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1.  Glycan-Receptor Binding of the Influenza A Virus H7N9 Hemagglutinin 
Cell  2013;153(7):1486-1493.
The advent of H7N9, in early 2013, is of concern for a number of reasons, including its capability to infect humans, the etiology of infection is unclear, and that, broadly the human population does not have pre-existing immunity to the H7 subtype. Earlier sequence analyses of H7N9 hemagglutinin (HA) point to amino acid changes that predicted human receptor binding and impinge on the antigenic characteristics of the HA. Herein we report that the H7N9 HA shows limited binding to human receptors; however, should a single amino acid mutation occur, this would result in structural changes within the receptor binding site that allow for extensive binding to human receptors present in upper respiratory tract. Furthermore, a subset of the H7N9 HA sequences demarcating coevolving amino acids appear to be in the antigenic regions of H7, which in turn could impact effectiveness of the current WHO recommended pre-pandemic H7 vaccines.
PMCID: PMC3746546  PMID: 23746830
2.  A role for IL-25 and IL-33–driven type-2 innate lymphoid cells in atopic dermatitis 
The Journal of Experimental Medicine  2013;210(13):2939-2950.
Type 2 innate lymphoid cells promote skin inflammation in mice and men, in part by producing IL-5 and IL-13 in response to IL-33
Type 2 innate lymphoid cells (ILC2s, nuocytes, NHC) require RORA and GATA3 for their development. We show that human ILC2s express skin homing receptors and infiltrate the skin after allergen challenge, where they produce the type 2 cytokines IL-5 and IL-13. Skin-derived ILC2s express the IL-33 receptor ST2, which is up-regulated during activation, and are enriched in lesional skin biopsies from atopic patients. Signaling via IL-33 induces type 2 cytokine and amphiregulin expression, and increases ILC2 migration. Furthermore, we demonstrate that E-cadherin ligation on human ILC2 dramatically inhibits IL-5 and IL-13 production. Interestingly, down-regulation of E-cadherin is characteristic of filaggrin insufficiency, a cardinal feature of atopic dermatitis (AD). ILC2 may contribute to increases in type 2 cytokine production in the absence of the suppressive E-cadherin ligation through this novel mechanism of barrier sensing. Using Rag1−/− and RORα-deficient mice, we confirm that ILC2s are present in mouse skin and promote AD-like inflammation. IL-25 and IL-33 are the predominant ILC2-inducing cytokines in this model. The presence of ILC2s in skin, and their production of type 2 cytokines in response to IL-33, identifies a role for ILC2s in the pathogenesis of cutaneous atopic disease.
PMCID: PMC3865470  PMID: 24323357
3.  To have or not to have another child: life cycle, health and cost considerations of Ghanaian women 
Social science & medicine (1982)  2012;74(7):966-972.
Given that fertility rates are high in most sub-Saharan countries, it is critically important to understand the drivers of the demand for children to inform population reduction policies. Yet little is known about the individual-level factors that drive the desire for fertility limitation. The desire to limit births may be driven by the achievement of family size targets. However, since children are born at different stages of the life course, fertility desires may also be influenced by past reproductive, socio-economic experiences, and perceptions about future welfare. In this study, the determinants of the desire to stop childbearing were analyzed at the individual-level using prospective longitudinal data (1998–2003) on the reproductive lives of women in six communities in southern Ghana. Using variation within-woman, we modeled the impact of changes in reproductive life cycle events, health status, perceptions of future household economic conditions, perceptions of the cost of additional children, and spousal interactions on a woman’s fertility preferences. We found that the desire to stop childbearing is influenced by reproductive life stage (such as age, parity); events (marital transitions, child death); perceptions of personal health (particularly anticipated demands of the next pregnancy on the woman’s health); the household’s economic welfare; and the overall subjective cost of children. The economic utility models which emphasize cost/benefit considerations, as well as the anthropological and sociological theories which emphasize norms, appear to be validated in this empirical analysis in that both subjective elements and normative considerations are incorporated into fertility decisions.
PMCID: PMC4052954  PMID: 22361092
Fertility Preferences; fertility limitation; sub-Saharan Africa; Ghana; longitudinal; childbearing desires; economic; health
4.  Plasma Septin9 versus Fecal Immunochemical Testing for Colorectal Cancer Screening: A Prospective Multicenter Study 
PLoS ONE  2014;9(6):e98238.
Screening improves outcomes related to colorectal cancer (CRC); however, suboptimal participation for available screening tests limits the full benefits of screening. Non-invasive screening using a blood based assay may potentially help reach the unscreened population.
To compare the performance of a new Septin9 DNA methylation based blood test with a fecal immunochemical test (FIT) for CRC screening.
Design: In this trial, fecal and blood samples were obtained from enrolled patients. To compare test sensitivity for CRC, patients with screening identified colorectal cancer (n = 102) were enrolled and provided samples prior to surgery. To compare test specificity patients were enrolled prospectively (n = 199) and provided samples prior to bowel preparation for screening colonoscopy.
Plasma and fecal samples were analyzed using the Epi proColon and OC Fit-Check tests respectively.
