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Sample records for previously identified human

  1. Human stool contains a previously unrecognized diversity of novel astroviruses

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    Zhao Guoyan

    2009-10-01

    Full Text Available Abstract Human astroviruses are a leading cause of gastrointestinal disease. Since their discovery in 1975, 8 closely related serotypes have been described in humans, and more recently, two new astrovirus species, astrovirus MLB1 and astrovirus VA1, were identified in diarrhea patients. In this study, we used consensus astrovirus primers targeting the RNA polymerase to define the diversity of astroviruses present in pediatric patients with diarrhea on two continents. From 416 stool specimens comprising two different cohorts from Vellore, India, 35 samples were positive. These positive samples were analyzed further by either sequencing of the ~400 bp amplicon generated by the consensus PCR or by performing additional RT-PCR specific for individual astroviruses. 19 samples contained the classic human astrovirus serotypes 1-8 while 7 samples were positive for the recently described astrovirus MLB1. Strikingly, from samples that were positive in the consensus PCR screen but negative in the specific PCR assays, five samples contained sequences that were highly divergent from all previously described astroviruses. Sequence analysis suggested that three novel astroviruses, tentatively named astroviruses VA2, MLB2 and VA3, were present in these five patient specimens (AstV-VA2 in 2 patients, AstV-MLB2 in 2 patients and AstV-VA3 in one patient. Using the same RT-PCR screening strategy, 13 samples out of 466 tested stool specimens collected in St. Louis, USA were positive. Nine samples were positive for the classic human astroviruses. One sample was positive for AstV-VA2, and 3 samples were positive for AstV-MLB2 demonstrating that these two viruses are globally widespread. Collectively, these findings underscore the tremendous diversity of astroviruses present in fecal specimens from diarrhea patients. Given that a significant fraction of diarrhea etiologies is currently unknown, it is plausible that these or other yet unrecognized astroviruses may be

  2. Change in knee flexor torque after fatiguing exercise identifies previous hamstring injury in football players.

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    Lord, C; Ma'ayah, F; Blazevich, A J

    2018-03-01

    Muscular fatigue and interlimb strength asymmetry are factors known to influence hamstring injury risk; however, limb-specific exacerbation of knee flexor (hamstrings) torque production after fatiguing exercise has previously been ignored. To investigate changes in muscular force production before and after sport-specific (repeated-sprint) and non-specific (knee extension-flexion) fatiguing exercise, and explore the sensitivity and specificity of isokinetic endurance (ie, muscle-specific) and single-leg vertical jump (ie, whole limb) tests to identify previous hamstring injury. Twenty Western Australia State League footballers with previous unilateral hamstring injury and 20 players without participated. Peak concentric knee extensor and flexor (180°∙s -1 ) torques were assessed throughout an isokinetic endurance test, which was then repeated alongside a single-leg vertical jump test before and after maximal repeated-sprint exercise. Greater reductions in isokinetic knee flexor torque (-16%) and the concentric hamstring:quadriceps peak torque ratio (-15%) were observed after repeated-sprint running only in the injured (kicking) leg and only in the previously injured subjects. Changes in (1) peak knee flexor torque after repeated-sprint exercise, and (2) the decline in knee flexor torque during the isokinetic endurance test measured after repeated-sprint exercise, correctly identified the injured legs (N = 20) within the cohort (N = 80) with 100% specificity and sensitivity. Decreases in peak knee flexor torque and the knee flexor torque during an isokinetic endurance test after repeated-sprint exercise identified previous hamstring injury with 100% accuracy. Changes in knee flexor torque, but not SLVJ, should be tested to determine its prospective ability to predict hamstring injury in competitive football players. © 2017 The Authors. Scandinavian Journal of Medicine & Science In Sports Published by John Wiley & Sons Ltd.

  3. Thyroid disease awareness is associated with high rates of identifying subjects with previously undiagnosed thyroid dysfunction.

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    Canaris, Gay J; Tape, Thomas G; Wigton, Robert S

    2013-04-16

    Conventional screening for hypothyroidism is controversial. Although hypothyroidism is underdiagnosed, many organizations do not recommend screening, citing low disease prevalence in unselected populations. We studied attendees at a thyroid health fair, hypothesizing that certain patient characteristics would enhance the yield of testing. We carried out an observational study of participants at a Michigan health fair that focused on thyroid disease. We collected patient-reported symptoms and demographics by questionnaire, and correlated these with the TSH values obtained through the health fair. 794 of 858 health fair attendees participated. Most were women, and over 40% reported a family history of thyroid disease. We identified 97 (12.2%) participants with previously unknown thyroid dysfunction. No symptom or combination of symptoms discriminated between hypothyroid and euthyroid individuals. Hypothyroid and euthyroid participants in the health fair reported each symptom with a similar prevalence (p > 0.01), a prevalence which was very high. In fact, when compared with a previously published case-control study that reported symptoms, the euthyroid health fair participants reported a higher symptom prevalence (range 3.9% to 66.3%, mean 31.5%), than the euthyroid individuals from the case-control study (range 2% to 54%, mean 17.4%). A high proportion of previously undiagnosed thyroid disease was identified at this health fair. We initially hypothesized symptoms would distinguish between thyroid function states. However, this was not the case in this health fair screening population. The prevalence of reported symptoms was similar and high in both euthyroid and hypothyroid participants. Because attendees were self-selected, it is possible that this health fair that focused on thyroid disease attracted participants specifically concerned about thyroid health. Despite the lack of symptom discrimination, the much higher prevalence of hypothyroidism in this study

  4. Streptococcus oralis previously identified as uncommon 'Streptococcus sanguis' in Behçet's disease.

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    Narikawa, S; Suzuki, Y; Takahashi, M; Furukawa, A; Sakane, T; Mizushima, Y

    1995-08-01

    The relation between the biochemical and serological properties of 'Streptococcus sanguis' was studied to characterize the strains isolated from dental plaque of patients with Behçet's disease and controls. Seven reference and 100 clinical strains preserved by the Behçet's Disease Research Committee of Japan were identified using established criteria and differentiated with antisera against Strep. oralis ATCC 10557, Strep. sanguis ATCC 10556 and 'Strep. sanguis' ST7, compatible with the criteria. Uncommon serovars (serotypes) KTH-1 (= ATCC 49298), KTH-2 (= ATCC 49296), KTH-3 (= ATCC KTH-4 (= ATCC 49297) and B220 (serovar KTH-1) with both IgA1 protease and neuraminidase (sialidase) were identified as Strep. oralis, whereas common serovars ST3 with IgA1 protease alone and ST7 without both enzymes were identified as Strep. sanguis and Strep. gordonii, respectively. Isolates previously ranked as uncommon serovars were identified as Strep. oralis, whereas the rest ranked as common serovars were identified as the same species as those of the grouping strains. A soft-agar technique was available for species identification except for Strep. oralis serovar KTH-1 reacting with the antiserum against Strep. gordonii ST7. The frequency of isolation of Strep. oralis was higher in Behçet's disease (52%) than in controls (38%), but no difference was observed between the properties of the two groups of isolates. Strep. oralis virulence factors may be involved in breach the mucosal barrier in patients with specific reactivity to these antigens and inducing Behçet's disease.

  5. From The Cover: Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation

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    Nollen, Ellen A. A.; Garcia, Susana M.; van Haaften, Gijs; Kim, Soojin; Chavez, Alejandro; Morimoto, Richard I.; Plasterk, Ronald H. A.

    2004-04-01

    Protein misfolding and the formation of aggregates are increasingly recognized components of the pathology of human genetic disease and hallmarks of many neurodegenerative disorders. As exemplified by polyglutamine diseases, the propensity for protein misfolding is associated with the length of polyglutamine expansions and age-dependent changes in protein-folding homeostasis, suggesting a critical role for a protein homeostatic buffer. To identify the complement of protein factors that protects cells against the formation of protein aggregates, we tested transgenic Caenorhabditis elegans strains expressing polyglutamine expansion yellow fluorescent protein fusion proteins at the threshold length associated with the age-dependent appearance of protein aggregation. We used genome-wide RNA interference to identify genes that, when suppressed, resulted in the premature appearance of protein aggregates. Our screen identified 186 genes corresponding to five principal classes of polyglutamine regulators: genes involved in RNA metabolism, protein synthesis, protein folding, and protein degradation; and those involved in protein trafficking. We propose that each of these classes represents a molecular machine collectively comprising the protein homeostatic buffer that responds to the expression of damaged proteins to prevent their misfolding and aggregation. protein misfolding | neurodegenerative diseases

  6. Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins

    International Nuclear Information System (INIS)

    Abulí, Anna; Morillas, Juan D; Rigau, Joaquim; Latorre, Mercedes; Fernández-Bañares, Fernando; Peña, Elena; Riestra, Sabino; Payá, Artemio; Jover, Rodrigo; Xicola, Rosa M; Llor, Xavier; Fernández-Rozadilla, Ceres; Carvajal-Carmona, Luis; Villanueva, Cristina M; Moreno, Victor; Piqué, Josep M; Carracedo, Angel; Castells, Antoni; Andreu, Montserrat; Ruiz-Ponte, Clara; Castellví-Bel, Sergi; Alonso-Espinaco, Virginia; Muñoz, Jenifer; Gonzalo, Victoria; Bessa, Xavier; González, Dolors; Clofent, Joan; Cubiella, Joaquin

