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1.  A randomized controlled trial of the effectiveness of a pre-recruitment primer letter to increase participation in a study of colorectal screening and surveillance 
Background
Recruiting cancer patients is a barrier often encountered in research trials. However, very few randomized trials explore strategies to improve participation rates. The purpose of this study was to evaluate the effectiveness of a pre-recruitment primer letter to recruit persons diagnosed with colorectal cancer for a research trial.
Methods
Potentially eligible participants were identified by the Victorian Cancer Registry. A total of 1,062 participants were randomized to receive either a mailed explanatory primer letter designed to encourage research participation, or no primer letter. Two weeks after the intervention, the Victorian Cancer Registry sought permission from patients to release their contact details to researchers. Those who agreed were contacted and invited to the study.
Results
Pre-recruitment encouragement was not effective at increasing recruitment, with no significant differences demonstrated between experimental groups. Overall, 40% (n = 425) consented to participate, 25% (n = 243) refused and 35% (n = 394) did not respond.
Conclusions
While this study demonstrated disappointing outcomes, pre-recruitment letters should not be ruled out as an approach altogether. Rather, future research should explore whether other factors to increase motivation, such as intensity and timing, are feasible and acceptable for contacting cancer patients.
Trial registration
Australian and New Zealand Clinical Trials Registry, ACTRN12609000628246
doi:10.1186/1471-2288-14-44
PMCID: PMC3975453  PMID: 24690533
Colorectal cancer; Patient recruitment; Population registers; Randomized controlled trials
2.  Application of 6,7-Indole Aryne Cycloaddition and Pd(0)-Catalyzed Suzuki-Miyaura and Buchwald-Hartwig Cross-Coupling Reactions for the Preparation of Annulated Indole Libraries 
ACS combinatorial science  2011;13(5):443-448.
The construction of an unprecedented class of an indole-based library, namely, a 6,7-annulated-4-substituted 93-member indole library, using a strategic combination of 6,7-indolyne cycloaddition and cross-coupling reactions under both Suzuki-Miyaura and Buchwald-Hartwig conditions is described. This work represents the first example of library development that employs the indole aryne methodology. Annulated indoles, with the exception of only a few biologically active natural products (i.e., the trikentrins, herbindoles, teleocidins, and nodulisporic acids), have no representation in the PubChem or MLSMR databases. These structural entities are therefore predicted to have unique chemical property space characteristics and a high probability of exhibiting interesting biological activity.
doi:10.1021/co2000289
PMCID: PMC3959986  PMID: 21668016
Indole; aryne; indolyne; cycloaddition; Suzuki-Miyaura; Buchwald-Hartwig; libraries
3.  TSLP-elicited basophil responses can mediate the pathogenesis of eosinophilic esophagitis 
Nature medicine  2013;19(8):1005-1013.
Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. EoE has become increasingly common, but current management strategies are nonspecific. Thus, there is an urgent need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis remains unknown. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE but was dependent on TSLP-elicited basophils. Therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. Critically, in human subjects with EoE, we observed elevated TSLP levels and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses. Together, these data suggest that the TSLP-basophil axis could be therapeutically targeted to treat EoE.
doi:10.1038/nm.3281
PMCID: PMC3951204  PMID: 23872715
4.  A Biophysical Basis for Mucus Solids Concentration as a Candidate Biomarker for Airways Disease 
PLoS ONE  2014;9(2):e87681.
In human airways diseases, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), host defense is compromised and airways inflammation and infection often result. Mucus clearance and trapping of inhaled pathogens constitute key elements of host defense. Clearance rates are governed by mucus viscous and elastic moduli at physiological driving frequencies, whereas transport of trapped pathogens in mucus layers is governed by diffusivity. There is a clear need for simple and effective clinical biomarkers of airways disease that correlate with these properties. We tested the hypothesis that mucus solids concentration, indexed as weight percent solids (wt%), is such a biomarker. Passive microbead rheology was employed to determine both diffusive and viscoelastic properties of mucus harvested from human bronchial epithelial (HBE) cultures. Guided by sputum from healthy (1.5–2.5 wt%) and diseased (COPD, CF; 5 wt%) subjects, mucus samples were generated in vitro to mimic in vivo physiology, including intermediate range wt% to represent disease progression. Analyses of microbead datasets showed mucus diffusive properties and viscoelastic moduli scale robustly with wt%. Importantly, prominent changes in both biophysical properties arose at ∼4 wt%, consistent with a gel transition (from a more viscous-dominated solution to a more elastic-dominated gel). These findings have significant implications for: (1) penetration of cilia into the mucus layer and effectiveness of mucus transport; and (2) diffusion vs. immobilization of micro-scale particles relevant to mucus barrier properties. These data provide compelling evidence for mucus solids concentration as a baseline clinical biomarker of mucus barrier and clearance functions.
