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1.  Genomic features separating ten strains of Neorhizobium galegae with different symbiotic phenotypes 
BMC Genomics  2015;16(1):348.
The symbiotic phenotype of Neorhizobium galegae, with strains specifically fixing nitrogen with either Galega orientalis or G. officinalis, has made it a target in research on determinants of host specificity in nitrogen fixation. The genomic differences between representative strains of the two symbiovars are, however, relatively small. This introduced a need for a dataset representing a larger bacterial population in order to make better conclusions on characteristics typical for a subset of the species. In this study, we produced draft genomes of eight strains of N. galegae having different symbiotic phenotypes, both with regard to host specificity and nitrogen fixation efficiency. These genomes were analysed together with the previously published complete genomes of N. galegae strains HAMBI 540T and HAMBI 1141.
The results showed that the presence of an additional rpoN sigma factor gene in the symbiosis gene region is a characteristic specific to symbiovar orientalis, required for nitrogen fixation. Also the nifQ gene was shown to be crucial for functional symbiosis in both symbiovars. Genome-wide analyses identified additional genes characteristic of strains of the same symbiovar and of strains having similar plant growth promoting properties on Galega orientalis. Many of these genes are involved in transcriptional regulation or in metabolic functions.
The results of this study confirm that the only symbiosis-related gene that is present in one symbiovar of N. galegae but not in the other is an rpoN gene. The specific function of this gene remains to be determined, however. New genes that were identified as specific for strains of one symbiovar may be involved in determining host specificity, while others are defined as potential determinant genes for differences in efficiency of nitrogen fixation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1576-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4417242  PMID: 25933608
Neorhizobium galegae; Symbiosis; Genome; rpoN; nifQ; Nitrogen fixation
2.  Early response to nanoparticles in the Arabidopsis transcriptome compromises plant defence and root-hair development through salicylic acid signalling 
BMC Genomics  2015;16(1):341.
The impact of nano-scaled materials on photosynthetic organisms needs to be evaluated. Plants represent the largest interface between the environment and biosphere, so understanding how nanoparticles affect them is especially relevant for environmental assessments. Nanotoxicology studies in plants allude to quantum size effects and other properties specific of the nano-stage to explain increased toxicity respect to bulk compounds. However, gene expression profiles after exposure to nanoparticles and other sources of environmental stress have not been compared and the impact on plant defence has not been analysed.
Arabidopsis plants were exposed to TiO2-nanoparticles, Ag-nanoparticles, and multi-walled carbon nanotubes as well as different sources of biotic (microbial pathogens) or abiotic (saline, drought, or wounding) stresses. Changes in gene expression profiles and plant phenotypic responses were evaluated. Transcriptome analysis shows similarity of expression patterns for all plants exposed to nanoparticles and a low impact on gene expression compared to other stress inducers. Nanoparticle exposure repressed transcriptional responses to microbial pathogens, resulting in increased bacterial colonization during an experimental infection. Inhibition of root hair development and transcriptional patterns characteristic of phosphate starvation response were also observed. The exogenous addition of salicylic acid prevented some nano-specific transcriptional and phenotypic effects, including the reduction in root hair formation and the colonization of distal leaves by bacteria.
This study integrates the effect of nanoparticles on gene expression with plant responses to major sources of environmental stress and paves the way to remediate the impact of these potentially damaging compounds through hormonal priming.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1530-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4417227  PMID: 25903678
Nanoparticles; Nanotoxycology; Arabidopsis; Defence; Transcriptome; Stress; Systemic acquired response
3.  Transcriptomic profiles of aging in purified human immune cells 
BMC Genomics  2015;16(1):333.
Transcriptomic studies hold great potential towards understanding the human aging process. Previous transcriptomic studies have identified many genes with age-associated expression levels; however, small samples sizes and mixed cell types often make these results difficult to interpret.
Using transcriptomic profiles in CD14+ monocytes from 1,264 participants of the Multi-Ethnic Study of Atherosclerosis (aged 55–94 years), we identified 2,704 genes differentially expressed with chronological age (false discovery rate, FDR ≤ 0.001). We further identified six networks of co-expressed genes that included prominent genes from three pathways: protein synthesis (particularly mitochondrial ribosomal genes), oxidative phosphorylation, and autophagy, with expression patterns suggesting these pathways decline with age. Expression of several chromatin remodeler and transcriptional modifier genes strongly correlated with expression of oxidative phosphorylation and ribosomal protein synthesis genes. 17% of genes with age-associated expression harbored CpG sites whose degree of methylation significantly mediated the relationship between age and gene expression (p < 0.05). Lastly, 15 genes with age-associated expression were also associated (FDR ≤ 0.01) with pulse pressure independent of chronological age.
