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1.  IL-9–mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation 
The Journal of Experimental Medicine  2013;210(13):2951-2965.
IL-9 acts as an autocrine amplifier of type 2 innate lymphoid cell function to promote tissue repair in the recovery phase of helminth-induced lung infection.
IL-9 fate reporter mice established type 2 innate lymphoid cells (ILC2s) as major producers of this cytokine in vivo. Here we focus on the role of IL-9 and ILC2s during the lung stage of infection with Nippostrongylus brasiliensis, which results in substantial tissue damage. IL-9 receptor (IL-9R)–deficient mice displayed reduced numbers of ILC2s in the lung after infection, resulting in impaired IL-5, IL-13, and amphiregulin levels, despite undiminished numbers of Th2 cells. As a consequence, the restoration of tissue integrity and lung function was strongly impaired in the absence of IL-9 signaling. ILC2s, in contrast to Th2 cells, expressed high levels of the IL-9R, and IL-9 signaling was crucial for the survival of activated ILC2s in vitro. Furthermore, ILC2s in the lungs of infected mice required the IL-9R to up-regulate the antiapoptotic protein BCL-3 in vivo. This highlights a unique role for IL-9 as an autocrine amplifier of ILC2 function, promoting tissue repair in the recovery phase after helminth-induced lung inflammation.
doi:10.1084/jem.20130071
PMCID: PMC3865473  PMID: 24249111
2.  The Earliest Giant Osprioneides Borings from the Sandbian (Late Ordovician) of Estonia 
PLoS ONE  2014;9(6):e99455.
The earliest Osprioneides kampto borings were found in bryozoan colonies of Sandbian age from northern Estonia (Baltica). The Ordovician was a time of great increase in the quantities of hard substrate removed by single trace makers. Increased predation pressure was most likely the driving force behind the infaunalization of larger invertebrates such as the Osprioneides trace makers in the Ordovician. It is possible that the Osprioneides borer originated in Baltica or in other paleocontinents outside of North America.
doi:10.1371/journal.pone.0099455
PMCID: PMC4047083  PMID: 24901511
3.  Molecular characterization of the transition to mid-life in Caenorhabditis elegans 
Age  2012;35(3):689-703.
We present an initial molecular characterization of a morphological transition between two early aging states. In previous work, an age score reflecting physiological age was developed using a machine classifier trained on images of worm populations at fixed chronological ages throughout their lifespan. The distribution of age scores identified three stable post-developmental states and transitions. The first transition occurs at day 5 post-hatching, where a significant percentage of the population exists in both state I and state II. The temperature dependence of the timing of this transition (Q10 ~ 1.17) is too low to be explained by a stepwise process with an enzymatic or chemical rate-limiting step, potentially implicating a more complex mechanism. Individual animals at day 5 were sorted into state I and state II groups using the machine classifier and analyzed by microarray expression profiling. Despite being isogenic, grown for the same amount of time, and indistinguishable by eye, these two morphological states were confirmed to be molecularly distinct by hierarchical clustering and principal component analysis of the microarray results. These molecular differences suggest that pharynx morphology reflects the aging state of the whole organism. Our expression profiling yielded a gene set that showed significant overlap with those from three previous age-related studies and identified several genes not previously implicated in aging. A highly represented group of genes unique to this study is involved in targeted ubiquitin-mediated proteolysis, including Skp1-related (SKR), F-box-containing, and BTB motif adaptors.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9401-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-012-9401-2
PMCID: PMC3636400  PMID: 22610697
Machine classifier; Biomarker of aging; Metastable aging state; Microarray analysis
4.  Magnetic Catheter Manipulation in the Interventional MRI Environment 
Purpose
To evaluate deflection capability of a prototype endovascular catheter, which is remotely magnetically steerable, for use in the interventional MRI environment.
Materials and Methods
Copper coils were mounted on the tips of commercially available 2.3 – 3.0 Fr microcatheters. The coils were fabricated in a novel manner by plasma vapor deposition of a copper layer followed by laser lithography of the layer into coils. Orthogonal helical (solenoid) and saddle-shaped (Helmholtz) coils were mounted on a single catheter tip. Microcatheters were tested in water bath phantoms in a 1.5T clinical MRI scanner, with variable simultaneous currents applied to the coils. Catheter tip deflection was imaged in the axial plane utilizing a “real-time” steady-state free precession (SSFP) MRI sequence. Degree of deflection and catheter tip orientation were measured for each current application.
Results
The catheter tip was clearly visible in the longitudinal and axial planes. Magnetic field artifacts were visible when the orthogonal coils at the catheter tip were energized. Variable amounts of current applied to a single coil demonstrated consistent catheter deflection in all water bath experiments. Changing current polarity reversed the observed direction of deflection, whereas current applied to two different coils resulted in deflection represented by the composite vector of individual coil activations. Microcatheter navigation through the vascular phantom was successful through control of applied current to one or more coils.