    2011-01-01

    Colorectal cancer (CRC) is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low-penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase) are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category) and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium. CRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in ADH1C, APC, CCDN1, IL6, IL8, IRS1, MTHFR, PPARG, VDR and ARL11, and 18 selected variants in the mucin gene family. None of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a P-value < 0.05 in EPICOLON stage 1 [rs698 in ADH1C (OR = 1.63, 95% CI = 1.06-2.50, P-value = 0.02, recessive), rs1800795 in IL6 (OR = 1.62, 95% CI = 1.10-2.37, P-value = 0.01, recessive), rs3803185 in ARL11 (OR = 1.58, 95% CI = 1.17-2.15, P-value = 0.007, codominant), and rs2102302 in GALNTL2 (OR = 1.20, 95% CI = 1.00-1.44, P-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06-1.69, P-value = 0.01, recessive). In the joint analysis for both stages, results were only significant for rs3803185 (OR = 1.12, 95% CI = 1

  7. Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins

    Directory of Open Access Journals (Sweden)

    Moreno Victor

    2011-08-01

    Full Text Available Abstract Background Colorectal cancer (CRC is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low-penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium. Methods CRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in ADH1C, APC, CCDN1, IL6, IL8, IRS1, MTHFR, PPARG, VDR and ARL11, and 18 selected variants in the mucin gene family. Results None of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a P-value ADH1C (OR = 1.63, 95% CI = 1.06-2.50, P-value = 0.02, recessive, rs1800795 in IL6 (OR = 1.62, 95% CI = 1.10-2.37, P-value = 0.01, recessive, rs3803185 in ARL11 (OR = 1.58, 95% CI = 1.17-2.15, P-value = 0.007, codominant, and rs2102302 in GALNTL2 (OR = 1.20, 95% CI = 1.00-1.44, P-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06-1.69, P-value = 0.01, recessive. In the joint analysis for both stages, results were only significant for rs3803185 (OR = 1

  8. Reproductive compatibility between mite populations previously identified as Euseius concordis (Acari: Phytoseiidae).

    Science.gov (United States)

    Noronha, Aloyséia Cristina da Silva; de Moraes, Gilberto José

    2004-01-01

    The objective of the present research is to study the reproductive compatibility between populations of predatory mites previously identified as Euseius concordis (Chant) based on morphological characteristics. Colonies of these mite populations were established in the lab with specimens collected from different localities and host plants. Reproductive compatibility was evaluated through crosses and backcrosses within and between populations and the subsequent observation of females' oviposition, over a period of 10 days. The levels of oviposition obtained in the crosses between individuals from the same population were higher than those obtained in the crosses between individuals from different populations. Results indicate the occurrence of post-mating reproductive incompatibility between the mite population from Petrolina and the other populations studied. Crosses and backcrosses between populations involving female mites from Petrolina did not produce offspring, although endospermatophores were present inside the spermathecas of those females. Oviposition was reduced, and only sons were obtained, in crosses between populations with males from Petrolina. Crosses of females from Pontes e Lacerda and males from Jaguariúna and vice versa produced only male progeny. Our results established that the populations originating from Arroio do Meio, Pontes e Lacerda, Jaguarúna and Viçosa, are reproductively compatible. However, the latter populations and the population from Petrolina are genetically isolated. Based on these results we suggest that more cytological and genetic studies are needed to establish if this reproductive isolation represents a species barrier.

  9. Targeted pathologic evaluation of bone marrow donors identifies previously undiagnosed marrow abnormalities.

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    Tilson, Matthew P; Jones, Richard J; Sexauer, Amy; Griffin, C A; Morsberger, Laura A; Batista, Denise A S; Small, Donald; Burns, Kathleen H; Gocke, Christopher D; Vuica-Ross, Milena; Borowitz, Michael J; Duffield, Amy S

    2013-08-01

    Potential bone marrow donors are screened to ensure the safety of both the donor and recipient. At our institution, potential donors with abnormal peripheral blood cell counts, a personal history of malignancy, or age >60 years are evaluated to ensure that they are viable candidates for donation. Evaluation of the marrow includes morphologic, flow cytometric, and cytogenetic studies. A total of 122 potential donors were screened between the years of 2001 and 2011, encompassing approximately 10% of all donors. Of the screened potential donors, the mean age was 59 years and there were 59 men and 63 women. The donors were screened because of age >60 years (n = 33), anemia (n = 22), cytopenias other than anemia (n = 27), elevated peripheral blood counts without a concurrent cytopenia (n = 20), elevated peripheral blood counts with a concurrent cytopenia (n = 10), history of malignancy (n = 4), abnormal peripheral blood differential (n = 3), prior graft failure (n = 1), history of treatment with chemotherapy (n = 1), and body habitus (n = 1). Marrow abnormalities were detected in 9% (11 of 122) of donors. These donors were screened because of anemia (5 of 22, 23%), age >60 years (2 of 33, 6%), history of malignancy (2 of 4, 50%), elevated peripheral blood counts (1 of 20, 5%), and body habitus (1 of 1, 100%). Abnormalities included plasma cell dyscrasia (n = 3), abnormal marrow cellularity (n = 3), clonal cytogenetic abnormalities (n = 2), low-grade myelodysplastic syndrome (1), a mutated JAK2 V617F allele (n = 1), and monoclonal B cell lymphocytosis (n = 1). Our experience indicates that extended screening of potential donors identifies a significant number of donors with previously undiagnosed marrow abnormalities. Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  10. 76 FR 59488 - Addition to the Identifying Information for an Individual Previously Designated Pursuant to...

    Science.gov (United States)

    2011-09-26

    ... information for the following individual who was previously designated pursuant to the Order: GRAJALES PUENTES...; Cedula No. 52455790 (Colombia) (individual) [SDNT] The listing now appears as follows: GRAJALES PUENTES...

  11. Using an epiphytic moss to identify previously unknown sources of atmospheric cadmium pollution

    Science.gov (United States)

    Geoffrey H. Donovan; Sarah E. Jovan; Demetrios Gatziolis; Igor Burstyn; Yvonne L. Michael; Michael C. Amacher; Vicente J. Monleon

    2016-01-01

    Urban networks of air-quality monitors are often too widely spaced to identify sources of air pollutants, especially if they do not disperse far from emission sources. The objectives of this study were to test the use of moss bio-indicators to develop a fine-scale map of atmospherically-derived cadmium and to identify the sources of cadmium in a complex urban setting....

  12. Detection of previously undiagnosed cases of COPD in a high-risk population identified in general practice

    DEFF Research Database (Denmark)

    Løkke, Anders; Ulrik, Charlotte Suppli; Dahl, Ronald

    2012-01-01

    Background and Aim: Under-diagnosis of COPD is a widespread problem. This study aimed to identify previously undiagnosed cases of COPD in a high-risk population identified through general practice. Methods: Participating GPs (n = 241) recruited subjects with no previous diagnosis of lung disease,...

  13. Intensive sampling identifies previously unknown chemotypes, population divergence and biosynthetic connections among terpenoids in Eucalyptus tricarpa.

    Science.gov (United States)

    Andrew, Rose L; Keszei, Andras; Foley, William J

    2013-10-01

    Australian members of the Myrtaceae produce large quantities of ecologically and economically important terpenes and display abundant diversity in both yield and composition of their oils. In a survey of the concentrations of leaf terpenes in Eucalyptus tricarpa (L.A.S. Johnson) L.A.S. Johnson & K.D. Hill, which were previously known from few samples, exceptional variability was found in composition. The aim was to characterize the patterns of variation and covariation among terpene components in this species and to use this information to enhance our understanding of their biosynthesis. There were marked discontinuities in the distributions of numerous compounds, including the overall proportions of mono- and sesquiterpenes, leading us to delineate three distinct chemotypes. Overall, positive covariation predominated, but negative covariation suggested competitive interactions involved in monoterpene synthesis. Two groups of covarying monoterpenes were found, each of which was positively correlated with a group of sesquiterpenes and negatively correlated with the alternate sesquiterpene group. These results imply substantial cross-talk between mono- and sesquiterpene biosynthesis pathways. However, only those compounds hypothesized to share final carbocation intermediates or post-processing steps were strongly positively correlated within chemotypes. This suggests that the broader patterns of covariation among groups of compounds may result from co-regulation of multiple biosynthetic genes, controlling the complex terpene profiles of the chemotypes of Eucalyptus. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Using an epiphytic moss to identify previously unknown sources of atmospheric cadmium pollution

    Energy Technology Data Exchange (ETDEWEB)