Comparing transcriptomic profiles of CD14+ monocytes to CD4+ T cells from a subset (n = 423) of the population, we identified 30 age-associated (FDR < 0.01) genes in common, while larger sets of differentially expressed genes were unique to either T cells (188 genes) or monocytes (383 genes). At the pathway level, a decline in ribosomal protein synthesis machinery gene expression with age was detectable in both cell types.
An overall decline in expression of ribosomal protein synthesis genes with age was detected in CD14+ monocytes and CD4+ T cells, demonstrating that some patterns of aging are likely shared between different cell types. Our findings also support cell-specific effects of age on gene expression, illustrating the importance of using purified cell samples for future transcriptomic studies. Longitudinal work is required to establish the relationship between identified age-associated genes/pathways and aging-related diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1522-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4417516  PMID: 25898983
Aging; Monocyte; T cell; Transcriptome; Mitochondrial ribosome; Translation; Protein synthesis; Ribonucleoprotein complex; Oxidative phosphorylation; Autophagy; Methylation
4.  The RNAi machinery controls distinct responses to environmental signals in the basal fungus Mucor circinelloides 
BMC Genomics  2015;16(1):237.
RNA interference (RNAi) is a conserved mechanism of genome defence that can also have a role in the regulation of endogenous functions through endogenous small RNAs (esRNAs). In fungi, knowledge of the functions regulated by esRNAs has been hampered by lack of clear phenotypes in most mutants affected in the RNAi machinery. Mutants of Mucor circinelloides affected in RNAi genes show defects in physiological and developmental processes, thus making Mucor an outstanding fungal model for studying endogenous functions regulated by RNAi. Some classes of Mucor esRNAs map to exons (ex-siRNAs) and regulate expression of the genes from which they derive. To have a broad picture of genes regulated by the silencing machinery during vegetative growth, we have sequenced and compared the mRNA profiles of mutants in the main RNAi genes by using RNA-seq. In addition, we have achieved a more complete phenotypic characterization of silencing mutants.
Deletion of any main RNAi gene provoked a deep impact in mRNA accumulation at exponential and stationary growth. Genes showing increased mRNA levels, as expected for direct ex-siRNAs targets, but also genes with decreased expression were detected, suggesting that, most probably, the initial ex-siRNA targets regulate the expression of other genes, which can be up- or down-regulated. Expression of 50% of the genes was dependent on more than one RNAi gene in agreement with the existence of several classes of ex-siRNAs produced by different combinations of RNAi proteins. These combinations of proteins have also been involved in the regulation of different cellular processes. Besides genes regulated by the canonical RNAi pathway, this analysis identified processes, such as growth at low pH and sexual interaction that are regulated by a dicer-independent non-canonical RNAi pathway.
This work shows that the RNAi pathways play a relevant role in the regulation of a significant number of endogenous genes in M. circinelloides during exponential and stationary growth phases and opens up an important avenue for in-depth study of genes involved in the regulation of physiological and developmental processes in this fungal model.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1443-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4417260  PMID: 25880254
Asexual sporulation; Sexual interaction; pH regulation; Non-canonical RNAi pathway; esRNAs; mRNA profiling
5.  Distribution in microbial genomes of genes similar to lodA and goxA which encode a novel family of quinoproteins with amino acid oxidase activity 
BMC Genomics  2015;16(1):231.
L-Amino acid oxidases (LAOs) have been generally described as flavoproteins that oxidize amino acids releasing the corresponding ketoacid, ammonium and hydrogen peroxide. The generation of hydrogen peroxide gives to these enzymes antimicrobial characteristics. They are involved in processes such as biofilm development and microbial competition. LAOs are of great biotechnological interest in different applications such as the design of biosensors, biotransformations and biomedicine.
The marine bacterium Marinomonas mediterranea synthesizes LodA, the first known LAO that contains a quinone cofactor. LodA is encoded in an operon that contains a second gene coding for LodB, a protein required for the post-translational modification generating the cofactor. Recently, GoxA, a quinoprotein with sequence similarity to LodA but with a different enzymatic activity (glycine oxidase instead of lysine-ε-oxidase) has been described. The aim of this work has been to study the distribution of genes similar to lodA and/or goxA in sequenced microbial genomes and to get insight into the evolution of this novel family of proteins through phylogenetic analysis.
Genes encoding LodA-like proteins have been detected in several bacterial classes. However, they are absent in Archaea and detected only in a small group of fungi of the class Agaromycetes. The vast majority of the genes detected are in a genome region with a nearby lodB-like gene suggesting a specific interaction between both partner proteins.
Sequence alignment of the LodA-like proteins allowed the detection of several conserved residues. All of them showed a Cys and a Trp that aligned with the residues that are forming part of the cysteine tryptophilquinone (CTQ) cofactor in LodA. Phylogenetic analysis revealed that LodA-like proteins can be clustered in different groups. Interestingly, LodA and GoxA are in different groups, indicating that those groups are related to the enzymatic activity of the proteins detected.
