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1.  Accuracy of Self-Reported Versus Measured Weight Over Adolescence and Young Adulthood: Findings From the National Longitudinal Study of Adolescent Health, 1996–2008 
American Journal of Epidemiology  2014;180(2):153-159.
Many studies rely on self-reports to capture population trends and trajectories in weight gain over adulthood, but the validity of self-reports is often considered a limitation. The purpose of this work was to examine long-term trajectories of self-reporting bias in a national sample of American youth. With 3 waves of data from the National Longitudinal Study of Adolescent Health (1996–2008), we used growth curve models to examine self-reporting bias in trajectories of weight gain across adolescence and early adulthood (ages 13–32 years). We investigated whether self-reporting bias is constant over time, or whether adolescents become more accurate in reporting their weight as they move into young adulthood, and we examined differences in self-reporting bias by sex, race/ethnicity, and attained education. Adolescent girls underreported their weight by 0.86 kg on average, and this rate of underreporting increased over early adulthood. In contrast, we found no evidence that boys underreported their weight either in adolescence or over the early adult years. For young men, self-reports of weight were unbiased estimates of measured weight among all racial/ethnic and educational subpopulations over adolescence and early adulthood.
doi:10.1093/aje/kwu133
PMCID: PMC4082345  PMID: 24944288
adolescence; bias; measurement; self-report; trajectories; weight; youth
2.  Impact of Maternal Hepatitis B Virus Coinfection on Mother-to-Child Transmission of Human Immunodeficiency Virus 
HIV medicine  2014;15(6):347-354.
Background
Despite high hepatitis B virus (HBV) endemicity in various resource-limited settings (RLS), the impact of maternal HIV-HBV coinfection on infant health outcomes has not been defined.
Method
This study determined the seroprevalence of HBV coinfection among HIV-infected pregnant women enrolled in the India six-week extended-dose nevirapine (SWEN) trial. The impact of maternal HIV-HBV coinfection on MTCT of HIV and infant mortality was assessed using univariate and multivariate logistic regression analysis.
Results
Among 689 HIV-infected pregnant Indian women, 32 (4.6%) had HBV coinfection (95% confidence interval [CI] 3.4, 5.3). HBV DNA was detectable in 18 (64%) of 28 HIV-HBV coinfected women; the median HBV viral load was 155 copies/mL (interquartile range [IQR] < 51–6741). Maternal HIV-HBV coinfection did not increase HIV transmission (adjusted odds ratio [aOR] 1.06, 95% CI 0.30, 3.66; p= 0.93). Increased odds of all-cause infant mortality was noted (aOR 3.12, 95% CI 0.67, 14.57; p=0.15), but was not statistically significant.
Conclusion
The prevalence of active maternal HBV co-infection in HIV-infected pregnant women in India was 4.6%. HIV-HBV coinfection was not independently associated with HIV transmission.
doi:10.1111/hiv.12120
PMCID: PMC4055515  PMID: 24422893
Hepatitis B virus infection; HIV/AIDS; infant mortality; perinatal infection; India; pregnancy; maternal-to-child transmission
3.  A Tiered Framework for Risk-Relevant Characterization and Ranking of Chemical Exposures: Applications to the National Children’s Study (NCS) 
A challenge for large-scale environmental health investigations such as the National Children’s Study (NCS), is characterizing exposures to multiple, co-occurring chemical agents with varying spatiotemporal concentrations and consequences modulated by biochemical, physiological, behavioral, socioeconomic, and environmental factors. Such investigations can benefit from systematic retrieval, analysis, and integration of diverse extant information on both contaminant patterns and exposure-relevant factors. This requires development, evaluation, and deployment of informatics methods that support flexible access and analysis of multiattribute data across multiple spatiotemporal scales. A new “Tiered Exposure Ranking” (TiER) framework, developed to support various aspects of risk-relevant exposure characterization, is described here, with examples demonstrating its application to the NCS. TiER utilizes advances in informatics computational methods, extant database content and availability, and integrative environmental/exposure/biological modeling to support both “discovery-driven” and “hypothesis-driven” analyses. “Tier 1” applications focus on “exposomic” pattern recognition for extracting information from multidimensional data sets, whereas second and higher tier applications utilize mechanistic models to develop risk-relevant exposure metrics for populations and individuals. In this article, “tier 1” applications of TiER explore identification of potentially causative associations among risk factors, for prioritizing further studies, by considering publicly available demographic/socioeconomic, behavioral, and environmental data in relation to two health endpoints (preterm birth and low birth weight). A “tier 2” application develops estimates of pollutant mixture inhalation exposure indices for NCS counties, formulated to support risk characterization for these endpoints. Applications of TiER demonstrate the feasibility of developing risk-relevant exposure characterizations for pollutants using extant environmental and demographic/socioeconomic data.
doi:10.1111/risa.12165
PMCID: PMC4158851  PMID: 24467550
Birth outcomes; Exposure Information System (EXIS); Modeling Environment for Total Risk studies (MENTOR); Prioritization and Ranking of Toxic Exposures with GIS Extension (PRoTEGE); risk-relevant exposure indices (EIs); Tiered Exposure Ranking (TiER) framework
4.  Amplified and Persistent Immune Responses Generated by Single-Cycle Replicating Adenovirus Vaccines 
Journal of Virology  2014;89(1):669-675.
