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1.  Synthesis, Photophysics, Electrochemistry and Electrogenerated Chemiluminescence of PEG-Modified BODIPY dyes in Organic and Aqueous Solutions 
A set polyethylene glycol (PEG) appended BODIPY architectures (BOPEG1 – BOPEG3) have been prepared and studied in CH2Cl2, H2O:CH3CN (1:1) and aqueous solutions. BOPEG1 and BOPEG2 both contain a short PEG chain and differ in substitution about the BODIPY framework. BOPEG3 is comprised of a fully substituted BODIPY moiety linked to a PEG polymer that is roughly 13 units in length. The photophysics and electrochemical properties of these compounds have been thoroughly characterized in CH2Cl2 and aqueous CH3CN solutions. The behavior of BOPEG1 – BOPEG3 correlates with established rules of BODIPY stability based on substitution about the BODIPY moiety. ECL for each of these compounds was also monitored. BOPEG1, which is unsubstituted at the 2- and 6-positions dimerized upon electrochemical oxidation while BOPEG2, which contains ethyl groups at the 2- and 6-positions, was much more robust and served as an excellent ECL luminophore. BOPEG3 is highly soluble in water due to the long PEG tether and demonstrated modest ECL activity in aqueous solutions using tri-n-propylamine (TPrA) as a coreactant. As such, BOPEG3 represents the first BODIPY derivative that has been shown to display ECL in water without the need for an organic cosolvent, and marks an important step in the development of BODIPY based ECL probes for various biosensing applications.
doi:10.1021/jp312166w
PMCID: PMC3633524  PMID: 23626863
ECL; Electrochemistry; Emission; Sensing
2.  Peptide-siRNA nanocomplexes targeting NF-κB subunit p65 suppress nascent experimental arthritis 
The Journal of Clinical Investigation  2014;124(10):4363-4374.
The NF-κB signaling pathway is implicated in various inflammatory diseases, including rheumatoid arthritis (RA); therefore, inhibition of this pathway has the potential to ameliorate an array of inflammatory diseases. Given that NF-κB signaling is critical for many immune cell functions, systemic blockade of this pathway may lead to detrimental side effects. siRNAs coupled with a safe and effective delivery nanoplatform may afford the specificity lacking in systemic administration of small-molecule inhibitors. Here we demonstrated that a melittin-derived cationic amphipathic peptide combined with siRNA targeting the p65 subunit of NF-κB (p5RHH-p65) noncovalently self-assemble into stable nanocomplexes that home to the inflamed joints in a murine model of RA. Specifically, administration of p5RHH-p65 siRNA nanocomplexes abrogated inflammatory cytokine expression and cellular influx into the joints, protected against bone erosions, and preserved cartilage integrity. The p5RHH-p65 siRNA nanocomplexes potently suppressed early inflammatory arthritis without affecting p65 expression in off-target organs or eliciting a humoral response after serial injections. These data suggest that this self-assembling, largely nontoxic platform may have broad utility for the specific delivery of siRNA to target and limit inflammatory processes for the treatment of a variety of diseases.
doi:10.1172/JCI75673
PMCID: PMC4191028  PMID: 25157820
3.  Phase I/II study of neoadjuvant bevacizumab, erlotinib and 5-fluorouracil with concurrent external beam radiation therapy in locally advanced rectal cancer 
Annals of Oncology  2014;25(1):121-126.
Anti-VEGF and anti-EGFR therapy in combination with chemoradiation have been studied separately in rectal cancer. In this study, we evaluate the combination of bevacizumab and erlotinib with chemoradiation. The purpose of this study is to determine the maximal tolerated dose of erlotinib when added to 5-fluorouracil (5-FU) chemoradiation and bevacizumab, and safety and efficacy of this combination in patients with locally advanced rectal cancer.
Background
To determine the maximal tolerated dose of erlotinib when added to 5-fluorouracil (5-FU) chemoradiation and bevacizumab and safety and efficacy of this combination in patients with locally advanced rectal cancer.
Patients and methods
Patients with Magnetic resonance imaging (MRI) or ultrasound defined T3 or T4 adenocarcinoma of the rectum and without evidence of metastatic disease were enrolled. Patients received infusional 5-FU 225 mg/M2/day continuously, along with bevacizumab 5 mg/kg days 14, 1, 15 and 29. Standard radiotherapy was administered to 50.4 Gy in 28 fractions. Erlotinib started at a dose of 50 mg orally daily and advanced by 50 mg increments in the subsequent cohort. Open total mesorectal excision was carried out 6–9 weeks following the completion of chemoradiation.
Results
Thirty-two patients received one of three dose levels of erlotinib. Erlotinib dose level of 100 mg was determined to be the maximally tolerated dose. Thirty-one patients underwent resection of the primary tumor, one refused resection. Twenty-seven patients completed study therapy, all of whom underwent resection. At least one grade 3–4 toxicity occurred in 46.9% of patients. Grade 3–4 diarrhea occurred in 18.8%. The pathologic complete response (pCR) for all patients completing study therapy was 33%. With a median follow-up of 2.9 years, there are no documented local recurrences. Disease-free survival at 3 years is 75.5% (confidence interval: 55.1–87.6%).