Genome mining has revealed for the first time the broad distribution of LodA-like proteins containing a CTQ cofactor in many different microbial groups. This study provides a platform to explore the potentially novel enzymatic activities of the proteins detected, the mechanisms of post-translational modifications involved in their synthesis, as well as their biological relevance.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1455-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4417212  PMID: 25886995
L-amino acid oxidase; Quinone cofactor; Post-translational modification; Lysine oxidase; Glycine oxidase
6.  A genetic map of cassava (Manihot esculenta Crantz) with integrated physical mapping of immunity-related genes 
BMC Genomics  2015;16(1):190.
Cassava, Manihot esculenta Crantz, is one of the most important crops world-wide representing the staple security for more than one billion of people. The development of dense genetic and physical maps, as the basis for implementing genetic and molecular approaches to accelerate the rate of genetic gains in breeding program represents a significant challenge. A reference genome sequence for cassava has been made recently available and community efforts are underway for improving its quality. Cassava is threatened by several pathogens, but the mechanisms of defense are far from being understood. Besides, there has been a lack of information about the number of genes related to immunity as well as their distribution and genomic organization in the cassava genome.
A high dense genetic map of cassava containing 2,141 SNPs has been constructed. Eighteen linkage groups were resolved with an overall size of 2,571 cM and an average distance of 1.26 cM between markers. More than half of mapped SNPs (57.4%) are located in coding sequences. Physical mapping of scaffolds of cassava whole genome sequence draft using the mapped markers as anchors resulted in the orientation of 687 scaffolds covering 45.6% of the genome. One hundred eighty nine new scaffolds are anchored to the genetic cassava map leading to an extension of the present cassava physical map with 30.7 Mb. Comparative analysis using anchor markers showed strong co-linearity to previously reported cassava genetic and physical maps. In silico based searching for conserved domains allowed the annotation of a repertory of 1,061 cassava genes coding for immunity-related proteins (IRPs). Based on physical map of the corresponding sequencing scaffolds, unambiguous genetic localization was possible for 569 IRPs.
This is the first study reported so far of an integrated high density genetic map using SNPs with integrated genetic and physical localization of newly annotated immunity related genes in cassava. These data build a solid basis for future studies to map and associate markers with single loci or quantitative trait loci for agronomical important traits. The enrichment of the physical map with novel scaffolds is in line with the efforts of the cassava genome sequencing consortium.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1397-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4417308  PMID: 25887443
Linkage mapping; Physical mapping; Genotyping by sequencing; Single nucleotide polymorphisms; Immunity-related genes
7.  Factors to preserve CpG-rich sequences in methylated CpG islands 
BMC Genomics  2015;16(1):144.
Mammalian CpG islands (CGIs) normally escape DNA methylation in all adult tissues and developmental stages. However, in our previous study we unexpectedly identified many methylated CGIs in human peripheral blood leukocytes. Methylated CpG dinucleotides convert to TpG dinucleotides through deaminization of their cytosine bases more frequently than hypomethylated CpG dinucleotides. Therefore, we wondered how methylated CGIs in germline or non-germline cells maintain their CpG-rich sequences. It is known that events such as germline hypomethylation, CpG selection, biased gene conversion (BGC), and frequent CpG fixation can contribute to the maintenance of CpG-rich sequences in methylated CGIs in germline or non-germline cells. However, it has not been investigated which of the processes maintain CpG-rich sequences of methylated CGIs in each genomic position.
In this study, we comprehensively examined the contribution of the processes described above to the maintenance of CpG-rich sequences in methylated CGIs in germline and non-germline cells which were classified by genomic positions. Approximately 60–80% of CGIs with high methylation in H1 cell line (H1-HM) in all the genomic positions showed a low average CpG → TpG/CpA substitution rate. In contrast, fewer than half the numbers of CGIs with H1-HM in all the genomic positions showed a low average CpG → TpG/CpA substitution rate and low levels of methylation in sperm cells (SPM-LM). Furthermore, a small fraction of CGIs with a low average CpG → TpG/CpA substitution rate and high levels of methylation in sperm cells (SPM-HM) showed CpG selection.
On the other hand, independent of the positions in genes, most CGIs with SPM-HM showed a slightly higher average TpG/CpA → CpG substitution rate compared with those with SPM-LM.
Relatively high numbers (approximately 60–80%) of CGIs with H1-HM in all the genomic positions preserve their CpG-rich sequences by a low CpG → TpG/CpA substitution rate caused mainly by their SPM-LM, and for those with SPM-HM partly by CpG selection and TpG/CpA → CpG fixation. BGC has little contribution to the maintenance of CpG-rich sequences of CGIs with SPM-HM which were classified by genomic positions.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1286-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4417305  PMID: 25879481
CpG island; DNA methylation; CpG selection; CpG fixation; Biased gene conversion
8.  Mixture SNPs effect on phenotype in genome-wide association studies 
BMC Genomics  2015;16(1):3.