ABSTRACT
Replication-competent adenoviral (RC-Ad) vectors generate exceptionally strong gene-based vaccine responses by amplifying the antigen transgenes they carry. While they are potent, they also risk causing adenovirus infections. More common replication-defective Ad (RD-Ad) vectors with deletions of E1 avoid this risk but do not replicate their transgene and generate markedly weaker vaccine responses. To amplify vaccine transgenes while avoiding production of infectious progeny viruses, we engineered “single-cycle” adenovirus (SC-Ad) vectors by deleting the gene for IIIa capsid cement protein of lower-seroprevalence adenovirus serotype 6. In mouse, human, hamster, and macaque cells, SC-Ad6 still replicated its genome but prevented genome packaging and virion maturation. When used for mucosal intranasal immunization of Syrian hamsters, both SC-Ad and RC-Ad expressed transgenes at levels hundreds of times higher than that of RD-Ad. Surprisingly, SC-Ad, but not RC-Ad, generated higher levels of transgene-specific antibody than RD-Ad, which notably climbed in serum and vaginal wash samples over 12 weeks after single mucosal immunization. When RD-Ad and SC-Ad were tested by single sublingual immunization in rhesus macaques, SC-Ad generated higher gamma interferon (IFN-γ) responses and higher transgene-specific serum antibody levels. These data suggest that SC-Ad vectors may have utility as mucosal vaccines.
IMPORTANCE This work illustrates the utility of our recently developed single-cycle adenovirus (SC-Ad6) vector as a new vaccine platform. Replication-defective (RD-Ad6) vectors produce low levels of transgene protein, which leads to minimal antibody responses in vivo. This study shows that replicating SC-Ad6 produces higher levels of luciferase and induces higher levels of green fluorescent protein (GFP)-specific antibodies than RD in a permissive Syrian hamster model. Surprisingly, although a replication-competent (RC-Ad6) vector produces more luciferase than SC-Ad6, it does not elicit comparable levels of anti-GFP antibodies in permissive hamsters. When tested in the larger rhesus macaque model, SC-Ad6 induces higher transgene-specific antibody and T cell responses. Together, these data suggest that SC-Ad6 could be a more effective platform for developing vaccines against more relevant antigens. This could be especially beneficial for developing vaccines for pathogens for which traditional replication-defective adenovirus vectors have not been effective.
doi:10.1128/JVI.02184-14
PMCID: PMC4301142  PMID: 25355873
5.  Adaptive and Unstructured Mesh Cleaving 
Procedia engineering  2014;82:266-278.
We propose a new strategy for boundary conforming meshing that decouples the problem of building tetrahedra of proper size and shape from the problem of conforming to complex, non-manifold boundaries. This approach is motivated by the observation that while several methods exist for adaptive tetrahedral meshing, they typically have difficulty at geometric boundaries. The proposed strategy avoids this conflict by extracting the boundary conforming constraint into a secondary step. We first build a background mesh having a desired set of tetrahedral properties, and then use a generalized stenciling method to divide, or “cleave”, these elements to get a set of conforming tetrahedra, while limiting the impacts cleaving has on element quality. In developing this new framework, we make several technical contributions including a new method for building graded tetrahedral meshes as well as a generalization of the isosurface stuffing and lattice cleaving algorithms to unstructured background meshes.
doi:10.1016/j.proeng.2014.10.389
PMCID: PMC4484869  PMID: 26137171
Meshing; Tetrahedral; Multimaterial; Unstructured; Bounded; Quality
6.  A Cysteine Zipper Stabilizes a Pre-Fusion F Glycoprotein Vaccine for Respiratory Syncytial Virus 
PLoS ONE  2015;10(6):e0128779.
