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1.  Effects of Castration on Expression of Lipid Metabolism Genes in the Liver of Korean Cattle 
Castration induces the accumulation of body fat and deposition of intramuscular fat in Korean cattle, resulting in improved beef quality. However, little is known about the metabolic adaptations in the liver following castration. To understand changes in lipid metabolism following castration, hepatic expression levels of lipid metabolism genes were compared between Korean bulls and steers. Steers had higher (p<0.001) hepatic lipids contents and higher (p<0.01) mRNA levels of lipogenic acetyl-CoA carboxylase. This differential gene expression may, in part, contribute to increased hepatic lipid content following the castration of bulls. However, we found no differences in the hepatic expression levels of genes related to triglyceride synthesis (mitochondrial glycerol-3-phosphate acyltransferase, diacylglycerol O-acyltransferase 1 and 2) and fatty acid (FA) oxidation (carnitine palmitoyltransferase 1A, C-4 to C-12 straight chain acyl-CoA dehydrogenase, very long chain acyl-CoA dehydrogenase) between bulls and steers. No differences in gene expression for very-low-density lipoprotein (VLDL) secretion, including apolipoprotein B mRNA and microsomal triglyceride transfer protein (MTTP) protein, were observed in the liver although MTTP mRNA levels were higher in steers compared to bulls. In conclusion, FA synthesis may contribute to increased hepatic lipid deposition in steers following castration. However, hepatic lipid metabolism, including triglyceride synthesis, FA oxidation, and VLDL secretion, was not significantly altered by castration. Our results suggest that hepatic lipid metabolism does not significantly contribute to increased body fat deposition in steers following castration.
doi:10.5713/ajas.14.0582
PMCID: PMC4283181  PMID: 25557684
Korean Cattle; Liver; Bulls; Steers; Gene Expression
2.  Transfer of maternal cytokines to suckling piglets: in vivo and in vitro models with implications for immunomodulation of neonatal immunity 
Maternal cytokines may play instructive roles in development of the neonatal immune system. However, cytokines in colostrum and milk and their transfer from mothers to neonates have not been well documented, except for TGF-β. Swine provide a unique model to study lactogenic cytokines because the sow's impermeable placenta prohibits transplacental passage. We investigated IL-6 and TNF-α (pro-inflammatory), IFN-γ and IL-12, (Th1), IL-10 and IL-4 (Th2) and TGF-β1 (Th3) concentrations in sow serum and colostrum/milk and serum of their suckling and weaned piglets and in age-matched colostrum-deprived gnotobiotic piglets. All cytokines were detected in colostrum/milk and correlated with concentrations in sow serum except for mammary-derived TNF-α and TGF-β1. Detection of IL-12 and TGF-β1 in pre-suckling and colostrum-deprived gnotobiotic piglet serum suggests constitutive production: other cytokines were undetectable confirming absence of transplacental transfer. Peak median cytokine concentrations in suckling piglet serum occurred at post-partum days 1-2 (IL-4>IL-6>IFN-γ>IL-10). The effects in vitro of physiologically relevant concentrations of the two predominant lactogenic cytokines (TGF-β1 and IL-4) on porcine naive B cell responses to lipopolysaccharide (LPS) and rotavirus (RV) were investigated. High (10ng/ml) TGF-β1 suppressed immunoglobulin secreting cell responses to LPS and rotavirus; low concentrations (0.1ng/ml) promoted isotype switching to IgA antibody. Interleukin-4 induced inverse dose-dependent (0.1>10ng/ml) isotype switching to IgA and enhanced IgM secreting cell responses to LPS and rotavirus. In summary, we documented the transfer and persistence of maternal cytokines from colostrum/milk to neonates and their potential role in Th-2 biased IgA responses and reduced immunologic responsiveness of neonates.
doi:10.1016/j.vetimm.2007.02.013
PMCID: PMC4094377  PMID: 17403542
Cytokines; Milk; Neonate; Swine; Th2 bias
3.  Effects of Water Models on Binding Affinity: Evidence from All-Atom Simulation of Binding of Tamiflu to A/H5N1 Neuraminidase 
The Scientific World Journal  2014;2014:536084.
The influence of water models SPC, SPC/E, TIP3P, and TIP4P on ligand binding affinity is examined by calculating the binding free energy ΔGbind of oseltamivir carboxylate (Tamiflu) to the wild type of glycoprotein neuraminidase from the pandemic A/H5N1 virus. ΔGbind is estimated by the Molecular Mechanic-Poisson Boltzmann Surface Area method and all-atom simulations with different combinations of these aqueous models and four force fields AMBER99SB, CHARMM27, GROMOS96 43a1, and OPLS-AA/L. It is shown that there is no correlation between the binding free energy and the water density in the binding pocket in CHARMM. However, for three remaining force fields ΔGbind decays with increase of water density. SPC/E provides the lowest binding free energy for any force field, while the water effect is the most pronounced in CHARMM. In agreement with the popular GROMACS recommendation, the binding score obtained by combinations of AMBER-TIP3P, OPLS-TIP4P, and GROMOS-SPC is the most relevant to the experiments. For wild-type neuraminidase we have found that SPC is more suitable for CHARMM than TIP3P recommended by GROMACS for studying ligand binding. However, our study for three of its mutants reveals that TIP3P is presumably the best choice for CHARMM.