Recently mixed linear models are used to address the issue of “missing" heritability in traditional Genome-wide association studies (GWAS). The models assume that all single-nucleotide polymorphisms (SNPs) are associated with the phenotypes of interest. However, it is more common that only a small proportion of SNPs have significant effects on the phenotypes, while most SNPs have no or very small effects. To incorporate this feature, we propose an efficient Hierarchical Bayesian Model (HBM) that extends the existing mixed models to enforce automatic selection of significant SNPs. The HBM models the SNP effects using a mixture distribution of a point mass at zero and a normal distribution, where the point mass corresponds to those non-associative SNPs.
We estimate the HBM using Gibbs sampling. The estimation performance of our method is first demonstrated through two simulation studies. We make the simulation setups realistic by using parameters fitted on the Framingham Heart Study (FHS) data. The simulation studies show that our method can accurately estimate the proportion of SNPs associated with the simulated phenotype and identify these SNPs, as well as adapt to certain model mis-specification than the standard mixed models. In addition, we analyze data from the FHS and the Health and Retirement Study (HRS) to study the association between Body Mass Index (BMI) and SNPs on Chromosome 16, and replicate the identified genetic associations. The analysis of the FHS data identifies 0.3% SNPs on Chromosome 16 that affect BMI, including rs9939609 and rs9939973 on the FTO gene. These two SNPs are in strong linkage disequilibrium with rs1558902 (Rsq =0.901 for rs9939609 and Rsq =0.905 for rs9939973), which has been reported to be linked with obesity in previous GWAS. We then replicate the findings using the HRS data: the analysis finds 0.4% of SNPs associated with BMI on Chromosome 16. Furthermore, around 25% of the genes that are identified to be associated with BMI are common between the two studies.
The results demonstrate that the HBM and the associated estimation algorithm offer a powerful tool for identifying significant genetic associations with phenotypes of interest, among a large number of SNPs that are common in modern genetics studies.
PMCID: PMC4417323  PMID: 25649116
Bayesian variable selection; Genome-wide association studies; Gibbs sampling
9.  Erratum 
Tissue Barriers  2016;4(2):e1179084.
PMCID: PMC4910832  PMID: 27358758
10.  Synthesis, Characterization, and DNA Binding Profile of a Macrocyclic β-Sheet Analogue of ARC Protein 
ACS Medicinal Chemistry Letters  2015;6(12):1220-1224.
ARC repressor (apoptosis repressor with caspase recruitment domain) is a protein which binds selectively to a specific sequence of DNA. In humans, ARC is primarily expressed in striated muscle tissue, which normally does not undergo rapid cell turnover. This suggests that ARC may play a protective role in the prevention against Duchenne Muscular Dystrophy and several types of tumors. In this Letter we report the synthesis, characterization, and conformational analysis of a β-sheet ARC repressor mimetic, based on the amino acid sequence of the β-sheet domain in the ARC protein. The ability of this β-sheet macrocycle to bind to double-stranded DNA was also evaluated using spectroscopic methods. Our data show that the synthetic peptide has a defined conformation and is able to bind DNA with reasonable affinity. These initial results lay the groundwork for the design of novel β-sheets folded peptides as valuable substitutes of transcription factor proteins in drug therapy.
Macrocyclic β-sheet mimetic of ARC protein able to bind to DNA.
PMCID: PMC4677364  PMID: 26713108
ARC repressor; DNA recognition; major groove; transcription factors; β-sheet macrocycles; solid phase peptide synthesis
12.  The HMGB1-RAGE Inflammatory Pathway: Implications for Brain Injury-Induced Pulmonary Dysfunction 
Antioxidants & Redox Signaling  2015;23(17):1316-1328.
Significance: Deceased patients who have suffered severe traumatic brain injury (TBI) are the largest source of organs for lung transplantation. However, due to severely compromised pulmonary lung function, only one-third of these patients are eligible organ donors, with far fewer capable of donating lungs (∼20%). As a result of this organ scarcity, understanding and controlling the pulmonary pathophysiology of potential donors are key to improving the health and long-term success of transplanted lungs. Recent Advances: Although the exact mechanism by which TBI produces pulmonary pathophysiology remains unclear, it may be related to the release of damage-associated molecular patterns (DAMPs) from the injured tissue. These heterogeneous, endogenous host molecules can be rapidly released from damaged or dying cells and mediate sterile inflammation following trauma. In this review, we highlight the interaction of the DAMP, high-mobility group box protein 1 (HMGB1) with the receptor for advanced glycation end-products (RAGE), and toll-like receptor 4 (TLR4). Critical Issues: Recently published studies are reviewed, implicating the release of HMGB1 as producing marked changes in pulmonary inflammation and physiology following trauma, followed by an overview of the experimental evidence demonstrating the benefits of blocking the HMGB1-RAGE axis. Future Directions: Targeting the HMGB1 signaling axis may increase the number of lungs available for transplantation and improve long-term benefits for organ recipient patient outcomes. Antioxid. Redox Signal. 23, 1316–1328.
