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1.  Parasite diversity of European Myotis species with special emphasis on Myotis myotis (Microchiroptera, Vespertilionidae) from a typical nursery roost 
Parasites & Vectors  2015;8:101.
Bats belong to one of the most species-rich orders within the Mammalia. They show a worldwide distribution, a high degree of ecological diversification as well as a high diversity of associated parasites and pathogens. Despite their prominent and unique role, the knowledge of their parasite-host-relationships as well as the mechanisms of co-evolutionary processes are, partly due to strict conservation regulations, scarce.
Juvenile specimens of the greater mouse-eared bat (Myotis myotis) from a roosting colony in Gladenbach (Hesse, Germany) were examined for their metazoan endo-and ectoparasite infections and pathogens. Morphometric data were recorded and the individuals were checked for Lyssavirus-specific antigen using a direct immunofluorescence test. For unambiguous species identification, the bats were analysed by cyt-b sequence comparison.
Myotis myotis were parasitized by the six insect and arachnid ectoparasite species, i.e. Ixodes ricinus, Ischnopsyllus octactenus, Ichoronyssus scutatus, Steatonyssus periblepharus, Spinturnix myoti and Cimex dissimilis. Additionally, the nematode Molinostrongylus alatus and the cestode Vampirolepis balsaci were recorded. Each bat was parasitized by at least four species. The parasites showed partially extreme rates of infection, never recorded before, with more than 1,440 parasites per single host. Ichoronyssus scutatus, Steatonyssus periblepharus, Vampirolepis balsaci and Molinostrongylus alatus are recorded for the first time in Germany. A checklist for Europe is presented containing records of 98 parasite species of 14 Myotis species.
The Myotis myotis from Gladenbach (Hesse, Germany) were parasitized by a diverse parasite fauna with high infestation rates. We assume that in juvenile Myotis the number of parasites is generally higher than in adults due to only later acquired immune competence and behavioural adaptations. Our results revealed new insights into parasite fauna of M. myotis and European bats in general. The finding of endoparasitic cyclophyllidean cestodes that have a two-host lifecycle is, considering the stationary behaviour of the juvenile bats, rather unusual and suggests a non-predatory transmission mechanism (e.g. via autoinfection).
A new insight gained from the collated literature was that the European wide composition of the Myotis parasite fauna is dominated by a few specific taxonomic groups in Europe.
PMCID: PMC4336729
Myotis myotis; Spinturnix myoti; Ectoparasites; Roosting place
2.  Intragenomic polymorphisms among high-copy loci: a genus-wide study of nuclear ribosomal DNA in Asclepias (Apocynaceae) 
PeerJ  2015;3:e718.
Despite knowledge that concerted evolution of high-copy loci is often imperfect, studies that investigate the extent of intragenomic polymorphisms and comparisons across a large number of species are rarely made. We present a bioinformatic pipeline for characterizing polymorphisms within an individual among copies of a high-copy locus. Results are presented for nuclear ribosomal DNA (nrDNA) across the milkweed genus, Asclepias. The 18S-26S portion of the nrDNA cistron of Asclepias syriaca served as a reference for assembly of the region from 124 samples representing 90 species of Asclepias. Reads were mapped back to each individual’s consensus and at each position reads differing from the consensus were tallied using a custom perl script. Low frequency polymorphisms existed in all individuals (mean = 5.8%). Most nrDNA positions (91%) were polymorphic in at least one individual, with polymorphic sites being less frequent in subunit regions and loops. Highly polymorphic sites existed in each individual, with highest abundance in the “noncoding” ITS regions. Phylogenetic signal was present in the distribution of intragenomic polymorphisms across the genus. Intragenomic polymorphisms in nrDNA are common in Asclepias, being found at higher frequency than any other study to date. The high and variable frequency of polymorphisms across species highlights concerns that phylogenetic applications of nrDNA may be error-prone. The new analytical approach provided here is applicable to other taxa and other high-copy regions characterized by low coverage genome sequencing (genome skimming).