doi:10.1371/journal.pone.0087681
PMCID: PMC3928107  PMID: 24558372
5.  Impact of Chorda Tympani Nerve Injury on Cell Survival, Axon Maintenance, and Morphology of the Chorda Tympani Nerve Terminal Field in the Nucleus of the Solitary Tract 
The Journal of comparative neurology  2012;520(11):2395-2413.
Chorda tympani nerve transection (CTX) has been useful to study the relationship between nerve and taste buds in fungiform papillae. This work demonstrated that the morphological integrity of taste buds depends on their innervation. Considerable research focused on the effects of CTX on peripheral gustatory structures, but much less research has focused on the central effects. Here, we explored how CTX affects ganglion cell survival, maintenance of injured peripheral axons, and the chorda tympani nerve terminal field organization in the nucleus of the solitary tract (NTS). After CTX in adult rats, the chorda tympani nerve was labeled with biotinylated dextran amine at 3, 7, 14, 30, and 60 days post-CTX to allow visualization of the terminal field associated with peripheral processes. There was a significant and persistent reduction of the labeled chorda tympani nerve terminal field volume and density in the NTS following CTX. Compared with controls, the volume of the labeled terminal field was not altered at 3 or 7 days post-CTX; however, it was significantly reduced by 44% and by 63% at 30 and 60 days post-CTX, respectively. Changes in the density of labeled terminal field in the NTS paralleled the terminal field volume results. The dramatic decrease in labeled terminal field size post-CTX cannot be explained by a loss of geniculate ganglion neurons or degeneration of central axons. Instead, the function and/or maintenance of the peripheral axonal process appear to be affected. These new results have implications for long-term functional and behavioral alterations.
doi:10.1002/cne.23044
PMCID: PMC3905605  PMID: 22237830
taste; gustatory; anterograde; axotomy; biotinylated dextran amine
6.  Large Scale Explorative Oligonucleotide Probe Selection for Thousands of Genetic Groups on a Computing Grid: Application to Phylogenetic Probe Design Using a Curated Small Subunit Ribosomal RNA Gene Database 
The Scientific World Journal  2014;2014:350487.
Phylogenetic Oligonucleotide Arrays (POAs) were recently adapted for studying the huge microbial communities in a flexible and easy-to-use way. POA coupled with the use of explorative probes to detect the unknown part is now one of the most powerful approaches for a better understanding of microbial community functioning. However, the selection of probes remains a very difficult task. The rapid growth of environmental databases has led to an exponential increase of data to be managed for an efficient design. Consequently, the use of high performance computing facilities is mandatory. In this paper, we present an efficient parallelization method to select known and explorative oligonucleotide probes at large scale using computing grids. We implemented a software that generates and monitors thousands of jobs over the European Computing Grid Infrastructure (EGI). We also developed a new algorithm for the construction of a high-quality curated phylogenetic database to avoid erroneous design due to bad sequence affiliation. We present here the performance and statistics of our method on real biological datasets based on a phylogenetic prokaryotic database at the genus level and a complete design of about 20,000 probes for 2,069 genera of prokaryotes.
doi:10.1155/2014/350487
PMCID: PMC3913353  PMID: 24516366
7.  The influence of commensal bacteria-derived signals on basophil-associated allergic inflammation 
Gut Microbes  2013;4(1):76-83.