    Donovan, Geoffrey H., E-mail: gdonovan@fs.fed.us [USDA Forest Service, PNW Research Station, 620 SW Main, Suite 400, Portland, OR 97205 (United States); Jovan, Sarah E., E-mail: sjovan@fs.fed.us [USDA Forest Service, PNW Research Station, 620 SW Main, Suite 400, Portland, OR 97205 (United States); Gatziolis, Demetrios, E-mail: dgatziolis@fs.fed.us [USDA Forest Service, PNW Research Station, 620 SW Main, Suite 400, Portland, OR 97205 (United States); Burstyn, Igor, E-mail: igor.burstyn@drexel.edu [Dornsife School of Public Health, Drexel University, Nesbitt Hall, 3215 Market St, Philadelphia, PA 19104 (United States); Michael, Yvonne L., E-mail: ylm23@drexel.edu [Dornsife School of Public Health, Drexel University, Nesbitt Hall, 3215 Market St, Philadelphia, PA 19104 (United States); Amacher, Michael C., E-mail: mcamacher1@outlook.com [USDA Forest Service, Logan Forest Sciences Laboratory, 860 North 1200 East, Logan, UT 84321 (United States); Monleon, Vicente J., E-mail: vjmonleon@fs.fed.us [USDA Forest Service, PNW Research Station, 3200 SW Jefferson Way, Corvallis, OR 97331 (United States)

    2016-07-15

    Urban networks of air-quality monitors are often too widely spaced to identify sources of air pollutants, especially if they do not disperse far from emission sources. The objectives of this study were to test the use of moss bio-indicators to develop a fine-scale map of atmospherically-derived cadmium and to identify the sources of cadmium in a complex urban setting. We collected 346 samples of the moss Orthotrichum lyellii from deciduous trees in December, 2013 using a modified randomized grid-based sampling strategy across Portland, Oregon. We estimated a spatial linear model of moss cadmium levels and predicted cadmium on a 50 m grid across the city. Cadmium levels in moss were positively correlated with proximity to two stained-glass manufacturers, proximity to the Oregon–Washington border, and percent industrial land in a 500 m buffer, and negatively correlated with percent residential land in a 500 m buffer. The maps showed very high concentrations of cadmium around the two stained-glass manufacturers, neither of which were known to environmental regulators as cadmium emitters. In addition, in response to our findings, the Oregon Department of Environmental Quality placed an instrumental monitor 120 m from the larger stained-glass manufacturer in October, 2015. The monthly average atmospheric cadmium concentration was 29.4 ng/m{sup 3}, which is 49 times higher than Oregon's benchmark of 0.6 ng/m{sup 3}, and high enough to pose a health risk from even short-term exposure. Both stained-glass manufacturers voluntarily stopped using cadmium after the monitoring results were made public, and the monthly average cadmium levels precipitously dropped to 1.1 ng/m{sup 3} for stained-glass manufacturer #1 and 0.67 ng/m{sup 3} for stained-glass manufacturer #2. - Highlights: • Bio-indicators are a valid method for measuring atmospheric pollutants • We used moss to map atmospheric cadmium in Portland, Oregon • Using a spatial linear model, we identified two

  15. Human papilloma virus identification in breast cancer patients with previous cervical neoplasia

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    James Sutherland Lawson

    2016-01-01

    Full Text Available Purpose: Women with human papilloma virus (HPV associated cervical neoplasia have a higher risk of developing breast cancer than the general female population. The purpose of this study was to (i identify high risk for cancer HPVs in cervical neoplasia and subsequent HPV positive breast cancers which developed in the same patients and (ii determine if these HPVs were biologically active.Methods: A range of polymerase chain reaction (PCR and immunohistochemical techniques were used to conduct a retrospective cohort study of cervical precancers and subsequent breast cancers in the same patients. Results: The same high risk HPV types were identified in both the cervical and breast specimens in 13 (46% of 28 patients. HPV type 18 was the most prevalent. HPVs appeared to be biologically active as demonstrated by the expression of HPV E7 proteins and the presence of HPV associated koilocytes. The average age of these patients diagnosed with breast cancer following prior cervical precancer was 51 years, as compared to 60 years for all women with breast cancer (p for difference = 0.001. Conclusions: These findings indicate that high risk HPVs can be associated with cervical neoplasia and subsequent young age breast cancer. However these associations are unusual and are a very small proportion of breast cancers. These outcomes confirm and extend the observations of 2 similar previous studies and offer one explanation for the increased prevalence of serious invasive breast cancer among young women.

  16. Identifying Requirements for Effective Human-Automation Teamwork

    Energy Technology Data Exchange (ETDEWEB)

    Jeffrey C. Joe; John O' Hara; Heather D. Medema; Johanna H. Oxstrand

    2014-06-01

    Previous studies have shown that poorly designed human-automation collaboration, such as poorly designed communication protocols, often leads to problems for the human operators, such as: lack of vigilance, complacency, and loss of skills. These problems often lead to suboptimal system performance. To address this situation, a considerable amount of research has been conducted to improve human-automation collaboration and to make automation function better as a “team player.” Much of this research is based on an understanding of what it means to be a good team player from the perspective of a human team. However, the research is often based on a simplified view of human teams and teamwork. In this study, we sought to better understand the capabilities and limitations of automation from the standpoint of human teams. We first examined human teams to identify the principles for effective teamwork. We next reviewed the research on integrating automation agents and human agents into mixed agent teams to identify the limitations of automation agents to conform to teamwork principles. This research resulted in insights that can lead to more effective human-automation collaboration by enabling a more realistic set of requirements to be developed based on the strengths and limitations of all agents.

  17. Activation of two forms of locomotion by a previously identified trigger interneuron for swimming in the medicinal leech.

    Science.gov (United States)

    Brodfuehrer, Peter D; McCormick, Kathryn; Tapyrik, Lauren; Albano, Alfonso M; Graybeal, Carolyn

    2008-03-01

    Higher-order projection interneurons that function in more than one behavior have been identified in a number of preparations. In this study, we document that stimulation of cell Tr1, a previously identified trigger interneuron for swimming in the medicinal leech, can also elicit the motor program for crawling in isolated nerve cords. We also show that motor choice is independent of the firing frequency of Tr1 and amount of spiking activity recorded extracellularly at three locations along the ventral nerve cord prior to Tr1 stimulation. On the other hand, during Tr1 stimulation there is a significant difference in the amount of activity elicited in the ventral nerve cord that correlates with the motor program activated. On average, Tr1 stimulation trials that lead to crawling elicit greater amounts of activity than in trials that lead to swimming.

  18. Metabolites of cannabidiol identified in human urine.

    Science.gov (United States)

    Harvey, D J; Mechoulam, R

    1990-03-01

    1. Urine from a dystonic patient treated with cannabidiol (CBD) was examined by g.l.c.-mass spectrometry for CBD metabolites. Metabolites were identified as their trimethylsilyl (TMS), [2H9]TMS, and methyl ester/TMS derivatives and as the TMS derivatives of the product of lithium aluminium deuteride reduction. 2. Thirty-three metabolites were identified in addition to unmetabolized CBD, and a further four metabolites were partially characterized. 3. The major metabolic route was hydroxylation and oxidation at C-7 followed by further hydroxylation in the pentyl and propenyl groups to give 1"-, 2"-, 3"-, 4"- and 10-hydroxy derivatives of CBD-7-oic acid. Other metabolites, mainly acids, were formed by beta-oxidation and related biotransformations from the pentyl side-chain and these were also hydroxylated at C-6 or C-7. The major oxidized metabolite was CBD-7-oic acid containing a hydroxyethyl side-chain. 4. Two 8,9-dihydroxy compounds, presumably derived from the corresponding epoxide were identified. 5. Also present were several cyclized cannabinoids including delta-6- and delta-1-tetrahydrocannabinol and cannabinol. 6. This is the first metabolic study of CBD in humans; most observed metabolic routes were typical of those found for CBD and related cannabinoids in other species.

  19. Cultivation-based multiplex phenotyping of human gut microbiota allows targeted recovery of previously uncultured bacteria

    DEFF Research Database (Denmark)

    Rettedal, Elizabeth; Gumpert, Heidi; Sommer, Morten

    2014-01-01

    show that carefully designed conditions enable cultivation of a representative proportion of human gut bacteria, enabling rapid multiplex phenotypic profiling. We use this approach to determine the phylogenetic distribution of antibiotic tolerance phenotypes for 16 antibiotics in the human gut...... microbiota. Based on the phenotypic mapping, we tailor antibiotic combinations to specifically select for previously uncultivated bacteria. Utilizing this method we cultivate and sequence the genomes of four isolates, one of which apparently belongs to the genus Oscillibacter; uncultivated Oscillibacter...