doi:10.1155/2014/536084
PMCID: PMC3929574  PMID: 24672329
4.  Infant motor development in rural Vietnam and intrauterine exposures to anaemia, iron deficiency and common mental disorders: a prospective community-based study 
Background
Antenatal anaemia, iron deficiency and common mental disorders (CMD) are prevalent in low- and middle-income countries. The aim of this study was to examine the direct and indirect effects of antenatal exposures to these risks and infant motor development.
Methods
A cohort of women who were pregnant with a single foetus and between 12 and 20 weeks pregnant in 50 randomly-selected rural communes in Ha Nam province was recruited. Participants provided data twice during pregnancy (early and late gestation) and twice after giving birth (8 weeks and 6 months postpartum). The Edinburgh Postnatal Depression Scale was used at all four data collection waves to detect CMD (score ≥ 4). Maternal anaemia (Hb < 11 g/dL) and iron deficiency (ferritin < 15 ng/mL) were evaluated at early and late gestation. Infants’ motor development was assessed by the Bayley of Infant and Toddler Development Motor Scales (BSID-M) at the age of six months. Direct and indirect effects of the exposures on the outcome were examined with Path analysis.
Results
In total, 497 of 523 (97%) eligible pregnant women were recruited and 418 mother-infant pairs provided complete data and were included in the analyses. The prevalence of anaemia was 21.5% in early pregnancy and 24.4% in late pregnancy. There was 4.1% iron deficiency at early pregnancy and 48.2% at late pregnancy. Clinically significant symptoms of CMD were apparent among 40% women in early pregnancy and 28% in late pregnancy. There were direct adverse effects on infant BSID-M scores at 6 months of age due to antenatal anaemia in late pregnancy (an estimated mean reduction of 2.61 points, 95% Confidence Interval, CI, 0.57 to 4.65) and CMD in early pregnancy (7.13 points, 95% CI 3.13 to 11.13). Iron deficiency and anaemia in early pregnancy were indirectly related to the outcome via anaemia during late pregnancy.
Conclusions
Antenatal anaemia, iron deficiency, and CMD have a negative impact on subsequent infant motor development. These findings highlight the need to improve the quality of antenatal care when developing interventions for pregnant women that aim to optimise early childhood development in low- and middle-income countries.
doi:10.1186/1471-2393-14-8
PMCID: PMC3890590  PMID: 24401012
Infant development; Pregnancy; Common mental disorders; Micronutrient deficiencies; Vietnam
5.  Lens-less surface second harmonic imaging 
Optics Express  2012;20(20):21953-21967.
Lens-less surface second harmonic generation imaging (SSHGI) is used to image an SHG active molecule, (S)-( + )-1,1’-bi-2-naphthol (SBN), incorporated into a lipid bilayer patterned with the 1951 United States Air Force resolution test target. Data show the coherent plane-wave nature of SHG allows direct imaging without the aid of a lens system. Lens-less SSHGI readily resolves line-widths as small as 223 μm at an object-image distance of 7.6 cm and line-widths of 397 μm at distances as far as 30 cm. Lens-less SSHGI simplifies the detection method, raises photon collection efficiency, and expands the field-of-view. These advantages allow greater throughput and make lens-less SSHGI a potentially valuable detection method for biosensors and medical diagnostics.
doi:10.1364/OE.20.021953
PMCID: PMC3601730  PMID: 23037346
(110.1650) Coherence imaging; (110.2970) Image detection systems; (190.4350) Nonlinear optics at surfaces; (240.6490) Spectroscopy, surface
6.  Childhood Intussusception: A Literature Review 
PLoS ONE  2013;8(7):e68482.
Background
Postlicensure data has identified a causal link between rotavirus vaccines and intussusception in some settings. As rotavirus vaccines are introduced globally, monitoring intussusception will be crucial for ensuring safety of the vaccine programs.
Methods
To obtain updated information on background rates and clinical management of intussusception, we reviewed studies of intussusception in children <18 years of age published since 2002. We assessed the incidence of intussusception by month of life among children <1 year of age, seasonality, method of diagnosis, treatment, and case-fatality.