Conclusion
Controlled catheter deflection is possible with laser lithographed multi-axis coil tipped catheters in the MRI environment.
doi:10.1016/j.jvir.2013.01.487
PMCID: PMC3674851  PMID: 23707097
5.  Hemorrhagic Shock Augments Nlrp3 Inflammasome Activation in The Lung through Impaired Pyrin Induction1 
Hemorrhagic shock (HS) promotes the development of systemic inflammatory response syndrome (SIRS) and organ injury by activating and priming the innate immune system for an exaggerated inflammatory response through, as of yet, unclear mechanisms. IL-1β also plays an important role in the development of post-HS SIRS and active IL-1β production is tightly controlled by the inflammasome. Pyrin, a protein of 781 amino-acids with pyrin domain (PYD) at the N-terminal, negatively regulates inflammasome activation through interaction with nucleotide-binding oligomerization domain-like receptor protein (NLRP). Expression of pyrin can be induced by LPS and cytokines, and IL-10 is a known potent inducer of pyrin expression in macrophages. In the present study, we tested the hypothesis that HS downregulates IL-10, and therefore decreases pyrin expression to promote inflammasome activation and subsequent IL-1β processing and secretion in the lungs. Our results show that LPS, while activating Nlrp3 inflammasome in the lungs, also induced pyrin expression, which in turn suppressed inflammasome activation. More importantly, LPS-mediated upregulation of IL-10 enhanced pyrin expression, which serves, particularly in later phases, as a potent negative feedback mechanism regulating inflammasome activation. However, HS-mediated suppression of IL-10 expression in alveolar macrophages (AM) attenuated the upregulation of pyrin in AM and lung endothelial cells, and thereby significantly enhanced inflammasome activation and IL-1β secretion in the lungs. This study demonstrates a novel mechanism by which HS suppresses negative feedback regulation of Nlrp3 inflammasome to enhance IL-1β secretion in response to subsequent LPS challenge, and so primes for inflammation.
doi:10.4049/jimmunol.1203182
PMCID: PMC3646900  PMID: 23585683
IL-1β; IL-10; alveolar macrophages; lung vascular endothelial cells
6.  Social status modifies estradiol activation of sociosexual behavior in female rhesus monkeys 
Hormones and behavior  2012;62(5):612-620.
Estrogen (E2) has activational effects on sexual motivation and mitigating effects on anxiety-like behaviors that can be attenuated with chronic exposure to psychosocial stress. Some studies suggest that this attenuation can be overcome by higher doses of E2, while others show that chronic psychosocial stress may alter the mechanisms of E2 function, thus reducing any positive benefit from higher doses of E2. To determine the interaction between psychosocial stress and E2 dose on behavior, we examined the scope of attenuation across a suite of socioemotional behaviors, including reproduction, affiliation, aggression, submission, and anxiety-like behaviors on 36 ovariectomized female rhesus monkeys. Females were exposed to graded psychosocial stress, established by an intrinsic female dominance hierarchy, where subordinate animals receive high amounts of harassment. Our data show that E2 dose-dependently increased sexual motivation and male-affiliation in dominant (e.g. low-stress) females, while subordinate females showed no positive effects of E2, even at higher doses. In addition, contact aggression was attenuated in dominant females, while non-contact aggression was attenuated in both dominant and middle-ranking females. These results suggest that the stress-induced attenuation of E2's activational effects on sexual behavior and affiliation with males may not be overcome with higher doses of E2. Furthermore, the observed behavioral consequences of psychosocial stress and E2 dose may be dependent on the behaviors of all the females in the social-group, and better resolution on these effects depends on isolating treatment to individuals within the group to minimize alterations in social-group interactions.
doi:10.1016/j.yhbeh.2012.09.010
PMCID: PMC4010104  PMID: 23046624
estradiol; sexual behavior; affiliation; social subordination; rhesus monkeys
7.  Safety of retained microcatheters: an evaluation of radiofrequency heating in endovascular microcatheters with nitinol, tungsten, and polyetheretherketone braiding at 1.5 T and 3 T 
Background
The use of ethylene-vinyl alcohol copolymer for liquid embolization of cranial vascular lesions has resulted in microcatheter fragments entrapped in patients following endovascular procedures. Undergoing subsequent diagnostic MRI examinations poses a safety concern due to the possibility of radiofrequency heating of the metallic braid incorporated into the microcatheter. Heating of nitinol, tungsten, and polyetheretherketone (PEEK) braided microcatheters was assessed and compared using a phantom model.