PMCID: PMC4304868  PMID: 25653903
Concerted evolution; Genome skimming; High-copy; Intragenomic polymorphism; Partial SNP (pSNP); Nuclear ribosomal DNA (nrDNA); Intra-individual site polymorphism; 2ISP; Asclepias; ITS
4.  How informative is the mouse for human gut microbiota research? 
Disease Models & Mechanisms  2015;8(1):1-16.
The microbiota of the human gut is gaining broad attention owing to its association with a wide range of diseases, ranging from metabolic disorders (e.g. obesity and type 2 diabetes) to autoimmune diseases (such as inflammatory bowel disease and type 1 diabetes), cancer and even neurodevelopmental disorders (e.g. autism). Having been increasingly used in biomedical research, mice have become the model of choice for most studies in this emerging field. Mouse models allow perturbations in gut microbiota to be studied in a controlled experimental setup, and thus help in assessing causality of the complex host-microbiota interactions and in developing mechanistic hypotheses. However, pitfalls should be considered when translating gut microbiome research results from mouse models to humans. In this Special Article, we discuss the intrinsic similarities and differences that exist between the two systems, and compare the human and murine core gut microbiota based on a meta-analysis of currently available datasets. Finally, we discuss the external factors that influence the capability of mouse models to recapitulate the gut microbiota shifts associated with human diseases, and investigate which alternative model systems exist for gut microbiota research.
PMCID: PMC4283646  PMID: 25561744
Gut microbiota; Humanized mouse models; Mouse core gut microbiota; Mouse models; Mouse pan-gut microbiota
7.  The Canadian birth place study: examining maternity care provider attitudes and interprofessional conflict around planned home birth 
Available birth settings have diversified in Canada since the integration of regulated midwifery. Midwives are required to offer eligible women choice of birth place; and 25-30% of midwifery clients plan home births. Canadian provincial health ministries have instituted reimbursement schema and regulatory guidelines to ensure access to midwives in all settings. Evidence from well-designed Canadian cohort studies demonstrate the safety and efficacy of midwife-attended home birth. However, national rates of planned home birth remain low, and many maternity providers do not support choice of birth place.
In this national, mixed-methods study, our team administered a cross-sectional survey, and developed a 17 item Provider Attitudes to Planned Home Birth Scale (PAPHB-m) to assess attitudes towards home birth among maternity providers. We entered care provider type into a linear regression model, with the PAPHB-m score as the outcome variable. Using Students’ t tests and ANOVA for categorical variables and correlational analysis (Pearson’s r) for continuous variables, we conducted provider-specific bivariate analyses of all socio-demographic, education, and practice variables (n=90) that were in both the midwife and physician surveys.
Median favourability scores on the PAPHB–m scale were very low among obstetricians (33.0), moderately low for family physicians (38.0) and very high for midwives (80.0), and 84% of the variance in attitudes could be accounted for by care provider type. Amount of exposure to planned home birth during midwifery or medical education and practice was significantly associated with favourability scores. Concerns about perinatal loss and lawsuits, discomfort with inter-professional consultations, and preference for the familiarity of the hospital correlated with less favourable attitudes to home birth. Among all providers, favourability scores were linked to beliefs about the evidence on safety of home birth, and confidence in their own ability to manage obstetric emergencies at a home birth.
Increasing the knowledge base among all maternity providers about planned home birth may increase favourability. Key learning competencies include criteria for birth site selection, management of obstetric emergencies at planned home births, critical appraisal of literature on safety of home birth, and inter-professional communication and collaboration when women are transferred from home to hospital.
PMCID: PMC4287472  PMID: 25352366
Home childbirth; Birth place; Inter-professional collaboration; Scale development; Physicians; Midwives; Psychometrics
9.  GP access — time for a radical solution? 
PMCID: PMC3750783  PMID: 23998824
10.  Early brain enlargement and elevated extra-axial fluid in infants who develop autism spectrum disorder 
Brain  2013;136(9):2825-2835.