Findings
We identified 82 studies from North America, Asia, Europe, Oceania, Africa, Eastern Mediterranean, and Central & South America that reported a total of 44,454 intussusception events. The mean incidence of intussusception was 74 per 100,000 (range: 9–328) among children <1 year of age, with peak incidence among infants 5–7 months of age. No seasonal patterns were observed. A radiographic modality was used to diagnose intussusception in over 95% of the cases in all regions except Africa where clinical findings or surgery were used in 65% of the cases. Surgical rates were substantially higher in Africa (77%) and Central and South America (86%) compared to other regions (13–29%). Case-fatality also was higher in Africa (9%) compared to other regions (<1%). The primary limitation of this review relates to the heterogeneity in intussusception surveillance across different regions.
Conclusion
This review of the intussusception literature from the past decade provides pertinent information that should facilitate implementation of intussusception surveillance for monitoring the postlicensure safety of rotavirus vaccines.
doi:10.1371/journal.pone.0068482
PMCID: PMC3718796  PMID: 23894308
7.  Inhibitory Effect of Breast Milk on Infectivity of Live Oral Rotavirus Vaccines 
Background
Live oral rotavirus vaccines have been less immunogenic and efficacious among children in poor developing countries compared with middle income and industrialized countries for reasons that are not yet completely understood. We assessed whether the neutralizing activity of breast milk could lower the titer of vaccine virus and explain this difference in vitro.
Methods
Breast milk samples were collected from mothers who were breast-feeding infants 4 to 29 weeks of age (ie, vaccine eligible age) in India (N = 40), Vietnam (N = 77), South Korea (N = 34), and the United States (N = 51). We examined breast milk for rotavirus-specific IgA and neutralizing activity against 3 rotavirus vaccine strains—RV1, RV5 G1, and 116E using enzyme immunoassays. The inhibitory effect of breast milk on RV1 was further examined by a plaque reduction assay.
Findings
Breast milk from Indian women had the highest IgA and neutralizing titers against all 3 vaccine strains, while lower but comparable median IgA and neutralizing titers were detected in breast milk from Korean and Vietnamese women, and the lowest titers were seen in American women. Neutralizing activity was greatest against the 2 vaccine strains of human origin, RV1 and 116E. This neutralizing activity in one half of the breast milk specimens from Indian women could reduce the effective titer of RV1 by ~2 logs, of 116E by 1.5 logs, and RV5 G1 strain by ~1 log more than that of breast milk from American women.
Interpretation
The lower immunogenicity and efficacy of rotavirus vaccines in poor developing countries could be explained, in part, by higher titers of IgA and neutralizing activity in breast milk consumed by their infants at the time of immunization that could effectively reduce the potency of the vaccine. Strategies to overcome this negative effect, such as delaying breast-feeding at the time of immunization, should be evaluated.
doi:10.1097/INF.0b013e3181e232ea
PMCID: PMC3704726  PMID: 20442687
rotavirus; RV1; RV5; neutralizing activity; breast milk
8.  T Cell Factor-1 and β-catenin control the development of memory-like CD8 thymocytes 
Innate memory-like CD8 thymocytes develop and acquire effector function during maturation in the absence of encounter with antigens. Here, we demonstrate that enhanced function of transcription factors T Cell Factor (TCF)-1 and β-catenin regulate the frequency of promyelocytic leukemia zinc finger (PLZF) expressing IL-4 producing thymocytes that promote the generation of Eomesodermin-expressing memory-like CD8 thymocytes in trans. By contrast, TCF1-deficient mice do not have PLZF-expressing thymocytes and Eomesodermin-expressing memory-like CD8 thymocytes. Generation of TCF1 and β-catenin-dependent memory-like CD8 thymocytes is non-cell intrinsic and requires the expression of IL-4 and IL-4 receptor. CD8 memory-like thymocytes migrate to the peripheral lymphoid organs and the memory-like CD8 T cells rapidly produce IFNγ. Thus, TCF1 and β-catenin regulate the generation of PLZF-expressing thymocytes and thereby facilitate the generation of memory-like CD8 T cells in the thymus.
doi:10.4049/jimmunol.1103729
PMCID: PMC3471543  PMID: 22492686
β-catenin; TCF1; IL4; IL4Rα; memory-like thymocytes
9.  Pro-inflammatory mediators disrupt glucose homeostasis in airway surface liquid ‡ 
The glucose concentration of the airway surface liquid (ASL) is much lower than blood and is tightly regulated by the airway epithelium. ASL glucose is elevated in patients with viral colds, cystic fibrosis, chronic obstructive pulmonary disease (COPD) and asthma. Elevated ASL glucose is also associated with increased incidence of respiratory infection. However, the mechanism by which ASL glucose increases under inflammatory conditions is unknown. The aim of this study was to investigate the effect of pro-inflammatory mediators (PIMs) on the mechanisms governing airway glucose homeostasis in polarised monolayers of human airway (H441) and primary human bronchial epithelial (HBE) cells. Monolayers were treated with TNF-α, IFN-γ and LPS over 72 hours. PIM treatment led to increase in ASL glucose concentration and significantly reduced H441 and HBE transepithelial resistance (RT). This decline in RT was associated with an increase in paracellular permeability of glucose. Similar enhanced rates of paracellular glucose flux were also observed across excised trachea from LPS-treated mice. Interestingly, PIMs enhanced glucose uptake across the apical, but not the basolateral, membrane of H441 and HBE monolayers. This increase was predominantly via phloretin-sensitive GLUT-mediated uptake, which coincided with an increase in GLUT2 and GLUT10 abundance. In conclusion, exposure of airway epithelial monolayers to PIMs results in increased paracellular glucose flux, and apical GLUT-mediated glucose uptake. However uptake was insufficient to limit glucose accumulation in ASL. These data provide for the first time, a mechanism to support clinical findings that ASL glucose concentration is increased in patients with airway inflammation.