For all samples, sensitivity for CRC detection was 73.3% (95% CI 63.9–80.9%) and 68.0% (95% CI 58.2–76.5%) for Septin9 and FIT, respectively. Specificity of the Epi proColon test was 81.5% (95% CI 75.5–86.3%) compared with 97.4% (95% CI 94.1–98.9%) for FIT. For paired samples, the sensitivity of the Epi proColon test (72.2% –95% CI 62.5–80.1%) was shown to be statistically non-inferior to FIT (68.0%–95% CI 58.2–76.5%). When test results for Epi proColon and FIT were combined, CRC detection was 88.7% at a specificity of 78.8%.
At a sensitivity of 72%, the Epi proColon test is non- inferior to FIT for CRC detection, although at a lower specificity. With negative predictive values of 99.8%, both methods are identical in confirming the absence of CRC.
Trial Registration NCT01580540
PMCID: PMC4046970  PMID: 24901436
5.  Prenatal Maternal and Possible Transgenerational Epigenetic Effects on Milk Production 
PLoS ONE  2014;9(6):e98928.
This study investigated whether the prenatal maternal environment in dairy cattle influences the postnatal milking performance of the resulting daughters and grand-daughters. Linear mixed models were used to analyse whole season milk production from ∼46000 Jersey and ∼123000 Holstein Friesian cows in their 1st and 2nd lactations. Variation in the prenatal environment was associated with a small but significant (P<0.05) proportion of the total phenotypic variation (0.010 to 0.015) in all traits in Holstein Friesian cows and in the first lactation milk volume (0.011) and milk protein (0.011), and the second lactation milk fat (0.015) in the Jersey breed. This indicates that the prenatal environment does influence the adult performance of the subsequent daughter. Associations between daughter performance and dam and grand-dam traits indicative of their prenatal environment were also estimated. A one litre increase in the dam’s herd test milk volume was associated with a 7.5 litre increase in the daughters’ whole season milk yield and a 1% increase in either the dams’ herd test milk fat or protein percentage was associated with a reduction in daughter whole season milk volume (−49.6 and −45.0 litres for dam fat and protein, respectively). Similar results between the grand-dam herd test traits ansd the daughters’ whole season milk production were observed with a 1% increase in either grand-dam milk fat or protein percentage associated with a reduction in daughter whole season milk yield (−34.7 and −9.7 litres for fat and protein, respectively). This study revealed that the prenatal environment of the dam and the grand-dam can influence milk production in the subsequent daughters, though the effects are small. The similarity of the results between the dam daughter and the grand-dam daughter analyses suggests that the majority of the prenatal maternal effects are mediated by epigenetic mechanisms.
PMCID: PMC4047075  PMID: 24901792
6.  Connecting lignin-degradation pathway with pre-treatment inhibitor sensitivity of Cupriavidus necator 
To produce lignocellulosic biofuels economically, the complete release of monomers from the plant cell wall components, cellulose, hemicellulose, and lignin, through pre-treatment and hydrolysis (both enzymatic and chemical), and the efficient utilization of these monomers as carbon sources, is crucial. In addition, the identification and development of robust microbial biofuel production strains that can tolerate the toxic compounds generated during pre-treatment and hydrolysis is also essential. In this work, Cupriavidus necator was selected due to its capabilities for utilizing lignin monomers and producing polyhydroxylbutyrate (PHB), a bioplastic as well as an advanced biofuel intermediate. We characterized the growth kinetics of C. necator in pre-treated corn stover slurry as well as individually in the pre-sence of 11 potentially toxic compounds in the saccharified slurry. We found that C. necator was sensitive to the saccharified slurry produced from dilute acid pre-treated corn stover. Five out of 11 compounds within the slurry were characterized as toxic to C. necator, namely ammonium acetate, furfural, hydroxymethylfurfural (HMF), benzoic acid, and p-coumaric acid. Aldehydes (e.g., furfural and HMF) were more toxic than the acetate and the lignin degradation products benzoic acid and p-coumaric acid; furfural was identified as the most toxic compound. Although toxic to C. necator at high concentration, ammonium acetate, benzoic acid, and p-coumaric acid could be utilized by C. necator with a stimulating effect on C. necator growth. Consequently, the lignin degradation pathway of C. necator was reconstructed based on genomic information and literature. The efficient conversion of intermediate catechol to downstream products of cis,cis-muconate or 2-hydroxymuconate-6-semialdehyde may help improve the robustness of C. necator to benzoic acid and p-coumaric acid as well as improve PHB productivity.
PMCID: PMC4034039  PMID: 24904560
Cupriavidus necator; pre-treatment inhibitor; saccharified slurry; deacetylation; lignin degradation; biofuel; polyhydroxylbutyrate (PHB); genomics
7.  Human Cytomegalovirus Fcγ Binding Proteins gp34 and gp68 Antagonize Fcγ Receptors I, II and III 
PLoS Pathogens  2014;10(5):e1004131.