Methods
Microcatheters coupled with fluoroptic temperature probes were embedded in a polyacrylamide gel within a head and torso phantom. Experiments were performed at 1.5 T and 3 T, analyzing the effects of different catheter immersion lengths, specific absorption rate (SAR) levels, short clinical scans, long clinical scans, and microcatheter fragment lengths.
Results
The maximal increase in temperature for the nitinol braided microcatheter during a 15 min scan was 3.06°C using the T1 fast spin echo sequence at 1.5 T and 0.45°C using the balanced steady state free precession sequence at 3 T. The same scans for fragment lengths of 9, 18, 36, and 72 cm produced maximal temperature rises of 0.68, 0.80, 1.70, and 1.07°C at 1.5 T, respectively. The temperature changes at 3 T for these fragment lengths were 0.66, 0.83, 1.07, and 0.72°C, respectively. The tungsten and PEEK braided microcatheters did not demonstrate heating.
Conclusions
Substantial heating of nitinol braided microcatheters occurred and was a function of SAR level and geometric considerations. SAR and time limitations on MR scanning are proposed for patients with this microcatheter entrapped in their vasculature. In contrast, tungsten and PEEK braided microcatheters showed potential safe use in MRI.
doi:10.1136/neurintsurg-2013-010746
PMCID: PMC3796159  PMID: 23685793
8.  Improved image analysis of DETECHIP® allows for increased specificity in drug discrimination 
DETECHIP® is a novel molecular sensing array being developed for the detection and identification of a variety of compounds including controlled substances. This easy to use technology has the ability to produce a unique identifying binary code for each substance tested. Original analysis methodology relied on human vision to classify color and fluorescence changes within the array. New digital color image analysis techniques using red-green-blue (RGB) color values provided a higher degree of specificity and greater consistency. This image analysis technique was able to detect more subtle changes in color and was therefore able to properly discriminate between substances that previously produced identical codes. This technique was also expanded to analyze changes in RGB color values individually, increasing the length of the code to 48 digits and therefore potentially providing a further increase in specificity. To show the applicability of this new method, a blind study was performed, correctly identifying two unknown analytes.
PMCID: PMC3989891  PMID: 24749001
Image analysis; Detection; Red Green Blue; Abused narcotics; Drugs; Cocaine; Caffeine
9.  Magnetically-assisted remote control (MARC) steering of endovascular catheters for interventional MRI: An equation for predicting deflection and experimental validation 
Medical physics  2007;34(8):3135-3142.
Direct current applied to wire coils wound at the tip of an endovascular catheter can be used to remotely steer a catheter under magnetic resonance imaging guidance. In this study, we derive and validate an equation that characterizes the relationship between the number of solenoid turns, applied current, catheter stiffness, magnetic field strength, and resulting catheter tip deflections.
Method and Materials
Solenoids of 50, 100, 150 turns were wound on separate 1.8F and 5F catheters. Varying currents were applied using a DC power supply in the MRI control room. Images were obtained with a 1.5 T or a 3 T MR scanner with the distal catheter suspended in the main scanner magnetic field in a water bath on the scanner bed. ssFSE and FIESTA fast imaging sequences were used. Deflection angles were measured on acquired sagittal images using eFilm software.
Results
Relationships between variables predicted by the derived equation, θ/sin(γ−θ) = nIAB/kθ, where θ is the deflection angle, n is the number of solenoidal turns, I is the current, A is the cross-sectional area of the catheter tip, B is the MR scanner main magnetic field, kθ is related to the catheter elastic modulus, and γ is the initial angle between the catheter tip and B, were observed (R2 = 0.935–0.987).
Conclusion
An equation that predicts catheter tip deflection has been derived and validated experimentally for MARC-steering of endovascular catheters in interventional MRI. Consequent accurate prediction of catheter tip behavior using this novel mechanism will enhance control of the endovascular catheter tip, as well as decrease the risk of procedural complications such as dissection and embolus formation.
PMCID: PMC3980585  PMID: 17879774
interventional radiology; MRI; catheter; catheterization; vascular disease
10.  Social stress and the polymorphic region of the serotonin reuptake transporter gene modify estradiol-induced changes on central monoamine concentrations in female rhesus monkeys 
Journal of neuroendocrinology  2013;25(4):321-328.
