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1.  Rethinking human visual attention: Spatial cueing effects and optimality of decisions by honeybees, monkeys and humans 
Vision research  2013;85:5-19.
Visual attention is commonly studied by using visuo-spatial cues indicating probable locations of a target and assessing the effect of the validity of the cue on perceptual performance and its neural correlates. Here, we adapt a cueing task to measure spatial cueing effects on the decisions of honeybees and compare their behavior to that of humans and monkeys in a similarly structured two-alternative forced-choice perceptual task. Unlike the typical cueing paradigm in which the stimulus strength remains unchanged within a block of trials, for the monkey and human studies we randomized the contrast of the signal to simulate more real world conditions in which the organism is uncertain about the strength of the signal. A Bayesian ideal observer that weights sensory evidence from cued and uncued locations based on the cue validity to maximize overall performance is used as a benchmark of comparison against the three animals and other suboptimal models: probability matching, ignore the cue, always follow the cue, and an additive bias/single decision threshold model. We find that the cueing effect is pervasive across all three species but is smaller in size than that shown by the Bayesian ideal observer. Humans show a larger cueing effect than monkeys and bees show the smallest effect. The cueing effect and overall performance of the honeybees allows rejection of the models in which the bees are ignoring the cue, following the cue and disregarding stimuli to be discriminated, or adopting a probability matching strategy. Stimulus strength uncertainty also reduces the theoretically predicted variation in cueing effect with stimulus strength of an optimal Bayesian observer and diminishes the size of the cueing effect when stimulus strength is low. A more biologically plausible model that includes an additive bias to the sensory response from the cued location, although not mathematically equivalent to the optimal observer for the case stimulus strength uncertainty, can approximate the benefits of the more computationally complex optimal Bayesian model. We discuss the implications of our findings on the field’s common conceptualization of covert visual attention in the cueing task and what aspects, if any, might be unique to humans.
PMCID: PMC3968950  PMID: 23298793
2.  IL-2 coordinates IL-2–producing and regulatory T cell interplay 
The Journal of Experimental Medicine  2013;210(12):2707-2720.
Regulation of IL-2–producing CD4+ T cell numbers is controlled by a quorum-sensing feedback loop as regulatory T cells sense the IL-2 produced.
Many species of bacteria use quorum sensing to sense the amount of secreted metabolites and to adapt their growth according to their population density. We asked whether similar mechanisms would operate in lymphocyte homeostasis. We investigated the regulation of the size of interleukin-2 (IL-2)–producing CD4+ T cell (IL-2p) pool using different IL-2 reporter mice. We found that in the absence of either IL-2 or regulatory CD4+ T (T reg) cells, the number of IL-2p cells increases. Administration of IL-2 decreases the number of cells of the IL-2p cell subset and, pertinently, abrogates their ability to produce IL-2 upon in vivo cognate stimulation, while increasing T reg cell numbers. We propose that control of the IL-2p cell numbers occurs via a quorum sensing–like feedback loop where the produced IL-2 is sensed by both the activated CD4+ T cell pool and by T reg cells, which reciprocally regulate cells of the IL-2p cell subset. In conclusion, IL-2 acts as a self-regulatory circuit integrating the homeostasis of activated and T reg cells as CD4+ T cells restrain their growth by monitoring IL-2 levels, thereby preventing uncontrolled responses and autoimmunity.
PMCID: PMC3832933  PMID: 24249704
3.  Sex-determining chromosomes and sexual dimorphism: insights from genetic mapping of sex expression in a natural hybrid Fragaria × ananassa subsp. cuneifolia 
Heredity  2012;110(5):430-438.
We studied the natural hybrid (Fragaria × ananassa subsp. cuneifolia) between two sexually dimorphic octoploid strawberry species (Fragaria virginiana and Fragaria chiloensis) to gain insight into the dynamics of sex chromosomes and the genesis of sexual dimorphism. Male sterility is dominant in both the parental species and thus will be inherited maternally, but the chromosome that houses the sex-determining region differs. Thus, we asked whether (1) the cytotypic composition of hybrid populations represents one or both maternal species, (2) the sex-determining chromosome of the hybrid reflects the location of male sterility within the maternal donor species and (3) crosses from the hybrid species show less sexual dimorphism than the parental species. We found that F. × ananassa subsp. cuneifolia populations consisted of both parental cytotypes but one predominated within each population. Genetic linkage mapping of two crosses showed dominance of male sterility similar to the parental species, however, the map location of male sterility reflected the maternal donor in one cross, but not the other. Moreover, female function mapped to a single region in the first cross, but to two regions in the second cross. Aside from components of female function (fruit set and seed set), other traits that have been found to be significantly sexually dimorphic in the pure species were either not dimorphic or were dimorphic in the opposite direction to the parental species. These results suggest that hybrids experience some disruption of dimorphism in secondary sexual traits, as well as novel location and number of quantitative trait locus (QTL) affecting sex function.