Commensal bacteria that colonize mammalian mucosal surfaces are reported to influence T helper type 2 (TH2) cytokine-dependent inflammation and susceptibility to allergic disease. However, the mechanisms that underlie these observations are only beginning to be understood. We recently utilized studies of murine model systems and atopic patient populations to elucidate a mechanism by which commensal bacteria-derived signals limit serum immunoglobulin E levels, influence basophil development and steady-state circulating basophil populations and regulate basophil-associated TH2 cell responses and allergic inflammation. In this addendum, we summarize the findings of our recent work and other developments in the field, discuss the broader implications of these findings and generate new hypotheses regarding our understanding of host-commensal relationships. These areas of investigation may be applicable to the development of new preventative or therapeutic approaches to reduce the burden of allergic disease.
doi:10.4161/gmic.22759
PMCID: PMC3555891  PMID: 23137965
commensal bacteria; allergy; atopy; basophil; hematopoiesis
8.  Comparative analysis of virus-host interactomes with a mammalian high- throughput protein complementation assay based on Gaussia princeps luciferase 
Methods (San Diego, Calif.)  2012;58(4):349-359.
Comparative interactomics is a strategy for inferring potential interactions among orthologous proteins or “iginterologs”. Herein we focus, in contrast to standard homology-based inference, on the divergence of protein interaction profiles among closely related organisms, showing that the approach can correlate specific traits to phenotypic differences. As a model, this new comparative interactomic approach was applied at a large scale to human papillomaviruses (HPVs) proteins. The oncogenic potential of HPVs is mainly determined by the E6 and E7 early proteins. We have mapped and overlapped the virus-host protein interaction networks of E6 and E7 proteins from 11 distinct HPV genotypes, selected for their different tropisms and pathologies. We generated robust and comprehensive datasets by combining two orthogonal protein interation assays: yeast two-hybrid (Y2H), and our recently described “High-Throughput Gaussia princeps Protein Complementation Assay” (HT-GPCA). HT-GPCA detects protein interaction by measuring the interaction-mediated reconstitution of activity of a split Gaussia princeps luciferase. Hierarchical clustering of interaction profiles recapitulated HPV phylogeny and was used to correlate specific virus-host interaction profiles with pathological traits, reflecting the distinct carcinogenic potentials of different HPVs. This comparative interactomics constitutes a reliable and powerful strategy to decipher molecular relationships in virtually any combination of microorganism-host interactions.
doi:10.1016/j.ymeth.2012.07.029
PMCID: PMC3546263  PMID: 22898364
comparative interactomics; HPV; E6; E7; interactome; complementation assay
9.  Mycobacterium tuberculosis Type VII Secreted Effector EsxH Targets Host ESCRT to Impair Trafficking 
PLoS Pathogens  2013;9(10):e1003734.
Mycobacterium tuberculosis (Mtb) disrupts anti-microbial pathways of macrophages, cells that normally kill bacteria. Over 40 years ago, D'Arcy Hart showed that Mtb avoids delivery to lysosomes, but the molecular mechanisms that allow Mtb to elude lysosomal degradation are poorly understood. Specialized secretion systems are often used by bacterial pathogens to translocate effectors that target the host, and Mtb encodes type VII secretion systems (TSSSs) that enable mycobacteria to secrete proteins across their complex cell envelope; however, their cellular targets are unknown. Here, we describe a systematic strategy to identify bacterial virulence factors by looking for interactions between the Mtb secretome and host proteins using a high throughput, high stringency, yeast two-hybrid (Y2H) platform. Using this approach we identified an interaction between EsxH, which is secreted by the Esx-3 TSSS, and human hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs/Hrs), a component of the endosomal sorting complex required for transport (ESCRT). ESCRT has a well-described role in directing proteins destined for lysosomal degradation into intraluminal vesicles (ILVs) of multivesicular bodies (MVBs), ensuring degradation of the sorted cargo upon MVB-lysosome fusion. Here, we show that ESCRT is required to deliver Mtb to the lysosome and to restrict intracellular bacterial growth. Further, EsxH, in complex with EsxG, disrupts ESCRT function and impairs phagosome maturation. Thus, we demonstrate a role for a TSSS and the host ESCRT machinery in one of the central features of tuberculosis pathogenesis.