PMCID: PMC4685484  PMID: 25751601
13.  Prey should hide more randomly when a predator attacks more persistently 
Journal of the Royal Society Interface  2015;12(113):20150861.
When being searched for and then (if found) pursued by a predator, a prey animal has a choice between choosing very randomly among hiding locations so as to be hard to find or alternatively choosing a location from which it is more likely to successfully flee if found. That is, the prey can choose to be hard to find or hard to catch, if found. In our model, capture of prey requires both finding it and successfully pursuing it. We model this dilemma as a zero-sum repeated game between predator and prey, with the eventual capture probability as the pay-off to the predator. We find that the more random hiding strategy is better when the chances of repeated pursuit, which are known to be related to area topography, are high. Our results extend earlier results of Gal and Casas, where there was at most only a single pursuit. In that model, hiding randomly was preferred by the prey when the predator has only a few looks. Thus, our new multistage model shows that the effect of more potential looks is opposite. Our results can be viewed as a generalization of search games to the repeated game context and are in accordance with observed escape behaviour of different animals.
PMCID: PMC4707860  PMID: 26631332
game theory; escape; repeated games; behavioural ecology
14.  Selective Capture of Glycoproteins Using Lectin-modified Nanoporous Gold Monolith 
Journal of chromatography. A  2015;1423:19-30.
The surface of nanoporous gold (np-Au) monoliths was modified via a flow method with the lectin Concanavalin A (Con A) to develop a substrate for separation and extraction of glycoproteins. Self-assembled monolayers (SAMs) of lipoic acid (LA) on the np-Au monoliths were prepared followed by activation of the terminal carboxyl groups to create amine reactive esters that were utilized in the immobilization of Con A. Thermogravimetric analysis (TGA) was used to determine the surface coverages of LA and Con A on np-Au monoliths which were found to be 1.31 × 1018 molecules m−2 and 1.85 × 1015 molecules m−2, respectively. An in situ solution depletion method was developed that enabled surface coverage characterization without damaging the substrate and suggesting the possibility of regeneration. Using this method, the surface coverages of LA and Con A were found to be 0.989 ×1018 molecules m−2 and 1.32 × 1015 molecules m−2, respectively. The selectivity of the Con A-modified np-Au monolith for the high mannose-containing glycoprotein ovalbumin (OVA) versus negative control non-glycosylated bovine serum albumin (BSA) was demonstrated by the difference in the ratio of the captured molecules to the immobilized Con A molecules, with OVA:Con A = 2.3 and BSA:Con A = 0.33. Extraction of OVA from a 1:3 mole ratio mixture with BSA was demonstrated by the greater amount of depletion of OVA concentration during the circulation with the developed substrate. A significant amount of captured OVA was eluted using α-methyl mannopyranoside as a competitive ligand. This work is motivated by the need to develop new materials for chromatographic separation and extraction substrates for use in preparative and analytical procedures in glycomics.
PMCID: PMC4659647  PMID: 26554297
nanoporous gold; chromatography; lectin; glycoprotein; monolith; glycomics
15.  Digital communication between clinician and patient and the impact on marginalised groups: a realist review in general practice 
The British Journal of General Practice  2015;65(641):e813-e821.
Increasingly, the NHS is embracing the use of digital communication technology for communication between clinicians and patients. Policymakers deem digital clinical communication as presenting a solution to the capacity issues currently faced by general practice. There is some concern that these technologies may exacerbate existing inequalities in accessing health care. It is not known what impact they may have on groups who are already marginalised in their ability to access general practice.
To assess the potential impact of the availability of digital clinician–patient communication on marginalised groups’ access to general practice in the UK.
Design and setting
Realist review in general practice.
A four-step realist review process was used: to define the scope of the review; to search for and scrutinise evidence; to extract and synthesise evidence; and to develop a narrative, including hypotheses.
Digital communication has the potential to overcome the following barriers for marginalised groups: practical access issues, previous negative experiences with healthcare service/staff, and stigmatising reactions from staff and other patients. It may reduce patient-related barriers by offering anonymity and offers advantages to patients who require an interpreter. It does not impact on inability to communicate with healthcare professionals or on a lack of candidacy. It is likely to work best in the context of a pre-existing clinician–patient relationship.
Digital communication technology offers increased opportunities for marginalised groups to access health care. However, it cannot remove all barriers to care for these groups. It is likely that they will remain disadvantaged relative to other population groups after their introduction.