  20. Association between previously identified loci affecting telomere length and coronary heart disease (CHD in Han Chinese population

    Directory of Open Access Journals (Sweden)

    Ding H

    2014-05-01

    Full Text Available Hui Ding,1 Fen Yan,1 Lin-Lin Zhou,2 Xiu-Hai Ji,3 Xin-Nan Gu,1 Zhi-Wei Tang,1 Ru-Hua Chen11Department of Pulmonary Medicine, The Affiliated Yixing People's Hospital, Jiangsu University, Zhenjiang, Jiangsu Province, 2Department of Cardiology, Affiliated Cixi Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, 3Department of Oncology, Affiliated Taicang Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu Province, People's Republic of ChinaPurpose: To replicate previously confirmed telomere-length loci in a Chinese Han population with coronary heart disease (CHD, and investigate these loci and the possibility of and age at onset of CHD.Patients and methods: 1514 CHD patients and 2470 normal controls were recruited. Medical data including age, sex, body mass index, lipid profiles, history of hypertension, type 2 diabetes mellitus, and dyslipidemia were collected from all the participants. Seven previously identified single-nucleotide polymorphisms (SNPs related to leucocyte telomere length were genotyped, including rs10936599 in TERC, rs2736100 in TERT, rs7675998 in NAF1, rs9420907 in OBFC1, rs8105767 in ZNF208, rs755017 in RTEL1, and rs11125529 in ACYP2.Results: No significant difference in genotype frequencies from the Hardy–Weinberg equilibrium test was noted for all tested SNPs both in the CHD patients and the normal controls. No polymorphism was observed for rs9420907, and AA genotype was noted in both the CHD patients and the controls. Neither the genotype nor the allele frequencies of rs2736100, rs8105767, rs11125529, and rs2967374 were significantly different between the CHD patients and the normal controls. For rs10936599 and rs755017, statistical difference was found for the allele frequency but not genotype. Distributions of genotype and allele were significantly different between the two groups for rs7675998. The odds ratio for carriers of CHD was 2.127 (95% confidence interval: 1.909–2.370 for the A allele of rs

  1. 2-methyl butyramide, a previously identified urine biomarker for Ascaris lumbricoides, is not present in infected Indonesian individuals.

    Science.gov (United States)

    Lagatie, Ole; Njumbe Ediage, Emmanuel; Pikkemaat, Jeroen A; Djuardi, Yenny; Stuyver, Lieven J

    2017-12-29

    ᅟ: Previous reports suggest that the 2-methyl butyramide and 2-methyl valeramide metabolites of Ascaris lumbricoides in urine of infected individuals could be considered as urinary biomarkers for active infection. We have developed an LC-MS method with a detection limit of 10 ng/mL using synthetic chemicals as reference material. Urine samples (n = 21) of infected individuals were analyzed for the presence of these metabolites, but they were not detected in any of the samples. Furthermore, the recorded 1 H-NMR spectrum for reference 2-methyl butyramide did not match with the spectrum that was described for the Ascaris metabolite. Based on these two observations, we concluded that the urinary biomarkers that were detected for A. lumbricoides infection are not 2-methyl butyramide nor 2-methylvaleramide. New discovery efforts will be required to identify the structure of these metabolite biomarkers in urine of infected individuals. Urine samples used in this study were collected as part of a clinical trial with trial number ISRCTN75636394 (12 November 2013).

  2. Transcriptomic analysis in a Drosophila model identifies previously implicated and novel pathways in the therapeutic mechanism in neuropsychiatric disorders

    Directory of Open Access Journals (Sweden)

    Priyanka eSingh

    2011-03-01

    Full Text Available We have taken advantage of a newly described Drosophila model to gain insights into the potential mechanism of antiepileptic drugs (AEDs, a group of drugs that are widely used in the treatment of several neurological and psychiatric conditions besides epilepsy. In the recently described Drosophila model that is inspired by pentylenetetrazole (PTZ induced kindling epileptogenesis in rodents, chronic PTZ treatment for seven days causes a decreased climbing speed and an altered CNS transcriptome, with the latter mimicking gene expression alterations reported in epileptogenesis. In the model, an increased climbing speed is further observed seven days after withdrawal from chronic PTZ. We used this post-PTZ withdrawal regime to identify potential AED mechanism. In this regime, treatment with each of the five AEDs tested, namely, ethosuximide (ETH, gabapentin (GBP, vigabatrin (VGB, sodium valproate (NaVP and levetiracetam (LEV, resulted in rescuing of the altered climbing behavior. The AEDs also normalized PTZ withdrawal induced transcriptomic perturbation in fly heads; whereas AED untreated flies showed a large number of up- and down-regulated genes which were enriched in several processes including gene expression and cell communication, the AED treated flies showed differential expression of only a small number of genes that did not enrich gene expression and cell communication processes. Gene expression and cell communication related upregulated genes in AED untreated flies overrepresented several pathways - spliceosome, RNA degradation, and ribosome in the former category, and inositol phosphate metabolism, phosphatidylinositol signaling, endocytosis and hedgehog signaling in the latter. Transcriptome remodeling effect of AEDs was overall confirmed by microarray clustering that clearly separated the profiles of AED treated and untreated flies. Besides being consistent with previously implicated pathways, our results provide evidence for a role of

  3. Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci

    Science.gov (United States)

    Zubair, Niha; Luis Ambite, Jose; Bush, William S.; Kichaev, Gleb; Lu, Yingchang; Manichaikul, Ani; Sheu, Wayne H-H.; Absher, Devin; Assimes, Themistocles L.; Bielinski, Suzette J.; Bottinger, Erwin P.; Buzkova, Petra; Chuang, Lee-Ming; Chung, Ren-Hua; Cochran, Barbara; Dumitrescu, Logan; Gottesman, Omri; Haessler, Jeffrey W.; Haiman, Christopher; Heiss, Gerardo; Hsiung, Chao A.; Hung, Yi-Jen; Hwu, Chii-Min; Juang, Jyh-Ming J.; Le Marchand, Loic; Lee, I-Te; Lee, Wen-Jane; Lin, Li-An; Lin, Danyu; Lin, Shih-Yi; Mackey, Rachel H.; Martin, Lisa W.; Pasaniuc, Bogdan; Peters, Ulrike; Predazzi, Irene; Quertermous, Thomas; Reiner, Alex P.; Robinson, Jennifer; Rotter, Jerome I.; Ryckman, Kelli K.; Schreiner, Pamela J.; Stahl, Eli; Tao, Ran; Tsai, Michael Y.; Waite, Lindsay L.; Wang, Tzung-Dau; Buyske, Steven; Ida Chen, Yii-Der; Cheng, Iona; Crawford, Dana C.; Loos, Ruth J.F.; Rich, Stephen S.; Fornage, Myriam; North, Kari E.; Kooperberg, Charles; Carty, Cara L.

    2016-01-01

    Abstract Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies. PMID:28426890

  4. Examination of Previously Published Data to Identify Patterns in the Social Representation of 'Hearing Aids' Across Countries.

    Science.gov (United States)

    Manchaiah, Vinaya; Ratinaud, Pierre; Tympas, Aristotle; Danermark, Berth; Germundsson, Per

    2018-04-01

    Societal factors seem to exercise a strong influence on hearing aid uptake, use, and satisfaction. In particular, knowledge, perception, and attitude of people will have bearing towards their and others health behavior and decisions. The current study aimed at understanding the perception of hearing aids by adults belonging to the general population in different countries. The study employed a crosssectional design. A sample of 404 adults from India, Iran, Portugal, and the United Kingdom were recruited by relying on a convenience sampling. Previously published data was re-analyzed but it was applied for different approach. Free association task was used to collect the data. They were asked to provide up to five words or phrases that come to mind when thinking about "hearing aids." The data was initially analyzed based on qualitative content analysis. This was followed by quantitative cluster analysis and chi square analysis. The content analysis suggested 39 main categories of responses related to hearing aids. The cluster analysis resulted in five main clusters, namely: 1) positive attitude, 2) external factors, 3) hearing aid use and satisfaction, 4) etiology, and 5) benefits and limitations of technology. A few demographic factors (i.e., education, occupation type, country) showed association with different clusters, although country of origin seemed to be associated with most clusters. The study provides us with unique insights into the perception of hearing aids by the general public, and additionally, the way demographic variables may influence these perceptions.

  5. Reciprocity, culture and human cooperation: previous insights and a new cross-cultural experiment.

    Science.gov (United States)

    Gächter, Simon; Herrmann, Benedikt

    2009-03-27

    Understanding the proximate and ultimate sources of human cooperation is a fundamental issue in all behavioural sciences. In this paper, we review the experimental evidence on how people solve cooperation problems. Existing studies show without doubt that direct and indirect reciprocity are important determinants of successful cooperation. We also discuss the insights from a large literature on the role of peer punishment in sustaining cooperation. The experiments demonstrate that many people are 'strong reciprocators' who are willing to cooperate and punish others even if there are no gains from future cooperation or any other reputational gains. We document this in new one-shot experiments, which we conducted in four cities in Russia and Switzerland. Our cross-cultural approach allows us furthermore to investigate how the cultural background influences strong reciprocity. Our results show that culture has a strong influence on positive and in especially strong negative reciprocity. In particular, we find large cross-cultural differences in 'antisocial punishment' of pro-social cooperators. Further cross-cultural research and experiments involving different socio-demographic groups document that the antisocial punishment is much more widespread than previously assumed. Understanding antisocial punishment is an important task for future research because antisocial punishment is a strong inhibitor of cooperation.