Prospective studies of infants at risk for autism spectrum disorder have provided important clues about the early behavioural symptoms of autism spectrum disorder. Diagnosis of autism spectrum disorder, however, is not currently made until at least 18 months of age. There is substantially less research on potential brain-based differences in the period between 6 and 12 months of age. Our objective in the current study was to use magnetic resonance imaging to identify any consistently observable brain anomalies in 6–9 month old infants who would later develop autism spectrum disorder. We conducted a prospective infant sibling study with longitudinal magnetic resonance imaging scans at three time points (6–9, 12–15, and 18–24 months of age), in conjunction with intensive behavioural assessments. Fifty-five infants (33 ‘high-risk’ infants having an older sibling with autism spectrum disorder and 22 ‘low-risk’ infants having no relatives with autism spectrum disorder) were imaged at 6–9 months; 43 of these (27 high-risk and 16 low-risk) were imaged at 12–15 months; and 42 (26 high-risk and 16 low-risk) were imaged again at 18–24 months. Infants were classified as meeting criteria for autism spectrum disorder, other developmental delays, or typical development at 24 months or later (mean age at outcome: 32.5 months). Compared with the other two groups, infants who developed autism spectrum disorder (n = 10) had significantly greater extra-axial fluid at 6–9 months, which persisted and remained elevated at 12–15 and 18–24 months. Extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarachnoid space, particularly over the frontal lobes. The amount of extra-axial fluid detected as early as 6 months was predictive of more severe autism spectrum disorder symptoms at the time of outcome. Infants who developed autism spectrum disorder also had significantly larger total cerebral volumes at both 12–15 and 18–24 months of age. This is the first magnetic resonance imaging study to prospectively evaluate brain growth trajectories from infancy in children who develop autism spectrum disorder. The presence of excessive extra-axial fluid detected as early as 6 months and the lack of resolution by 24 months is a hitherto unreported brain anomaly in infants who later develop autism spectrum disorder. This is also the first magnetic resonance imaging evidence of brain enlargement in autism before age 2. These findings raise the potential for the use of structural magnetic resonance imaging to aid in the early detection of children at risk for autism spectrum disorder or other neurodevelopmental disorders.
PMCID: PMC3754460  PMID: 23838695
autism; magnetic resonance imaging; infant brain development; cerebrospinal fluid; external hydrocephalus
12.  Hyb-Seq: Combining target enrichment and genome skimming for plant phylogenomics1 
Applications in Plant Sciences  2014;2(9):apps.1400042.
• Premise of the study: Hyb-Seq, the combination of target enrichment and genome skimming, allows simultaneous data collection for low-copy nuclear genes and high-copy genomic targets for plant systematics and evolution studies.
• Methods and Results: Genome and transcriptome assemblies for milkweed (Asclepias syriaca) were used to design enrichment probes for 3385 exons from 768 genes (>1.6 Mbp) followed by Illumina sequencing of enriched libraries. Hyb-Seq of 12 individuals (10 Asclepias species and two related genera) resulted in at least partial assembly of 92.6% of exons and 99.7% of genes and an average assembly length >2 Mbp. Importantly, complete plastomes and nuclear ribosomal DNA cistrons were assembled using off-target reads. Phylogenomic analyses demonstrated signal conflict between genomes.
• Conclusions: The Hyb-Seq approach enables targeted sequencing of thousands of low-copy nuclear exons and flanking regions, as well as genome skimming of high-copy repeats and organellar genomes, to efficiently produce genome-scale data sets for phylogenomics.
PMCID: PMC4162667  PMID: 25225629
genome skimming; Hyb-Seq; nuclear loci; phylogenomics; species tree; target enrichment
13.  A basal thunnosaurian from Iraq reveals disparate phylogenetic origins for Cretaceous ichthyosaurs 
Biology Letters  2013;9(4):20130021.