Author Summary
Mycobacterium tuberculosis (Mtb) causes the disease tuberculosis, one of the world's most deadly infections. The host immune system can't eradicate Mtb because it grows within macrophages, cells that normally kill bacteria. One of the intracellular survival strategies of Mtb is to avoid delivery to lysosomes, a phenomenon described over 40 years ago, but for which the mechanism and molecular details remain incomplete. Mtb possess specialized secretion systems (Type VII secretion systems; TSSS) that transfer particular proteins out of the bacteria, but how these proteins promote infection is not well understood. In this study, we used a high stringency yeast two-hybrid system to identify interactions between secreted effectors from Mtb and human host factors. We identified ninety-nine such interactions and focused our attention on the interaction between EsxH, secreted by Esx-3, a TSSS of Mtb, and Hrs, a component of the host ESCRT machinery. We provide evidence that Mtb EsxH directly targets host Hrs to disrupt delivery of bacteria to lysosomes. Thus, this study demonstrates the role of a TSSS effector and the ESCRT machinery in what is one of the central features of tuberculosis pathogenesis, thereby providing molecular insight into why humans can't clear Mtb infection.
doi:10.1371/journal.ppat.1003734
PMCID: PMC3814348  PMID: 24204276
10.  Extensive Rewiring and Complex Evolutionary Dynamics in a C. elegans Multiparameter Transcription Factor Network 
Molecular cell  2013;51(1):116-127.
SUMMARY
Gene duplication results in two identical paralogs that diverge through mutation, leading to loss or gain of interactions with other biomolecules. Here, we comprehensively characterize such network rewiring for C. elegans transcription factors (TFs) within and across four newly delineated molecular networks. Remarkably, we find that even highly similar TFs often have different interaction degree and partners. In addition, we find that most TF families have a member that is highly connected in multiple networks. Further, different TF families have opposing correlations between network connectivity and phylogenetic age, suggesting that they are subject to different evolutionary pressures. Finally, TFs that have similar partners in one network generally do not in another, indicating a lack of pressure to retain cross-network similarity. Our multiparameter analyses provide an unprecedented glimpse into the evolutionary dynamics that shaped TF networks.
doi:10.1016/j.molcel.2013.05.018
PMCID: PMC3794439  PMID: 23791784
11.  Disentangling Coordination among Functional Traits Using an Individual-Centred Model: Impact on Plant Performance at Intra- and Inter-Specific Levels 
PLoS ONE  2013;8(10):e77372.
Background
Plant functional traits co-vary along strategy spectra, thereby defining trade-offs for resource acquisition and utilization amongst other processes. A main objective of plant ecology is to quantify the correlations among traits and ask why some of them are sufficiently closely coordinated to form a single axis of functional specialization. However, due to trait co-variations in nature, it is difficult to propose a mechanistic and causal explanation for the origin of trade-offs among traits observed at both intra- and inter-specific level.
Methodology/Principal Findings
Using the Gemini individual-centered model which coordinates physiological and morphological processes, we investigated with 12 grass species the consequences of deliberately decoupling variation of leaf traits (specific leaf area, leaf lifespan) and plant stature (height and tiller number) on plant growth and phenotypic variability. For all species under both high and low N supplies, simulated trait values maximizing plant growth in monocultures matched observed trait values. Moreover, at the intraspecific level, plastic trait responses to N addition predicted by the model were in close agreement with observed trait responses. In a 4D trait space, our modeling approach highlighted that the unique trait combination maximizing plant growth under a given environmental condition was determined by a coordination of leaf, root and whole plant processes that tended to co-limit the acquisition and use of carbon and of nitrogen.
Conclusion/Significance
Our study provides a mechanistic explanation for the origin of trade-offs between plant functional traits and further predicts plasticity in plant traits in response to environmental changes. In a multidimensional trait space, regions occupied by current plant species can therefore be viewed as adaptive corridors where trait combinations minimize allometric and physiological constraints from the organ to the whole plant levels. The regions outside this corridor are empty because of inferior plant performance.
doi:10.1371/journal.pone.0077372
PMCID: PMC3793938  PMID: 24130879
12.  The Gene Ontology (GO) Cellular Component Ontology: integration with SAO (Subcellular Anatomy Ontology) and other recent developments 
Background
The Gene Ontology (GO) (http://www.geneontology.org/) contains a set of terms for describing the activity and actions of gene products across all kingdoms of life. Each of these activities is executed in a location within a cell or in the vicinity of a cell. In order to capture this context, the GO includes a sub-ontology called the Cellular Component (CC) ontology (GO-CCO). The primary use of this ontology is for GO annotation, but it has also been used for phenotype annotation, and for the annotation of images. Another ontology with similar scope to the GO-CCO is the Subcellular Anatomy Ontology (SAO), part of the Neuroscience Information Framework Standard (NIFSTD) suite of ontologies. The SAO also covers cell components, but in the domain of neuroscience.