Human cytomegalovirus (HCMV) establishes lifelong infection with recurrent episodes of virus production and shedding despite the presence of adaptive immunological memory responses including HCMV immune immunoglobulin G (IgG). Very little is known how HCMV evades from humoral and cellular IgG-dependent immune responses, the latter being executed by cells expressing surface receptors for the Fc domain of IgG (FcγRs). Remarkably, HCMV expresses the RL11-encoded gp34 and UL119-118-encoded gp68 type I transmembrane glycoproteins which bind Fcγ with nanomolar affinity. Using a newly developed FcγR activation assay, we tested if the HCMV-encoded Fcγ binding proteins (HCMV FcγRs) interfere with individual host FcγRs. In absence of gp34 or/and gp68, HCMV elicited a much stronger activation of FcγRIIIA/CD16, FcγRIIA/CD32A and FcγRI/CD64 by polyclonal HCMV-immune IgG as compared to wildtype HCMV. gp34 and gp68 co-expression culminates in the late phase of HCMV replication coinciding with the emergence of surface HCMV antigens triggering FcγRIII/CD16 responses by polyclonal HCMV-immune IgG. The gp34- and gp68-dependent inhibition of HCMV immune IgG was fully reproduced when testing the activation of primary human NK cells. Their broad antagonistic function towards FcγRIIIA, FcγRIIA and FcγRI activation was also recapitulated in a gain-of-function approach based on humanized monoclonal antibodies (trastuzumab, rituximab) and isotypes of different IgG subclasses. Surface immune-precipitation showed that both HCMV-encoded Fcγ binding proteins have the capacity to bind trastuzumab antibody-HER2 antigen complexes demonstrating simultaneous linkage of immune IgG with antigen and the HCMV inhibitors on the plasma membrane. Our studies reveal a novel strategy by which viral FcγRs can compete for immune complexes against various Fc receptors on immune cells, dampening their activation and antiviral immunity.
Author Summary
Herpes viruses persist lifelong continuously alternating between latency and virus production and transmission. The latter events occur despite the presence of immune IgG antibodies. IgG acts by neutralization of virions and activation of immune cells bearing one or more surface receptors, called FcγRs, recognizing the constant Fc domain of IgG. Activating FcγRs induce a wide range of immune responses, including antibody dependent cellular cytotoxicity (ADCC) of virus-infected cells by natural killer (NK) cells, cytokine secretion and the uptake of immune complexes to enhance antigen presentation to T cells. We demonstrate that the HCMV glycoproteins RL11/gp34 and UL119-118/gp68 block IgG-mediated activation of FcγRs. A novel reporter cell-based assay was used to test FcγRs individually and assess their relative susceptibility to each antagonist. This approach revealed that gp34 and gp68 block triggering of activating FcγRs, i.e. FcγRI (CD64), FcγRII (CD32A) and FcγRIII (CD16). Co-immunoprecipitation showed the formation of ternary complexes containing IgG, IgG-bound antigen and the viral antagonists on the cell surface. Assigning the redundant abilities of HCMV to hinder IgG effector responses to the viral Fc binding proteins, we discuss gp34 and gp68 as potential culprits which might contribute to the limited efficacy of therapeutic IgG against HCMV.
PMCID: PMC4022731  PMID: 24830376
8.  Impact of emergency department probiotic treatment of pediatric gastroenteritis: study protocol for the PROGUT (Probiotic Regimen for Outpatient Gastroenteritis Utility of Treatment) randomized controlled trial 
Trials  2014;15:170.
The burden of acute gastroenteritis on children and their families continues to be enormous. Probiotics, defined as viable microbial preparations that have a beneficial effect on the health of the host, represent a rapidly expanding field. Although clinical trials in children with gastroenteritis have been performed, most have significant flaws, and guidelines do not consistently endorse their use.
PROGUT is a randomized, placebo-controlled, double-blind, five-center, Canadian, emergency department trial. Children aged 3 months to 48 months who present between November 2013 and June 2017 with <72 hours of gastroenteritis symptoms will be assessed for eligibility. A total of 886 children will be randomized (1:1 allocation via an internet based, third party, randomization service) to receive 5 days of a combination probiotic agent (Lactobacillus rhamnosus and L. helveticus) or placebo. All participants, caregivers, and outcome assessors will be blinded to group assignment. The study includes three key outcomes: 1) clinical - the development of moderate to severe disease following an emergency department (ED) evaluation that employs a validated clinical score (Modified Vesikari Scale); 2) safety - side effect; and 3) mechanism - fecal secretory immunoglobulin A levels.
Definitive data are lacking to guide the clinical use of probiotics in children with acute gastroenteritis. Hence, probiotics are rarely prescribed by North American physicians. However, the following current trends obligate an urgent assessment: 1) probiotics are sold as food supplements, and manufacturers can encourage their use while their relevance has yet to be established; 2) North American and European government agencies remain concerned about their value and safety; 3) some institutions are now recommending the routine use of probiotics; and 4) parents of affected children are often providing probiotics. With probiotic consumption increasing in the absence of solid evidence, there is a need to conduct this definitive trial to overcome the limitations of prior work in this field.
Trial registration NCT01853124; first registered 9 May 2013.
PMCID: PMC4037747  PMID: 24885220
Probiotics; Emergencies; Pediatrics; Gastroenteritis; Randomized controlled trial; Adverse effects; Immunoglobulin A
9.  Clinical Causes of Inflammation in Peritoneal Dialysis Patients 
Inflammation at both systemic and local intraperitoneal levels commonly affects peritoneal dialysis (PD) patients. Interest in inflammatory markers as targets of therapeutic intervention has been considerable as they are recognised as predictors of poor clinical outcomes. However, prior to embarking on strategies to reduce inflammatory burden, it is of paramount importance to define the underlying processes that drive the chronic active inflammatory status. The present review aims to comprehensively describe clinical causes of inflammation in PD patients to which potential future strategies may be targeted.