  6. Effect of previous exhaustive exercise on metabolism and fatigue development during intense exercise in humans

    DEFF Research Database (Denmark)

    Iaia, F. M.; Perez-Gomez, J.; Nordsborg, Nikolai

    2010-01-01

    The present study examined how metabolic response and work capacity are affected by previous exhaustive exercise. Seven subjects performed an exhaustive cycle exercise ( approximately 130%-max; EX2) after warm-up (CON) and 2 min after an exhaustive bout at a very high (VH; approximately 30 s), high...... during a repeated high-intensity exercise lasting 1/2-2 min....

  7. A comparison between previous and present histologic assessments of chronic hepatitis C viral infections in humans

    OpenAIRE

    Assy, N; Minuk, GY

    1999-01-01

    AIM To compare the previously employed classification of liver histology (minimal, chronic persistent hepatitis, chronic active hepatitis and cirrhosis) with a new classification recently described by Sheuer et al (activity grade and fibrosis stage) in percutaneous liver biopsies from patients with chronic hepatitis C viral infections.

  8. Sexual Liberalism-Conservatism: the effect of human values, gender, and previous sexual experience.

    Science.gov (United States)

    Guerra, Valeschka M; Gouveia, Valdiney V; Sousa, Deliane M; Lima, Tiago J; Freires, Leogildo A

    2012-08-01

    Despite theoretical associations, there is a lack of empirical studies on the axiological basis of sexual liberalism-conservatism. Two studies demonstrated important associations between these constructs for young adults. In Study 1, participants were 353 undergraduate students with a mean age of 20.13 (SD = 1.84), who completed the Sexual Liberalism-Conservatism Scale and the Basic Values Survey. In Study 2, participants were 269 undergraduate students, with a mean age of 20.3 (SD = 1.82), who completed a social desirability scale in addition to Study 1 instruments. Results showed how values can predict sexual liberalism-conservatism after controlling for social desirability. Attitudes towards one's own sexual behavior were more conservative whereas attitudes towards other's sexual behavior were more liberal. Gender was not a significant predictor of sexual attitudes whereas previous sexual experience showed a significant association to this construct. In general, results corroborated previous findings, showing that participants with a tendency to present socially desirable answers also tended to present themselves as sexually conservative.

  9. Human Development in Romania: A Comparative Approach to Identifying Shortcomings

    Directory of Open Access Journals (Sweden)

    Robert STEFAN

    2017-12-01

    Full Text Available Following the research carried out by the economist Mahbub ul Haq, derived from the studies of Amartya Sen on human capabilities, in 1990, the United Nations Development Programme (UNDP published its first Human Development Report. It introduced the notion that development of a country is not merely equal to economic growth, but has the ultimate purpose of enriching human life by expanding people’s choices. Thus, Human Development seeks to reveal the fundamental role of human life: that of reaching its full potential. Even after 28 years since the fall of communism, the political environment in Romania continues to be unsopportive of proper development. This study seeks to identify the shortcomings of the primary dimensions of Human Development in Romania and hopefully make a firm and rhetorical call to action.

  10. Proteogenomic Analysis Identifies a Novel Human SHANK3 Isoform

    Directory of Open Access Journals (Sweden)

    Fahad Benthani

    2015-05-01

    Full Text Available Mutations of the SHANK3 gene have been associated with autism spectrum disorder. Individuals harboring different SHANK3 mutations display considerable heterogeneity in their cognitive impairment, likely due to the high SHANK3 transcriptional diversity. In this study, we report a novel interaction between the Mutated in colorectal cancer (MCC protein and a newly identified SHANK3 protein isoform in human colon cancer cells and mouse brain tissue. Hence, our proteogenomic analysis identifies a new human long isoform of the key synaptic protein SHANK3 that was not predicted by the human reference genome. Taken together, our findings describe a potential new role for MCC in neurons, a new human SHANK3 long isoform and, importantly, highlight the use of proteomic data towards the re-annotation of GC-rich genomic regions.

  11. Experimental dengue virus challenge of human subjects previously vaccinated with live attenuated tetravalent dengue vaccines.

    Science.gov (United States)

    Sun, Wellington; Eckels, Kenneth H; Putnak, J Robert; Lyons, Arthur G; Thomas, Stephen J; Vaughn, David W; Gibbons, Robert V; Fernandez, Stefan; Gunther, Vicky J; Mammen, Mammen P; Statler, John D; Innis, Bruce L

    2013-03-01

    Protection against dengue requires immunity against all 4 serotypes of dengue virus (DENV). Experimental challenge may be useful in evaluating vaccine-induced immunity. Ten subjects previously vaccinated with a live attenuated tetravalent dengue vaccine (TDV) and 4 DENV-naive control subjects were challenged by subcutaneous inoculation of either 10(3) plaque-forming units (PFU) of DENV-1 or 10(5) PFU of DENV-3. Two additional subjects who did not develop DENV-3 neutralizing antibody (NAb) from TDV were revaccinated with 10(4) PFU of live attenuated DENV-3 vaccine to evaluate memory response. All 5 TDV recipients were protected against DENV-1 challenge. Of the 5 TDV recipients challenged with DENV-3, 2 were protected. All DENV-3-challenge subjects who developed viremia also developed elevated liver enzyme levels, and 2 had values that were >10 times greater than normal. Of the 2 subjects revaccinated with DENV-3 vaccine, 1 showed a secondary response to DENV-2, while neither showed such response to DENV-3. All 4 control subjects developed dengue fever from challenge. Protection was associated with presence of NAb, although 1 subject was protected despite a lack of measurable NAb at the time of DENV-1 challenge. Vaccination with TDV induced variable protection against subcutaneous challenge. DENV-3 experimental challenge was associated with transient but marked elevations of transaminases.

  12. Natural expansion versus translocation in a previously human-persecuted bird of prey.

    Science.gov (United States)

    Morandini, Virginia; de Benito, Elena; Newton, Ian; Ferrer, Miguel

    2017-06-01

    Many threatened species in Europe have been expanding their distributions during recent decades owing to protection measures that overcome historical human activity that has limited their distributions. Range expansion has come about via two processes, natural expansion from existing range and reintroductions to new ranges. Reintroductions may prove to be a better way to establish populations because individuals are less subject to competitive relationships lowering breeding success than individuals expanding from existing populations. Whether this is true, however, remains uncertain. We compared success of breeding pairs of an expanding and a reintroduced population of spanish imperial eagles monitored for over 15 years in the south of Spain. We found significant differences in productivity between breeding pairs of each population. Newly established territories in reintroduction areas were almost three times more productive than new territories established as individuals expanded out from an existing population. We conclude that among these eagle populations reintroduced to new areas may fare as well or better than individuals expanding out form existing populations.

  13. In situ hybridization of bat chromosomes with human (TTAGGGn probe, after previous digestion with Alu I

    Directory of Open Access Journals (Sweden)

    Karina de Cassia Faria

    2002-01-01

    Full Text Available The purpose of this work was to verify the ability of the enzyme Alu I to cleave and/or remove satellite DNA sequences from heterochromatic regions in chromosomes of bats, by identifying the occurrence of modifications in the pattern of fluorescence in situ hybridization with telomeric DNA. The localization and fluorescence intensity of the telomeric DNA sites of the Alu-digested and undigested chromosomes of species Eumops glaucinus, Carollia perspicillata, and Platyrrhinus lineatus were analyzed. Telomeric sequences were detected at the termini of chromosomes of all three species, although, in C. perspicillata, the signals were very faint or absent in most chromosomes. This finding was interpreted as being due to a reduced number of copies of the telomeric repeat, resulting from extensive telomeric association and/or rearrangements undergone by the chromosomes of Carollia. Fluorescent signals were also observed in centromeric and pericentromeric regions in several two-arm chromosomes of E. glaucinus and C. perspicillata. In E. glaucinus and P. lineatus, some interstitial and terminal telomeric sites were observed to be in association with regions of constitutive heterochromatin and ribosomal DNA (NORs. After digestion, these telomeric sites showed a significant decrease in signal intensity, indicating that enzyme Alu I cleaves and/or removes part of the satellite DNA present in these regions. These results suggest that the telomeric sequence is a component of the heterochromatin, and that the C-band- positive regions of bat chromosomes have a different DNA composition.

  14. Revitalizing urban waterfronts: identifying indicators for human well-being

    Directory of Open Access Journals (Sweden)

    Jungho Nam

    2016-08-01

    Full Text Available Waterfront cities worldwide have begun the process of regenerating and developing their formerly industrial waterfronts into land uses that reflect a post-industrial economic vision of mixed urban uses supporting a diverse economy and wide range of infrastructure. These revitalization projects require distinct planning and management tactics to determine project-defined successes inclusive of economic, ecological, and human well-being perspectives. While empirically developed templates for economic and ecological measures exist, the multi-dimensionality and subjective nature of human well-being is more difficult to assess. Through an extensive review of indicator frameworks and expert interviews, our research proposes an organizational, yet adaptable, human well-being indicators framework for the management and development of urban waterfront revitalization projects. We analyze the framework through the lens of two waterfront projects in the Puget Sound region of the United States and identify several key factors necessary to developing project-specific human well-being indicator frameworks for urban waterfront revitalization projects. These factors include: initially specify goals and objectives of a given project, acknowledge contextual conditions including prospective land uses and projected users, identify the stage of development or management to use appropriate indicators for that stage, and develop and utilize data sources that are at a similar scale to the size of the project.