Description
Recently, the GO-CCO was enriched in content and links to the Biological Process and Molecular Function branches of GO as well as to other ontologies. This was achieved in several ways. We carried out an amalgamation of SAO terms with GO-CCO ones; as a result, nearly 100 new neuroscience-related terms were added to the GO. The GO-CCO also contains relationships to GO Biological Process and Molecular Function terms, as well as connecting to external ontologies such as the Cell Ontology (CL). Terms representing protein complexes in the Protein Ontology (PRO) reference GO-CCO terms for their species-generic counterparts. GO-CCO terms can also be used to search a variety of databases.
Conclusions
In this publication we provide an overview of the GO-CCO, its overall design, and some recent extensions that make use of additional spatial information. One of the most recent developments of the GO-CCO was the merging in of the SAO, resulting in a single unified ontology designed to serve the needs of GO annotators as well as the specific needs of the neuroscience community.
doi:10.1186/2041-1480-4-20
PMCID: PMC3852282  PMID: 24093723
Gene ontology; Cellular component ontology; Subcellular anatomy ontology; Neuroscience; Annotation; Ontology language; Ontology integration; Neuroscience information framework
13.  Postnatal Development of Chorda Tympani Axons in the Rat Nucleus of the Solitary Tract 
The Journal of comparative neurology  2012;520(14):3217-3235.
The chorda tympani nerve (CT), one of three nerves that convey gustatory information to nucleus of the solitary tract (NTS), displays terminal field reorganization after postnatal day 15 in the rat. Aiming to gain insight into mechanisms of this phenomenon, CT axon projection field and terminal morphology in NTS subdivisions were examined using tract tracing, light microscopy, and immuno-electron microscopy at four postnatal ages: P15, P25, P35, and adult. The CT axons that innervated NTS rostrolateral subdivision both in the adult and in P15 rats were morphologically distinct from those that innervated the rostrocentral, gustatory subdivision. In both subdivisions, CT terminals reached morphological maturity before P15. Rostrolateral, but not rostrocentral axons, went through substantial axonal branch elimination after P15. Rostrocentral CT synapses, however, redistribute onto postsynaptic targets in the following weeks. CT terminal preference for GABAergic postsynaptic targets was drastically reduced after P15. Furthermore, CT synapses became a smaller component of the total synaptic input to the rostrocentral NTS after P35. The results underlined that CT axons in rostrocentral and rostrolateral subdivisions represent two distinct populations of CT input, displaying different morphological properties and structural reorganization mechanisms during postnatal development.
doi:10.1002/cne.23093
PMCID: PMC3418376  PMID: 22430892
Development; Chorda Tympani; Gustatory; Taste; Electron Microscopy
14.  Relationship between Birth Weight and Metabolic Status in Obese Adolescents 
ISRN Obesity  2013;2013:490923.
Objective. To examine the relationships between birth weight and body mass index, percent body fat, blood lipids, glycemia, insulin resistance, adipokines, blood pressure, and endothelial function in a cohort of obese adolescents. Design and Methods. Ninety-five subjects aged 10–16 years (mean age 13.5 years) with a body mass index >95th centile (mean [±SEM] 33.0 ± 0.6) were utilized from two prospective studies for obesity prevention prior to any interventions. The mean term birth weight was 3527 ± 64 g (range 1899–4990 g;). Results. Body mass index z-score correlated positively with birth weight (r2 = 0.05, P = 0.03), but not percent body fat. Insulin resistance negatively correlated with birth weight (r2 = 0.05, P < 0.001), as did fasting plasma insulin (r2 = 0.05, P < 0.001); both being significantly greater for subjects of small versus large birth weight (Δ Homeostasis Model Assessment = 2.5 and Δ insulin = 10 pmol/L for birth weight <2.5 kg versus >4.5 kg). Adiponectin, but not leptin, blood pressure z-scores or peripheral arterial tomography values positively correlated with birth weight (r2 = 0.07, P = 0.008). Conclusions. Excess body mass index in obese adolescents was positively related to birth weight. Birth weight was not associated with cardiovascular risk factors but represented a significant determinant of insulin resistance.
doi:10.1155/2013/490923
PMCID: PMC3901987  PMID: 24555145
15.  Gene Ontology annotation of sequence-specific DNA binding transcription factors: setting the stage for a large-scale curation effort 
Transcription factors control which information in a genome becomes transcribed to produce RNAs that function in the biological systems of cells and organisms. Reliable and comprehensive information about transcription factors is invaluable for large-scale network-based studies. However, existing transcription factor knowledge bases are still lacking in well-documented functional information.