Conclusions
Erlotinib added to infusional 5-FU, bevacizumab and radiation in patients with locally advanced rectal cancer is relatively well tolerated and associated with an encouraging pCR.
Clinicaltrials.gov
NCT00307736.
doi:10.1093/annonc/mdt516
PMCID: PMC4271130  PMID: 24356623
rectal cancer; radiation; bevacizumab; erlotinib
4.  The association of preterm birth with severe asthma and atopic dermatitis; a national cohort study 
Background
Asthma and atopic dermatitis are both regarded as atopic diseases. Being born too early is associated with increased risk of asthma, but some studies have indicated that the opposite might be true for atopic dermatitis. We explored in more detail the associations between preterm birth, asthma, and atopic dermatitis.
Methods
We analyzed data from Norwegian registries with prospectively collected data. All live births in Norway from 1967 through 2001 were followed through 2005 by linking the Medical Birth Registry of Norway to the National Insurance Scheme and to Statistics Norway. Only severe asthma and atopic dermatitis were registered in the National Insurance Scheme.
Results
Of a total of 1,760,821 children, we identified 9,349 cases (0.5%) with severe asthma and 6,930 cases (0.4%) with severe atopic dermatitis. Compared with children born at term (37–41 weeks’ gestation), preterm birth was associated with increased odds for severe asthma (odds ratio (OR) 1.7 (95% confidence interval (CI): 1.6–1.8) for 32–36 weeks’ gestation and OR 3.6 (95% CI: 3.1–4.2) for 23–31 weeks) and decreased odds for severe atopic dermatitis (OR 0.9 (95% CI: 0.8–1.0) for 32–36 weeks’ gestation and OR 0.7 (95% CI: 0.5–1.0) for 23–31 weeks). Adjustment for perinatal and socio-demographic factors weakened the association between gestational age and severe asthma, while slightly strengthening the association between gestational age and severe atopic dermatitis.
Conclusions
Preterm birth was associated with increased risk for severe asthma and decreased risk for severe atopic dermatitis.
doi:10.1111/pai.12170
PMCID: PMC3895460  PMID: 24298940
Premature birth; Atopic dermatitis; Asthma; Pregnancy complications; Gestational age
5.  Does CHA2DS2-VASc Improve Stroke Risk Stratification in Postmenopausal Women with Atrial Fibrillation? 
The American journal of medicine  2013;126(12):10.1016/j.amjmed.2013.05.023.
Background
Risk stratification of atrial fibrillation patients with a CHADS2 score of < 2 remains imprecise, particularly in women. Our objectives were to validate the CHADS2 and CHA2DS2-VASc stroke risk scores in a healthy cohort of American women with atrial fibrillation and to determine whether CHA2DS2-VASc further risk stratifies individuals with a CHADS2 score of < 2.
Methods
We identified a cohort of 5,981 women with atrial fibrillation not on warfarin at baseline (mean age 65.9±7.2 years) enrolled in the Women's Health Initiative and followed for a median of 11.8 years. Univariate and multivariate proportional hazards analyses were used to examine these two risk scores with main outcome measures being annualized event rates of ischemic stroke or transient ischemic attack stratified by risk score.
Results
Annualized stroke/ transient ischemic attack rates ranged from 0.36-2.43% with increasing CHADS2 score (0-4+) (hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.45-1.71 for each 1 point increase) and 0.20-2.02% with increasing CHA2DS2-VASc score (1-6+) (HR 1.50, 95% CI 1.41-1.60 for each 1 point increase). CHA2DS2-VASc had a higher c statistic than CHADS2: 0.67 (95% CI 0.65-0.69) vs. 0.65 (95% CI 0.62-0.67), p < 0.01. For CHADS2 scores < 2, stroke risk almost doubled with every additional CHA2DS2-VASc point.
Conclusions
Although both CHADS2, and CHA2DS2-VASc are predictive of stroke risk in post-menopausal women with atrial fibrillation, CHA2DS2-VASc further risk-stratifies patients with a CHADS2 score < 2.
doi:10.1016/j.amjmed.2013.05.023
PMCID: PMC3883047  PMID: 24139523
atrial fibrillation; CHADS2; CHA2DS2-VASc; stroke; women
6.  Synthesis, Electrochemistry and Electrogenerated Chemiluminesce of two BODIPY-Appended Bipyridine Homologues 
Journal of the American Chemical Society  2013;135(36):13558-13566.
Two new 2,2’-bipyridine (bpy) derivatives containing ancillary BODIPY chromophores attached at the 5- and 5’-positions (BB3) or 6- and 6’-positions (BB4) were prepared and characterized. In this work, the basic photophysics, electrochemistry and electrogenerated chemiluminescence (ECL) of BB3 and BB4 are compared with those previously reported for a related bpy-BODIPY derivative (BB2) (J. Phys. Chem. C 2011, 115, 17993–18001). Cyclic voltammetry revealed that BB3 and BB4 display reversible 2e− oxidation and reduction waves, which consist of two closely spaced (50 – 70 mV) 1e− events. This redox behavior is consistent with the frontier molecular orbitals calculated for BB3 and BB4 and indicates that the 2,2’-bipyridine spacer of each bpy- BODIPY homologue does not facilitate efficient electronic communication between the tethered indacene units. In the presence of a coreactant such as tri-n-propylamine (TPA) or benzoyl peroxide (BPO), BB3 and BB4 exhibit strong ECL and produce spectra that are very similar to their corresponding photoluminescence profiles. The ECL signal obtained under annihilation conditions, however, is significantly different and is characterized by two distinct bands. One of these bands is centered at ~570 nm and is attributed to emission via an S- or T-route. The second band, occurs at longer wavelengths and is centered around ~740 nm. The shape and concentration dependence of this long-wavelength ECL signal is not indicative of emission from an excimer or aggregate, but rather is suggests that a new emissive species is formed from the bpy-BODIPY luminophores during the annihilation process.