PMCID: PMC3630810  PMID: 23169558
Fragaria ; hybrid; sexual dimorphism; sex chromosome; male sterility
4.  Sawfly taxa (Hymenoptera, Symphyta) described by Edward Newman and Charles Healy 
ZooKeys  2014;83-98.
Type specimens of seven nominal species of sawfly described by Edward Newman and one by Charles Healy were studied. This material is housed in the Oxford University Museum of Natural History, United Kingdom. The following new synonymies are proposed (valid names in parentheses): Hartigia Schiødte, 1839 (Phylloecus Newman, 1838), Cephus helleri Taschenberg, 1871 (Phylloecus faunus Newman, 1838) and Euura gallae Newman, 1837 (Euura mucronata (Hartig, 1837)). The type species of Euura Newman, 1837 and Euura subgenus Gemmura E. L. Smith, 1968 belong to the same taxonomic species, Euura mucronata (Hartig, 1837), so that these genus group names become new synonyms. Lectotypes are designated for Phyllotoma tormentillae Healy, 1868, Fenusa ianthe Newman, 1837, Fenusa parviceps Newman, 1837, Selandria pallida Newman, 1837 and Phylloecus faunus Newman, 1838. 26 new combinations are proposed for species formerly placed in Hartigia and here transferred to Phylloecus, and 4 original combinations are re-instated as valid.
PMCID: PMC3978228  PMID: 24715803
Taxonomy; Tenthredinidae; Cephidae; Euura; Phylloecus; Hartigia; new synonyms; new combinations
5.  An empirical evaluation of two-stage species tree inference strategies using a multilocus dataset from North American pines 
As it becomes increasingly possible to obtain DNA sequences of orthologous genes from diverse sets of taxa, species trees are frequently being inferred from multilocus data. However, the behavior of many methods for performing this inference has remained largely unexplored. Some methods have been proven to be consistent given certain evolutionary models, whereas others rely on criteria that, although appropriate for many parameter values, have peculiar zones of the parameter space in which they fail to converge on the correct estimate as data sets increase in size.
Here, using North American pines, we empirically evaluate the behavior of 24 strategies for species tree inference using three alternative outgroups (72 strategies total). The data consist of 120 individuals sampled in eight ingroup species from subsection Strobus and three outgroup species from subsection Gerardianae, spanning ∼47 kilobases of sequence at 121 loci. Each “strategy” for inferring species trees consists of three features: a species tree construction method, a gene tree inference method, and a choice of outgroup. We use multivariate analysis techniques such as principal components analysis and hierarchical clustering to identify tree characteristics that are robustly observed across strategies, as well as to identify groups of strategies that produce trees with similar features. We find that strategies that construct species trees using only topological information cluster together and that strategies that use additional non-topological information (e.g., branch lengths) also cluster together. Strategies that utilize more than one individual within a species to infer gene trees tend to produce estimates of species trees that contain clades present in trees estimated by other strategies. Strategies that use the minimize-deep-coalescences criterion to construct species trees tend to produce species tree estimates that contain clades that are not present in trees estimated by the Concatenation, RTC, SMRT, STAR, and STEAC methods, and that in general are more balanced than those inferred by these other strategies.
When constructing a species tree from a multilocus set of sequences, our observations provide a basis for interpreting differences in species tree estimates obtained via different approaches that have a two-stage structure in common, one step for gene tree estimation and a second step for species tree estimation. The methods explored here employ a number of distinct features of the data, and our analysis suggests that recovery of the same results from multiple methods that tend to differ in their patterns of inference can be a valuable tool for obtaining reliable estimates.
PMCID: PMC4021425  PMID: 24678701
6.  Effects of socioeconomic position and clinical risk factors on spontaneous and iatrogenic preterm birth 
The literature shows a variable and inconsistent relationship between socioeconomic position and preterm birth. We examined risk factors for spontaneous and iatrogenic preterm birth, with a focus on socioeconomic position and clinical risk factors, in order to explain the observed inconsistency.