Psychosocial stress exposure is linked to a disruption of emotional regulation that can manifest as anxiety and depression. Women are more likely to suffer from such psychopathologies than men, indicating that gender-based differences in gonadal steroids may be a key factor in the etiology of stress-induced adverse health outcomes. Estradiol (E2) positively influences mood and cognition in females, an effect likely related to E2’s ability to modulate the serotonin and dopamine neurotransmitter systems. Furthermore, genetic variation due to the polymorphism in the promoter region of the gene (SLC6A4) encoding the serotonin transporter (5HTTLPR) also can influence E2’s ability to modulate behavior and physiology. However, it remains uncertain whether exposure to social stress interacts with the 5HTTLPR to influence E2-induced changes in behavior and physiology. The present study used ovariectomized adult female rhesus monkeys to investigate acute and chronic effects of E2 on central monoamine metabolite concentrations using CSF sampling. We further assessed how E2-induced changes in monoamine metabolite levels are modified by the unpredictable stress of social subordination and the 5HTTLPR polymorphism. Levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA) decreased significantly during chronic E2 treatment only in dominant females with the long promoter length of SLC6A4. Chronic administration of E2 decreased levels of the dopamine metabolite dihydrophenylacetic acid (DOPAC) in a manner independent of the social status, 5HTTLPR genotype, or their interactions. Overall levels of dopamine and serotonin metabolites were increased in subordinate females but this effect of social stress was not influenced by 5HTTLPR genotype. Together, these data emphasize how E2 can modulate central neurotransmitter systems and indicate that social subordination in female monkeys is a valid model for examining how chronic psychosocial stress alters sensitivity to E2. Future studies are necessary to elaborate how changes in central neurotransmitter metabolism due to E2 and prolonged exposure to stress affect behavior and physiology.
doi:10.1111/jne.12009
PMCID: PMC3605214  PMID: 23253112
Psychosocial stress; estradiol; serotonin reuptake polymorphism; monkeys
11.  Lifetime exposure to arsenic in drinking water and bladder cancer: a population-based case–control study in Michigan, USA 
Cancer causes & control : CCC  2010;21(5):745-757.
Objective
Arsenic in drinking water has been linked with the risk of urinary bladder cancer, but the dose–response relationships for arsenic exposures below 100 µg/L remain equivocal. We conducted a population-based case–control study in southeastern Michigan, USA, where approximately 230,000 people were exposed to arsenic concentrations between 10 and 100 µg/L.
Methods
This study included 411 bladder cancer cases diagnosed between 2000 and 2004, and 566 controls recruited during the same period. Individual lifetime exposure profiles were reconstructed, and residential water source histories, water consumption practices, and water arsenic measurements or modeled estimates were determined at all residences. Arsenic exposure was estimated for 99% of participants’ person-years.
Results
Overall, an increase in bladder cancer risk was not found for time-weighted average lifetime arsenic exposure >10 µg/L when compared with a reference group exposed to <1 µg/L (odds ratio (OR) = 1.10; 95% confidence interval (CI): 0.65, 1.86). Among ever-smokers, risks from arsenic exposure >10 µg/L were similarly not elevated when compared to the reference group (OR = 0.94; 95% CI: 0.50, 1.78).
Conclusions
We did not find persuasive evidence of an association between low-level arsenic exposure and bladder cancer. Selecting the appropriate exposure metric needs to be thoughtfully considered when investigating risk from low-level arsenic exposure.
doi:10.1007/s10552-010-9503-z
PMCID: PMC3962589  PMID: 20084543
Age factors; Arsenicals; Environmental exposure; Residential mobility; Urinary bladder
13.  Expression and Purification of Chaperone-Active Recombinant Clusterin 
PLoS ONE  2014;9(1):e86989.
Clusterin was the first described secreted mammalian chaperone and is implicated as being a key player in both intra- and extracellular proteostasis. Its unique combination of structural features and biological chaperone activity has, however, previously made it very challenging to express and purify the protein in a correctly processed and chaperone-active form. While there are multiple reports in the literature describing the use of recombinant clusterin, all of these reports suffer from one or more of the following shortcomings: details of the methods used to produce the protein are poorly described, the product is incompletely (if at all) characterised, and purity (if shown) is in many cases inadequate. The current report provides the first well validated method to economically produce pure chaperone-active recombinant clusterin. The method was developed after trialling expression in cultured bacterial, yeast, insect and mammalian cells, and involves the expression of recombinant clusterin from stably transfected HEK293 cells in protein-free medium. The product is expressed at between 7.5 and 10 µg/ml of culture, and is readily purified by a combination of immunoaffinity, cation exchange and size exclusion chromatography. The purified product was shown to be glycosylated, correctly proteolytically cleaved into α- and β-subunits, and have chaperone activity similar to that of human plasma clusterin. This new method creates the opportunity to use mutagenesis and metabolic labelling approaches in future studies to delineate functionally important sites within clusterin, and also provides a theoretically unlimited supply of recombinant clusterin which may in the future find applications in the development of therapeutics.
doi:10.1371/journal.pone.0086989
PMCID: PMC3900688  PMID: 24466307
14.  Prevalence of peripheral blood parasitaemia, anaemia and low birthweight among pregnant women in a suburban area in coastal Ghana 
The Pan African Medical Journal  2014;17(Suppl 1):3.