PMCID: PMC4033334  PMID: 24895536
10.  Exemestane Versus Anastrozole in Postmenopausal Women With Early Breast Cancer: NCIC CTG MA.27—A Randomized Controlled Phase III Trial 
Journal of Clinical Oncology  2013;31(11):1398-1404.
In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non–cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss.
Patients and Methods
We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease–free survival, incidence of contralateral new primary breast cancer, and safety.
In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease–free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms.
This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor–positive breast cancer.
PMCID: PMC3612593  PMID: 23358971
11.  Effect of mechanical disruption on the effectiveness of three reactors used for dilute acid pretreatment of corn stover Part 1: chemical and physical substrate analysis 
There is considerable interest in the conversion of lignocellulosic biomass to liquid fuels to provide substitutes for fossil fuels. Pretreatments, conducted to reduce biomass recalcitrance, usually remove at least some of the hemicellulose and/or lignin in cell walls. The hypothesis that led to this research was that reactor type could have a profound effect on the properties of pretreated materials and impact subsequent cellulose hydrolysis.
Corn stover was dilute-acid pretreated using commercially relevant reactor types (ZipperClave® (ZC), Steam Gun (SG) and Horizontal Screw (HS)) under the same nominal conditions. Samples produced in the SG and HS achieved much higher cellulose digestibilities (88% and 95%, respectively), compared to the ZC sample (68%). Characterization, by chemical, physical, spectroscopic and electron microscopy methods, was used to gain an understanding of the effects causing the digestibility differences. Chemical differences were small; however, particle size differences appeared significant. Sum-frequency generation vibrational spectra indicated larger inter-fibrillar spacing or randomization of cellulose microfibrils in the HS sample. Simons’ staining indicated increased cellulose accessibility for the SG and HS samples. Electron microscopy showed that the SG and HS samples were more porous and fibrillated because of mechanical grinding and explosive depressurization occurring with these two reactors. These structural changes most likely permitted increased cellulose accessibility to enzymes, enhancing saccharification.
Dilute-acid pretreatment of corn stover using three different reactors under the same nominal conditions gave samples with very different digestibilities, although chemical differences in the pretreated substrates were small. The results of the physical and chemical analyses of the samples indicate that the explosive depressurization and mechanical grinding with these reactors increased enzyme accessibility. Pretreatment reactors using physical force to disrupt cell walls increase the effectiveness of the pretreatment process.
PMCID: PMC3999883  PMID: 24713111
Reactor; dilute acid pretreatment; biomass; cellulose properties; substrate accessibility; digestibility
12.  Integrating Water Flow, Locomotor Performance and Respiration of Chinese Sturgeon during Multiple Fatigue-Recovery Cycles 
PLoS ONE  2014;9(4):e94345.
The objective of this study is to provide information on metabolic changes occurring in Chinese sturgeon (an ecologically important endangered fish) subjected to repeated cycles of fatigue and recovery and the effect on swimming capability. Fatigue-recovery cycles likely occur when fish are moving through the fishways of large dams and the results of this investigation are important for fishway design and conservation of wild Chinese sturgeon populations. A series of four stepped velocity tests were carried out successively in a Steffensen-type swimming respirometer and the effects of repeated fatigue-recovery on swimming capability and metabolism were measured. Significant results include: (1) critical swimming speed decreased from 4.34 bl/s to 2.98 bl/s; (2) active oxygen consumption (i.e. the difference between total oxygen consumption and routine oxygen consumption) decreased from 1175 mgO2/kg to 341 mgO2/kg and was the primary reason for the decrease in Ucrit; (3) excess post-exercise oxygen consumption decreased from 36 mgO2/kg to 22 mgO2/kg; (4) with repeated step tests, white muscle (anaerobic metabolism) began contributing to propulsion at lower swimming speeds. Therefore, Chinese sturgeon conserve energy by swimming efficiently and have high fatigue recovery capability. These results contribute to our understanding of the physiology of the Chinese sturgeon and support the conservation efforts of wild populations of this important species.
PMCID: PMC3979774  PMID: 24714585
13.  A randomized trial of sodium-restriction on kidney function, fluid volume and adipokines in CKD patients 
BMC Nephrology  2014;15:57.
Dietary sodium restriction is a key management strategy in chronic kidney disease (CKD). Recent evidence has demonstrated short-term reduction in blood pressure (BP) and proteinuria with sodium restriction, however the effect on other cardiovascular-related risk factors requires investigation in CKD.
The LowSALT CKD study involved 20 hypertensive Stage III-IV CKD patients counselled by a dietitian to consume a low-sodium diet (<100 mmol/day). The study was a randomised crossover trial comparing 2 weeks of high-sodium (additional 120 mmol sodium tablets) and low-sodium intake (placebo). Measurements were taken after each crossover arm including BP (peripheral and central), adipokines (inflammation markers and adiponectin), volume markers (extracellular-to-intracellular [E/I] fluid ratio; N-terminal pro-brain natriuretic peptide [NT-proBNP]), kidney function (estimated Glomerular Filtration Rate [eGFR]) and proteinuria (urine protein-creatinine ratio [PCR] and albumin-creatinine ratio [ACR]). Outcomes were compared using paired t-test for each cross-over arm.