Recombinant subunit vaccines should contain minimal non-pathogen motifs to reduce potential off-target reactivity. We recently developed a vaccine antigen against respiratory syncytial virus (RSV), which comprised the fusion (F) glycoprotein stabilized in its pre-fusion trimeric conformation by “DS-Cav1” mutations and by an appended C-terminal trimerization motif or “foldon” from T4-bacteriophage fibritin. Here we investigate the creation of a cysteine zipper to allow for the removal of the phage foldon, while maintaining the immunogenicity of the parent DS-Cav1+foldon antigen. Constructs without foldon yielded RSV F monomers, and enzymatic removal of the phage foldon from pre-fusion F trimers resulted in their dissociation into monomers. Because the native C terminus of the pre-fusion RSV F ectodomain encompasses a viral trimeric coiled-coil, we explored whether introduction of cysteine residues capable of forming inter-protomer disulfides might allow for stable trimers. Structural modeling indicated the introduced cysteines to form disulfide “rings”, with each ring comprising a different set of inward facing residues of the coiled-coil. Three sets of rings could be placed within the native RSV F coiled-coil, and additional rings could be added by duplicating portions of the coiled-coil. High levels of neutralizing activity in mice, equivalent to that of the parent DS-Cav1+foldon antigen, were elicited by a 4-ring stabilized RSV F trimer with no foldon. Structure-based alteration of a viral coiled-coil to create a cysteine zipper thus allows a phage trimerization motif to be removed from a candidate vaccine antigen.
doi:10.1371/journal.pone.0128779
PMCID: PMC4476739  PMID: 26098893
7.  Nanohydroxyapatite-reinforced chitosan composite hydrogel for bone tissue repair in vitro and in vivo 
Background
Bone loss during trauma, surgeries, and tumor resection often results in critical-sized bone defects that need to be filled with substitutionary materials. Complications associated with conventional grafting techniques have led to the development of bioactive tissue-engineered bone scaffolds. The potential application of hydrogels as three-dimensional (3D) matrices in tissue engineering has gained attention in recent years because of the superior sensitivity, injectability, and minimal invasive properties of hydrogels. Improvements in the bioactivity and mechanical strength of hydrogels can be achieved with the addition of ceramics. Based on the features required for bone regeneration, an injectable thermosensitive hydrogel containing zinc-doped chitosan/nanohydroxyapatite/beta-glycerophosphate (Zn-CS/nHAp/β-GP) was prepared and characterized, and the effect of nHAp on the hydrogel was examined.
Methods
Hydrogels (Zn-CS/β-GP, Zn-CS/nHAp/β-GP) were prepared using the sol–gel method. Characterization was carried out by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDX), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD) as well as swelling, protein adsorption, and exogenous biomineralization studies. Expression of osteoblast marker genes was determined by real-time reverse transcriptase polymerase chain reaction (RT-PCR) and western blot analyses. In vivo bone formation was studied using a rat bone defect model system.
Results
The hydrogels exhibited sol–gel transition at 37°C. The presence of nHAp in the Zn-CS/nHAp/β-GP hydrogel enhanced swelling, protein adsorption, and exogenous biomineralization. The hydrogel was found to be non-toxic to mesenchymal stem cells. The addition of nHAp to the hydrogel also enhanced osteoblast differentiation under osteogenic conditions in vitro and accelerated bone formation in vivo as seen from the depositions of apatite and collagen.
Conclusions
The synthesized injectable hydrogel (Zn-CS/nHAp/β-GP) showed its potential toward bone formation at molecular and cellular levels in vitro and in vivo. The current findings demonstrate the importance of adding nHAp to the hydrogel, thereby accelerating potential clinical application toward bone regeneration.
doi:10.1186/s12951-015-0099-z
PMCID: PMC4464993  PMID: 26065678
Chitosan; Zinc; nHAp; β-Glycerophosphate; Runx2; Bone
8.  Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus 
Science (New York, N.Y.)  2013;342(6158):592-598.
Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under five years of age. We sought to engineer a viral antigen that provides greater protection than currently available vaccines and focused on antigenic site Ø, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies. Structure-based design yielded stabilized versions of RSV F that maintained antigenic site Ø when exposed to extremes of pH, osmolality, and temperature. Six RSV F-crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability. Immunization with site Ø-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.
doi:10.1126/science.1243283
PMCID: PMC4461862  PMID: 24179220
9.  The ETTAA study protocol: a UK-wide observational study of ‘Effective Treatments for Thoracic Aortic Aneurysm’ 
BMJ Open  2015;5(6):e008147.
Introduction
Chronic thoracic aortic aneurysm (CTAA) affecting the arch or descending aorta is an indolent but life-threatening condition with a rising prevalence as the UK population ages. Treatment may be in the form of open surgical repair (OSR) surgery, endovascular stent grafting (ESG) or best medical therapy (BMT). Currently, there is no consensus on the best management strategy, and no UK-specific economic studies that assess outcomes beyond the chosen procedure, but this is required in the context of greater demand for treatment and limited National Health Service (NHS) resources.