doi:10.4049/jimmunol.1200718
PMCID: PMC3605804  PMID: 22623330
Glucose; airway; inflammation; GLUT2; GLUT10; cytokines; LPS
11.  RefZ Facilitates the Switch from Medial to Polar Division during Spore Formation in Bacillus subtilis 
Journal of Bacteriology  2012;194(17):4608-4618.
During sporulation, Bacillus subtilis redeploys the division protein FtsZ from midcell to the cell poles, ultimately generating an asymmetric septum. Here, we describe a sporulation-induced protein, RefZ, that facilitates the switch from a medial to a polar FtsZ ring placement. The artificial expression of RefZ during vegetative growth converts FtsZ rings into FtsZ spirals, arcs, and foci, leading to filamentation and lysis. Mutations in FtsZ specifically suppress RefZ-dependent division inhibition, suggesting that RefZ may target FtsZ. During sporulation, cells lacking RefZ are delayed in polar FtsZ ring formation, spending more time in the medial and transition stages of FtsZ ring assembly. A RefZ-green fluorescent protein (GFP) fusion localizes in weak polar foci at the onset of sporulation and as a brighter midcell focus at the time of polar division. RefZ has a TetR DNA binding motif, and point mutations in the putative recognition helix disrupt focus formation and abrogate cell division inhibition. Finally, chromatin immunoprecipitation assays identified sites of RefZ enrichment in the origin region and near the terminus. Collectively, these data support a model in which RefZ helps promote the switch from medial to polar division and is guided by the organization of the chromosome. Models in which RefZ acts as an activator of FtsZ ring assembly near the cell poles or as an inhibitor of the transient medial ring at midcell are discussed.
doi:10.1128/JB.00378-12
PMCID: PMC3415491  PMID: 22730127
12.  Comparison of Medium, Temperature, and Length of Incubation for Detection of Vancomycin-Resistant Enterococcus 
Journal of Clinical Microbiology  2012;50(7):2503-2505.
Campylobacter (Campy; BD Diagnostics, Sparks, MD), Spectra VRE (Remel, Lenexa, KS), and bile-esculin-azide-vancomycin (BEAV; Remel) agars were compared for their ability to detect vancomycin-resistant enterococci (VRE) in 750 stool specimens. The media were compared at 24 h and 48 h of incubation at 35°C and 42°C. When incubated for 24 h at 35°C, Campy was the most sensitive (97.8%) and specific (99.9%) but was comparable to Spectra, which has a sensitivity of 95.6% and a specificity of 99.1%, whereas BEAV was significantly less sensitive (90%) and specific (96.1%). Incubation at 42°C or extended incubation at 35°C for 48 h yielded no advantage over incubation at 35°C for 24 h.
doi:10.1128/JCM.00479-12
PMCID: PMC3405587  PMID: 22535989
13.  Stabilizing Additives Added during Cell Lysis Aid in the Solubilization of Recombinant Proteins 
PLoS ONE  2012;7(12):e52482.
Insoluble recombinant proteins are a major issue for both structural genomics and enzymology research. Greater than 30% of recombinant proteins expressed in Escherichia coli (E. coli) appear to be insoluble. The prevailing view is that insolubly expressed proteins cannot be easily solubilized, and are usually sequestered into inclusion bodies. However, we hypothesize that small molecules added during the cell lysis stage can yield soluble protein from insoluble protein previously screened without additives or ligands. We present a novel screening method that utilized 144 additive conditions to increase the solubility of recombinant proteins expressed in E. coli. These selected additives are natural ligands, detergents, salts, buffers, and chemicals that have been shown to increase the stability of proteins in vivo. We present the methods used for this additive solubility screen and detailed results for 41 potential drug target recombinant proteins from infectious organisms. Increased solubility was observed for 80% of the recombinant proteins during the primary and secondary screening of lysis with the additives; that is 33 of 41 target proteins had increased solubility compared with no additive controls. Eleven additives (trehalose, glycine betaine, mannitol, L-Arginine, potassium citrate, CuCl2, proline, xylitol, NDSB 201, CTAB and K2PO4) solubilized more than one of the 41 proteins; these additives can be easily screened to increase protein solubility. Large-scale purifications were attempted for 15 of the proteins using the additives identified and eight (40%) were prepared for crystallization trials during the first purification attempt. Thus, this protocol allowed us to recover about a third of seemingly insoluble proteins for crystallography and structure determination. If recombinant proteins are required in smaller quantities or less purity, the final success rate may be even higher.
doi:10.1371/journal.pone.0052482
PMCID: PMC3527557  PMID: 23285060
14.  DIRAS2 is Associated with Adult ADHD, Related Traits, and Co-Morbid Disorders 
Neuropsychopharmacology  2011;36(11):2318-2327.