doi:10.1021/ja406731f
PMCID: PMC4238283  PMID: 23980850
Electrochemistry; Electrogenerated Chemiluminescence; Long-Wavelength Emission; BODIPY; Bipyridine Derivatives
7.  Natural discourse reference generation reduces cognitive load in spoken systems 
Natural language engineering  2010;17(3):311-329.
The generation of referring expressions is a central topic in computational linguistics. Natural referring expressions – both definite references like ‘the baseball cap’ and pronouns like ‘it’ – are dependent on discourse context. We examine the practical implications of context-dependent referring expression generation for the design of spoken systems. Currently, not all spoken systems have the goal of generating natural referring expressions. Many researchers believe that the context-dependency of natural referring expressions actually makes systems less usable. Using the dual-task paradigm, we demonstrate that generating natural referring expressions that are dependent on discourse context reduces cognitive load. Somewhat surprisingly, we also demonstrate that practice does not improve cognitive load in systems that generate consistent (context-independent) referring expressions. We discuss practical implications for spoken systems as well as other areas of referring expression generation.
doi:10.1017/S1351324910000227
PMCID: PMC4199659  PMID: 25328423
8.  Identification of DNA Methylation Changes in Newborns Related to Maternal Smoking during Pregnancy 
Environmental Health Perspectives  2014;122(10):1147-1153.
Background: Maternal smoking during pregnancy is associated with significant infant morbidity and mortality, and may influence later disease risk. One mechanism by which smoking (and other environmental factors) might have long-lasting effects is through epigenetic modifications such as DNA methylation.
Objectives: We conducted an epigenome-wide association study (EWAS) investigating alterations in DNA methylation in infants exposed in utero to maternal tobacco smoke, using the Norway Facial Clefts Study.
Methods: The Illumina HumanMethylation450 BeadChip was used to assess DNA methylation in whole blood from 889 infants shortly after delivery. Of 889 mothers, 287 reported smoking—twice as many smokers as in any previous EWAS of maternal smoking. CpG sites related to maternal smoking during the first trimester were identified using robust linear regression.
Results: We identified 185 CpGs with altered methylation in infants of smokers at genome-wide significance (q-value < 0.05; mean Δβ = ± 2%). These correspond to 110 gene regions, of which 7 have been previously reported and 10 are newly confirmed using publicly available results. Among these 10, the most noteworthy are FRMD4A, ATP9A, GALNT2, and MEG3, implicated in processes related to nicotine dependence, smoking cessation, and placental and embryonic development.
Conclusions: Our study identified 10 genes with newly established links to maternal smoking. Further, we note differences between smoking-related methylation changes in newborns and adults, suggesting possible distinct effects of direct versus indirect tobacco smoke exposure as well as potential differences due to age. Further work would be needed to determine whether these small changes in DNA methylation are biologically or clinically relevant. The methylation changes identified in newborns may mediate the association between in utero maternal smoking exposure and later health outcomes.
Citation: Markunas CA, Xu Z, Harlid S, Wade PA, Lie RT, Taylor JA, Wilcox AJ. 2014. Identification of DNA methylation changes in newborns related to maternal smoking during pregnancy. Environ Health Perspect 122:1147–1153; http://dx.doi.org/10.1289/ehp.1307892
doi:10.1289/ehp.1307892
PMCID: PMC4181928  PMID: 24906187
9.  Randomized Clinical Trial of Lansoprazole for Poorly Controlled Asthma in Children 
Context
Asymptomatic gastroesophageal reflux (GER) is prevalent in children with asthma. It is not known whether treatment of GER with a proton-pump inhibitor (PPI) improves asthma control.
Objective
To determine whether lansoprazole is effective in reducing asthma symptoms in children without overt GER.
Design, Setting, and Patients
A multicenter, randomized, masked, placebo controlled, parallel clinical trial comparing lansoprazole to placebo in children with poor asthma control on inhaled corticosteroid treatment conducted at 18 academic clinical centers. Participants were followed for 24 weeks. A subgroup had an esophageal pH study before randomization.
Intervention
Children received either lansoprazole (15 mg daily < 30 kg; 30 mg ≥ 30 kg) or placebo, 1:1 allocation ratio.
Main outcome
The primary outcome was the change in Asthma Control score (ACQ, range from 0 to 6). Secondary outcomes included lung function measures, asthma-related quality of life and acute episodes of poor asthma control.