Here, we provide guidelines for a curation strategy, which constitutes a robust framework for using the controlled vocabularies defined by the Gene Ontology Consortium to annotate specific DNA binding transcription factors (DbTFs) based on experimental evidence reported in literature. Our standardized protocol and workflow for annotating specific DNA binding RNA polymerase II transcription factors is designed to document high-quality and decisive evidence from valid experimental methods. Within a collaborative biocuration effort involving the user community, we are now in the process of exhaustively annotating the full repertoire of human, mouse and rat proteins that qualify as DbTFs in as much as they are experimentally documented in the biomedical literature today. The completion of this task will significantly enrich Gene Ontology-based information resources for the research community.
Database URL: www.tfcheckpoint.org
doi:10.1093/database/bat062
PMCID: PMC3753819  PMID: 23981286
16.  SMAD4–dependent barrier constrains prostate cancer growth and metastatic progression 
Nature  2011;470(7333):269-273.
Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression1. Here,we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFβ/BMP–SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment con-firmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.
doi:10.1038/nature09677
PMCID: PMC3753179  PMID: 21289624
17.  Periciliary Brush Promotes the Lung Health by Separating the Mucus Layer from Airway Epithelia 
Science (New York, N.Y.)  2012;337(6097):937-941.
Mucus clearance is the primary defense mechanism that protects airways from inhaled infectious and toxic agents. In the current Gel-on-Liquid mucus clearance model mucus gel is propelled on top of a “watery” periciliary layer surrounding the cilia. However, this model fails to explain the formation of distinct mucus layer in health or why mucus clearance fails in disease. We propose a Gel-on-Brush model in which the periciliary layer is occupied by membrane spanning mucins and mucopolysaccharides densely tethered to the airway surface. This brush prevents mucus penetration into the periciliary space and causes mucus to form a distinct layer. The relative osmotic moduli of the mucus and periciliary brush layers explain both the stability of mucus clearance in health and its failure in airway disease.
doi:10.1126/science.1223012
PMCID: PMC3633213  PMID: 22923574
18.  Automated Synthesis of a Library of Triazolated 1,2,5-Thiadiazepane 1,1-Dioxides via a Double aza-Michael Strategy 
ACS combinatorial science  2012;14(8):456-459.
The construction of a 96-member library of triazolated 1,2,5-thiadiazepane 1,1-dioxides was performed on a Chemspeed Accelerator (SLT-100) automated parallel synthesis platform, culminating in the successful preparation of 94 out of 96 possible products. The key step, a one-pot, sequential elimination, double-aza-Michael reaction, and [3+2] Huisgen cycloaddition pathway has been automated and utilized in the production of two sets of triazolated sultam products.
doi:10.1021/co300049u
PMCID: PMC3656823  PMID: 22853708
19.  Minimally Invasive Total Hip Arthroplasty Using a Transpiriformis Approach: A Preliminary Report 
Background
Continuing efforts have been made to develop minimally invasive surgery techniques for THA. One of the most commonly performed of these techniques is the mini-posterior approach. All reported series using this approach describe surgical detachment of the short external rotators of the hip. In 2008, Penenberg et al. described an innovative surgical technique that preserves the short external rotators. We present the results of a single-incision modification of this technique in 135 patients.
Description of Technique
This technique is based on preservation of all of the short external rotators of the hip with the exception of the piriformis or conjoined tendon. This single-incision technique required the development of specialized instrumentation for exposure and reaming of the acetabulum. The specialized retractors also successfully minimized trauma to the skin and subcutaneous tissue.
Methods
For the 135 patients undergoing THA with this technique, we analyzed demographic and operative data. We recorded complications, evaluated postoperative clinical function using the Harris hip score, and assessed cup abduction angle, cup anteversion, and stem alignment on radiographs. Minimum followup was 14 months (mean, 22 months; range, 14–33 months).