Several linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locus contains the brain-expressed GTP-binding RAS-like 2 gene (DIRAS2) thought to regulate neurogenesis. As DIRAS2 is a positional and functional ADHD candidate gene, we conducted an association study in 600 patients suffering from adult ADHD (aADHD) and 420 controls. Replication samples consisted of 1035 aADHD patients and 1381 controls, as well as 166 families with a child affected from childhood ADHD. Given the high degree of co-morbidity with ADHD, we also investigated patients suffering from bipolar disorder (BD) (n=336) or personality disorders (PDs) (n=622). Twelve single-nucleotide polymorphisms (SNPs) covering the structural gene and the transcriptional control region of DIRAS2 were analyzed. Four SNPs and two haplotype blocks showed evidence of association with ADHD, with nominal p-values ranging from p=0.006 to p=0.05. In the adult replication samples, we obtained a consistent effect of rs1412005 and of a risk haplotype containing the promoter region (p=0.026). Meta-analysis resulted in a significant common OR of 1.12 (p=0.04) for rs1412005 and confirmed association with the promoter risk haplotype (OR=1.45, p=0.0003). Subsequent analysis in nuclear families with childhood ADHD again showed an association of the promoter haplotype block (p=0.02). rs1412005 also increased risk toward BD (p=0.026) and cluster B PD (p=0.031). Additional SNPs showed association with personality scores (p=0.008–0.048). Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders.
doi:10.1038/npp.2011.120
PMCID: PMC3176568  PMID: 21750579
adult ADHD; linkage; genome-wide association; ras pathway; association study; bipolar disorder; biological psychiatry; neurogenetics; depression; unipolar/bipolar; development/developmental disorders; adult ADHD; linkage; genome-wide association study; ras pathway
15.  An Early Reduction in Treg Cells Correlates with Enhanced Local Inflammation in Cutaneous Leishmaniasis in CCR6-Deficient Mice 
PLoS ONE  2012;7(9):e44499.
Resistance to Leishmania major infection is dependent on the development of a cell-mediated Th1 immune response in resistant C57BL/6 mice whereas Th2-prone BALB/c mice develop non-healing lesions after infection. The chemokine receptor CCR6 is shared by anti-inflammatory regulatory T cells and pro-inflammatory Th17 cells. In a recent study we showed that C57BL/6 mice deficient in CCR6 exhibited enhanced footpad swelling and impaired T helper cell migration indicated by reduced recruitment of total T helper cells into the skin after infection and a reduced delayed type hypersensitivity reaction. Based on these findings we tested whether the lack of CCR6 alters Treg or Th17 cell responses during the course of Leishmania major infection. When we analyzed T cell subsets in the lymph nodes of CCR6-deficient mice, Th17 cell numbers were not different. However, reduced numbers of Treg cells paralleled with a stronger IFNγ response. Furthermore, the early increase in IFNγ-producing cells correlated with increased local tissue inflammation at later time points. Our data indicate an important role of CCR6 for Treg cells and a redundant role for Th17 cells in a Th1 cell-driven anti-parasitic immune response against Leishmania major parasites in resistant C57BL/6 mice.
doi:10.1371/journal.pone.0044499
PMCID: PMC3460949  PMID: 23028548
16.  Evaluating the New York City Emergency Department Syndromic Surveillance for Monitoring Influenza Activity during the 2009-10 Influenza Season 
PLoS Currents  2012;4:e500563f3ea181.