We carried out a retrospective population-based cohort study of all singleton deliveries in Nova Scotia from 1988 to 2003. Data were obtained from the Nova Scotia Atlee Perinatal Database and the federal income tax T1 Family Files. Separate logistic models were used to quantify the association between socioeconomic position, clinical risk factors and spontaneous preterm birth and iatrogenic preterm birth.
The study population included 132,714 singleton deliveries and the rate of preterm birth was 5.5%. Preterm birth rates were significantly higher among the women in the lowest (versus the highest) family income group for spontaneous (rate ratio 1.14, 95% confidence interval (CI) 1.03, 1.25) but not iatrogenic preterm birth (rate ratio 0.95, 95% CI 0.75, 1.19). Adjustment for maternal characteristics attenuated the family income-spontaneous preterm birth relationship but strengthened the relationship with iatrogenic preterm birth. Clinical risk factors such as hypertension were differentially associated with spontaneous (rate ratio 3.92, 95% CI 3.47, 4.44) and iatrogenic preterm (rate ratio 14.1, 95% CI 11.4, 17.4) but factors such as diabetes mellitus were not (rate ratio 4.38, 95% CI 3.21, 5.99 for spontaneous and 4.02, 95% CI 2.07, 7.80 for iatrogenic preterm birth).
Socioeconomic position and clinical risk factors have different effects on spontaneous and iatrogenic preterm. Recent temporal increases in iatrogenic preterm birth appear to be responsible for the inconsistent relationship between socioeconomic position and preterm birth.
PMCID: PMC3987165  PMID: 24670050
Spontaneous preterm birth; Iatrogenic preterm birth; Risk factors; Pregnancy complications; Socioeconomic status
7.  The Immunogenetic Architecture of Autoimmune Disease 
The development of most autoimmune diseases includes a strong heritable component. This genetic contribution to disease ranges from simple Mendelian inheritance of causative alleles to the complex interactions of multiple weak loci influencing risk. The genetic variants responsible for disease are being discovered through a range of strategies from linkage studies to genome-wide association studies. Despite the rapid advances in genetic analysis, substantial components of the heritable risk remain unexplained, either owing to the contribution of an as-yet unidentified, “hidden,” component of risk, or through the underappreciated effects of known risk loci. Surprisingly, despite the variation in genetic control, a great deal of conservation appears in the biological processes influenced by risk alleles, with several key immunological pathways being modified in autoimmune diseases covering a broad spectrum of clinical manifestations. The primary translational potential of this knowledge is in the rational design of new therapeutics to exploit the role of these key pathways in influencing disease. With significant further advances in understanding the genetic risk factors and their biological mechanisms, the possibility of genetically tailored (or “personalized”) therapy may be realized.
Genetic risk variants associated with various autoimmune diseases, from rheumatoid arthritis to type 1 diabetes, are often similar. For example, most autoimmune diseases, if not all, are associated with the human leukocyte antigen (HLA) region.
PMCID: PMC3282406  PMID: 22383754
9.  Circadian glucocorticoid oscillations promote learning-dependent synapse formation and maintenance 
Nature neuroscience  2013;16(6):698-705.
Excessive glucocorticoid exposure during chronic stress causes synapse loss and learning impairment. Under normal physiological conditions, glucocorticoid activity oscillates in synchrony with the circadian rhythm. Whether and how endogenous glucocorticoid oscillations modulate synaptic plasticity and learning is unknown. Here we show that circadian glucocorticoid peaks promote postsynaptic dendritic spine formation in the mouse cortex after motor skill learning, whereas troughs are required for stabilizing newly formed spines that are important for long-term memory retention. Conversely, chronic and excessive exposure to glucocorticoids eliminates learning-associated new spines and disrupts previously acquired memories. Furthermore, we show that glucocorticoids promote rapid spine formation through a non-transcriptional mechanism by means of the LIM kinase–cofilin pathway and increase spine elimination through transcriptional mechanisms involving mineralocorticoid receptor activation. Together, these findings indicate that tightly regulated circadian glucocorticoid oscillations are important for learning-dependent synaptic formation and maintenance. They also delineate a new signaling mechanism underlying these effects.
PMCID: PMC3896394  PMID: 23624512
10.  Modulation of mutagenesis in eukaryotes by DNA replication fork dynamics and quality of nucleotide pools 
The rate of mutations in eukaryotes depends on a plethora of factors and is not immediately derived from the fidelity of DNA polymerases (Pols). Replication of chromosomes containing the anti-parallel strands of duplex DNA occurs through the copying of leading and lagging strand templates by a trio of Pols α, δ and ε, with the assistance of Pol ζ and Y-family Pols at difficult DNA template structures or sites of DNA damage. The parameters of the synthesis at a given location are dictated by the quality and quantity of nucleotides in the pools, replication fork architecture, transcription status, regulation of Pol switches, and structure of chromatin. The result of these transactions is a subject of survey and editing by DNA repair.