Introduction
Malaria and anaemia have adverse effects in pregnant women and on the birth weight of infants in malaria endemic areas. P. falciparum malaria, the most virulent species continues to be a major health problem in sub-Saharan Africa. This study was carried out to establish the prevalence of pregnancy-associated malaria and its associated consequences including maternal anaemia and low birthweight (LBW) deliveries and placental malaria among pregnant women in a sub-urban area in coastal Ghana.
Methods
A facility-based investigation was carried out among 320 pregnant women seeking antenatal care in a hospital in suburban coastal Ghana. Information on the use of Insecticide Treated Nets (ITNs) and Intermittent Preventive Treatment in pregnancy (IPTp) were collected using a structured questionnaire at enrolment. Venous blood was collected for microscopy and screening for Glucose 6-phosphate dehydrogenase (G6PD) deficiency. Haemoglobin concentration was obtained from an automatic blood analyzer. Placental smears and birth weight measurements were taken at delivery.
Resuls
The prevalence of Plasmodium falciparum parasitaemia was 5%. The mean haemoglobin (Hb) level at registration was 11.44g/dL (95% CI 11.29 – 11.80). Placental blood parasitaemia and low birthweight were 2.5% and 3% respectively. ITN possession was 31.6% with 5.4% usage. The IPTp coverage was 55%.
Conclusion
The prevalence of malaria and anaemia among the pregnant women were low at enrolment. Placental blood parasitaemia and LBW at delivery were also low. These are clear indications of the high coverage of the IPTp. Increase in ITN use will further improve birthweight outcomes and reduce placental malaria.
doi:10.11694/pamj.supp.2014.17.1.3541
PMCID: PMC3946255  PMID: 24624240
Malaria prevalence; pregnancy; anaemia; birthweight; ITNs; IPTp
16.  Detecting Concentration of Analytes with DETECHIP: A Molecular Sensing Array 
Journal of sensor technology  2013;3(3):10.4236/jst.2013.33015.
DETECHIP® is a detection system made of various sensors that has been shown to detect and discriminate between small molecules of interest, including various illicit and over-the-counter drugs. Previously, detection was normalized to a single concentration of analyte. Now this detection assay can detect concentration differences in analytes via red, green, and blue color value changes and shifts in the UV-Vis spectra of the assay. To determine the concentrations differences, the exposed assays were scanned on a flatbed scanner and the images were analyzed for individual RGB values with a custom macro in ImageJ, an image analysis program. Increasing concentrations of the analyte resulted in greater differences in color values between control and analyte wells. These differences showed a linear relationship to concentration change, some with correlation coefficients greater than 98%. This work expands the capability of DETECHIP to give information about the concentration of analyte when the analyte identity is known.
doi:10.4236/jst.2013.33015
PMCID: PMC3883435  PMID: 24409399
Colorimetric Arrays; Sensors; Analyte Concentration; RGB Analysis; Drug Detection
17.  The relation of developmental changes in brain serotonin transporter (5HTT) and 5HT1A receptor binding to emotional behavior in female rhesus monkeys: effects of social status and 5HTT genotype 
Neuroscience  2012;228:83-100.
The goal of the present study was to examine how social subordination stress and 5HTT polymorphisms affect the development of brain serotonin (5HT) systems during the pubertal transition in female rhesus monkeys. We also examined associations with developmental changes in emotional reactivity in response to a standardized behavioral test, the Human Intruder (HI). Our findings provide the first longitudinal evidence of developmental increases in 5HT1A receptor and 5HTT binding in the brain of female primates from pre- to peripuberty. The increase in 5HT1A BPND in these socially housed female rhesus monkeys is a robust finding, occurring across all groups, regardless of social status or 5HTT genotype, and occurring in left and right hemispheres of all prefrontal regions studied, as well as amygdala, hippocampus, hypothalamus, and raphe nuclei. 5HTT BPND also showed an increase with age in raphe, anterior cingulate cortex, and dorsolateral prefrontal cortex. These changes in brain 5HT systems take place as females establish more adult-like patterns of social behavior, as well as during the HI paradigm. Indeed, the main developmental changes in behavior during the HI (increase in freezing and decrease in submission/appeasement) were related to neurodevelopmental increases in 5HT1A receptors and 5HTT, because the associations between these behaviors and 5HT endpoints emerge at peripuberty. We detected an effect of social status on 5HT1A BPND in the hypothalamus and on 5HTT BPND in the orbitofrontal cortex, with subordinates showing higher BPND than dominants in both cases during the pubertal transition. No main effects of 5HTT genotype were observed for 5HT1A or 5HTT BPND. Our findings indicate that adolescence in female rhesus monkeys is a period of central 5HT reorganization, partly influenced by exposure to the social stress of subordination, that likely functions to integrate adrenal and gonadal systems and shape the behavioral response to emotionally challenging social situations.
doi:10.1016/j.neuroscience.2012.10.016
PMCID: PMC3607538  PMID: 23079633
social stress; serotonin transporter polymorphisms; nonhuman primates; [18F]FEmZIENT; p-[18F]MPPF
18.  Social and emotional predictors of the tempo of puberty in female rhesus monkeys 
Psychoneuroendocrinology  2012;38(1):67-83.