PMCID: PMC4655735  PMID: 26622034
access to health care; communication; doctor-patient relations; general practice
16.  Coronary Artery Disease Severity and Cardiovascular Biomarkers in Patients with Peripheral Artery Disease 
Cardiovascular mortality in peripheral artery disease (PAD) patients is higher in critical limb ischemia (CLI) than in intermittent claudication (IC). We sought to evaluate differential characteristics of coronary artery disease (CAD) severity and prognostic biomarkers for cardiovascular events between CLI and IC patients. Coronary angiography was performed on 242 PAD patients (age 73 ± 8 years) with either CLI or IC. High-sensitivity troponin T (hs-TnT), eicosapentaenoic acid–arachidonic acid ratio (EPA/AA), and lipoprotein(a), as biomarkers for prognostic factors, were measured from blood samples. The study patients were divided into a CLI-group (n = 42) and IC-group (n = 200). The Gensini score as an indicator of coronary angiographic severity was higher in the CLI-group than in the IC-group (39.1 ± 31.2 vs. 8.5 ± 8.3, p < 0.0001). Hs-TnT and lipoprotein(a) values were higher in the CLI-group than in the IC-group (0.152 ± 0.186 ng/mL vs. 0.046 ± 0.091, p < 0.0001, 45.9 ± 23.3 mg/dL vs. 26.2 ± 27.7, p = 0.0002, respectively) and EPA/AA was lower in the CLI-group than in the IC-group (0.22 ± 0.11 vs. 0.38 ± 0.29, p = 0.0049, respectively). Greater CAD severity, higher hs-TnT, and lipoprotein(a), and lower EPA/AA were observed in the CLI-group, which may explain higher cardiovascular events in patients with CLI.
PMCID: PMC4656161  PMID: 26648670
coronary artery; cardiovascular disease; peripheral artery disease; claudication; critical limb ischemia; cardiac biomarkers; cardiac catheterization
17.  Ipsilesional Motor-Evoked Potential Absence in Pediatric Hemiparesis Impacts Tracking Accuracy of the Less Affected Hand 
This study analyzed the relationship between electrophysiological responses to transcranial magnetic stimulation (TMS), finger tracking accuracy, and volume of neural substrate in children with congenital hemiparesis. Nineteen participants demonstrating an ipsilesional motor-evoked potential (MEP) were compared with eleven participants showing an absent ipsilesional MEP response. Comparisons of finger tracking accuracy from the affected and less affected hands and ipsilesional/contralesional (I/C) volume ratio for the primary motor cortex (M1) and posterior limb of internal capsule (PLIC) were done using two-sample t-tests. Participants showing an ipsilesional MEP response demonstrated superior tracking performance from the less affected hand (p = 0.016) and significantly higher I/C volume ratios for M1 (p= 0.028) and PLIC (p = 0.005) compared to participants without an ipsilesional MEP response. Group differences in finger tracking accuracy from the affected hand were not significant. These results highlight differentiating factors amongst children with congenital hemiparesis showing contrasting MEP responses: less affected hand performance and preserved M1 and PLIC volume. Along with MEP status, these factors pose important clinical implications in pediatric stroke rehabilitation. These findings may also reflect competitive developmental processes associated with the preservation of affected hand function at the expense of some function in the less affected hand.
PMCID: PMC4670029  PMID: 26426515
stroke; transcranial magnetic stimulation; pediatrics; corticospinal tract; motor-evoked potential; hemiparesis
18.  Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice 
Cell metabolism  2015;22(6):983-996.
The gut microbiota plays a key role in host metabolism. Toll-Like Receptor 5 (TLR5), a flagellin receptor, is required for gut microbiota homeostasis. Accordingly, TLR5 deficient (T5KO) mice are prone to develop microbiota-dependent metabolic syndrome. Here we observed that T5KO mice display elevated neutral lipids with a compositional increase of oleate [C18:1 (n9)] relative to wild-type littermates. Increased oleate contribution to hepatic lipids and liver SCD1 expression were both microbiota-dependent. Analysis of short chain fatty acids (SCFA) and 13C-acetate label incorporation revealed elevated SCFA in ceca and hepatic portal blood and, increased liver de novo lipogenesis in T5KO mice. Dietary SCFA further aggravated metabolic syndrome in T5KO mice. Deletion of hepatic SCD1 not only prevented hepatic neutral lipid oleate enrichment but also ameliorated metabolic syndrome in T5KO mice. Collectively, these results underscore the key role of the gut microbiota-liver axis in the pathogenesis of metabolic diseases.
Graphical Abstract
PMCID: PMC4670569  PMID: 26525535
Toll-like receptor 5; Gut bacteria; Short chain fatty acids; Hepatic neutral lipids; Monounsaturated fatty acids; Low-grade inflammation; Metabolic diseases
19.  Bile Duct Injury—from Injury to Repair: an Analysis of Management and Outcome 
The Indian Journal of Surgery  2013;77(Suppl 2):536-542.