Results
There were no dislocations, no sciatic nerve palsies, no wound complications, and low transfusion rates (8%). The postoperative Harris hip score averaged 96.5 (range, 87–100). Overall acetabular cup abduction angle averaged 41° (range, 21°–49°) and anteversion averaged 21° (range, 15°–27°). Four percent and 2% of femoral components were inserted into more than 2° varus and 2° valgus alignment, respectively.
Conclusions
This technique shows promise as an alternative tissue-sparing method for minimally invasive THA.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
Electronic supplementary material
The online version of this article (doi:10.1007/s11999-011-2225-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s11999-011-2225-z
PMCID: PMC3392401  PMID: 22215476
20.  Dovetailing biology and chemistry: integrating the Gene Ontology with the ChEBI chemical ontology 
BMC Genomics  2013;14:513.
Background
The Gene Ontology (GO) facilitates the description of the action of gene products in a biological context. Many GO terms refer to chemical entities that participate in biological processes. To facilitate accurate and consistent systems-wide biological representation, it is necessary to integrate the chemical view of these entities with the biological view of GO functions and processes. We describe a collaborative effort between the GO and the Chemical Entities of Biological Interest (ChEBI) ontology developers to ensure that the representation of chemicals in the GO is both internally consistent and in alignment with the chemical expertise captured in ChEBI.
Results
We have examined and integrated the ChEBI structural hierarchy into the GO resource through computationally-assisted manual curation of both GO and ChEBI. Our work has resulted in the creation of computable definitions of GO terms that contain fully defined semantic relationships to corresponding chemical terms in ChEBI.
Conclusions
The set of logical definitions using both the GO and ChEBI has already been used to automate aspects of GO development and has the potential to allow the integration of data across the domains of biology and chemistry. These logical definitions are available as an extended version of the ontology from http://purl.obolibrary.org/obo/go/extensions/go-plus.owl.
doi:10.1186/1471-2164-14-513
PMCID: PMC3733925  PMID: 23895341
21.  DALI: Vitamin D and lifestyle intervention for gestational diabetes mellitus (GDM) prevention: an European multicentre, randomised trial – study protocol 
Background
Gestational diabetes mellitus (GDM) is an increasing problem world-wide. Lifestyle interventions and/or vitamin D supplementation might help prevent GDM in some women.
Methods/design
Pregnant women at risk of GDM (BMI≥29 (kg/m2)) from 9 European countries will be invited to participate and consent obtained before 19+6 weeks of gestation. After giving informed consent, women without GDM will be included (based on IADPSG criteria: fasting glucose<5.1mmol; 1 hour glucose <10.0 mmol; 2 hour glucose <8.5 mmol) and randomized to one of the 8 intervention arms using a 2×(2×2) factorial design: (1) healthy eating (HE), 2) physical activity (PA), 3) HE+PA, 4) control, 5) HE+PA+vitamin D, 6) HE+PA+placebo, 7) vitamin D alone, 8) placebo alone), pre-stratified for each site. In total, 880 women will be included with 110 women allocated to each arm. Between entry and 35 weeks of gestation, women allocated to a lifestyle intervention will receive 5 face-to-face, and 4 telephone coaching sessions, based on the principles of motivational interviewing. The lifestyle intervention includes a discussion about the risks of GDM, a weight gain target <5kg and either 7 healthy eating ‘messages’ and/or 5 physical activity ‘messages’ depending on randomization. Fidelity is monitored by the use of a personal digital assistance (PDA) system. Participants randomized to the vitamin D intervention receive either 1600 IU vitamin D or placebo for daily intake until delivery. Data is collected at baseline measurement, at 24–28 weeks, 35–37 weeks of gestation and after delivery. Primary outcome measures are gestational weight gain, fasting glucose and insulin sensitivity, with a range of obstetric secondary outcome measures including birth weight.
Discussion
DALI is a unique Europe-wide randomised controlled trial, which will gain insight into preventive measures against the development of GDM in overweight and obese women.
Trial registration
ISRCTN70595832
doi:10.1186/1471-2393-13-142
PMCID: PMC3710199  PMID: 23829946
Gestational diabetes mellitus; Pregnancy; Lifestyle intervention; Randomised controlled trial; Healthy eating; Physical activity; Overweight; Motivational interviewing; Prevention; Vitamin D
22.  Bacillus subtilis natto: a non-toxic source of poly-γ-glutamic acid that could be used as a cryoprotectant for probiotic bacteria 
AMB Express  2013;3:36.
