strategies. Using a single submission form, users can run several motif discovery programs and score, cluster and visualize the results. In addition, the Bayesian motif discovery program THEME can be used to determine the class of transcription factors that is most likely to regulate a set of sequences. Input can be provided as a list of gene or probe identifiers. Used with the default settings, WebMOTIFS accurately identifies biologically relevant motifs from diverse data in several species. WebMOTIFS is freely available at
PMCID: PMC1933171  PMID: 17584794
13.  Shell shock 
PMCID: PMC1079480  PMID: 15121824
15.  Recovery of human skin impedance in vivo after lontophoresis: Effect of metal ions 
AAPS PharmSci  2000;2(3):38-44.
The objective of this study was to investigate the effect of the counter-ion (cation) on the recovery of human skin impedance after iontophoresis in vivo. A series of metal chloride aqueous solutions (NaCl, KCl, CaCl2, and MgCl2) was investigated: first at the same concentration (133 mmol/L) and then at the same ionic strength as a NaCl solution at 133 mmol/L. The influence of hydration alone was also examined as a control. The recovery of human skin impedance was followed in the frequency range 1–1,000 Hz, over a 30-minute period after iontophoresis during which 3 impedance spectra were recorded. The results revealed that at t=30 minutes post-iontophoresis, skin impedance was approximately 3 times greater than the value immediately after the cessation of current passage. However, the results showed that the nature of the cation had no effect on recovery, regardless of whether the ions were at the same concentration or at an equivalent ionic strength. A simple parallel RC-equivalent circuit model for skin was used to determine the resistive (R) and capacitive (C) contributions to skin impedance. An analysis of variance on the calculated R and C values did not show any differences between the electrolytes used at the 2 different ionic strengths.
PMCID: PMC2761134  PMID: 11741239

Results 1-15 (15)