Results
306 children were enrolled from April 2011 to August 2010, the median age was 11. The mean change (95% confidence interval (CI)) in the ACQ score was −0.1 (−0.2, 0.1) and −0.2 (−0.4, −0.1) units for the lansoprazole and placebo groups, respectively (P=0.12). There were no detectable treatment differences in secondary outcomes (mean (95% CI) for FEV1(0.00 (−0.08, 0.08)), asthma quality of life (−0.1 (−0.4, 0.1) or episodes of poor asthma control, hazard ratio of 1.18 (95% CI 0.91, 1.53). Among the 115 children with esophageal pH studies, the prevalence of GER was 43%. In the subgroup with a positive pH study, no treatment effect for lansoprazole versus placebo was observed for any asthma outcome. Children treated with lansoprazole reported more upper respiratory infections (63% vs 49%, P=0.02), sore throats (52% vs 39%, P=0.02), and bronchitis (7% vs 2%, P=0.05).
Conclusion
Among children with poorly controlled asthma without symptoms of GER who were using inhaled corticosteroids, the addition of lansoprazole, as compared to placebo, did not improve symptoms nor lung function but was associated with increased adverse events.
doi:10.1001/jama.2011.2035
PMCID: PMC4153372  PMID: 22274684
10.  Photocatalytic Conversion of CO2 to CO using Rhenium Bipyridine Platforms Containing Ancillary Phenyl or BODIPY Moieties 
ACS catalysis  2013;3(8):1685-1692.
Harnessing of solar energy to drive the reduction of carbon dioxide to fuels requires the development of efficient catalysts that absorb sunlight. In this work, we detail the synthesis, electrochemistry and photophysical properties of a set of homologous fac-ReI(CO)3 complexes containing either an ancillary phenyl (8) or BODIPY (12) substituent. These studies demonstrate that both the electronic properties of the rhenium center and BODIPY chromophore are maintained for these complexes. Photolysis studies demonstrate that both assemblies 8 and 12 are competent catalysts for the photochemical reduction of CO2 to CO in DMF using triethanolamine (TEOA) as a sacrificial reductant. Both compounds 8 and 12 display TOFs for photocatalytic CO production upon irradiation with light (λex ≥ 400 nm) of ~5 hr−1 with TON values of approximately 20. Although structural and photophysical measurements demonstrate that electronic coupling between the BODIPY and fac-ReI(CO)3 units is limited for complex 12, this work clearly shows that the photoactive BODIPY moiety is tolerated during catalysis and does not interfere with the observed photochemistry. When taken together, these results provide a clear roadmap for the development of advanced rhenium bipyridine complexes bearing ancillary BODIPY groups for the efficient photocatalytic reduction of CO2 using visible light.
doi:10.1021/cs400332y
PMCID: PMC3763851  PMID: 24015374
BODIPY; carbon dioxide; catalysis; electrochemistry; photochemistry; rhenium bipyridine derivatives
11.  Improvement in β-Cell Secretory Capacity After Human Islet Transplantation According to the CIT07 Protocol 
Diabetes  2013;62(8):2890-2897.
The Clinical Islet Transplantation 07 (CIT07) protocol uses antithymocyte globulin and etanercept induction, islet culture, heparinization, and intensive insulin therapy with the same low-dose tacrolimus and sirolimus maintenance immunosuppression as in the Edmonton protocol. To determine whether CIT07 improves engrafted islet β-cell mass, our center measured β-cell secretory capacity from glucose-potentiated arginine tests at days 75 and 365 after transplantation and compared those results with the results previously achieved by our group using the Edmonton protocol and normal subjects. All subjects were insulin free, with CIT07 subjects receiving fewer islet equivalents from a median of one donor compared with two donors for Edmonton protocol subjects. The acute insulin response to glucose-potentiated arginine (AIRpot) was greater in the CIT07 protocol than in the Edmonton protocol and was less in both cohorts than in normal subjects, with similar findings for C-peptide. The CIT07 subjects who completed reassessment at day 365 exhibited increasing AIRpot by trend relative to that of day 75. These data indicate that engrafted islet β-cell mass is markedly improved with the CIT07 protocol, especially given more frequent use of single islet donors. Although several peritransplant differences may have each contributed to this improvement, the lack of deterioration in β-cell secretory capacity over time in the CIT07 protocol suggests that low-dose tacrolimus and sirolimus are not toxic to islets.
doi:10.2337/db12-1802
PMCID: PMC3717864  PMID: 23630300
12.  Whole Exome Sequencing Identifies a Causal RBM20 Mutation in a Large Pedigree with Familial Dilated Cardiomyopathy 
Background
Whole exome sequencing (WES) is a powerful technique for Mendelian disease gene discovery. However, variant prioritization remains a challenge. We applied WES to identify the causal variant in a large family with familial dilated cardiomyopathy (DMC) of unknown etiology.
Methods and Results
A large family with autosomal dominant, familial DCM was identified. Exome capture and sequencing was performed in 3 remotely related, affected subjects predicted to share <0.1% of their genomes by descent. Shared variants were filtered for rarity, evolutionary conservation, and predicted functional significance, and remaining variants were filtered against 71 locally generated exomes. Variants were also prioritized using the Variant Annotation Analysis and Search Tool (VAAST). Final candidates were validated by Sanger sequencing and tested for segregation. There were 664 shared heterozygous nonsense, missense, or splice site variants, of which 26 were rare (minor allele frequency ≤ 0.001 or not reported) in two public databases. Filtering against internal exomes reduced the number of candidates to 2, and of these, a single variant (c.1907 G>A) in RBM20, segregated with disease status and was absent in unaffected internal reference exomes. Bioinformatic prioritization with VAAST supported this result.