PMCID: PMC3893020  PMID: 23055184
DNA polymerases; nucleotide pools; mutagenesis; Okazaki fragments
11.  Mast Cells Play No Role in the Pathogenesis of Postoperative Ileus Induced by Intestinal Manipulation 
PLoS ONE  2014;9(1):e85304.
Intestinal manipulation (IM) during abdominal surgery results in intestinal inflammation leading to hypomotility or ileus. Mast cell activation is thought to play a crucial role in the pathophysiology of postoperative ileus (POI). However, this conclusion was mainly drawn using mast cell-deficient mouse models with abnormal Kit signaling. These mice also lack interstitial cells of Cajal (ICC) resulting in aberrant gastrointestinal motility even prior to surgery, compromising their use as model to study POI. To avoid these experimental weaknesses we took advantage of a newly developed knock-in mouse model, Cpa3Cre/+, devoid of mast cells but with intact Kit signaling.
The role of mast cells in the development of POI and intestinal inflammation was evaluated assessing gastrointestinal transit and muscularis externa inflammation after IM in two strains of mice lacking mast cells, i.e. KitW-sh/W-sh and Cpa3Cre/+ mice, and by use of the mast cell stabilizer cromolyn.
KitW-sh/W-sh mice lack ICC networks and already revealed significantly delayed gastrointestinal transit even before surgery. IM did not further delay intestinal transit, but induced infiltration of myeloperoxidase positive cells, expression of inflammatory cytokines and recruitment of monocytes and neutrophils into the muscularis externa. On the contrary, Cpa3Cre/+ mice have a normal network of ICC and normal gastrointestinal. Surprisingly, IM in Cpa3Cre/+ mice caused delay in gut motility and intestinal inflammation as in wild type littermates mice (Cpa3+/+). Furthermore, treatment with the mast cell inhibitor cromolyn resulted in an inhibition of mast cells without preventing POI.
Here, we confirm that IM induced mast cell degranulation. However, our data demonstrate that mast cells are not required for the pathogenesis of POI in mice. Although there might be species differences between mouse and human, our results argue against mast cell inhibitors as a therapeutic approach to shorten POI.
PMCID: PMC3887017  PMID: 24416383
12.  miRNAs control the maintenance of thymic epithelia and their competence for T lineage commitment and thymocyte selection 
Thymic epithelial cells provide unique cues for the life-long selection and differentiation of a repertoire of functionally diverse T cells. Rendered miRNA deficient, these stromal cells in the mouse lose their capacity to instruct the commitment of haematopoietic precursors to a T cell fate, to effect thymocyte positive selection and to achieve promiscuous gene expression required for central tolerance induction. Over time, the microenvironment created by miRNA-deficient thymic epithelia assumes the cellular composition and structure of peripheral lymphoid tissue where thympoiesis fails to be supported. These findings emphasize a global role for miRNA in the maintenance and function of the thymic epithelial cell scaffold and establish a novel mechanism how these cells control peripheral tissue antigen expression to prompt central immunological tolerance.
PMCID: PMC3675876  PMID: 22972926
13.  Horizontal Transfer of DNA from the Mitochondrial to the Plastid Genome and Its Subsequent Evolution in Milkweeds (Apocynaceae) 
Genome Biology and Evolution  2013;5(10):1872-1885.
Horizontal gene transfer (HGT) of DNA from the plastid to the nuclear and mitochondrial genomes of higher plants is a common phenomenon; however, plastid genomes (plastomes) are highly conserved and have generally been regarded as impervious to HGT. We sequenced the 158 kb plastome and the 690 kb mitochondrial genome of common milkweed (Asclepias syriaca [Apocynaceae]) and found evidence of intracellular HGT for a 2.4-kb segment of mitochondrial DNA to the rps2–rpoC2 intergenic spacer of the plastome. The transferred region contains an rpl2 pseudogene and is flanked by plastid sequence in the mitochondrial genome, including an rpoC2 pseudogene, which likely provided the mechanism for HGT back to the plastome through double-strand break repair involving homologous recombination. The plastome insertion is restricted to tribe Asclepiadeae of subfamily Asclepiadoideae, whereas the mitochondrial rpoC2 pseudogene is present throughout the subfamily, which confirms that the plastid to mitochondrial HGT event preceded the HGT to the plastome. Although the plastome insertion has been maintained in all lineages of Asclepiadoideae, it shows minimal evidence of transcription in A. syriaca and is likely nonfunctional. Furthermore, we found recent gene conversion of the mitochondrial rpoC2 pseudogene in Asclepias by the plastid gene, which reflects continued interaction of these genomes.