A cascade of neuroendocrine events regulates the initiation and progression of female puberty. However, the factors that determine the timing of these events across individuals are still uncertain. While the consequences of puberty on subsequent emotional development and adult behavior have received significant attention, what is less understood are the social and environmental factors that actually alter the initiation and progression of puberty. In order to more fully understand what factors influence pubertal timing in females, the present study quantified social and emotional behavior; stress physiology; and growth and activity measures in juvenile female rhesus monkeys to determine what best predicts eventual puberty. Based on previous reports, we hypothesized that increased agonistic behavior resulting from subordinate status in their natal group, in combination with slowed growth, reduced prosocial behavior, and increased emotional reactivity would predict delayed puberty. The analyses were restricted to behavioral and physiological measures obtained prior to the onset of puberty, defined as menarche. Together, our findings indicate that higher rates of aggression but lower rates of submission received from group mates; slower weight gain; and greater emotional reactivity, evidenced by higher anxiety, distress and appeasing behaviors, and lower cortisol responsivity in response to a potentially threatening situation, predicts delayed puberty. Together the combination of these variables accounted for 58% of the variance in the age of menarche, 71% in age at first ovulation, and 45% in the duration of adolescent sterility. While early puberty may be more advantageous for the individual from a fertility standpoint, it presents significant health risks, including increased risk for a number of estrogen dependent cancers and as well as the emergence of mood disorders during adulthood. On the other hand, it is possible that increased emotional reactivity associated with delayed puberty could persist, increasing the risk for emotional dysregulation to socially challenging situations. The data argue for prospective studies that will determine how emotional reactivity shown to be important for pubertal timing is affected by early social experience and temperament, and how these stress-related variables contribute to body weight accumulation, affecting the neuroendocrine regulation of puberty.
doi:10.1016/j.psyneuen.2012.04.021
PMCID: PMC3442129  PMID: 22658962
menarche; first ovulation; puberty; emotionality; and social stress
19.  Evaluation of Polycyclic Aromatic Hydrocarbons Using Analytical Methods, Toxicology, and Risk Assessment Research: Seafood Safety after a Petroleum Spill as an Example 
Background: Polycyclic aromatic hydrocarbons (PAHs) are abundant and widespread environmental chemicals. They are produced naturally and through man-made processes, and they are common in organic media, including petroleum. Several PAHs are toxic, and a subset exhibit carcinogenic activity. PAHs represent a range of chemical structures based on two or more benzene rings and, depending on their source, can exhibit a variety of side modifications resulting from oxygenation, nitrogenation, and alkylation.
Objectives: Here we discuss the increasing ability of contemporary analytical methods to distinguish not only different chemical structures among PAHs but also their concentrations in environmental media. Using seafood contamination following the Deepwater Horizon accident as an example, we identify issues that are emerging in the PAH risk assessment process because of increasing analytical sensitivity for individual PAHs, and we describe the paucity of toxicological literature for many of these compounds.
Discussion: PAHs, including the large variety of chemically modified or substituted PAHs, are naturally occurring and may constitute health risks if human populations are exposed to hazardous levels. However, toxicity evaluations have not kept pace with modern analytic methods and their increased ability to detect substituted PAHs. Therefore, although it is possible to measure these compounds in seafood and other media, we do not have sufficient information on the potential toxicity of these compounds to incorporate them into human health risk assessments and characterizations.
Conclusions: Future research efforts should strategically attempt to fill this toxicological knowledge gap so human health risk assessments of PAHs in environmental media or food can be better determined. This is especially important in the aftermath of petroleum spills.
Citation: Wickliffe J, Overton E, Frickel S, Howard J, Wilson M, Simon B, Echsner S, Nguyen D, Gauthe D, Blake D, Miller C, Elferink C, Ansari S, Fernando H, Trapido E, Kane A. 2014. Evaluation of polycyclic aromatic hydrocarbons using analytical methods, toxicology, and risk assessment research: seafood safety after a petroleum spill as an example. Environ Health Perspect 122:6–9; http://dx.doi.org/10.1289/ehp.1306724
doi:10.1289/ehp.1306724
PMCID: PMC3888570  PMID: 24213154
20.  Magnetic resonance imaging characterization of circumferential and longitudinal strain under various coronary interventions in swine 
World Journal of Radiology  2013;5(12):472-483.
AIM: To compare the acute changes in circumferential and longitudinal strain after exposing a coronary artery to various interventions in swine.