BP-lowering benefits of a low-sodium intake (peripheral BP (mean ± SD) 148/82 ± 21/12 mmHg) from high-sodium (159/87 ± 15/10 mmHg) intake were reflected in central BP and a reduction in eGFR, PCR, ACR, NTproBNP and E/I ratio. There was no change in inflammatory markers, total or high molecular weight adiponectin.
Short-term benefits of sodium restriction on BP were reflected in significant change in kidney function and fluid volume parameters. Larger, long-term adequately powered trials in CKD are necessary to confirm these results.
Trial registration
Universal Trial Number U1111-1125-2149 registered on 13/10/2011; Australian New Zealand Clinical Trials Registry Number ACTRN12611001097932 registered on 21/10/2011.
PMCID: PMC3994521  PMID: 24708818
Dietary sodium; Nutrition; Chronic kidney disease; Cardiovascular disease; Blood pressure; Kidney function; Inflammation
14.  The Caenorhabditis elegans Myc-Mondo/Mad Complexes Integrate Diverse Longevity Signals 
PLoS Genetics  2014;10(4):e1004278.
The Myc family of transcription factors regulates a variety of biological processes, including the cell cycle, growth, proliferation, metabolism, and apoptosis. In Caenorhabditis elegans, the “Myc interaction network” consists of two opposing heterodimeric complexes with antagonistic functions in transcriptional control: the Myc-Mondo:Mlx transcriptional activation complex and the Mad:Max transcriptional repression complex. In C. elegans, Mondo, Mlx, Mad, and Max are encoded by mml-1, mxl-2, mdl-1, and mxl-1, respectively. Here we show a similar antagonistic role for the C. elegans Myc-Mondo and Mad complexes in longevity control. Loss of mml-1 or mxl-2 shortens C. elegans lifespan. In contrast, loss of mdl-1 or mxl-1 increases longevity, dependent upon MML-1:MXL-2. The MML-1:MXL-2 and MDL-1:MXL-1 complexes function in both the insulin signaling and dietary restriction pathways. Furthermore, decreased insulin-like/IGF-1 signaling (ILS) or conditions of dietary restriction increase the accumulation of MML-1, consistent with the notion that the Myc family members function as sensors of metabolic status. Additionally, we find that Myc family members are regulated by distinct mechanisms, which would allow for integrated control of gene expression from diverse signals of metabolic status. We compared putative target genes based on ChIP-sequencing data in the modENCODE project and found significant overlap in genomic DNA binding between the major effectors of ILS (DAF-16/FoxO), DR (PHA-4/FoxA), and Myc family (MDL-1/Mad/Mxd) at common target genes, which suggests that diverse signals of metabolic status converge on overlapping transcriptional programs that influence aging. Consistent with this, there is over-enrichment at these common targets for genes that function in lifespan, stress response, and carbohydrate metabolism. Additionally, we find that Myc family members are also involved in stress response and the maintenance of protein homeostasis. Collectively, these findings indicate that Myc family members integrate diverse signals of metabolic status, to coordinate overlapping metabolic and cytoprotective transcriptional programs that determine the progression of aging.
Author Summary
Transcription factors are essential proteins that regulate the expression of genes and play an important role in most biological processes. The results of our study presented here demonstrate for the first time a role in aging for a small family of transcription factors in the nematode worm Caenorhabditis elegans. Importantly, these proteins have close relatives in higher organisms, including humans that influence metabolism, cell replication, and have been implicated in the development of cancer. Moreover, the loss of one homologue has also been implicated in Williams-Beuren syndrome, a disease characterized in part by signs of premature aging. Our data demonstrate that these transcription factors function within insulin/IGF-1 signaling and dietary restriction, two highly conserved pathways that link nutrient sensing to longevity. Taken together, our findings provide exciting new insight into a family of proteins that may be essential for linking nutrient sensing to longevity and have implications for the improvement of human healthspan.
PMCID: PMC3974684  PMID: 24699255
15.  Intraobserver reliability of contact pachymetry in children 
Central corneal thickness (CCT) is an important measurement in the treatment and management of pediatric glaucoma and potentially of refractive error, but data regarding reliability of CCT measurement in children are limited. The purpose of this study was to evaluate the reliability of CCT measurement using handheld contact pachymetry in children.
We conducted a multicenter intraobserver test–retest reliability study of more than 3,400 healthy eyes in children aged from birth to 17 years using a handheld contact pachymeter (Pachmate DGH55) in two clinical settings—with topical anesthesia in the office and under general anesthesia in a surgical facility.
The overall standard error of measurement, including only measurements with standard deviation ≤5 μm, was 8 μm; the corresponding coefficient of repeatability, or limits within which 95% of test–retest differences fell, was ±22.3 μm. However, standard error of measurement increased as CCT increased, from 6.8 μm for CCT less than 525 μm, to 12.9 μm for CCT 625 μm and higher. The standard error of measurement including measurements with standard deviation >5 μm was 10.5 μm. Age, sex, race/ethnicity group, and examination setting did not influence the magnitude of test–retest differences.
CCT measurement reliability in children using the Pachmate DGH55 handheld contact pachymeter is similar to that reported for adults. Because thicker CCT measurements are less reliable than thinner measurements, a second measure may be helpful when the first exceeds 575 μm. Reliability is also improved by disregarding measurements with instrument-reported standard deviations >5 μm.