  15. Semi-automated knowledge discovery: identifying and profiling human trafficking

    Science.gov (United States)

    Poelmans, Jonas; Elzinga, Paul; Ignatov, Dmitry I.; Kuznetsov, Sergei O.

    2012-11-01

    We propose an iterative and human-centred knowledge discovery methodology based on formal concept analysis. The proposed approach recognizes the important role of the domain expert in mining real-world enterprise applications and makes use of specific domain knowledge, including human intelligence and domain-specific constraints. Our approach was empirically validated at the Amsterdam-Amstelland police to identify suspects and victims of human trafficking in 266,157 suspicious activity reports. Based on guidelines of the Attorney Generals of the Netherlands, we first defined multiple early warning indicators that were used to index the police reports. Using concept lattices, we revealed numerous unknown human trafficking and loverboy suspects. In-depth investigation by the police resulted in a confirmation of their involvement in illegal activities resulting in actual arrestments been made. Our human-centred approach was embedded into operational policing practice and is now successfully used on a daily basis to cope with the vastly growing amount of unstructured information.

  16. Treatment response in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission

    DEFF Research Database (Denmark)

    Alenius, Malin; Hammarlund-Udenaes, Margareta; Honoré, Per Gustaf Hartvig

    2009-01-01

    ; underestimating residual symptoms, negative symptoms, and side effects; or being to open for individual interpretation. The aim of this study was to present and evaluate a new method of classification according to treatment response and, thus, to identify patients in functional remission. METHOD: A naturalistic......, cross-sectional study was performed using patient interviews and information from patient files. The new classification method CANSEPT, which combines the Camberwell Assessment of Need rating scale, the Udvalg for Kliniske Undersøgelser side effect rating scale (SE), and the patient's previous treatment...... history (PT), was used to group the patients according to treatment response. CANSEPT was evaluated by comparison of expected and observed results. RESULTS: In the patient population (n = 123), the patients in functional remission, as defined by CANSEPT, had higher quality of life, fewer hospitalizations...

  17. Evolutionary Analysis Predicts Sensitive Positions of MMP20 and Validates Newly- and Previously-Identified MMP20 Mutations Causing Amelogenesis Imperfecta

    Directory of Open Access Journals (Sweden)

    Barbara Gasse

    2017-06-01

    Full Text Available Amelogenesis imperfecta (AI designates a group of genetic diseases characterized by a large range of enamel disorders causing important social and health problems. These defects can result from mutations in enamel matrix proteins or protease encoding genes. A range of mutations in the enamel cleavage enzyme matrix metalloproteinase-20 gene (MMP20 produce enamel defects of varying severity. To address how various alterations produce a range of AI phenotypes, we performed a targeted analysis to find MMP20 mutations in French patients diagnosed with non-syndromic AI. Genomic DNA was isolated from saliva and MMP20 exons and exon-intron boundaries sequenced. We identified several homozygous or heterozygous mutations, putatively involved in the AI phenotypes. To validate missense mutations and predict sensitive positions in the MMP20 sequence, we evolutionarily compared 75 sequences extracted from the public databases using the Datamonkey webserver. These sequences were representative of mammalian lineages, covering more than 150 million years of evolution. This analysis allowed us to find 324 sensitive positions (out of the 483 MMP20 residues, pinpoint functionally important domains, and build an evolutionary chart of important conserved MMP20 regions. This is an efficient tool to identify new- and previously-identified mutations. We thus identified six functional MMP20 mutations in unrelated families, finding two novel mutated sites. The genotypes and phenotypes of these six mutations are described and compared. To date, 13 MMP20 mutations causing AI have been reported, making these genotypes and associated hypomature enamel phenotypes the most frequent in AI.

  18. Grouping Parturients by Parity, Previous-Cesarean, and Mode of Delivery (P-C-MoD Classification) Better Identifies Groups at Risk for Postpartum Hemorrhage.

    Science.gov (United States)

    Reichman, Orna; Gal, Micahel; Sela, Hen Y; Khayyat, Izzat; Emanuel, Michael; Samueloff, Arnon

    2016-10-01

    Objective We aimed to create a clinical classification to better identify parturients at risk for postpartum hemorrhage (PPH). Method A retrospective cohort, including all women who delivered at a single tertiary care medical center, between 2006 and 2014. Parturients were grouped by parity and history of cesarean delivery (CD): primiparas, multipara, and multipara with previous CD. Each were further subgrouped by mode of delivery (spontaneous vaginal delivery [SVD], operative vaginal delivery [OVD], emergency or elective CD). In all, 12 subgroups, based on parity, previous cesarean, and mode of delivery, formed the P-C-MoD classification. PPH was defined as a decrease of ≥3 gram% hemoglobin from admission and/or transfusion of blood products. Univariate analysis followed by multivariate analysis was performed to assess risk for PPH, controlling for confounders. Results The crude rate of PPH among 126,693 parturients was 7%. The prevalence differed significantly among independent risk factors: primiparity, 14%; multiparity, 4%; OVD, 22%; and CD, 15%. The P-C-MoD classification, segregated better between parturients at risk for PPH. The prevalence of PPH was highest for primiparous undergoing OVD (27%) compared with multiparous with SVD (3%), odds ratio [OR] = 12.8 (95% confidence interval [CI],11.9-13.9). These finding were consistent in the multivariate analysis OR = 13.1 (95% CI,12.1-14.3). Conclusion Employing the P-C-MoD classification more readily identifies parturients at risk for PPH and is superior to estimations based on single risk factors. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  19. Identifying and modeling the structural discontinuities of human interactions

    Science.gov (United States)

    Grauwin, Sebastian; Szell, Michael; Sobolevsky, Stanislav; Hövel, Philipp; Simini, Filippo; Vanhoof, Maarten; Smoreda, Zbigniew; Barabási, Albert-László; Ratti, Carlo

    2017-04-01

    The idea of a hierarchical spatial organization of society lies at the core of seminal theories in human geography that have strongly influenced our understanding of social organization. Along the same line, the recent availability of large-scale human mobility and communication data has offered novel quantitative insights hinting at a strong geographical confinement of human interactions within neighboring regions, extending to local levels within countries. However, models of human interaction largely ignore this effect. Here, we analyze several country-wide networks of telephone calls - both, mobile and landline - and in either case uncover a systematic decrease of communication induced by borders which we identify as the missing variable in state-of-the-art models. Using this empirical evidence, we propose an alternative modeling framework that naturally stylizes the damping effect of borders. We show that this new notion substantially improves the predictive power of widely used interaction models. This increases our ability to understand, model and predict social activities and to plan the development of infrastructures across multiple scales.

  20. Markers for Ongoing or Previous Hepatitis E Virus Infection Are as Common in Wild Ungulates as in Humans in Sweden.

    Science.gov (United States)

    Roth, Anette; Lin, Jay; Magnius, Lars; Karlsson, Marie; Belák, Sándór; Widén, Frederik; Norder, Heléne

    2016-09-19

    Hepatitis E virus (HEV) is a human pathogen with zoonotic spread, infecting both domestic and wild animals. About 17% of the Swedish population is immune to HEV, but few cases are reported annually, indicating that most infections are subclinical. However, clinical hepatitis E may also be overlooked. For identified cases, the source of infection is mostly unknown. In order to identify whether HEV may be spread from wild game, the prevalence of markers for past and/or ongoing infection was investigated in sera and stool samples collected from 260 hunted Swedish wild ungulates. HEV markers were found in 43 (17%) of the animals. The most commonly infected animal was moose ( Alces alces ) with 19 out of 69 animals (28%) showing HEV markers, followed by wild boar ( Sus scrofa ) with 21 out of 139 animals (15%), roe deer ( Capreolus capreolus ) with 2 out of 30 animals, red deer ( Cervus elaphus ) with 1 out of 15 animals, and fallow deer ( Dama dama ) 0 out of 7 animals. Partial open reading frame 1 (ORF1) of the viral genomes from the animals were sequenced and compared with those from 14 endemic human cases. Phylogenetic analysis revealed that three humans were infected with HEV strains similar to those from wild boar. These results indicate that wild animals may be a source of transmission to humans and could be an unrecognized public health concern.

  1. HIV gene expression from intact proviruses positioned in bacterial artificial chromosomes at integration sites previously identified in latently infected T cells

    International Nuclear Information System (INIS)

    Eipers, Peter G.; Salazar-Gonzalez, Jesus F.; Morrow, Casey D.

    2011-01-01

    HIV integration predominantly occurs in introns of transcriptionally active genes. To study the impact of the integration site on HIV gene expression, a complete HIV-1 provirus (with GFP as a fusion with Nef) was inserted into bacterial artificial chromosomes (BACs) at three sites previously identified in latent T cells of patients: topoisomerase II (Top2A), DNA methyltransferase 1 (DNMT1), or basic leucine transcription factor 2 (BACH2). Transfection of BAC-HIV into 293 T cells resulted in a fourfold difference in production of infectious HIV-1. Cell lines were established that contained BAC-Top2A, BAC-DNMT1, or BAC-BACH2, but only BAC-DNMT1 spontaneously produced virus, albeit at a low level. Stimulation with TNF-α resulted in virus production from four of five BAC-Top2A and all BAC-DNMT1 cell lines, but not from the BAC-BACH2 lines. The results of these studies highlight differences between integration sites identified in latent T cells to support virus production and reactivation from latency.