Methods and analysis
This is a prospective, multicentre observational study with statistical and economic modelling of patients with CTAA affecting the arch or descending aorta. We aim to gain an understanding of how treatments are currently chosen, and to determine the clinical effectiveness and cost-effectiveness of the three available treatment strategies (BMT, ESG and OSR). This will be achieved by: (1) following consecutive patients who are referred to the teams collaborating in this proposal and collecting data regarding quality of life (QoL), medical events and hospital stays over a maximum of 5 years; (2) statistical analysis of the comparative effectiveness of the three treatments; and (3) economic modelling of the comparative cost-effectiveness of the three treatments. Primary study outcomes are: aneurysm growth, QoL, freedom from reintervention, freedom from death or permanent neurological injury, incremental cost per quality-adjusted life year gained.
Ethics and dissemination
The study will generate an evidence base to guide patients and clinicians to determine the indications and timing of treatment, as well as informing healthcare decision-makers about which treatments the NHS should provide. The study has achieved ethical approval and will be disseminated primarily in the form of a Health Technology Assessment monograph at its completion.
Trial registration number
ISRCTN04044627.
doi:10.1136/bmjopen-2015-008147
PMCID: PMC4458682  PMID: 26038360
VASCULAR MEDICINE
10.  The Location of Displaced New Orleans Residents in the Year After Hurricane Katrina 
Demography  2014;51(3):753-775.
Using individual data from the restricted version of the American Community Survey, we examined the displacement locations of pre–Hurricane Katrina adult residents of New Orleans in the year after the hurricane. More than one-half (53 %) of adults had returned to—or remained in—the New Orleans metropolitan area, with just under one-third of the total returning to the dwelling in which they resided prior to Hurricane Katrina. Among the remainder, Texas was the leading location of displaced residents, with almost 40 % of those living away from the metropolitan area (18 % of the total), followed by other locations in Louisiana (12 %), the South region of the United States other than Louisiana and Texas (12 %), and elsewhere in the United States (5 %). Black adults were considerably more likely than nonblack adults to be living elsewhere in Louisiana, in Texas, and elsewhere in the South. The observed race disparity was not accounted for by any of the demographic or socioeconomic covariates in the multinomial logistic regression models. Consistent with hypothesized effects, we found that following Hurricane Katrina, young adults (aged 25–39) were more likely to move further away from New Orleans and that adults born outside Louisiana were substantially more likely to have relocated away from the state.
doi:10.1007/s13524-014-0284-y
PMCID: PMC4048822  PMID: 24599750
Hurricane Katrina; New Orleans population; Migration; Displacement; Disaster
11.  Generational and Time Period Differences in American Adolescents’ Religious Orientation, 1966–2014 
PLoS ONE  2015;10(5):e0121454.
In four large, nationally representative surveys (N = 11.2 million), American adolescents and emerging adults in the 2010s (Millennials) were significantly less religious than previous generations (Boomers, Generation X) at the same age. The data are from the Monitoring the Future studies of 12th graders (1976–2013), 8th and 10th graders (1991–2013), and the American Freshman survey of entering college students (1966–2014). Although the majority of adolescents and emerging adults are still religiously involved, twice as many 12th graders and college students, and 20%–40% more 8th and 10th graders, never attend religious services. Twice as many 12th graders and entering college students in the 2010s (vs. the 1960s–70s) give their religious affiliation as “none,” as do 40%–50% more 8th and 10th graders. Recent birth cohorts report less approval of religious organizations, are less likely to say that religion is important in their lives, report being less spiritual, and spend less time praying or meditating. Thus, declines in religious orientation reach beyond affiliation to religious participation and religiosity, suggesting a movement toward secularism among a growing minority. The declines are larger among girls, Whites, lower-SES individuals, and in the Northeastern U.S., very small among Blacks, and non-existent among political conservatives. Religious affiliation is lower in years with more income inequality, higher median family income, higher materialism, more positive self-views, and lower social support. Overall, these results suggest that the lower religious orientation of Millennials is due to time period or generation, and not to age.
doi:10.1371/journal.pone.0121454
PMCID: PMC4427319  PMID: 25962174
12.  Comprehensive molecular characterization of human adipocytes reveals a transient brown phenotype 
Background
Functional brown adipose tissue (BAT), involved in energy expenditure, has recently been detected in substantial amounts in adults. Formerly overlooked BAT has now become an attractive anti-obesity target.