PMCID: PMC3639436  PMID: 23622447
16.  Effect of mechanical disruption on the effectiveness of three reactors used for dilute acid pretreatment of corn stover Part 2: morphological and structural substrate analysis 
Lignocellulosic biomass is a renewable, naturally mass-produced form of stored solar energy. Thermochemical pretreatment processes have been developed to address the challenge of biomass recalcitrance, however the optimization, cost reduction, and scalability of these processes remain as obstacles to the adoption of biofuel production processes at the industrial scale. In this study, we demonstrate that the type of reactor in which pretreatment is carried out can profoundly alter the micro- and nanostructure of the pretreated materials and dramatically affect the subsequent efficiency, and thus cost, of enzymatic conversion of cellulose.
Multi-scale microscopy and quantitative image analysis was used to investigate the impact of different biomass pretreatment reactor configurations on plant cell wall structure. We identify correlations between enzymatic digestibility and geometric descriptors derived from the image data. Corn stover feedstock was pretreated under the same nominal conditions for dilute acid pretreatment (2.0 wt% H2SO4, 160°C, 5 min) using three representative types of reactors: ZipperClave® (ZC), steam gun (SG), and horizontal screw (HS) reactors. After 96 h of enzymatic digestion, biomass treated in the SG and HS reactors achieved much higher cellulose conversions, 88% and 95%, respectively, compared to the conversion obtained using the ZC reactor (68%). Imaging at the micro- and nanoscales revealed that the superior performance of the SG and HS reactors could be explained by reduced particle size, cellular dislocation, increased surface roughness, delamination, and nanofibrillation generated within the biomass particles during pretreatment.
Increased cellular dislocation, surface roughness, delamination, and nanofibrillation revealed by direct observation of the micro- and nanoscale change in accessibility explains the superior performance of reactors that augment pretreatment with physical energy.
PMCID: PMC4022059  PMID: 24690534
Biomass conversion; Dilute acid pretreatment; Severity factor; Quantitative image analysis; Delamination; Nanofibrillation
17.  Identification of biomarkers that distinguish chemical contaminants based on gene expression profiles 
BMC Genomics  2014;15:248.
High throughput transcriptomics profiles such as those generated using microarrays have been useful in identifying biomarkers for different classification and toxicity prediction purposes. Here, we investigated the use of microarrays to predict chemical toxicants and their possible mechanisms of action.
In this study, in vitro cultures of primary rat hepatocytes were exposed to 105 chemicals and vehicle controls, representing 14 compound classes. We comprehensively compared various normalization of gene expression profiles, feature selection and classification algorithms for the classification of these 105 chemicals into14 compound classes. We found that normalization had little effect on the averaged classification accuracy. Two support vector machine (SVM) methods, LibSVM and sequential minimal optimization, had better classification performance than other methods. SVM recursive feature selection (SVM-RFE) had the highest overfitting rate when an independent dataset was used for a prediction. Therefore, we developed a new feature selection algorithm called gradient method that had a relatively high training classification as well as prediction accuracy with the lowest overfitting rate of the methods tested. Analysis of biomarkers that distinguished the 14 classes of compounds identified a group of genes principally involved in cell cycle function that were significantly downregulated by metal and inflammatory compounds, but were induced by anti-microbial, cancer related drugs, pesticides, and PXR mediators.
Our results indicate that using microarrays and a supervised machine learning approach to predict chemical toxicants, their potential toxicity and mechanisms of action is practical and efficient. Choosing the right feature and classification algorithms for this multiple category classification and prediction is critical.
PMCID: PMC4051169  PMID: 24678894
Biomarker; Microarray; Hepatocytes; Chemical; Classification
18.  Analysis of Early Hypertension and Clinical Outcome With Bevacizumab: Results From Seven Phase III Studies 
The Oncologist  2013;18(3):273-280.
To assess the prognostic and predictive value of bevacizumab-related hypertension, hypertension and efficacy outcomes for seven company-sponsored placebo-controlled phase III studies of bevacizumab were analyzed. Early treatment-related BP increases were not found to have general prognostic importance for patients with advanced cancer.
Hypertension is associated with antivascular endothelial growth factor treatment, but the clinical implications of hypertension are uncertain. To assess the prognostic and predictive value of bevacizumab-related hypertension, a comprehensive analysis of whether hypertension and efficacy outcomes are associated was conducted on seven company-sponsored placebo-controlled phase III studies of bevacizumab.
Patient-specific data were available from 6,486 patients with metastatic colorectal, breast, non-small cell lung, pancreatic, and renal cell cancers. Primary hypertension endpoint was a blood pressure (BP) increase of >20 mmHg systolic or >10 mmHg diastolic within the first 60 days of treatment. Additional endpoints included other predefined thresholds of change in BP and severity of hypertension graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events. To analyze the general prognostic importance of an early BP increase, multivariate Cox regression models were used to assess the correlation between BP changes and progression-free (PFS) and overall survival (OS) outcomes in the control groups. To analyze whether early BP increases could predict for benefit from bevacizumab, similar analyses were conducted in the bevacizumab-treated and control groups.
In six of seven studies, early BP increase was neither predictive of clinical benefit from bevacizumab nor prognostic for the course of the disease. For study AVF2107g, early increased BP was associated with longer PFS and OS times in the bevacizumab group but shorter OS time in the control group.