Objective: To use laboratory data to assess the specificity of syndromes used by the New York City emergency department (ED) syndromic surveillance system to monitor influenza activity. Design: For the period from October 1, 2009 through March 31, 2010, we examined the correlation between citywide ED syndrome assignment and laboratory-confirmed influenza and respiratory syncytial virus (RSV). In addition, ED syndromic data from five select NYC hospitals were matched at the patient and visit level to corresponding laboratory reports of influenza and RSV. The matched dataset was used to evaluate syndrome assignment by disease and to calculate the sensitivity and specificity of the influenza-like illness (ILI) syndrome. Results: Citywide ED visits for ILI correlated well with influenza laboratory diagnoses (R=0.92). From October 1, 2009, through March 31, 2010, there were 264,532 ED visits at the five select hospitals, from which the NYC Department of Health and Mental Hygiene (DOHMH) received confirmatory laboratory reports of 655 unique cases of influenza and 1348 cases of RSV. The ED visit of most (56%) influenza cases had been categorized in the fever/flu syndrome; only 15% were labeled ILI. Compared to other influenza-related syndromes, ILI had the lowest sensitivity (15%) but the highest specificity (90%) for laboratory-confirmed influenza. Sensitivity and specificity varied by age group and influenza activity level. Conclusions: The ILI syndrome in the NYC ED syndromic surveillance system served as a specific but not sensitive indicator for influenza during the 2009-2010 influenza season. Despite its limited sensitivity, the ILI syndrome can be more informative for tracking influenza trends than the fever/flu or respiratory syndromes because it is less likely to capture cases of other respiratory viruses. However, ED ILI among specific age groups should be interpreted alongside laboratory surveillance data. ILI remains a valuable tool for monitoring influenza activity and trends as it facilitates comparisons nationally and across jurisdictions and is easily communicated to the public.
doi:10.1371/500563f3ea181
PMCID: PMC3441153  PMID: 22984645
17.  High-Throughput Screening of Drug-Lipid Membrane Interactions via Counter-Propagating Second Harmonic Generation Imaging 
Analytical Chemistry  2011;83(15):5979-5988.
Here we report the use of counter-propagating second harmonic generation (SHG) to image the interactions between the local anesthetic tetracaine and a multi-component planar supported lipid bilayer array in a label-free manner. The lipid bilayer arrays, prepared using a 3D continuous flow microspotter, allow the effects of lipid phase and cholesterol content on tetracaine binding to be examined simultaneously. SHG images show that tetracaine has a higher binding affinity to liquid-crystalline phase lipids than to solid-gel phase lipids. The presence of 28 mol % cholesterol decreased the binding affinity of tetracaine to bilayers composed of the mixed chain lipid, 1-steroyl-2-oleoyl-sn-glycero-3-phophocholine (SOPC) and the saturated lipids 1,2-dimyristoyl-sn-glycero-3-phophocholine (DMPC) and 1,2-dipamitoyl-sn-glycero-3-phophocholine (DPPC) while having no effect on di-unsaturated 1,2-dioleoyl-sn-glycero-3-phophocholine (DOPC). The maximum surface excess of tetracaine increases with the degree of unsaturation of the phospholipids and decreases with cholesterol in the lipid bilayers. The paper demonstrates that SHG imaging is a sensitive technique that can directly image and quantitatively measure the association of a drug to a multi-component lipid bilayer array, providing a high-throughput means to assess drug-membrane interactions.
doi:10.1021/ac2009614
PMCID: PMC3328353  PMID: 21696170
18.  Natural mood foods: The actions of polyphenols against psychiatric and cognitive disorders 
Nutritional Neuroscience  2012;15(3):127-133.
Objectives
Polyphenols, natural compounds found in plant-based foods, possess special properties that can battle oxidative stress and stimulate the activation of molecules that aid in synaptic plasticity, a process that underlies cognitive function. Unlike many traditional treatments, polyphenols affect a broad range of mechanisms in the brain that can assist in the maintenance of cognitive and mental health, as well as the recovery from neurodegenerative diseases. Examining the molecular basis underlying the link between food intake and brain function has presented the exciting possibility of using diet as a viable method to battle cognitive and psychiatric disorders.
Methods
We will discuss the molecular systems that link polyphenols, the gut, and the brain, as well as introduce published human and animal studies demonstrating the effects of polyphenol consumption on brain plasticity and cognition.
Results
By influencing cellular energy metabolism and modulating the signaling pathways of molecules involved with brain plasticity, dietary factors – formerly recognized for just their effects on bodily systems – have emerged as affecters of the brain.
Conclusion
Thus, the consumption of diets enriched with polyphenols may present the potential of dietary manipulation as a non-invasive, natural, and inexpensive therapeutic means to support a healthy brain.
doi:10.1179/1476830511Y.0000000035
PMCID: PMC3355196  PMID: 22334236
BDNF; Cognition; Metabolism; Polyphenol; Psychiatric disorder; Synaptic plasticity
19.  The National Asthma Survey—New York State: Association of the Home Environment with Current Asthma Status 
Public Health Reports  2010;125(6):877-887.
SYNOPSIS
Objectives
The National Asthma Survey—New York State (NYS), a telephone survey of NYS residents, was conducted in 2002–2003 to further understand the burden of asthma among adults and children and to identify health, socioeconomic, behavioral, and environmental factors associated with asthma.
Methods
A total of 1,412 households with at least one member with current asthma and 2,290 control households answered questions about their home environment (e.g., presence of asthma triggers and practices that promote or reduce common asthma triggers).