Methods and results
Molecular characterization of human brown and white adipocytes, using a myriad of techniques including high-throughput RNA sequencing and functional assays, showed that PAZ6 and SW872 cells exhibit classical molecular and phenotypic markers of brown and white adipocytes, respectively. However, the pre-adipocyte cell line SGBS presents a versatile phenotype. A transit expression of classical brown markers such as UCP1 and PPARγ peaked and declined at day 28 post-differentiation initiation. Conversely, white adipocyte markers, including Tcf21, showed reciprocal behavior. Interestingly, leptin levels peaked at day 28 whereas the highest adiponectin mRNA levels were detected at day 14 of differentiation. Phenotypic analysis of the abundance and shape of lipid droplets were consistent with the molecular patterns. Accordingly, the oxidative capacity of SGBS adipocytes peaked on differentiation day 14 and declined progressively towards differentiation day 28.
Conclusions
Our studies have unveiled a new phenotype of human adipocytes, providing a tool to identify molecular gene expression patterns and pathways involved in the conversion between white and brown adipocytes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0480-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-015-0480-6
PMCID: PMC4438513  PMID: 25925588
Obesity; SGBS cells; Human adipocytes; Non-shivering thermogenesis; BAT; WAT; Beige adipocytes
13.  Adrenalectomy for isolated metastasis from operable non-small-cell lung cancer 
A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was ‘in [patients with isolated adrenal metastasis from operable/operated non-small cell lung cancer] is [adrenalectomy] superior [to chemo/radiotherapy alone for achieving long-term survival]?’ Altogether >160 papers were found using the reported search, of which 3 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that the body of evidence is small, retrospective and not formally controlled. As such interpretation is limited by selection bias in assignment of patients. These limitations notwithstanding, surgical resection is associated with prolonged survival for patients with isolated adrenal metastasis from non-small cell lung cancer (NSCLC). Patient selection is probably critical. Factors that are important are: otherwise early tumour, node (TN) status of the lung primary and R0 resection, long disease-free interval and confidence that there are no other sites of metastasis. Patients with ipsilateral adrenal metastasis may derive the greatest survival benefit from adrenalectomy, since spread to the ipsilateral gland may occur via direct lymphatic channels in the retroperitoneum. Involvement of the contralateral adrenal may signify haematogenous spread and therefore, a more aggressive process. Adrenalectomy must be accompanied by regional lymph node clearance to reduce the chance of further spread from the adrenal itself.
doi:10.1093/icvts/ivt526
PMCID: PMC3957285  PMID: 24357471
Review; Adrenalectomy; Neoplasm metastasis; Adrenal gland neoplasms; Adrenal gland; Carcinoma non-small-cell lung
14.  Biophysical significance of the inner mitochondrial membrane structure on the electrochemical potential of mitochondria 
The available literature supports the hypothesis that the morphology of the inner mitochondrial membrane is regulated by different energy states, that the three-dimensional morphology of cristae is dynamic and that both are related to biochemical function. Examination of the correlation between the inner mitochondrial membrane (IMM) structure and mitochondrial energetic function is critical to an understanding of the links between meso-scale morphology and function in progressive mitochondrial dysfunction such as aging, neurodegeneration, and disease. To investigate this relationship, we develop a model to examine the effects of three-dimensional IMM morphology on the electrochemical potential of mitochondria. The 2D axisymmetric finite element method is used to simulate mitochondrial electric potential and proton concentration distribution. This simulation model demonstrates that the proton motive force (PMF) produced on the membranes of cristae can be higher than that on the inner boundary membrane. The model also shows that high proton concentration in cristae can be induced by the morphology-dependent electric potential gradient along the outer side of the IMM. Furthermore, simulation results show that a high PMF is induced by the large surface-to-volume ratio of an individual crista, whereas a high capacity for ATP synthesis can primarily be achieved by increasing the surface area of an individual crista. The mathematical model presented here provides compelling support for the idea that morphology at the meso-scale is a significant driver of mitochondrial function.
PMCID: PMC4315510  PMID: 24483502
15.  Computational fluid dynamics modeling of transport and deposition of pesticides in an aircraft cabin 
Spraying of pesticides in aircraft cabins is required by some countries as part of a disinsection process to kill insects that pose a public health threat. However, public health concerns remain regarding exposures of cabin crew and passengers to pesticides in aircraft cabins. While large scale field measurements of pesticide residues and air concentrations in aircraft cabins scenarios are expensive and time consuming, Computational Fluid Dynamics (CFD) models provide an effective alternative for characterizing concentration distributions and exposures. This study involved CFD modeling of a twin-aisle 11 row cabin mockup with heated manikins, mimicking a part of a fully occupied Boeing 767 cabin. The model was applied to study the flow and deposition of pesticides under representative scenarios with different spraying patterns (sideways and overhead) and cabin air exchange rates (low and high). Corresponding spraying experiments were conducted in the cabin mockup, and pesticide deposition samples were collected at the manikin’s lap and seat top for a limited set of five seats. The CFD model performed well for scenarios corresponding to high air exchange rates, captured the concentration profiles for middle seats under low air exchange rates, and underestimated the concentrations at window seats under low air exchange rates. Additionally, both the CFD and experimental measurements showed no major variation in deposition characteristics between sideways and overhead spraying. The CFD model can estimate concentration fields and deposition profiles at very high resolutions, which can be used for characterizing the overall variability in air concentrations and surface loadings. Additionally, these model results can also provide a realistic range of surface and air concentrations of pesticides in the cabin that can be used to estimate potential exposures of cabin crew and passengers to these pesticides.