Early treatment-related BP increases do not predict clinical benefit from bevacizumab based on PFS or OS outcomes. BP increases do not appear to have general prognostic importance for patients with advanced cancer.
PMCID: PMC3607523  PMID: 23485622
Bevacizumab; Hypertension; Clinical outcome; Prognostic factor; Predictive factor
19.  Chromatin: Receiver and Quarterback for Cellular Signals 
Cell  2013;152(4):685-689.
Signal transduction pathways ultimately converge upon sequence-specific DNA binding factors to reprogram gene expression and affect necessary changes in cellular growth or behavior. Transcription factors, in turn, team up with chromatin modifying activities, including enzymes that post-translationally modify histones. Chromatin is also dynamically modified to regulate DNA accessibility for replication and repair. However, chromatin is not simply an endpoint for signaling pathways. Histone modifications can relay signals to other proteins to trigger more immediate responses than can be achieved through altered gene transcription. Such signaling might be especially important to time-urgent processes such as the execution of cell cycle check points, chromosome segregation, or exit from mitosis. In addition, histone modifying enzymes often have multiple non-histone substrates, and coordination of activity towards different targets might direct signals both to and from chromatin.
PMCID: PMC3644977  PMID: 23375745
20.  Memory regulatory T cells reside in human skin 
The Journal of Clinical Investigation  2014;124(3):1027-1036.
Regulatory T cells (Tregs), which are characterized by expression of the transcription factor Foxp3, are a dynamic and heterogeneous population of cells that control immune responses and prevent autoimmunity. We recently identified a subset of Tregs in murine skin with properties typical of memory cells and defined this population as memory Tregs (mTregs). Due to the importance of these cells in regulating tissue inflammation in mice, we analyzed this cell population in humans and found that almost all Tregs in normal skin had an activated memory phenotype. Compared with mTregs in peripheral blood, cutaneous mTregs had unique cell surface marker expression and cytokine production. In normal human skin, mTregs preferentially localized to hair follicles and were more abundant in skin with high hair density. Sequence comparison of TCRs from conventional memory T helper cells and mTregs isolated from skin revealed little homology between the two cell populations, suggesting that they recognize different antigens. Under steady-state conditions, mTregs were nonmigratory and relatively unresponsive; however, in inflamed skin from psoriasis patients, mTregs expanded, were highly proliferative, and produced low levels of IL-17. Taken together, these results identify a subset of Tregs that stably resides in human skin and suggest that these cells are qualitatively defective in inflammatory skin disease.
PMCID: PMC3934172  PMID: 24509084
21.  Tetracycline to Prevent Epidermal Growth Factor Receptor Inhibitor-Induced Skin Rashes: Results of a Placebo-Controlled Trial from the North Central Cancer Treatment Group (N03CB)1 
Cancer  2008;113(4):847-853.
Epidermal growth factor receptor inhibitors are effective cancer therapies, but they cause a rash in greater than 50% of patients. This study tested tetracycline for rash prevention.
This placebo-controlled, double-blinded trial enrolled patients who were starting cancer treatment with an epidermal growth factor receptor inhibitor. Patients could not have had a rash at enrollment. All were randomly assigned to either tetracycline 500 milligrams orally twice a day for 28 days versus a placebo. Patients were monitored for rash (monthly physician assessment and weekly patient-reported questionnaires), quality of life (SKINDEX-16), and adverse events. Monitoring occurred during the 4-week intervention and then for an additional 4 weeks. The primary objective was to compare the incidence of rash between study arms, and 30 patients per arm provided a 90% probability of detecting a 40% difference in incidence with a p-value of 0.05 (2-sided).
Sixty-one evaluable patients were enrolled, and arms were well balanced on baseline characteristics, rates of drop out, and rates of discontinuation of the epidermal growth factor receptor inhibitor. Rash incidence was comparable across arms. Physicians reported that 16 tetracycline-treated patients (70%) and 22 placebo-exposed patients (76%) developed a rash (p=0.61). Tetracycline appears to have lessened rash severity, although high drop out rates invite caution in interpreting findings. By week 4, physician-reported grade 2 rash occurred in 17% of tetracycline-treated patients (n=4) and in 55% of placebo-exposed patients (n=16); (p=0.04). Tetracycline-treated patients reported better scores, as per the SKINDEX-16, on certain quality of life parameters, such as skin burning or stinging, skin irritation, and being bothered by a persistence/recurrence of a skin condition. Adverse events were comparable across arms.
Tetracycline did not prevent epidermal growth factor receptor inhibitor-induced rashes and cannot be clinically recommended for this purpose. However, preliminary observations of diminished rash severity and improved quality of life suggest this antibiotic merits further study.
PMCID: PMC3918166  PMID: 18543329
22.  Clinical update for the diagnosis and treatment of Clostridium difficile infection 
Clostridium difficile infection (CDI) presents a rapidly evolving challenge in the battle against hospital-acquired infections. Recent advances in CDI diagnosis and management include rapid changes in diagnostic approach with the introduction of newer tests, such as detection of glutamate dehydrogenase in stool and polymerase chain reaction to detect the gene for toxin production, which will soon revolutionize the diagnostic approach to CDI. New medications and multiple medical society guidelines have introduced changing concepts in the definitions of severity of CDI and the choice of therapeutic agents, while rapid expansion of data on the efficacy of fecal microbiota transplantation heralds a revolutionary change in the management of patients suffering multiple relapses of CDI. Through a comprehensive review of current medical literature, this article aims to offer an intensive review of the current state of CDI diagnosis, discuss the strengths and limitations of available laboratory tests, compare both current and future treatments options and offer recommendations for best practice strategies.