PMCID: PMC3814198  PMID: 24029811
Asclepias syriaca; gene conversion; horizontal gene transfer; mitochondrial genome; phylogeny; plastome
14.  Rapamycin increases survival in ALS mice lacking mature lymphocytes 
Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease. Disease pathophysiology is complex and not yet fully understood, but is proposed to include the accumulation of misfolded proteins, as aggregates are present in spinal cords from ALS patients and in ALS model organisms. Increasing autophagy is hypothesized to be protective in ALS as it removes these aggregates. Rapamycin is frequently used to increase autophagy, but is also a potent immune suppressor. To properly assess the role of rapamycin-induced autophagy, the immune suppressive role of rapamycin should be negated.
Autophagy is increased in the spinal cord of ALS mice. Dietary supplementation of rapamycin increases autophagy, but does not increase the survival of mutant SOD1 mice. To measure the effect of rapamycin in ALS independent of immunosuppression, we tested the effect of rapamycin in ALS mice deficient of mature lymphocytes. Our results show that rapamycin moderately increases the survival of these ALS mice deficient of mature lymphocytes.
Rapamycin could suppress protective immune responses while enhancing protective autophagy reactions during the ALS disease process. While these opposing effects can cancel each other out, the use of immunodeficient mice allows segregation of effects. Our results indicate that maximal therapeutic benefit may be achieved through the use of compounds that enhance autophagy without causing immune suppression.
PMCID: PMC3847677  PMID: 24025516
Autophagy; Rapamycin; Neurodegeneration; Amyotrophic lateral sclerosis; Motor neuron disease; Sirolimus; Rapamune; Immunosuppression
15.  Targeted Sequence Capture Provides Insight into Genome Structure and Genetics of Male Sterility in a Gynodioecious Diploid Strawberry, Fragaria vesca ssp. bracteata (Rosaceae) 
G3: Genes|Genomes|Genetics  2013;3(8):1341-1351.
Gynodioecy is a sexual system wherein females coexist with hermaphrodites. It is of interest not only because male-sterile plants are advantageous in plant breeding but also because it can be a crucial step in the evolutionary transition to entirely separate sexes (dioecy) from a hermaphroditic ancestor. The gynodioecious diploid wild strawberry, Fragaria vesca ssp. bracteata (Rosaceae), is a member of a clade with both dioecious and cultivated species, making it an ideal model in which to study the genetics of male sterility. To create a genetic map of F. v. ssp. bracteata, we identified informative polymorphisms from genomic sequencing (3−5x coverage) of two outbred plants from the same population. Using targeted enrichment, we sequenced 200 bp surrounding each of 6575 polymorphisms in 48 F1 offspring, yielding genotypes at 98% of targeted sites with mean coverage >100x, plus more than 600-kb high-coverage nontargeted sequence. With the resulting linkage map of 7802 stringently filtered markers (5417 targeted), we assessed recombination rates and genomic incongruities. Consistent with past work in strawberries, male sterility is dominant, segregates 1:1, and maps to a single location in the female. Further mapping an additional 55 offspring places male sterility in a gene-dense, 338-kb region of chromosome 4. The region is not syntenic with the sex-determining regions in the closely related octoploids, F. chiloensis and F. virginiana, suggesting either independent origins or translocation. The 57 genes in this region do not include protein families known to control male sterility and thus suggest alternate mechanisms for the suppression of male function.
PMCID: PMC3737174  PMID: 23749450
pollen; sex chromosome; sex determination; trait mapping; translocations
17.  Early and Prolonged Exposure to Reward Delay: Effects on Impulsive Choice and Alcohol Self-administration in Male Rats 
Naturally occurring impulsive choice has been found to positively predict alcohol consumption in rats. However, the extent to which experimental manipulation of impulsive choice may modify alcohol consumption remains unclear. In the present study, we sought to: (a) train low levels of impulsive choice in rats using early, prolonged exposure to reward delay, and (b) determine the effects of this manipulation on subsequent alcohol consumption. During a prolonged training regimen, three groups of male, adolescent Long-Evans rats (21-22 days old at intake) responded on a single lever for food rewards delivered after either a progressively increasing delay, a fixed delay, or no delay. Post-tests of impulsive choice were conducted, as was an evaluation of alcohol consumption using a limited-access, two-bottle test. Following delay-exposure training, both groups of delay-exposed rats made significantly fewer impulsive choices than did rats in the no-delay group. In addition, fixed-delay rats consumed significantly more alcohol during daily, 30-min sessions than no-delay rats. Possible mechanisms of these effects are discussed, as is the significance of these findings to nonhuman models of addiction.