Cretaceous ichthyosaurs have typically been considered a small, homogeneous assemblage sharing a common Late Jurassic ancestor. Their low diversity and disparity have been interpreted as indicative of a decline leading to their Cenomanian extinction. We describe the first post-Triassic ichthyosaur from the Middle East, Malawania anachronus gen. et sp. nov. from the Early Cretaceous of Iraq, and re-evaluate the evolutionary history of parvipelvian ichthyosaurs via phylogenetic and cladogenesis rate analyses. Malawania represents a basal grade in thunnosaurian evolution that arose during a major Late Triassic radiation event and was previously thought to have gone extinct during the Early Jurassic. Its pectoral morphology appears surprisingly archaic, retaining a forefin architecture similar to that of its Early Jurassic relatives. After the initial latest Triassic radiation of early thunnosaurians, two subsequent large radiations produced lineages with Cretaceous representatives, but the radiation events themselves are pre-Cretaceous. Cretaceous ichthyosaurs therefore include distantly related lineages, with contrasting evolutionary histories, and appear more diverse and disparate than previously supposed.
PMCID: PMC3730615  PMID: 23676653
Parvipelvia; Baracromia; Malawania anachronus; Early Cretaceous
14.  Anti-apoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3+ regulatory T cells 
Nature immunology  2013;14(9):959-965.
Foxp3+ regulatory T (Treg) cells are a crucial immunosuppressive population of CD4+ T cells, yet the homeostatic processes and survival programs that maintain the Treg cell pool are poorly understood. Here we report that peripheral Treg cells markedly alter their proliferative and apoptotic rates to rapidly restore numerical deficit through an interleukin 2–dependent and costimulation-dependent process. By contrast, excess Treg cells are removed by attrition, dependent on the Bim-initiated Bak- and Bax-dependent intrinsic apoptotic pathway. The antiapoptotic proteins Bcl-xL and Bcl-2 were dispensable for survival of Treg cells, whereas Mcl-1 was critical for survival of Treg cells, and the loss of this antiapoptotic protein caused fatal autoimmunity. Together, these data define the active processes by which Treg cells maintain homeostasis via critical survival pathways.
PMCID: PMC4128388  PMID: 23852275
15.  Patient-reporting improves estimates of postoperative complication rates: a prospective cohort study in gynaecological oncology 
British Journal of Cancer  2013;109(3):623-632.
Most studies use hospital data to calculate postoperative complication rates (PCRs). We report on improving PCR estimates through use of patient-reporting.
A prospective cohort study of major surgery performed at 10 UK gynaecological cancer centres was undertaken. Hospitals entered the data contemporaneously into an online database. Patients were sent follow-up letters to capture postoperative complications. Grade II–V (Clavien–Dindo classification) patient-reported postoperative complications were verified from hospital records. Postoperative complication rate was defined as the proportion of surgeries with a Grade II–V postoperative complication.
Patient replies were received for 1462 (68%) of 2152 surgeries undertaken between April 2010 and February 2012. Overall, 452 Grade II–V (402 II, 50 III–V) complications were reported in 379 of the 1462 surgeries. This included 172 surgeries with 200 hospital-reported complications and 231 with 280 patient-reported complications. All (100% concordance) 36 Grade III–V and 158 of 280 (56.4% concordance) Grade II patient-reported complications were verified on hospital case-note review. The PCR using hospital-reported data was 11.8% (172 out of 1462; 95% CI 11–14), patient-reported was 15.8% (231 out of 1462; 95% CI 14–17.8), hospital and verified patient-reported was 19.4% (283 out of 1462; 95% CI 17.4–21.4) and all data were 25.9% (379 out of 1462; 95% CI 24–28). After excluding Grade II complications, the hospital and patient verified Grade III–V PCR was 3.3% (48 out of 1462; 95% CI 2.5–4.3).
This is the first prospective study of postoperative complications we are aware of in gynaecological oncology to include the patient-reported data. Patient-reporting is invaluable for obtaining complete information on postoperative complications. Primary care case-note review is likely to improve verification rates of patient-reported Grade II complications.
PMCID: PMC3738134  PMID: 23846170
patient-reported; postoperative complications; follow-up; gynaecological oncology surgery; UKGOSOC
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
24.  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
25.  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

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