doi:10.1016/j.atmosenv.2012.11.019
PMCID: PMC4310242  PMID: 25642134
CFD; Pesticide; Pyrethroid; Permethrin; Airliner cabin; Disinsection
16.  Arab gene geography: From population diversities to personalized medical genomics 
Global Cardiology Science & Practice  2014;2014(4):394-408.
Genetic disorders are not equally distributed over the geography of the Arab region. While a number of disorders have a wide geographical presence encompassing 10 or more Arab countries, almost half of these disorders occur in a single Arab country or population. Nearly, one-third of the genetic disorders in Arabs result from congenital malformations and chromosomal abnormalities, which are also responsible for a significant proportion of neonatal and perinatal deaths in Arab populations. Strikingly, about two-thirds of these diseases in Arab patients follow an autosomal recessive mode of inheritance. High fertility rates together with increased consanguineous marriages, generally noticed in Arab populations, tend to increase the rates of genetic and congenital abnormalities. Many of the nearly 500 genes studied in Arab people revealed striking spectra of heterogeneity with many novel and rare mutations causing large arrays of clinical outcomes. In this review we provided an overview of Arab gene geography, and various genetic abnormalities in Arab populations, including disorders of blood, metabolic, circulatory and neoplasm, and also discussed their associated molecules or genes responsible for the cause of these disorders. Although studying Arab-specific genetic disorders resulted in a high value knowledge base, approximately 35% of genetic diseases in Arabs do not have a defined molecular etiology. This is a clear indication that comprehensive research is required in this area to understand the molecular pathologies causing diseases in Arab populations.
doi:10.5339/gcsp.2014.54
PMCID: PMC4355514  PMID: 25780794
Arab populations; neolithic; population genetics; gene geography; genetic disorders; neoplasms
17.  Enhancement of Mucosal Immunogenicity of Viral Vectored Vaccines by the NKT Cell Agonist Alpha-Galactosylceramide as Adjuvant 
Vaccines  2014;2(4):686-706.
Gene-based vaccination strategies, specifically viral vectors encoding vaccine immunogens are effective at priming strong immune responses. Mucosal routes offer practical advantages for vaccination by ease of needle-free administration, and immunogen delivery at readily accessible oral/nasal sites to efficiently induce immunity at distant gut and genital tissues. However, since mucosal tissues are inherently tolerant for induction of immune responses, incorporation of adjuvants for optimal mucosal vaccination strategies is important. We report here the effectiveness of alpha-galactosylceramide (α-GalCer), a synthetic glycolipid agonist of natural killer T (NKT) cells, as an adjuvant for enhancing immunogenicity of vaccine antigens delivered using viral vectors by mucosal routes in murine and nonhuman primate models. Significant improvement in adaptive immune responses in systemic and mucosal tissues was observed by including α-GalCer adjuvant for intranasal immunization of mice with vesicular stomatitis virus vector encoding the model antigen ovalbumin and adenoviral vectors expressing HIV env and Gag antigens. Activation of NKT cells in systemic and mucosal tissues along with significant increases in adaptive immune responses were observed in rhesus macaques immunized by intranasal and sublingual routes with protein or adenovirus vectored antigens when combined with α-GalCer adjuvant. These results support the utility of α-GalCer adjuvant for enhancing immunogenicity of mucosal vaccines delivered using viral vectors.
doi:10.3390/vaccines2040686
PMCID: PMC4278383  PMID: 25553254
adenovirus vector; vesicular stomatitis viral vector; intranasal; HIV vaccine; Rhesus macaques; alpha-galactosylceramide; mucosal immunity; NKT cells
18.  Identification and use of the sugarcane bacilliform virus enhancer in transgenic maize 
BMC Plant Biology  2014;14:359.
Background
Transcriptional enhancers are able to increase transcription from heterologous promoters when placed upstream, downstream and in either orientation, relative to the promoter. Transcriptional enhancers have been used to enhance expression of specific promoters in transgenic plants and in activation tagging studies to help elucidate gene function.