PMCID: PMC3686290  PMID: 23356729
impulsive choice; delay discounting; alcohol self-administration; lever press; rat
18.  Olmsted syndrome: exploration of the immunological phenotype 
Olmsted syndrome is a rare congenital skin disorder presenting with periorifical hyperkeratotic lesions and mutilating palmoplantar keratoderma, which is often associated with infections of the keratotic area. A recent study identified de novo mutations causing constitutive activation of TRPV3 as a cause of the keratotic manifestations of Olmsted syndrome.
Genetic, clinical and immunological profiling was performed on a case study patient with the clinical diagnosis of Olmsted syndrome.
The patient was found to harbour a previously undescribed 1718G-C transversion in TRPV3, causing a G573A point mutation. In depth clinical and immunological analysis found multiple indicators of immune dysregulation, including frequent dermal infections, inflammatory infiltrate in the affected skin, hyper IgE production and elevated follicular T cells and eosinophils in the peripheral blood.
These results provide the first comprehensive assessment of the immunological features of Olmsted syndrome. The systemic phenotype of hyper IgE and persistent eosinophilia suggest a primary or secondary role of immunological processes in the pathogenesis of Olmsted syndrome, and have important clinical consequences with regard to the treatment of Olmsted syndrome patients.
PMCID: PMC3662572  PMID: 23692804
Olmsted syndrome; TRPV3; IgE; Eosinophil; Follicular T cell
19.  Inflammation-associated enterotypes, host genotype, cage and inter-individual effects drive gut microbiota variation in common laboratory mice 
Genome Biology  2013;14(1):R4.
Murine models are a crucial component of gut microbiome research. Unfortunately, a multitude of genetic backgrounds and experimental setups, together with inter-individual variation, complicates cross-study comparisons and a global understanding of the mouse microbiota landscape. Here, we investigate the variability of the healthy mouse microbiota of five common lab mouse strains using 16S rDNA pyrosequencing.
We find initial evidence for richness-driven, strain-independent murine enterotypes that show a striking resemblance to those in human, and which associate with calprotectin levels, a marker for intestinal inflammation. After enterotype stratification, we find that genetic, caging and inter-individual variation contribute on average 19%, 31.7% and 45.5%, respectively, to the variance in the murine gut microbiota composition. Genetic distance correlates positively to microbiota distance, so that genetically similar strains have more similar microbiota than genetically distant ones. Specific mouse strains are enriched for specific operational taxonomic units and taxonomic groups, while the 'cage effect' can occur across mouse strain boundaries and is mainly driven by Helicobacter infections.
The detection of enterotypes suggests a common ecological cause, possibly low-grade inflammation that might drive differences among gut microbiota composition in mammals. Furthermore, the observed environmental and genetic effects have important consequences for experimental design in mouse microbiome research.
PMCID: PMC4053703  PMID: 23347395
20.  Beta-2 microglobulin is important for disease progression in a murine model for amyotrophic lateral sclerosis 
Beta-2 microglobulin (β2m) is an essential component of the major histocompatibility complex (MHC) class I proteins and in the nervous system β2m is predominantly expressed in motor neurons. As β2m can promote nerve regeneration, we investigated its potential role in amyotrophic lateral sclerosis (ALS) by investigating its expression level as well as the effect of genetically removing β2m on the disease process in mutant superoxide dismutase 1 (SOD1G93A) mice, a model of ALS. We observed a strong upregulation of β2m in motor neurons during the disease process and ubiquitous removal of β2m dramatically shortens the disease duration indicating that β2m plays an essential and positive role during the disease process. We hypothesize that β2m contributes to plasticity that is essential for muscle reinnervation. Absence of this plasticity will lead to faster muscle denervation and counteracting this process could be a relevant therapeutic target.
PMCID: PMC3857886  PMID: 24368896
beta-2 microglobulin; amyotrophic lateral sclerosis; motor neuron; neurodegeneration; motor neuron disease
21.  Antigen Recognition By Autoreactive Cd4+ Thymocytes Drives Homeostasis Of The Thymic Medulla 
PLoS ONE  2012;7(12):e52591.