  2. Identifying and annotating human bifunctional RNAs reveals their versatile functions.

    Science.gov (United States)

    Chen, Geng; Yang, Juan; Chen, Jiwei; Song, Yunjie; Cao, Ruifang; Shi, Tieliu; Shi, Leming

    2016-10-01

    Bifunctional RNAs that possess both protein-coding and noncoding functional properties were less explored and poorly understood. Here we systematically explored the characteristics and functions of such human bifunctional RNAs by integrating tandem mass spectrometry and RNA-seq data. We first constructed a pipeline to identify and annotate bifunctional RNAs, leading to the characterization of 132 high-confidence bifunctional RNAs. Our analyses indicate that bifunctional RNAs may be involved in human embryonic development and can be functional in diverse tissues. Moreover, bifunctional RNAs could interact with multiple miRNAs and RNA-binding proteins to exert their corresponding roles. Bifunctional RNAs may also function as competing endogenous RNAs to regulate the expression of many genes by competing for common targeting miRNAs. Finally, somatic mutations of diverse carcinomas may generate harmful effect on corresponding bifunctional RNAs. Collectively, our study not only provides the pipeline for identifying and annotating bifunctional RNAs but also reveals their important gene-regulatory functions.

  3. Treatment response in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission.

    Science.gov (United States)

    Alenius, Malin; Hammarlund-Udenaes, Margareta; Hartvig, Per; Sundquist, Staffan; Lindström, Leif

    2009-01-01

    Various approaches have been made over the years to classify psychotic patients according to inadequate treatment response, using terms such as treatment resistant or treatment refractory. Existing classifications have been criticized for overestimating positive symptoms; underestimating residual symptoms, negative symptoms, and side effects; or being to open for individual interpretation. The aim of this study was to present and evaluate a new method of classification according to treatment response and, thus, to identify patients in functional remission. A naturalistic, cross-sectional study was performed using patient interviews and information from patient files. The new classification method CANSEPT, which combines the Camberwell Assessment of Need rating scale, the Udvalg for Kliniske Undersøgelser side effect rating scale (SE), and the patient's previous treatment history (PT), was used to group the patients according to treatment response. CANSEPT was evaluated by comparison of expected and observed results. In the patient population (n = 123), the patients in functional remission, as defined by CANSEPT, had higher quality of life, fewer hospitalizations, fewer psychotic symptoms, and higher rate of workers than those with the worst treatment outcome. In the evaluation, CANSEPT showed validity in discriminating the patients of interest and was well tolerated by the patients. CANSEPT could secure inclusion of correct patients in the clinic or in research.

  4. Identifying Malaria Transmission Foci for Elimination Using Human Mobility Data.

    Science.gov (United States)

    Ruktanonchai, Nick W; DeLeenheer, Patrick; Tatem, Andrew J; Alegana, Victor A; Caughlin, T Trevor; Zu Erbach-Schoenberg, Elisabeth; Lourenço, Christopher; Ruktanonchai, Corrine W; Smith, David L

    2016-04-01

    Humans move frequently and tend to carry parasites among areas with endemic malaria and into areas where local transmission is unsustainable. Human-mediated parasite mobility can thus sustain parasite populations in areas where they would otherwise be absent. Data describing human mobility and malaria epidemiology can help classify landscapes into parasite demographic sources and sinks, ecological concepts that have parallels in malaria control discussions of transmission foci. By linking transmission to parasite flow, it is possible to stratify landscapes for malaria control and elimination, as sources are disproportionately important to the regional persistence of malaria parasites. Here, we identify putative malaria sources and sinks for pre-elimination Namibia using malaria parasite rate (PR) maps and call data records from mobile phones, using a steady-state analysis of a malaria transmission model to infer where infections most likely occurred. We also examined how the landscape of transmission and burden changed from the pre-elimination setting by comparing the location and extent of predicted pre-elimination transmission foci with modeled incidence for 2009. This comparison suggests that while transmission was spatially focal pre-elimination, the spatial distribution of cases changed as burden declined. The changing spatial distribution of burden could be due to importation, with cases focused around importation hotspots, or due to heterogeneous application of elimination effort. While this framework is an important step towards understanding progressive changes in malaria distribution and the role of subnational transmission dynamics in a policy-relevant way, future work should account for international parasite movement, utilize real time surveillance data, and relax the steady state assumption required by the presented model.

  5. Delta-like ligand 4 identifies a previously uncharacterized population of inflammatory dendritic cells that plays important roles in eliciting allogeneic T cell responses in mice.

    Science.gov (United States)

    Mochizuki, Kazuhiro; Xie, Fang; He, Shan; Tong, Qing; Liu, Yongnian; Mochizuki, Izumi; Guo, Yajun; Kato, Koji; Yagita, Hideo; Mineishi, Shin; Zhang, Yi

    2013-04-01

    Graft-versus-host disease (GVHD) reflects an exaggerated inflammatory allogeneic T cell response in hosts receiving allogeneic hematopoietic stem cell transplantation (HSCT). Inhibition of pan-Notch receptor signaling in donor T cells causes reduction of GVHD. However, which Notch ligand(s) in what APCs is important for priming graft-versus-host reaction remains unknown. We demonstrate that δ-like ligand-4 (Dll4) and Dll4-positive (Dll4(high)) inflammatory dendritic cells (i-DCs) play important roles in eliciting allogeneic T cell responses. Host-type Dll4(high) i-DCs occurred in the spleen and intestine of HSCT mice during GVHD induction phase. These Dll4(high) i-DCs were CD11c(+)B220(+)PDCA-1(+), resembling plasmacytoid dentritic cells (pDCs) of naive mice. However, as compared with unstimulated pDCs, Dll4(high) i-DCs expressed higher levels of costimulatory molecules, Notch ligands Jagged1 and Jagged2, and CD11b, and produced more Ifnb and Il23 but less Il12. In contrast, Dll4-negative (Dll4(low)) i-DCs were CD11c(+)B220(-)PDCA-1(-), and had low levels of Jagged1. In vitro assays showed that Dll4(high) i-DCs induced significantly more IFN-γ- and IL-17-producing effector T cells (3- and 10-fold, respectively) than Dll4(low) i-DCs. This effect could be blocked by anti-Dll4 Ab. In vivo administration of Dll4 Ab reduced donor-alloreactive effector T cells producing IFN-γ and IL-17 in GVHD target organs, leading to reduction of GVHD and improved survival of mice after allogeneic HSCT. Our findings indicate that Dll4(high) i-DCs represent a previously uncharacterized i-DC population distinctive from steady state DCs and Dll4(low) i-DCs. Furthermore, Dll4 and Dll4(high) i-DCs may be beneficial targets for modulating allogeneic T cell responses, and could facilitate the discovery of human counterparts of mouse Dll4(high) i-DCs.

  6. Delta-like Ligand 4 Identifies a Previously Uncharacterized Population of Inflammatory Dendritic Cells That Plays Important Roles in Eliciting Allogeneic T-cell Responses in Mice1

    Science.gov (United States)

    Mochizuki, Kazuhiro; Xie, Fang; He, Shan; Tong, Qing; Liu, Yongnian; Mochizuki, Izumi; Guo, Yajun; Kato, Koji; Yagita, Hideo; Mineishi, Shin; Zhang, Yi

    2013-01-01

    Graft-versus-host disease (GVHD) reflects an exaggerated inflammatory allogeneic T-cell response in hosts receiving allogeneic hematopoietic stem cell transplantation (HSCT). Inhibition of pan-Notch receptor signaling in donor T cells causes reduction of GVHD. However, which Notch ligand(s) in what antigen-presenting cells are important for priming GVH reaction remains unknown. We demonstrate that δ-like ligand-4 (Dll4) and Dll4-positive (Dll4hi) inflammatory dendritic cells (i-DCs) play important roles in eliciting allogeneic T-cell responses. Host-type Dll4hi i-DCs occurred in the spleen and intestine of HSCT mice during GVHD induction phase. These Dll4hi i-DCs were CD11c+B220+PDCA-1+, resembling plasmacytoid DCs (pDCs) of naïve mice. However, as compared to unstimulated pDCs, Dll4hi i-DCs expressed higher levels of costimulatory molecules, Notch ligands Jagged1 and Jagged2 and CD11b and, produced more Ifnb and Il23 but less Il12. In contrast, Dll4-negative (Dll4lo) i-DCs were CD11c+B220−PDCA-1−, and had low levels of Jagged1. In vitro assays showed that Dll4hi i-DCs induced significantly more IFN-γ- and IL-17-producing effector T cells (3- and 10-fold, respectively) than Dll4lo i-DCs. This effect could be blocked by anti-Dll4 antibody. In vivo administration of Dll4 antibody reduced donor alloreactive effector T cells producing IFN-γ and IL-17 in GVHD target organs, leading to reduction of GVHD and improved survival of mice after allogeneic HSCT. Our findings indicate that Dll4hi i-DCs represent a previously uncharacterized i-DC population distinctive from steady state DCs and Dll4lo i-DCs. Furthermore, Dll4 and Dll4hi i-DCs may be beneficial targets for modulating allogeneic T-cell responses, and could facilitate the discovery of human counterparts of mouse Dll4hi i-DCs. PMID:23440416