Results
A transcriptional enhancer from the Sugarcane Bacilliform Virus - Ireng Maleng isolate (SCBV-IM) that can cause increased transcription when integrated into the the genome near maize genes has been identified. In transgenic maize, the SCBV-IM promoter was shown to be comparable in strength to the maize ubiquitin 1 promoter in young leaf and root tissues. The promoter was dissected to identify sequences that confer high activity in transient assays. Enhancer sequences were identified and shown to increase the activity of a heterologous truncated promoter. These enhancer sequences were shown to be more active when arrayed in 4 copy arrays than in 1 or 2 copy arrays. When the enhancer array was transformed into maize plants it caused an increase in accumulation of transcripts of genes near the site of integration in the genome.
Conclusions
The SCBV-IM enhancer can activate transcription upstream or downstream of genes and in either orientation. It may be a useful tool to activate enhance from specific promoters or in activation tagging.
doi:10.1186/s12870-014-0359-3
PMCID: PMC4302606  PMID: 25526789
Promoter; Enhancer; Transcription; Transgenic plant; Transient assay
19.  Modeling Flight Attendants’ Exposures to Pesticide in Disinsected Aircraft Cabins 
Environmental science & technology  2013;47(24):14275-14281.
Aircraft cabin disinsection is required by some countries to kill insects that may pose risks to public health and native ecological systems. A probabilistic model has been developed by considering the microenvironmental dynamics of the pesticide in conjunction with the activity patterns of flight attendants, to assess their exposures and risks to pesticide in disinsected aircraft cabins under three scenarios of pesticide application. Main processes considered in the model are microenvironmental transport and deposition, volatilization, and transfer of pesticide when passengers and flight attendants come in contact with the cabin surfaces. The simulated pesticide airborne mass concentration and surface mass loadings captured measured ranges reported in the literature. The medians (means±standard devitions) of daily total exposures intakes were 0.24 (3.8±10.0), 1.4 (4.2±5.7) and 0.15 (2.1±3.2) μg/(day kg BW) for scenarios of Residual Application, Preflight and Top-of-Descent spraying, respectively. Exposure estimates were sensitive to parameters corresponding to pesticide deposition, body surface area and weight, surface-to-body transfer efficiencies, and efficiency of adherence to skin. Preflight spray posed 2.0 and 3.1 times higher pesticide exposure risk levels for flight attendants in disinsected aircraft cabins than Top-of-Descent spray and Residual Application, respectively.
doi:10.1021/es403613h
PMCID: PMC3920731  PMID: 24251734
20.  Three synchronous, sporadic and separate periampullary and pancreatic tumors: more than a coincidence? 
Three sporadic, synchronous, and separate lesions in the ampulla of Vater and the head of the pancreas presented in an 81-year-old male. One was symptomatic and two were incidental. One was detected preoperatively (the ampullary lesion) and two by examination of the resected specimen (the neuroendocrine and pancreatic carcinomas). The case is summarized and the literature and the issue of commonality are reviewed.
doi:10.1186/1477-7819-12-382
PMCID: PMC4301858  PMID: 25494951
Pancreas; Synchronous; Pancreatic adenocarcinoma; Neuroendocrine tumor; Adenosquamous
21.  Specificity Rendering ‘Hot-Spots’ for Aurora Kinase Inhibitor Design: The Role of Non-Covalent Interactions and Conformational Transitions 
PLoS ONE  2014;9(12):e113773.
The present study examines the conformational transitions occurring among the major structural motifs of Aurora kinase (AK) concomitant with the DFG-flip and deciphers the role of non-covalent interactions in rendering specificity. Multiple sequence alignment, docking and structural analysis of a repertoire of 56 crystal structures of AK from Protein Data Bank (PDB) has been carried out. The crystal structures were systematically categorized based on the conformational disposition of the DFG-loop [in (DI) 42, out (DO) 5 and out-up (DOU) 9], G-loop [extended (GE) 53 and folded (GF) 3] and αC-helix [in (CI) 42 and out (CO) 14]. The overlapping subsets on categorization show the inter-dependency among structural motifs. Therefore, the four distinct possibilities a) 2W1C (DI, CI, GE) b) 3E5A (DI, CI, GF) c) 3DJ6 (DI, CO, GF) d) 3UNZ (DOU, CO, GF) along with their co-crystals and apo-forms were subjected to molecular dynamics simulations of 40 ns each to evaluate the variations of individual residues and their impact on forming interactions. The non-covalent interactions formed by the 157 AK co-crystals with different regions of the binding site were initially studied with the docked complexes and structure interaction fingerprints. The frequency of the most prominent interactions was gauged in the AK inhibitors from PDB and the four representative conformations during 40 ns. Based on this study, seven major non-covalent interactions and their complementary sites in AK capable of rendering specificity have been prioritized for the design of different classes of inhibitors.
doi:10.1371/journal.pone.0113773
PMCID: PMC4259475  PMID: 25485544
22.  Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study 
PLoS ONE  2014;9(12):e113632.
Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK) model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS), which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker measurements, including a systematic characterization of uncertainties in exposure and dose estimation for a vulnerable population.
doi:10.1371/journal.pone.0113632
PMCID: PMC4256163  PMID: 25474635
23.  Nanotechnology in food processing sector-An assessment of emerging trends 
Use of nanoscience based technology in the food industry is fast emerging as new area for research and development. Several research groups including private companies in the industry have initiated research programmes for exploring the wide scope of nanotechnology into the value chain of food processing and manufacturing. This paper discusses the current focus of research in this area and assesses its potential impacts. Using the developed relational database framework with R&D indicators like literature and patent documents for assessment of the potential of nanotechnology in food sector, a model to organize and map nanoresearch areas to the food processing sector was developed. The study indicates that the about five basic categories of nanotechnology applications and functionalities currently in the development of food sector, include food processing, packaging, nutraceuticals delivery, food safety and functional foods.
doi:10.1007/s13197-012-0873-y
PMCID: PMC3722391  PMID: 24425990
Nanotechnology; Food processing sector; R&D indicators
24.  Anticancer Active Homoisoflavone from the Underground Bulbs of Ledebouria hyderabadensis 
Pharmacognosy Research  2014;6(4):303-305.
Background:
Ledebouria is a genus of deciduous or weakly evergreen bulbs in the Hyacinthaceae family. This is recognized as the first collection made of the new taxon Ledebouria hyderabadensis, exist in the Hyderabad city of Andhra Pradesh, India.
Objective:
The goal of this work was to investigate the phytochemical constituents present in the new specifies and also to evaluate the cytotoxic properties of the extracts and pure compounds against human cancer cell lines.
Materials and Methods:
The anticancer activity was evaluated in in vitro mode by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test.
Results:
Phytochemical investigation of underground bulbs of indigenous, rare, and recently identified herb L. hyderabadensis yielded a bioactive homoisoflavanone, Scillascillin 1. The structure of the compound was established on the basis of various nuclear magnetic resonance and mass spectral data. The compound Scillascillin was isolated for the first time from L. hyderabadensis. In vitro anticancer activity, performed using MTT assay, showed compound 1 as significantly active against human cancer cell lines MCF-7 (breast cancer) and DU-145 (prostate cancer) with inhibitory concentration (IC)50 values 9.59 and 11.32 μg/ml respectively when compared with herb methanol extract (IC50 values 36.21 and 44.86 μg/ml respectively).
doi:10.4103/0974-8490.138272
PMCID: PMC4166818  PMID: 25276067
Anticancer activity; Hyacinthaceae; Ledebouria hyderabadensis; Scillascillin
25.  Cine CT without a respiratory surrogate in planning of stereotactic radiotherapy for non-small cell lung cancer 
Purpose
To determine whether cine computed tomography (CT) can serve as an alternative to four-dimensional (4D)-CT by providing tumor motion information and producing equivalent target volumes when contoured upon for radiation treatment planning without a respiratory surrogate.
Methods and Materials
Cine CT images from a commercial CT scanner were used to form maximum intensity projection (MIP) and respiratory-averaged CT (RACT) image sets. These image sets then were used together to define targets for radiotherapy. Phantoms oscillating under irregular motion were used to assess differences between contouring on cine CT and 4D-CT. We also retrospectively reviewed image sets for 27 patients at our institution who received stereotactic radiotherapy for stage I non-small cell lung cancer. Patients were included if tumor motion was greater than 1 cm. Lesions were first contoured using MIP and RACT image sets processed from cine CT, then with 4D-CT MIP and 10-phase image sets. Mean ratios of volume magnitude were compared with intraobserver variation, mean centroid shifts were calculated, and volume overlap was assessed with the normalized Dice similarity coefficient index.
Results
The phantom studies demonstrated that cine CT captured a greater extent of irregular tumor motion than 4D-CT, producing a larger tumor volume. The patient studies demonstrated that gross tumor defined on cine imaging was similar to or slightly larger than that defined on 4D-CT.
Conclusions
Cine CT is a promising alternative to 4D-CT for stereotactic radiation treatment planning.
doi:10.1016/j.ijrobp.2008.04.047
PMCID: PMC4160118  PMID: 18644683
4D-CT; cine CT; contouring

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