The thymic medulla is dedicated for purging the T-cell receptor (TCR) repertoire of self-reactive specificities. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process because they express numerous peripheral tissue-restricted self-antigens. Although it is well known that medulla formation depends on the development of single-positive (SP) thymocytes, the mechanisms underlying this requirement are incompletely understood. We demonstrate here that conventional SP CD4+ thymocytes bearing autoreactive TCRs drive a homeostatic process that fine-tunes medullary plasticity in adult mice by governing the expansion and patterning of the medulla. This process exhibits strict dependence on TCR-reactivity with self-antigens expressed by mTECs, as well as engagement of the CD28-CD80/CD86 costimulatory axis. These interactions induce the expression of lymphotoxin α in autoreactive CD4+ thymocytes and RANK in mTECs. Lymphotoxin in turn drives mTEC development in synergy with RANKL and CD40L. Our results show that Ag-dependent interactions between autoreactive CD4+ thymocytes and mTECs fine-tune homeostasis of the medulla by completing the signaling axes implicated in mTEC expansion and medullary organization.
PMCID: PMC3531460  PMID: 23300712
22.  Trends in postpartum hemorrhage from 2000 to 2009: a population-based study 
Postpartum hemorrhage, a major cause of maternal death and severe maternal morbidity, increased in frequency in Canada between 1991 and 2004. We carried out a study to describe the epidemiology of postpartum hemorrhage in British Columbia, Canada, between 2000 and 2009.
The study population included all women residents of British Columbia who delivered between 2000 and 2009. Data on postpartum hemorrhage by subtypes and severity were obtained from the British Columbia Perinatal Data Registry. Among women with postpartum hemorrhage, severe cases were identified by the use of blood transfusions or procedures to control bleeding. Rates of postpartum hemorrhage and changes over time were assessed using rates, rate ratios and 95% confidence intervals (CI).
The rate of postpartum hemorrhage increased by 27% (95% CI 21-34%) between 2000 and 2009 (from 6.3% to 8.0%), while atonic postpartum hemorrhage rates increased by 33% (95% CI 26-41%) from 4.8% to 6.4%. Atonic postpartum hemorrhage with blood transfusion increased from 17.8 to 25.5 per 10,000 deliveries from 2000 to 2009 and atonic postpartum hemorrhage with either suturing of the uterus, ligation of pelvic vessels or embolization increased from 1.8 to 5.6 per 10,000 deliveries from 2001 to 2009. The increase in atonic postpartum hemorrhage was most evident between 2006 and 2009 and occurred across regions, hospitals and various maternal, fetal and obstetric characteristics.
Atonic postpartum hemorrhage and severe atonic postpartum hemorrhage increased in British Columbia between 2000 and 2009. Further research is required to identify the cause of the increase.
PMCID: PMC3534600  PMID: 23057683
23.  Type I interferon and pattern recognition receptor signaling following particulate matter inhalation 
Welding, a process that generates an aerosol containing gases and metal-rich particulates, induces adverse physiological effects including inflammation, immunosuppression and cardiovascular dysfunction. This study utilized microarray technology and subsequent pathway analysis as an exploratory search for markers/mechanisms of in vivo systemic effects following inhalation. Mice were exposed by inhalation to gas metal arc – stainless steel (GMA-SS) welding fume at 40 mg/m3 for 3 hr/d for 10 d and sacrificed 4 hr, 14 d and 28 d post-exposure. Whole blood cells, aorta and lung were harvested for global gene expression analysis with subsequent Ingenuity Pathway Analysis and confirmatory qRT-PCR. Serum was collected for protein profiling.
The novel finding was a dominant type I interferon signaling network with the transcription factor Irf7 as a central component maintained through 28 d. Remarkably, these effects showed consistency across all tissues indicating a systemic type I interferon response that was complemented by changes in serum proteins (decreased MMP-9, CRP and increased VCAM1, oncostatin M, IP-10). In addition, pulmonary expression of interferon α and β and Irf7 specific pattern recognition receptors (PRR) and signaling molecules (Ddx58, Ifih1, Dhx58, ISGF3) were induced, an effect that showed specificity when compared to other inflammatory exposures. Also, a canonical pathway indicated a coordinated response of multiple PRR and associated signaling molecules (Tlr7, Tlr2, Clec7a, Nlrp3, Myd88) to inhalation of GMA-SS.