Despite advances in speciality care, mortality and morbidity remain the most important issues in the management of post-cholecystectomy bile duct injuries. We analysed the peri-operative management of post-cholecystectomy bile duct injuries to assess their outcomes. Of 150 patients with post-cholecystectomy bile duct injuries, 13 patients who presented with strictured hepaticojejunostomy were excluded from the analysis. The records of the remaining 137 patients were analysed for type of presentation, management and follow-up. Of 137 injuries, 88 were open and 49 were laparoscopic. Various presentations include acute bile duct injury (n = 5), bile collection (n = 45), external biliary fistula (n = 46) and stricture (n = 41). After initial management, three patients died (sepsis, n = 2; pseudoaneurysmal bleed, n = 1). Of 107 patients who underwent definitive repair, three died (portal hypertension, n = 2; sepsis, n = 1). At median follow-up of 30 months, 100 patients had good outcome (grade A, B), and only 4 had bad outcome (grade C, D) as per McDonald grading. Peritonitis and sepsis in the early phase and portal hypertension and cirrhosis in the late phase are the main causes of mortality in patients sustaining bile duct injury during cholecystectomy. Successful management in a specialist hepatobiliary centre can limit the morbidity in more than 90 % cases.
PMCID: PMC4692882  PMID: 26730060
Bile duct injury; Benign biliary stricture; Hepaticojejunostomy; External biliary fistula
20.  Adolescent Alcohol Exposure Amplifies the Incentive Value of Reward-Predictive Cues Through Potentiation of Phasic Dopamine Signaling 
Neuropsychopharmacology  2015;40(13):2873-2885.
Adolescent alcohol use remains a major public health concern due in part to well-established findings implicating the age of onset in alcohol use in the development of alcohol use disorders and persistent decision-making deficits in adults. We have previously demonstrated that moderate adolescent alcohol consumption in rats promotes suboptimal decision making and an associated perturbation in mesolimbic dopamine transmission in adulthood. Dopamine-dependent incentive learning processes are an integral component of value-based decision making and a fundamental element to many theoretical accounts of addiction. Thus we tested the hypothesis that adolescent alcohol use selectively alters incentive learning processes through perturbation of mesolimbic dopamine systems. To assess incentive learning, behavioral and neurochemical measurements were made during the acquisition, maintenance, extinction, and reacquisition of a Pavlovian conditioned approach procedure in adult rats with a history of adolescent alcohol consumption. We show that moderate adolescent alcohol consumption potentiates stimulus-evoked phasic dopamine transmission, measured in vivo by fast-scan cyclic voltammetry, in adulthood and biases individuals toward a dopamine-dependent incentive learning strategy. Moreover, we demonstrate that animals exposed to alcohol in adolescence are more sensitive to an unexpected variation in reward outcomes. This pattern of phasic dopamine signaling and the associated bias in learning may provide a mechanism for the well-documented vulnerability of individuals with early-life alcohol use for alcohol use disorders in adulthood.
PMCID: PMC4864623  PMID: 25971592
21.  Removal of sialoliths using the intraoral approach in 15 horses 
The Canadian Veterinary Journal  2016;57(6):647-650.
This study describes the use of an intraoral approach for sialolith removal in horses. All horses resumed their previous activity after surgery. Sialoliths were composed mainly of calcium carbonate, containing a nidus of plant material. The removal of sialoliths via an intraoral approach results in a high success rate with minimal complications.
PMCID: PMC4866672  PMID: 27247466
22.  The role of eating frequency on relative weight in urban school-age children 
Pediatric obesity  2015;10(6):442-447.
The role of eating frequency on relative weight in childhood is not well understood.
To clarify this relationship by assessing the cross-sectional and prospective relationships of weekday eating frequency with BMI z-score (BMIz) and change in BMIz in a sample of schoolchildren.
Eating frequency, the average number of reported daily eating occasions, was assessed using two weekday 24-hour diet recalls. BMIz was measured at baseline, 6-months, and 1-year in 155 urban schoolchildren, ages 9-15 years. Multiple linear regression models were used.
Cross-sectional analyses at baseline suggest that BMIz was 0.23 units lower for each additional reported eating occasion (regression coefficient=-0.23; 95% CI: -0.44, -0.07). From baseline to 6-months, BMIz increased by 0.03 units for each additional reported eating occasion (regression coefficient= 0.03; 95% CI: 0.01, 0.05). This relationship was no longer statistically significant at 1-year (regression coefficient= 0.01; 95% CI: -0.01, 0.03).
Findings suggest that the relationship of eating frequency with BMIz differs from that of change in BMIz. This difference may be due to methodological deficiencies of cross-sectional studies, challenges of dietary assessment, or differences in eating patterns among normal and overweight youth. Controlled trials are needed further clarify this relationship.
PMCID: PMC4495000  PMID: 25565335
Body Mass Index (BMI) Z-score; Childhood obesity; Eating behaviors; Eating frequency; Snacking
23.  Evaluating Alcoholics Anonymous Sponsor Attributes Using Conjoint Analysis 
Addictive behaviors  2015;51:12-17.