PMCID: PMC3951810  PMID: 24729930
Clostridium difficile; Antibiotic-associated diarrhea; Fidaxomicin; Rifaximin; Fecal transplantation; Probiotics
23.  Fast Gated EPR Imaging of the Beating Heart: Spatiotemporally-Resolved 3D Imaging of Free Radical Distribution during the Cardiac Cycle 
In vivo or ex vivo electron paramagnetic resonance imaging (EPRI) is a powerful technique for determining the spatial distribution of free radicals and other paramagnetic species in living organs and tissues. However, applications of EPRI have been limited by long projection acquisition times and the consequent fact that rapid gated EPRI was not possible. Hence in vivo EPRI typically provided only time-averaged information. In order to achieve direct gated EPRI, a fast EPR acquisition scheme was developed to decrease EPR projection acquisition time down to 10 – 20 ms, along with corresponding software and instrumentation to achieve fast gated EPRI of the isolated beating heart with submillimeter spatial resolution in as little as 2 to 3 minutes. Reconstructed images display temporal and spatial variations of the free radical distribution, anatomical structure, and contractile function within the rat heart during the cardiac cycle.
PMCID: PMC3394889  PMID: 22473660
EPR imaging; gated cardiac imaging; free radical metabolism; redox state; nitroxide; paramagnetic probe
24.  Treatment Outcomes of a Crisis Intervention Program for Dementia With Severe Psychiatric Complications: The Kansas Bridge Project 
The Gerontologist  2012;53(1):102-112.
Purpose: Although declines in memory and attention are hallmark symptoms of Alzheimer’s disease (AD), noncognitive symptoms are prevalent. Over 80% of individuals will experience neuropsychiatric symptoms, which complicates symptom profiles. Research indicates a community-integrated response to dementia crisis can reduce negative consequences attributed to crisis including increased caregiver burden, increased health care costs, and premature institutionalizations.
Design and methods: The Kansas Dementia Crisis Bridge Project is a multidisciplinary collaboration to provide direct support in critical situations to reduce psychiatric rehospitalizations. Coordinators provided counsel and dementia education to families throughout critical period of acute neuropsychiatric symptoms, facilitated professional involvement, and provided crisis prevention planning through crisis review. The Neuropsychiatric Inventory Questionnaire and Geriatric Depression Scale were used to measure the impact of neuropsychiatric symptoms and Bridge interventions on patient and caregivers.
Results: The Bridge project significantly reduced patient anxiety, depression, resistance to care, impulsive behavior, verbal outbursts, and wandering. Caregivers reported significantly reduced anxiety, apathy, resistance to care, and less distress over patient neuropsychiatric symptoms. Caregivers also reported increased confidence in managing difficult behaviors, and the project effectively reduced or resolved neuropsychiatric crisis. The project delayed nursing home placement for community-dwelling patients.
Implications: Crisis support models like the Bridge project reduce strain on care-delivery systems by incorporating nonpharmacological interventions, assisting families with communication, and reducing family distress during symptom crises. Although much of AD research focuses on disease-modifying medical interventions, aging and care systems in the state must simultaneously move towards dependency-modifying care interventions.
Decision Editor: Rachel Pruncho, PhD
PMCID: PMC3605939  PMID: 22936530
Dementia; Neuropsychiatric; Psychiatric; Neuropsychological; Assessment
25.  Immediate versus delayed zoledronic acid for prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen-N03CC 
Postmenopausal women with breast cancer (BC) are at increased risk for bone loss. Bisphosphonates improve bone mineral density (BMD) in normal postmenopausal women. The purpose of this study was to determine if immediate treatment with zoledronic acid preserves BMD in postmenopausal women with BC starting letrozole after tamoxifen. Postmenopausal women with BC completing tamoxifen were treated with daily letrozole 2.5 mg/vitamin D 400 I.U., calcium 500 mg twice daily and were randomized to upfront or delayed zoledronic acid 4 mg every 6 months. Patients in the delayed arm were only given zoledronic acid if they developed a post-baseline BMD T score <−2.0 or had a fracture. The primary endpoint was the mean percent change in lumbar spine (LS) BMD at 1 year. About 558 women enrolled; 395 provided 1 year BMD data. The upfront arm experienced a mean change of +3.66% in LS BMD versus -1.66% for the delayed group (P < 0.001). Changes at the femoral neck/total hip were also greater for the upfront versus delayed arms (P < 0.001; P < 0.001) with differences persisting at 2 years. Patients in the delayed arm were more likely to experience a clinically meaningful 5% loss of BMD at all sites versus the upfront zoledronate group. Patients in the upfront arm were slightly more likely to report limb edema, fatigue, fever, nausea and jaw osteonecrosis(1%). Upfront zoledronic acid prevents bone loss in postmenopausal women with BC starting letrozole after tamoxifen.
PMCID: PMC3907065  PMID: 19214743
Breast cancer; Aromatase inhibitor; Bone loss; Zoledronic acid

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