It is common practice to freeze dry probiotic bacteria to improve their shelf life. However, the freeze drying process itself can be detrimental to their viability. The viability of probiotics could be maintained if they are administered within a microbially produced biodegradable polymer - poly-γ-glutamic acid (γ-PGA) - matrix. Although the antifreeze activity of γ-PGA is well known, it has not been used for maintaining the viability of probiotic bacteria during freeze drying. The aim of this study was to test the effect of γ-PGA (produced by B. subtilis natto ATCC 15245) on the viability of probiotic bacteria during freeze drying and to test the toxigenic potential of B. subtilis natto. 10% γ-PGA was found to protect Lactobacillus paracasei significantly better than 10% sucrose, whereas it showed comparable cryoprotectant activity to sucrose when it was used to protect Bifidobacterium breve and Bifidobacterium longum. Although γ-PGA is known to be non-toxic, it is crucial to ascertain the toxigenic potential of its source, B. subtilis natto. Presence of six genes that are known to encode for toxins were investigated: three component hemolysin (hbl D/A), three component non-haemolytic enterotoxin (nheB), B. cereus enterotoxin T (bceT), enterotoxin FM (entFM), sphingomyelinase (sph) and phosphatidylcholine-specific phospholipase (piplc). From our investigations, none of these six genes were present in B. subtilis natto. Moreover, haemolytic and lecithinase activities were found to be absent. Our work contributes a biodegradable polymer from a non-toxic source for the cryoprotection of probiotic bacteria, thus improving their survival during the manufacturing process.
doi:10.1186/2191-0855-3-36
PMCID: PMC3720193  PMID: 23829836
Probiotics; γ-PGA; Cryoprotectant; Toxicity; Bifidobacteria; Lactobacillus
23.  Teaching Global Public Health in the Undergraduate Liberal Arts: A Survey of 50 Colleges 
Undergraduate public health and global health studies are usually found at universities with graduate programs in the disciplines. Following the experience of teaching a short course in global health within the liberal arts, we reviewed global and public health offerings at 50 liberal arts colleges for the 2009–2010 academic year. Forty-two percent had a track, concentration, or program, and 30% had global or public health student organizations. All colleges listed at least one course in the fields, with the highest number in the social sciences. However, many colleges had not coordinated them into a theme. Values of a liberal arts education are found in the study of global and public health: social responsibility, critical thinking, ethical reasoning, and knowledge of the wider world. We propose identifying these programs within the undergraduate liberal arts as global public health. Capturing interest in global public health will enhance the curriculum and student experience.In this day and age, when the world is so fluid with regard to news and information, the knowledge that unnecessary deaths are occurring and that health care lags so far behind in some regions cannot be ignored. From the standpoint of basic human rights, suffering and inequity cannot be tolerated.Williams College student during a global health short course
doi:10.4269/ajtmh.2012.11-0571
PMCID: PMC3391034  PMID: 22764284
24.  The Human Gut Chip “HuGChip”, an Explorative Phylogenetic Microarray for Determining Gut Microbiome Diversity at Family Level 
PLoS ONE  2013;8(5):e62544.
Evaluating the composition of the human gut microbiota greatly facilitates studies on its role in human pathophysiology, and is heavily reliant on culture-independent molecular methods. A microarray designated the Human Gut Chip (HuGChip) was developed to analyze and compare human gut microbiota samples. The PhylArray software was used to design specific and sensitive probes. The DNA chip was composed of 4,441 probes (2,442 specific and 1,919 explorative probes) targeting 66 bacterial families. A mock community composed of 16S rRNA gene sequences from intestinal species was used to define the threshold criteria to be used to analyze complex samples. This was then experimentally verified with three human faecal samples and results were compared (i) with pyrosequencing of the V4 hypervariable region of the 16S rRNA gene, (ii) metagenomic data, and (iii) qPCR analysis of three phyla. When compared at both the phylum and the family level, high Pearson's correlation coefficients were obtained between data from all methods. The HuGChip development and validation showed that it is not only able to assess the known human gut microbiota but could also detect unknown species with the explorative probes to reveal the large number of bacterial sequences not yet described in the human gut microbiota, overcoming the main inconvenience encountered when developing microarrays.
doi:10.1371/journal.pone.0062544
PMCID: PMC3656878  PMID: 23690942

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