METHODS: Percutaneous balloon angioplasty catheter was guided to location aid device (LAD) under X-ray fluoroscopy to create different patterns of ischemic insults. Pigs (n = 32) were equally divided into 4 groups: controls, 90 min LAD occlusion/reperfusion, LAD microembolization, and combined LAD occlusion/microembolization/reperfusion. Three days after interventions, cine, tagged and viability magnetic resonance imaging (MRI) were acquired to measure and compare left and right circumferential strain, longitudinal strain and myocardial viability, respectively. Measurements were obtained using HARP and semi-automated threshold method and statistically analyzed using unpaired t-test. Myocardial and vascular damage was characterized microscopically.
RESULTS: Coronary microemboli caused greater impairment in l left ventricular (LV) circumferential strain and dyssynchrony than LAD occlusion/reperfusion despite the significant difference in the extent of myocardial damage. Microemboli also caused significant decrease in peak systolic strain rate of remote myocardium and LV dyssynchrony. Cine MRI demonstrated the interaction between LV and right ventricular (RV) at 3 d after interventions. Compensatory increase in RV free wall longitudinal strain was seen in response to all interventions. Viability MRI, histochemical staining and microscopy revealed different patterns of myocardial damage and microvascular obstruction.
CONCLUSION: Cine MRI revealed subtle changes in LV strain caused by various ischemic insults. It also demonstrated the interaction between the right and left ventricles after coronary interventions. Coronary microemboli with and without acute myocardial infarction (AMI) cause complex myocardial injury and ventricular dysfunction that is not replicated in solely AMI.
doi:10.4329/wjr.v5.i12.472
PMCID: PMC3874504  PMID: 24379934
Magnetic resonance imaging; Percutaneous coronary interventions; Acute myocardial infarct; Microembolization; Myocardial strain
21.  Ensembl 2014 
Nucleic Acids Research  2013;42(D1):D749-D755.
Ensembl (http://www.ensembl.org) creates tools and data resources to facilitate genomic analysis in chordate species with an emphasis on human, major vertebrate model organisms and farm animals. Over the past year we have increased the number of species that we support to 77 and expanded our genome browser with a new scrollable overview and improved variation and phenotype views. We also report updates to our core datasets and improvements to our gene homology relationships from the addition of new species. Our REST service has been extended with additional support for comparative genomics and ontology information. Finally, we provide updated information about our methods for data access and resources for user training.
doi:10.1093/nar/gkt1196
PMCID: PMC3964975  PMID: 24316576
22.  Rapid Intrinsic Fluorescence Method for Direct Identification of Pathogens in Blood Cultures 
mBio  2013;4(6):e00865-13.
ABSTRACT
A positive blood culture is a critical result that requires prompt identification of the causative agent. This article describes a simple method to identify microorganisms from positive blood culture broth within the time taken to perform a Gram stain (<20 min). The method is based on intrinsic fluorescence spectroscopy (IFS) of whole cells and required development of a selective lysis buffer, aqueous density cushion, optical microcentrifuge tube, and reference database. A total of 1,121 monomicrobial-positive broth samples from 751 strains were analyzed to build a database representing 37 of the most commonly encountered species in bloodstream infections or present as contaminants. A multistage algorithm correctly classified 99.6% of unknown samples to the Gram level, 99.3% to the family level, and 96.5% to the species level. There were no incorrect results given at the Gram or family classification levels, while 0.8% of results were discordant at the species level. In 8/9 incorrect species results, the misidentified isolate was assigned to a species of the same genus. This unique combination of selective lysis, density centrifugation, and IFS can rapidly identify the most common microbial species present in positive blood cultures. Faster identification of the etiologic agent may benefit the clinical management of sepsis. Further evaluation is now warranted to determine the performance of the method using clinical blood culture specimens.
IMPORTANCE
Physicians often require the identity of the infective agent in order to make life-saving adjustments to empirical therapy or to switch to less expensive and/or more targeted antimicrobials. However, standard identification procedures take up to 2 days after a blood culture is signaled positive, and even most rapid molecular techniques take several hours to provide a result. Other techniques are faster (e.g., matrix-assisted laser desorption ionization–time of flight [MALDI-TOF] mass spectrometry) but require time-consuming manual processing steps and expensive equipment. There remains a clear need for a simple, inexpensive method to rapidly identify microorganisms directly from positive blood cultures. The promising new method described in this research article can identify microorganisms in minutes by optical spectroscopy, thus permitting the lab to simultaneously report the presence of a positive blood culture and the organism’s identity.
doi:10.1128/mBio.00865-13
PMCID: PMC3870241  PMID: 24255123
23.  Elevated dry-season malaria prevalence associated with fine-scale spatial patterns of environmental risk: a case–control study of children in rural Malawi 
Malaria Journal  2013;12:407.