Conclusions
WES of remotely related DCM subjects from a large, multiplex family, followed by systematic filtering, identified a causal RBM20 mutation without the need for linkage analysis.
doi:10.1161/CIRCGENETICS.113.000011
PMCID: PMC3895490  PMID: 23861363
genetic heart disease; exome; congestive heart failure
13.  Randomized Controlled Trial of Strain-Specific Probiotic Formulation (Renadyl) in Dialysis Patients 
BioMed Research International  2014;2014:568571.
Background. Primary goal of this randomized, double-blind, placebo-controlled crossover study of Renadyl in end-stage renal disease patients was to assess the safety and efficacy of Renadyl measured through improvement in quality of life or reduction in levels of known uremic toxins. Secondary goal was to investigate the effects on several biomarkers of inflammation and oxidative stress. Methods. Two 2-month treatment periods separated by 2-month washout and crossover, with physical examinations, venous blood testing, and quality of life questionnaires completed at each visit. Data were analyzed with SAS V9.2. Results. 22 subjects (79%) completed the study. Observed trends were as follows (none reaching statistical significance): decline in WBC count (−0.51 × 109/L, P = 0.057) and reductions in levels of C-reactive protein (−8.61 mg/L, P = 0.071) and total indoxyl glucuronide (−0.11 mg%, P = 0.058). No statistically significant changes were observed in other uremic toxin levels or measures of QOL. Conclusions. Renadyl appeared to be safe to administer to ESRD patients on hemodialysis. Stability in QOL assessment is an encouraging result for a patient cohort in such advanced stage of kidney disease. Efficacy could not be confirmed definitively, primarily due to small sample size and low statistical power—further studies are warranted.
doi:10.1155/2014/568571
PMCID: PMC4132402  PMID: 25147806
14.  Barriers to Colorectal Cancer Screening Among Publicly Insured Urban Women: No Knowledge of Tests and No Clinician Recommendation 
Objectives
To assess barriers to colorectal cancer screening among urban publicly insured women and to evaluate how barriers among underscreened urban women have changed between 2001 and 2007-2008.
Methods
Eligible women were selected using Medicaid Managed Care Organization (MMCO) administrative data. MMCO outreach staff interviewed women by phone between October 2007 and February 2008, and assessed their barriers to colorectal cancer screening. We compared the results of these interviews with interviews conducted in 2001 with women in community health center waiting rooms.
Results
Thirty percent of overdue women had never heard of either colonoscopy or sigmoidoscopy, and 55% had never heard of home fecal occult blood testing (FOBT). Among overdue women who had heard of colonoscopy or sigmoidoscopy, 33% reported misconceptions and 28% reported worry as a barrier. No clinician recommendation was the most commonly reported barrier to home FOBT (44%) and was also reported as a barrier to endoscopy by 22% of women. Between 2001 and 2007-2008, the proportion of women reporting that they had not received a clinician's recommendation for endoscopy or home FOBT increased significantly.
Conclusions
A lack of information, no clinician recommendation, misconceptions, and worry persist as barriers to colon cancer screening among this underscreened urban population. An increased focus on clinician recommendation and patient education about stool-based as well as endoscopic screening methods could lead to greater screening compliance.
PMCID: PMC4083754  PMID: 22046852
colorectal cancer; screening; barriers; women's health; urban population
15.  The Alien Limb Phenomenon 
Journal of neurology  2013;260(7):1880-1888.
Background
Alien limb phenomenon refers to involuntary motor activity of a limb in conjunction with the feeling of estrangement from that limb. Alien limb serves as a diagnostic feature of corticobasal syndrome.
Objective
Our objective was to determine the differential diagnoses of alien limb and to determine the features in a large group of patients with the alien limb with different underlying etiologies.
Methods
We searched the Mayo Clinic Medical Records Linkage system to identify patients with the diagnosis of alien limb seen between January 1, 1996, and July 11, 2011.
Results
One hundred fifty patients with alien limb were identified. Twenty two were followed in the Alzheimer’s Disease Research Center. Etiologies of alien limb included corticobasal syndrome (n=108), stroke (n=14), Creutzfeldt Jacob disease (n=9), Hereditary diffuse leukoencephalopathy with spheroids (n=5), tumor (n=4), progressive multifocal leukoencephalopathy(n=2), demyelinating disease (n=2), progressive dementia not otherwise specified (n=2), posterior reversible encephalopathy syndrome (n=1), corpus callosotomy (n=1), intracerebral hemorrhage (n=1) and thalamic dementia (n=1). Ten of fourteen cerebrovascular cases were right hemisphere in origin. All cases involved the parietal lobe. Of the 44 patients with corticobasal syndrome from the Alzheimer’s Disease Research Center cohort, 22 had alien limb, and 73% had the alien limb affecting the left extremities. Left sided corticobasal syndrome was significantly associated with the presence of alien limb (p=0.004).