This methodological approach has the potential to identify consistent, prominent and/or novel pathways and provides insight into mechanisms that contribute to pulmonary and systemic effects following toxicant exposure.
PMCID: PMC3537608  PMID: 22776377
Microarray; Welding; Interferon regulatory factor 7; Cardiovascular disease; Chromium; Biomarker; Pattern recognition receptor; Whole blood cell gene expression; Aorta; Inhalation
24.  Separating the wheat from the chaff: mitigating the effects of noise in a plastome phylogenomic data set from Pinus L. (Pinaceae) 
Through next-generation sequencing, the amount of sequence data potentially available for phylogenetic analyses has increased exponentially in recent years. Simultaneously, the risk of incorporating ‘noisy’ data with misleading phylogenetic signal has also increased, and may disproportionately influence the topology of weakly supported nodes and lineages featuring rapid radiations and/or elevated rates of evolution.
We investigated the influence of phylogenetic noise in large data sets by applying two fundamental strategies, variable site removal and long-branch exclusion, to the phylogenetic analysis of a full plastome alignment of 107 species of Pinus and six Pinaceae outgroups. While high overall phylogenetic resolution resulted from inclusion of all data, three historically recalcitrant nodes remained conflicted with previous analyses. Close investigation of these nodes revealed dramatically different responses to data removal. Whereas topological resolution and bootstrap support for two clades peaked with removal of highly variable sites, the third clade resolved most strongly when all sites were included. Similar trends were observed using long-branch exclusion, but patterns were neither as strong nor as clear. When compared to previous phylogenetic analyses of nuclear loci and morphological data, the most highly supported topologies seen in Pinus plastome analysis are congruent for the two clades gaining support from variable site removal and long-branch exclusion, but in conflict for the clade with highest support from the full data set.
These results suggest that removal of misleading signal in phylogenomic datasets can result not only in increased resolution for poorly supported nodes, but may serve as a tool for identifying erroneous yet highly supported topologies. For Pinus chloroplast genomes, removal of variable sites appears to be more effective than long-branch exclusion for clarifying phylogenetic hypotheses.
PMCID: PMC3475122  PMID: 22731878
Phylogenetic noise; Plastome; Pinus; Chloroplast
25.  Motivational Interviewing for encouraging quit attempts among unmotivated smokers: study protocol of a randomized, controlled, efficacy trial 
BMC Public Health  2012;12:456.
Although the current Clinical Practice Guideline recommend Motivational Interviewing for use with smokers not ready to quit, the strength of evidence for its use is rated as not optimal. The purpose of the present study is to address key methodological limitations of previous studies by ensuring fidelity in the delivery of the Motivational Interviewing intervention, using an attention-matched control condition, and focusing on unmotivated smokers whom meta-analyses have indicated may benefit most from Motivational Interviewing. It is hypothesized that MI will be more effective at inducing quit attempts and smoking cessation at 6-month follow-up than brief advice to quit and an intensity-matched health education condition.
A sample of adult community resident smokers (N = 255) who report low motivation and readiness to quit are being randomized using a 2:2:1 treatment allocation to Motivational Interviewing, Health Education, or Brief Advice. Over 6 months, participants in Motivational Interviewing and Health Education receive 4 individual counseling sessions and participants in Brief Advice receive one brief in-person individual session at baseline. Rigorous monitoring and independent verification of fidelity will assure the counseling approaches are distinct and delivered as planned. Participants complete surveys at baseline, week 12 and 6-month follow-up to assess demographics, smoking characteristics, and smoking outcomes. Participants who decide to quit are provided with a self-help guide to quitting, help with a quit plan, and free pharmacotherapy. The primary outcome is self-report of one or more quit attempts lasting at least 24 hours between randomization and 6-month follow-up. The secondary outcome is biochemically confirmed 7-day point prevalence cessation at 6-month follow-up. Hypothesized mediators of the presumed treatment effect on quit attempts are greater perceived autonomy support and autonomous motivation. Use of pharmacotherapy is a hypothesized mediator of Motivational Interviewing’s effect on cessation.
This trial will provide the most rigorous evaluation to date of Motivational Interviewing’s efficacy for encouraging unmotivated smokers to make a quit attempt. It will also provide effect-size estimates of MI’s impact on smoking cessation to inform future clinical trials and inform the Clinical Practice Guideline.
Trial registration NCT01188018
PMCID: PMC3487752  PMID: 22713093
Smoking; Motivational Interviewing; Health education; Brief advice

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