Results
For children younger than 18 years of age, we found statistically significant positive associations between current asthma and the presence of mold (adjusted odds ratio [AOR] = 2.1, 95% confidence interval [CI] 1.3, 3.3), air cleaners (AOR=1.5, 95% CI 1.1, 2.1), dehumidifiers (AOR=2.0, 95% CI 1.4, 2.7), and humidifiers (AOR=1.6, 95% CI 1.1, 2.3). For adults, there were statistically significant positive associations with the presence of mold (AOR=2.5, 95% CI 1.8, 3.4), air cleaners (AOR=2.2, 95% CI 1.7, 2.8), and humidifiers (AOR=1.4, 95% CI 1.1, 1.8). There were no statistically significant associations with the presence of cockroaches, pets, or tobacco smoke, while use of a wood-burning stove or fireplace was significantly more prevalent in control homes.
Conclusions
Asthma guidelines emphasize the importance of reducing triggers in the home as part of a multifaceted approach to asthma control. Despite these guidelines, many asthma triggers (specifically, mold) were as prevalent or more so in the homes of New Yorkers with asthma as compared with control households. Public health interventions in NYS should focus on educating households about potential asthma triggers and their sources and teach methods to prevent, reduce, or eliminate them.
PMCID: PMC2966669  PMID: 21121233
20.  Acceptance of a pandemic influenza vaccine: a systematic review of surveys of the general public 
Introduction:
The effectiveness of pandemic vaccine campaigns such as the H1N1 vaccine rollout is dependent on both the vaccines’ effectiveness and the general public’s willingness to be vaccinated. It is therefore critical to understand the factors that influence the decision of members of the public whether to get vaccinated with new, emergently released vaccines.
Methods:
A systematic review of English language quantitative surveys was conducted to identify consistent predictors of the decision to accept or decline any (pre)pandemic vaccine, including the H1N1 influenza A vaccine. A total of ten studies were included in this review and all pertained to the 2009 H1N1 influenza A pandemic. Respondents’ willingness to receive a pandemic vaccine ranged from 8%–67% across the ten studies. The factors reported to be consistent predictors of the intention to vaccinate were: risk of infection, proximity or severity of the public health event, severity of personal consequences resulting from the illness, harm or adverse events from the vaccine, acceptance of previous vaccination, and ethnicity. Age and sex were the demographic variables examined most frequently across the ten studies and there was no consistent association between these variables and the intention to accept or reject a pandemic vaccine.
Conclusion:
Some predictors of the intention to accept or decline a (pre)pandemic vaccine or the H1N1 influenza A vaccine are consistently identified by surveys. Understanding the important factors influencing the acceptance of a pandemic vaccine by individual members of the public may help inform strategies to improve vaccine uptake during future pandemics.
doi:10.2147/IDR.S23174
PMCID: PMC3215344  PMID: 22114512
pandemic; H1N1 influenza A; emergent vaccine; personal risk; demographic
21.  Structure of triosephosphate isomerase from Cryptosporidium parvum  
The crystal structure of the ubiquitous glycolytic enzyme triosephosphate isomerase from C. parvum in the open-loop conformation was determined at a resolution of 1.55 Å.
Cryptosporidium parvum is one of several Cryptosporidium spp. that cause the parasitic infection cryptosporidiosis. Cryptosporidiosis is a diarrheal infection that is spread via the fecal–oral route and is commonly caused by contaminated drinking water. Triosephosphate isomerase is an enzyme that is ubiquitous to all organisms that perform glycolysis. Triosephosphate isomerase catalyzes the formation of glyceraldehyde 3-phosphate from dihydroxyacetone phosphate, which is a critical step to ensure the maximum ATP production per glucose molecule. In this paper, the 1.55 Å resolution crystal structure of the open-loop form of triosephosphate isomerase from C. parvum Iowa II is presented. An unidentified electron density was found in the active site.
doi:10.1107/S1744309111019178
PMCID: PMC3169408  PMID: 21904056
glycolysis; triosephosphate; triosephosphate isomerases; metabolism; Cryptosporidium parvum
22.  Genes Involved in the Repression of Mutacin I Production in Streptococcus mutans 
Microbiology (Reading, England)  2009;155(Pt 2):551-556.
Streptococcus mutans is considered a primary pathogen for human dental caries. Its ability to produce a variety of peptide antibiotics called mutacins may play an important role in its invasion and establishment in the dental biofilm. S. mutans strain UA140 produces two types of mutacins, the lantibiotic mutacin I and the non-lantibitoc mutacin IV. In a previous study, we constructed a random insertional-mutation library to screen for genes involved in regulating mutacin I production, and found 25 genes/operons that have a positive effect on mutacin I production. In this study, we continued our previous work to identify genes that are negatively involved in mutacin I production. By using a high phosphate BHI plate that inhibited mutacin I production of the wild-type, we isolated 77 clones that consistently produced mutacin I under repressive conditions. From the 34 clones that we were able to obtain a sequence, 17 unique genes were identified. These genes encompass a variety of functional groups including the central metabolism, surface binding, sugar transport, and unknown functions. Some of the 17 mutations were further characterized and shown to increase mutacin gene expression during growth when it is usually not expressed in the wild-type. These results further demonstrate an intimate and intricate connection between mutacin production and the overall cellular homeostasis.