Conclusions
These findings support the notion that the alien limb phenomenon is partially related to damage underlying the parietal cortex, especially the right parietal, disconnecting it from other cortical areas.
doi:10.1007/s00415-013-6898-y
PMCID: PMC3914666  PMID: 23572346
Alien limb; corticobasal syndrome
16.  Effects of resource variation during early life and adult social environment on contest outcomes in burying beetles: a context-dependent silver spoon strategy? 
Good early nutritional conditions may confer a lasting fitness advantage over individuals suffering poor early conditions (a ‘silver spoon’ effect). Alternatively, if early conditions predict the likely adult environment, adaptive plastic responses might maximize individual performance when developmental and adult conditions match (environmental-matching effect). Here, we test for silver spoon and environmental-matching effects by manipulating the early nutritional environment of Nicrophorus vespilloides burying beetles. We manipulated nutrition during two specific early developmental windows: the larval environment and the post-eclosion environment. We then tested contest success in relation to variation in adult social environmental quality experienced (defined according to whether contest opponents were smaller (good environment) or larger (poor environment) than the focal individual). Variation in the larval environment influenced adult body size but not contest success per se for a given adult social environment experienced (an ‘indirect’ silver spoon effect). Variation in post-eclosion environment affected contest success dependent on the quality of the adult environment experienced (a context-dependent ‘direct’ silver spoon effect). By contrast, there was no evidence for environmental-matching. The results demonstrate the importance of social environmental context in determining how variation in nutrition in early life affects success as an adult.
doi:10.1098/rspb.2013.3102
PMCID: PMC4024278  PMID: 24789890
silver spoon; environmental-matching; social environment; resource holding potential; developmental effects
17.  The triple line pattern on carotid intima media thickness imaging and its relationship to cardiovascular risk factors in patients on lipid lowering therapy 
Background
Carotid intima media thickness (CIMT) infrequently identifies a triple line pattern (TLP) in the visualization of the internal elastic lamina. We examined the prevalence and predictors of the TLP among a consecutive series of subjects enrolled in a CIMT clinical trial, and also the effects of lipid lowering therapy.
Methods
Baseline CIMT studies of subjects with known heart disease, or high risk for heart disease, were evaluated from a single site of the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis trial (N=120). One sonographer obtained four views of the right and left far wall common CIMT, using a 13 MHz ultrasound probe. Images were blindly reviewed for the presence of the TLP. The TLP was defined as absent (0), possible (1), or definite (2). A composite score from all four views was calculated. A patient was defined as having the TLP if the composite score was ≥4. Univariate predictors of the TLP were explored. Follow-up ultrasounds at 14 months were also reviewed for presence of the TLP.
Results
The prevalence of the TLP at baseline was 22.5%. Among cardiovascular risk variables, systolic blood pressure was significantly higher in subjects displaying the TLP (141.3±15.6 mmHg versus 133.1±18.4 mmHg; P=0.036). There were no differences among those with, and without, the TLP, with respect to other cardiovascular risk variables (age, sex, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, C-reactive protein, glucose, weight, waist girth, tobacco use, medications, quantitative CIMT), or image quality. During ongoing lipid lowering therapy, the prevalence of the TLP increased to 54.2% (P<0.001). However, it was unrelated to changes in lipid concentrations or cardiovascular risk variables.
Conclusion
The TLP in CIMT imaging is commonly identifiable using high-frequency ultrasound, and appears to be associated with higher systolic blood pressure. Its prevalence and incidence is unrelated to lipid parameters.
doi:10.2147/VHRM.S47538
PMCID: PMC4074186  PMID: 25018635
risk factors; HTN; atherosclerosis; CIMT
18.  Diffuse anaplastic leptomeningeal oligodendrogliomatosis mimicking neurosarcoidosis 
Neurology: Clinical Practice  2013;3(3):261-265.
Diffuse leptomeningeal oligodendrogliomatosis is a rare, frequently fatal CNS malignancy that most often affects children.1 Although potentially treatable with chemotherapy and radiation, the radiologic findings are nonspecific and pathologic confirmation of the diagnosis is difficult. We describe an adult patient whose initial presentation mimicked neurosarcoidosis. Despite extensive imaging abnormalities, 3 biopsies were required before the diagnosis of diffuse leptomeningeal oligodendrogliomatosis was confirmed.
doi:10.1212/CPJ.0b013e318296f23d
PMCID: PMC3721246  PMID: 23914328
19.  Enhanced Deoxyribozyme-Catalyzed RNA Ligation in the Presence of Organic Cosolvents 
Biopolymers  2013;99(6):10.1002/bip.22191.