Alcoholics Anonymous (AA) considers sponsorship an important element of the AA program, especially in early recovery. 225 adult individuals who had experience as either a sponsor, sponsee, or both, participated in a hypothetical sponsor ranking exercise where five attributes were varied across three levels. Conjoint analysis was used to compute part-worth utility of the attributes and their levels for experience, knowledge, availability, confidentiality, and goal-setting. Differences in utilities by attribute were found where confidentiality had the greatest overall possible impact on utility and sponsor knowledge had the least. These findings suggest qualitative differences in sponsors may impact their effectiveness. Future research on AA should continue to investigate sponsor influence on an individual’s overall recovery trajectory.
PMCID: PMC4558395  PMID: 26186375
conjoint analysis; Alcoholics Anonymous; AA; sponsorship; sponsor; sponsee; part-worth utility
24.  Psychophysical Testing in Rodent Models of Glaucomatous optic neuropathy 
Experimental eye research  2015;141:154-163.
Processing of visual information begins in the retina, with photoreceptors converting light stimuli into neural signals. Ultimately, signals are transmitted to the brain through signaling networks formed by interneurons, namely bipolar, horizontal and amacrine cells providing input to retinal ganglion cells (RGCs), which form the optic nerve with their axons. As part of the chronic nature of glaucomatous optic neuropathy, the increasing and irreversible damage and ultimately loss of neurons, RGCs in particular, occurs following progressive damage to the optic nerve head (ONH), eventually resulting in visual impairment and visual field loss. There are two behavioral assays that are typically used to assess visual deficits in glaucoma rodent models, the visual water task and the optokinetic drum. The visual water task can assess an animal’s ability to distinguish grating patterns that are associated with an escape from water. The optokinetic drum relies on the optomotor response, a reflex turning of the head and neck in the direction of the visual stimuli, which usually consists of rotating black and white gratings. This reflex is a physiological response critical for keeping the image stable on the retina. Driven initially by the neuronal input from direction-selective RGCs, this reflex is comprised of a number of critical sensory and motor elements. In the presence of repeatable and defined stimuli, this reflex is extremely well suited to analyze subtle changes in the circuitry and performance of retinal neurons. Increasing the cycles of these alternating gratings per degree, or gradually reducing the contrast of the visual stimuli, threshold levels can be determined at which the animal is no longer tracking the stimuli, and thereby visual function of the animal can be determined non-invasively. Integrating these assays into an array of outcome measures that determine multiple aspects of visual function is a central goal in vision research and can be realized, for example, by the combination of measuring optomotor reflex function with electroretinograms (ERGs) and optical coherence tomography (OCT) of the retina. These structure-function correlations in vivo are urgently needed to identify disease mechanisms as potential new targets for drug development. Such a combination of the experimental assessment of the optokinetic reflex (OKN) or optomotor reflex (OMR) with other measures of retinal structure and function is especially valuable for research on GON. The chronic progression of the disease is characterized by a gradual decrease in function accompanied by a concomitant increase in structural damage to the retina, therefore the assessment of subtle changes is key to determining the success of novel intervention strategies.
PMCID: PMC4628867  PMID: 26144667
accessory optic system; glaucoma; lateral geniculate nucleus; optical coherence tomography; optokinetic; nystagmus; optomotor reflex; optic nerve head; retinal ganglion cell; superior colliculus; vestibular-ocular reflex
25.  ICU capacity strain and adherence to prophylaxis guidelines 
Journal of critical care  2015;30(6):1303-1309.
To examine the relationship between different measures of capacity strain and adherence to prophylaxis guidelines in the intensive care unit (ICU).
Materials and Methods
We conducted a retrospective cohort study within the Project IMPACT database. We used multivariable logistic regression to examine relationships between ICU capacity strain and appropriate usage of venous thromboembolism prophylaxis (VTEP) and stress ulcer prophylaxis (SUP).
Of 776,905 patient-days eligible for VTEP, appropriate therapy was provided on 68%. Strain as measured by proportion of new admissions (OR 0.91, 95% CI 0.90 – 0.91) and census (OR 0.97, 95% CI 0.97 – 0.98) was associated with decreased odds of receiving VTEP. With increasing strain as measured by new admissions, the degradation of VTEP utilization was more severe in ICUs with closed (OR 0.85, 95% CI 0.83 – 0.88) than open (OR 0.91, 95% CI 0.91 – 0.92) staffing models (interaction p-value < 0.001). Of 185,425 patient-days eligible for SUP, 48% received appropriate therapy. Administration of SUP was not significantly influenced by any measure of strain.
Rising capacity strain in the ICU reduces the odds that patients will receive appropriate VTEP but not SUP. The variability among different types of ICUs in the extent to which strain degraded VTEP use suggests opportunities for systems improvement.
PMCID: PMC4628874  PMID: 26376062
surge capacity; intensive care units; venous thromboembolism; gastrointestinal hemorrhage; prophylaxis

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