doi:10.1099/mic.0.021303-0
PMCID: PMC2946218  PMID: 19202103
23.  An Oral versus Intranasal Prime/Boost Regimen Using Attenuated Human Rotavirus or VP2 and VP6 Virus-Like Particles with Immunostimulating Complexes Influences Protection and Antibody-Secreting Cell Responses to Rotavirus in a Neonatal Gnotobiotic Pig Model ▿ 
We determined the impact of mucosal prime/boost regimens and vaccine type (attenuated Wa human rotavirus [AttHRV] or nonreplicating Wa 2/6 rotavirus-like particles [VLP]) on protection and antibody-secreting cell (ASC) responses to HRV in a neonatal gnotobiotic pig disease model. Comparisons of delivery routes for AttHRV and evaluation of nonreplicating VLP vaccines are important as alternative vaccine approaches to overcome risks associated with live oral vaccines. Groups of neonatal gnotobiotic pigs were vaccinated using combinations of oral (PO) and intranasal (IN) inoculation routes as follows: (i) 3 oral doses of AttHRV (AttHRV3×PO); (ii) AttHRV3×IN; (iii) AttHRVPO, then 2/6VLP2×IN; (iv) AttHRVIN, then 2/6VLP2×IN; and (v) mock-inoculated controls. Subsets of pigs from each group were challenged with virulent Wa HRV [P1A(8) G1] (4 weeks post-primary inoculation) to assess protection. The AttHRVPO+2/6VLP2×IN pigs had the highest protection rates against virus shedding and diarrhea (71% each); however, these rates did not differ statistically among the vaccine groups, except for the AttHRVIN+2/6VLPIN group, which had a significantly lower protection rate (17%) against diarrhea. The isotype, magnitude, and tissue distribution of ASCs were analyzed by enzyme-linked immunospot assay. The highest mean numbers of virus-specific IgG and IgA ASCs were observed pre- and postchallenge in both intestinal and systemic lymphoid tissues of the AttHRVPO+2/6VLPIN group. Thus, the AttHRVPO+2/6VLPIN vaccine regimen using immunostimulating complexes (ISCOM) and multiple mucosal inductive sites, followed by AttHRV3×PO or IN regimens, were the most effective vaccine regimens, suggesting that either AttHRVPO+2/6VLPIN or AttHRV3×IN may be an alternative approach to AttHRV3×PO for inducing protective immunity against rotavirus diarrhea.
doi:10.1128/CVI.00395-09
PMCID: PMC2837955  PMID: 20107005
24.  Meta-Analysis of Genome-Wide Linkage Scans of Attention Deficit Hyperactivity Disorder 
Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome-wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, there has been limited replications between the various independent datasets. The current study gathered the results from all seven of the ADHD linkage scans and performed a Genome Scan Meta Analysis (GSMA) to identify the genomic region with most consistent linkage evidence across the studies. Genome-wide significant linkage (PSR=0.00034, POR=0.04) was identified on chromosome 16 between 64 and 83 Mb. In addition there are nine other genomic regions from the GSMA showing nominal or suggestive evidence of linkage. All these linkage results may be informative and focus the search for novel ADHD susceptibility genes.
doi:10.1002/ajmg.b.30878
PMCID: PMC2890047  PMID: 18988193
ADHD; GSMA; linkage
25.  Label-Free Detection of Drug-Membrane Association using Ultraviolet-Visible Sum-Frequency Generation 
Drug-membrane interactions play a crucial role in the pharmacology and activity of drugs. The measurement of drug association to lipid membranes has conventionally been measured by fluorescence and other spectroscopic methods. However, a main disadvantage of fluorescence labeling of drugs is that the introduction of fluorophores may change the molecules physical properties, such as charge, hydrophobic or hydrophilic character and structure. To circumvent these problems, Ultraviolet-Visible Sum Frequency Generation (UV-Vis SFG) has been developed as an ultra-sensitive and label-free technique to detect small-molecule drug association to lipid membranes. Four different classes of drugs, a non-steroidal anti-inflammatory drug (ibuprofen), antibiotic (azithromycine), anti-fungal (tolnaftate), and local anesthetic (tetracaine), were examined. Drug association was measured on planar supported lipid bilayers (PSLBs) of 1,2-dioleoyl-sn-glycero-3-phophocholine (DOPC). Equilibrium association constants of the drugs were obtained and correlate well to the partition coefficients of the drugs in a liposome membrane-water system. UV-Vis SFG is a powerful and novel technique to directly measure the association of drugs to a single biological membrane without chemical modification.
doi:10.1021/ja8070607
PMCID: PMC2867465  PMID: 19140762

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