Deoxyribozyme and aptamer selections are typically conducted in aqueous buffer solutions. Using nonaqueous cosolvents in selection experiments will help expand the activity of deoxyribozymes with non-oligonucleotide substrates and will allow identification of new aptamers for nonprotein targets. We undertook in vitro selections utilizing a small amount of methanol in the reaction to keep the herbicides alachlor and atrazine in solution with the goal of identifying deoxyribozymes that require these herbicides for activity. The resulting deoxyribozymes successfully catalyze RNA ligation, but do not require alachlor or atrazine. Surprisingly, some of these deoxyribozymes displayed better catalytic activity in the presence of methanol over just aqueous buffer. We investigated several organic cosolvents to see if this enhancement was limited to methanol and found that other cosolvents, including ethanol, DMSO, and DMF, supported activity; in some cases, greater enhancement was observed. On the basis of these results, we tested two other previously identified RNA-ligating deoxyribozymes to assess their tolerance of cosolvents and determined that different deoxyribozymes showed different responses to the cosolvents. Our results demonstrate that deoxyribozymes can tolerate and, in some cases, display enhanced activity in alternative solvent conditions. These findings will facilitate the development of responsive deoxyribozyme systems utilizing components with limited water solubility.
doi:10.1002/bip.22191
PMCID: PMC3848697  PMID: 23529690
deoxyribozyme; DNAzyme; in vitro selection; RNA ligation
20.  Contrasting Strategies of Photosynthetic Energy Utilization Drive Lifestyle Strategies in Ecologically Important Picoeukaryotes 
Metabolites  2014;4(2):260-280.
The efficiency with which absorbed light is converted to net growth is a key property for estimating global carbon production. We previously showed that, despite considerable evolutionary distance, Dunaliella tertiolecta (Chlorophyceae) and Thalassiosira weissflogii (Bacillariophyceae) share a common strategy of photosynthetic energy utilization and nearly identical light energy conversion efficiencies. These findings suggested that a single model might be appropriate for describing relationships between measures of phytoplankton production. This conclusion was further evaluated for Ostreococcus tauri RCC1558 and Micromonas pusilla RCC299 (Chlorophyta, Prasinophyceae), two picoeukaryotes with contrasting geographic distributions and swimming abilities. Nutrient-dependent photosynthetic efficiencies in O. tauri were similar to the previously studied larger algae. Specifically, absorption-normalized gross oxygen and carbon production and net carbon production were independent of nutrient limited growth rate. In contrast, all measures of photosynthetic efficiency were strongly dependent on nutrient availability in M. pusilla. This marked difference was accompanied by a diminished relationship between Chla:C and nutrient limited growth rate and a remarkably greater efficiency of gross-to-net energy conversion than the other organisms studied. These results suggest that the cost-benefit of decoupling pigment concentration from nutrient availability enables motile organisms to rapidly exploit more frequent encounters with micro-scale nutrient patches in open ocean environments.
doi:10.3390/metabo4020260
PMCID: PMC4101506  PMID: 24957026
phytoplankton; metabolism; motility; Micromonas pusilla; Ostreococcus tauri; photosynthesis; energy utilization; carbon allocation; partitioning; primary production
21.  Quantitative genetic versions of Hamilton's rule with empirical applications 
Hamilton's theory of inclusive fitness revolutionized our understanding of the evolution of social interactions. Surprisingly, an incorporation of Hamilton's perspective into the quantitative genetic theory of phenotypic evolution has been slow, despite the popularity of quantitative genetics in evolutionary studies. Here, we discuss several versions of Hamilton's rule for social evolution from a quantitative genetic perspective, emphasizing its utility in empirical applications. Although evolutionary quantitative genetics offers methods to measure each of the critical parameters of Hamilton's rule, empirical work has lagged behind theory. In particular, we lack studies of selection on altruistic traits in the wild. Fitness costs and benefits of altruism can be estimated using a simple extension of phenotypic selection analysis that incorporates the traits of social interactants. We also discuss the importance of considering the genetic influence of the social environment, or indirect genetic effects (IGEs), in the context of Hamilton's rule. Research in social evolution has generated an extensive body of empirical work focusing—with good reason—almost solely on relatedness. We argue that quantifying the roles of social and non-social components of selection and IGEs, in addition to relatedness, is now timely and should provide unique additional insights into social evolution.
doi:10.1098/rstb.2013.0358
PMCID: PMC3982660  PMID: 24686930
inclusive fitness theory; indirect genetic effects; kin selection; quantitative genetics; relatedness; social selection
22.  Elements of the B Cell Signalosome Are Differentially Affected by Mercury Intoxication 
Autoimmune Diseases  2014;2014:239358.
It has been suggested that environmental exposures to mercury contribute to autoimmune disease. Disruption of BCR signaling is associated with failure of central tolerance and autoimmunity, and we have previously shown that low levels of Hg2+ interfere with BCR signaling. In this report we have employed multiparametric phosphoflow cytometry, as well as a novel generalization of the Overton algorithm from one- to two-dimensional unimodal distributions to simultaneously monitor the effect of low level Hg2+ intoxication on activation of ERK and several upstream elements of the BCR signaling pathway in WEHI-231 B cells. We have found that, after exposure to low levels of Hg2+, only about a third of the cells are sensitive to the metal. For those cells which are sensitive, we confirm our earlier work that activation of ERK is attenuated but now report that Hg2+ has little upstream effect on the Btk tyrosine kinase. On the other hand, we find that signaling upstream through the Syk tyrosine kinase is actually augmented, as is upstream activation of the B cell signalosome scaffolding protein BLNK.
doi:10.1155/2014/239358
PMCID: PMC4024408  PMID: 24876949
23.  ALOX5 Polymorphism Associates with Increased Leukotriene Production and Reduced Lung Function and Asthma Control in Children with Poorly Controlled Asthma 
Background
Identification of risk factors for reduced asthma control could improve the understanding and treatment of asthma. A promoter polymorphism in the 5-lipoxygenase gene affects gene expression and response to asthma therapy but its impact on disease control remains unclear.