Background
Understanding the role of local environmental risk factors for malaria in holo-endemic, poverty-stricken settings will be critical to more effectively implement- interventions aimed at eventual elimination. Household-level environmental drivers of malaria risk during the dry season were investigated in rural southern Malawi among children < five years old in two neighbouring rural Traditional Authority (TA) regions dominated by small-scale agriculture.
Methods
Ten villages were randomly selected from TA Sitola (n = 6) and Nsamala (n = 4). Within each village, during June to August 2011, a census was conducted of all households with children under-five and recorded their locations with a geographic position system (GPS) device. At each participating house, a nurse administered a malaria rapid diagnostic test (RDT) to children under five years of age, and a questionnaire to parents. Environmental data were collected for each house, including land cover within 50-m radius. Variables found to be significantly associated with P. falciparum infection status in bivariate analysis were included in generalized linear models, including multivariate logistic regression (MLR) and multi-level multivariate logistic regression (MLLR). Spatial clustering of RDT status, environmental factors, and Pearson residuals from MLR and MLLR were analysed using the Getis-Ord Gi* statistic.
Results
Of 390 children enrolled from six villages in Sitola (n = 162) and four villages in Nsamala (n = 228), 45.6% tested positive (n = 178) for Plasmodium infection by RDT. The MLLR modelled the statistical relationship of Plasmodium positives and household proximity to agriculture (<25-m radius), controlling for the child sex and age (in months), bed net ownership, elevation, and random effects intercepts for village and TA-level unmeasured factors. After controlling for area affects in MLLR, proximity to active agriculture remained a significant predictor of positive RDT result (OR 2.80, 95% CI 1.41-5.55). Mapping of Pearson residuals from MLR showed significant clustering (Gi* z > 2.58, p < 0.01) predominantly within TA Sitola, while residuals from MLLR showed no such clustering.
Conclusion
This study provides evidence for significant, dry-season heterogeneity of malaria prevalence strongly linked to peridomestic land use, and particularly of elevated risk associated with nearby crop production.
doi:10.1186/1475-2875-12-407
PMCID: PMC3833815  PMID: 24206777
24.  Influence of Peptide Dipoles and Hydrogen Bonds on Reactive Cysteine pKa Values in Fission Yeast DJ-1 
The FEBS journal  2012;279(22):4111-4120.
Cysteine residues with depressed pKa values are critical for the functions of many proteins. Several types of interactions can stabilize cysteine thiolate anions, including hydrogen bonds between thiol(ate)s and nearby residues as well as electrostatic interactions involving charged residues or dipoles. Dipolar stabilization of thiolates by peptide groups has been suggested to play a particularly important role near the N-termini of α-helices. Using a combination of X-ray crystallography, site-directed mutagenesis, and spectroscopic methods, we show that the reactive cysteine residue (Cys111) in Schizosaccharomyces pombe DJ-1 experiences a 0.6 unit depression of its thiol pKa as a consequence of a hydrogen bond donated by a threonine sidechain (Thr114) to a nearby peptide carbonyl oxygen at the N-terminus of an α-helix. This extended hydrogen bonded interaction is consistent with a sum of dipoles model whereby the distal hydrogen bond polarizes and strengthens the direct hydrogen bond between the proximal amide hydrogen and the cysteine thiol(ate). Therefore, our results suggest that the local dipolar enhancement of hydrogen bonds can appreciably stabilize cysteine thiolate formation. However, the substitution of a valine residue with a proline at the i+3 position has only a minor effect (0.3 units) on the pKa of Cys111. As proline has a reduced peptide dipole moment, this small effect suggests that a more extended helix macrodipolar effect does not play a major role in this system.
doi:10.1111/febs.12004
PMCID: PMC3484204  PMID: 22971103
cysteine pKa; peptide dipole; DJ-1 superfamily; X-ray crystallography; redox biochemistry
25.  TEC and MAPK Kinase Signalling Pathways in T helper (TH) cell Development, TH2 Differentiation and Allergic Asthma 
Significant advances in our understanding of the signalling events during T cell development and differentiation have been made in the past few decades. It is clear that ligation of the T cell receptor (TCR) triggers a series of proximal signalling cascades regulated by an array of protein kinases. These orchestrated and highly regulated series of events, with differential requirements of particular kinases, highlight the disparities between αβ+CD4+ T cells. Throughout this review we summarise both new and old studies, highlighting the role of Tec and MAPK in T cell development and differentiation with particular focus on T helper 2 (TH2) cells. Finally, as the allergy epidemic continues, we feature the role played by TH2 cells in the development of allergy and provide a brief update on promising kinase inhibitors that have been tested in vitro, in pre-clinical disease models in vivo and into clinical studies.
doi:10.4172/2155-9899.S12-011
PMCID: PMC3792371  PMID: 24116341

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