Objective
We sought to determine if the ALOX5 promoter SP1 tandem repeat polymorphism was associated with changes in cysteinyl leukotriene production, lung function, airway inflammation and asthma control score.
Methods
We analyzed 270 children 6-17 years old with poorly controlled asthma enrolled in a 6-month clinical trial (NCT00604851). In secondary analysis, we associated the ALOX5 promoter SP1 tandem repeat polymorphism genotype (rs59439148) with asthma outcomes using both additive and recessive genetic models. We evaluated FEV1 percent predicted, symptom control, exhaled nitric oxide and urinary LTE4 levels.
Results
14.8% (40/270) of all children (and 28% (38/135) of African Americans) carried 2 non-5 repeat variant alleles of rs59439148. Children who were homozygous for variant alleles had significantly higher urinary LTE4 levels (38 versus 30 nmol/mol creatinine, p=.0134), significantly worse FEV1% predicted (84 versus 91, p=.017), and a trend toward worse asthma control. FEV1% predicted values were significantly negatively correlated with urinary LTE4 (r = -0.192, p=.009).
Conclusion and Clinical Relevance
Carrying two copies of a minor variant ALOX5 promoter SP1 tandem repeat allele contributes to increased cysLT exposure as determined by urinary LTE4 levels, reduced lung function, and potentially worse asthma control. ALOX5 promoter SP1 tandem repeat genotype may be a risk factor for worse asthma outcomes.
doi:10.1111/cea.12076
PMCID: PMC3633142  PMID: 23600541
Asthma; Children; ALOX5; 5-Lipoxygenase; Leukotriene; Asthma Control; FEV1; Exhaled Nitric Oxide; Genetic Association
24.  Physical activity during pregnancy and language development in the offspring 
Background
In rodents, physical activity during pregnancy has been associated with improved learning and memory in the offspring. We used data from the Avon Longitudinal Study of Parents and Children (born 1991-1992) to investigate maternal physical activity during pregnancy and offspring language development.
Methods
At 18 weeks of gestation, women reported the hours per week they participated in eleven leisure-time physical activities and the hours per week spent in general physical activity (leisure, household, occupational, etc.). Caregivers completed a modified MacArthur Infant Communication scale at 15 months. Verbal IQ was measured at age 8 years. Regression analysis was used to examine the associations of physical activity with MacArthur score (>75th percentile) and verbal IQ. The number of participants available for analyses ranged from 4517 to 7162.
Results
Children of women in the two highest quintiles of leisure activity (compared with no leisure activity) were more likely to have high 15-month MacArthur scores (Adjusted odds ratio (95% Confidence Interval): 1.2 [0.9, 1.4] and 1.4 [1.1, 1.7], respectively). Leisure activity was not associated with IQ; while general physical activity was linked with lower verbal IQ (1 and 3 points lower for the two highest quintiles).
Conclusions
The most robust finding was a transient increase in offspring vocabulary score at young ages with maternal leisure activity. Differences in the associations with leisure-time physical activity compared with general physical activity need further exploration.
doi:10.1111/ppe.12046
PMCID: PMC3646544  PMID: 23574417
exercise; cognition; child development; physical activity
25.  Synthesis, Electrochemistry and Photophysics of a Family of Phlorin Macrocycles that Display Cooperative Fluoride Binding 
A homologous set of 5,5-dimethylphlorin macrocycles in which the identity of one aryl ring is systematically varied has been prepared. These derivatives contain ancillary pentaflurophenyl (3H(PhlF)), mesityl (3H(PhlMes)), 2,6-bismethoxyphenyl (3H(PhlOMe)), 4-nitrophenyl (3H(PhlNO2)) or 4-tert-butylcarboxyphenyl (3H(PhlCO2tBu)) groups at the 15-meso-position. These porphyrinoids were prepared in good yields (35 – 50%) and display unusual multielectron redox and photochemical properties. Each phlorin can be oxidized up to three times at modest potentials and can be reduced twice. The electron-donating and releasing properties of the ancillary aryl substituent attenuate the potentials of these redox events; phlorins containing electron-donating aryl groups are easier to oxidize and harder to reduce, while the opposite trend is observed for phlorins containing electron-withdrawing functionalities. Phlorin substitution also has a pronounced effect on the observed photophysics, as introduction of electron-releasing aryl groups on the periphery of the macrocycle is manifest in larger emission quantum yields and longer fluorescence lifetimes. Each phlorin displays an intriguing supramolecular chemistry and can bind 2 equivalents of fluoride. This binding is allosteric in nature and the strength of halide binding correlates with the ability of the phlorin to stabilize the buildup of charge. Moreover, fluoride binding to generate complexes of the form 3H(PhlR)·2F− modulates the redox potentials of the parent phlorin. As such, titration of phlorin with a source of fluoride represents a facile method to tune the ability of this class of porphyrinoid to absorb light and engage in redox chemistry.
doi:10.1021/ja401391z
PMCID: PMC3671758  PMID: 23594346

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