  7. Individual human scent as a forensic identifier using mantrailing.

    Science.gov (United States)

    Woidtke, Leif; Dreßler, Jan; Babian, Carsten

    2018-01-01

    Specially trained dogs have long been used by law enforcement agencies to help in criminal investigations and in searching for missing persons. Still, it is unclear which components of human scent released into the environment contribute to successful searches of individuals. In this study, saliva and axillary sweat samples were taken from a total of 190 people. Additionally, DNA was extracted from whole blood of seven different people and used as an odour sample as well. Overall 675 tests (trails) were performed during a period of 18 months. The ability to track individuals with the odour samples mentioned above was examined with seven dogs, four of which were specially-trained dogs (mantrailer) from the Saxony Police. Results indicated that specially-trained police dogs can track a person with an average success rate of 82% and correctly identify the absence of an odour track with an average success rate of 97% under various conditions. Private rescue dogs were less successful with an average success rate of 65% and 75% respectively. These data suggest that the potential error rate of a well-trained handler team is low and can be a useful tool for law enforcement personnel. Saliva, as a reference odour source, was found to be particularly suitable for the search. The results of the study suggest that the components contained in axillary sweat, saliva and DNA extracted from whole blood are sufficient, serving as a key stimulus for individualized searches. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Comparative Genomics Identifies a Potential Marker of Human-Virulent Anaplasma phagocytophilum

    Science.gov (United States)

    Al-Khedery, Basima; Barbet, Anthony F.

    2014-01-01

    We have previously described a comparative genome analysis of nine strains of Anaplasma phagocytophilum that showed similarity between strains infecting humans and U.S. dogs and a more distant relationship with horse and ruminant strains. This suggested that it may be possible to distinguish human-infective strains using simple DNA sequence-based diagnostic tests. This would be of epidemiologic significance in identifying and tracking the presence of virulent strains in tick vector populations. Further analysis identified a gene that was present in several strains, including U.S. Ap-variant 1 (ruminant), MRK (horse), and European sheep, but was deleted in strains infecting U.S. humans and dogs, suggesting that it could be a useful marker of human virulence. A simple PCR test was developed to identify the presence/absence of this gene. The PCR test discriminated A. phagocytophilum strains from clinically affected humans and U.S. dogs from the strains more distantly related in genome sequence. This warrants further testing of globally diverse A. phagocytophilum strains to examine world-wide conservation of this gene. PMID:25437606

  9. Identifying Novel Clinical Surrogates to Assess Human Bone Fracture Toughness.

    Science.gov (United States)

    Granke, Mathilde; Makowski, Alexander J; Uppuganti, Sasidhar; Does, Mark D; Nyman, Jeffry S

    2015-07-01

    Fracture risk does not solely depend on strength but also on fracture toughness; ie, the ability of bone material to resist crack initiation and propagation. Because resistance to crack growth largely depends on bone properties at the tissue level, including collagen characteristics, current X-ray based assessment tools may not be suitable to identify age-related, disease-related, or treatment-related changes in fracture toughness. To identify useful clinical surrogates that could improve the assessment of fracture resistance, we investigated the potential of (1)H nuclear magnetic resonance spectroscopy (NMR) and reference point indentation (RPI) to explain age-related variance in fracture toughness. Harvested from cadaveric femurs (62 human donors), single-edge notched beam (SENB) specimens of cortical bone underwent fracture toughness testing (R-curve method). NMR-derived bound water showed the strongest correlation with fracture toughness properties (r = 0.63 for crack initiation, r = 0.35 for crack growth, and r = 0.45 for overall fracture toughness; p toughness properties were best explained by a combination of NMR properties including pore water and RPI-derived tissue stiffness with age as a significant covariate (adjusted R(2)  = 53.3%, 23.9%, and 35.2% for crack initiation, crack growth, and overall toughness, respectively; p toughness and emphasize the utility of a multimodal assessment of fracture resistance. Exploring the mechanistic origin of fracture toughness, glycation-mediated nonenzymatic collagen crosslinks and intracortical porosity are possible determinants of bone fracture toughness and could explain the sensitivity of NMR to changes in fracture toughness. Assuming fracture toughness is clinically important to the ability of bone to resist fracture, our results suggest that improvements in fracture risk assessment could potentially be achieved by accounting for water distribution (quantitative ultrashort echo time magnetic

  10. A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder

    Directory of Open Access Journals (Sweden)

    David G Ashbrook

    2015-07-01

    Full Text Available Bipolar disorder (BD is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium’s bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis.We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1 and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG and TNR influence intercellular signaling in the striatum.

  11. Effects of human atrial natriuretic peptide on myocardial performance and energetics in heart failure due to previous myocardial infarction.

    Science.gov (United States)

    Ozawa, Toru; Shinke, Toshiro; Shite, Junya; Takaoka, Hideyuki; Inoue, Nobutaka; Matsumoto, Hidenari; Watanabe, Satoshi; Yoshikawa, Ryohei; Otake, Hiromasa; Matsumoto, Daisuke; Ogasawara, Daisuke; Yokoyama, Mitsuhiro; Hirata, Ken-ichi

    2015-09-01

    Human atrial natriuretic peptide (hANP) and spontaneous nitric oxide (NO) donor share cyclic guanosine monophosphate (cGMP) as a second messenger, but their effect on myocardium may differ. We compared the effect of hANP and sodium nitroprusside (SNP) on left ventricular (LV) mechano-energetics in heart failure (HF). Ten patients with HF due to previous myocardial infarction (LV ejection fraction: 45±3%) were instrumented with conductance and coronary sinus thermodilution catheters. LV contractility (Ees: slope of end-systolic pressure-volume relation) and the ratio of LV stroke work (SW) to myocardial oxygen consumption (SW/MVO2=mechanical efficiency) were measured in response to intravenous infusion of ANP (0.05 μg/kg/min) or SNP (0.3 μg/kg/min) to lower blood pressure by at least 10 mmHg, and changes in plasma cGMP. SNP had no effect on Ees, SW, or MVO2, thus SW/MVO2 remained unchanged (40.54±5.84% to 36.59±5.72%, p=0.25). ANP increased Ees, and decreased MVO2 with preserved SW, resulting in improved SW/MVO2 (40.49±6.35% to 50.30±7.96%, p=0.0073). Infusion of ANP (10.42-34.95 pmol/ml, p=0.0003) increased cGMP levels, whereas infusion of SNP had no effect (10.42-12.23 pmol/ml, p=0.75). Compared to SNP, the ANP-dependent increase in cGMP may ameliorate myocardial inotropy and energetics in HF. Copyright © 2015. Published by Elsevier Ltd.

  12. Functional characterization of two newly identified Human Endogenous Retrovirus coding envelope genes

    Directory of Open Access Journals (Sweden)

    Heidmann Thierry

    2005-03-01

    Full Text Available Abstract A recent in silico search for coding sequences of retroviral origin present in the human genome has unraveled two new envelope genes that add to the 16 genes previously identified. A systematic search among the latter for a fusogenic activity had led to the identification of two bona fide genes, named syncytin-1 and syncytin-2, most probably co-opted by primate genomes for a placental function related to the formation of the syncytiotrophoblast by cell-cell fusion. Here, we show that one of the newly identified envelope gene, named envP(b, is fusogenic in an ex vivo assay, but that its expression – as quantified by real-time RT-PCR on a large panel of human tissues – is ubiquitous, albeit with a rather low value in most tissues. Conversely, the second envelope gene, named envV, discloses a placenta-specific expression, but is not fusogenic in any of the cells tested. Altogether, these results suggest that at least one of these env genes may play a role in placentation, but most probably through a process different from that of the two previously identified syncytins.

  13. Efficient Culture Adaptation of Hepatitis C Virus Recombinants with Genotype-Specific Core-NS2 by Using Previously Identified Mutations

    DEFF Research Database (Denmark)

    Scheel, Troels Kasper Høyer; Gottwein, Judith M; Carlsen, Thomas H R

    2011-01-01

    Hepatitis C virus (HCV) is an important cause of chronic liver disease, and interferon-based therapy cures only 40 to 80% of patients, depending on HCV genotype. Research was accelerated by genotype 2a (strain JFH1) infectious cell culture systems. We previously developed viable JFH1-based...... mutations did not adapt to culture. Universal adaptive effects of mutations in NS3 (Q1247L, I1312V, K1398Q, R1408W, and Q1496L) and NS5A (V2418L) were investigated for JFH1-based genotype 1 to 5 core-NS2 recombinants; several mutations conferred adaptation to H77C (1a), J4 (1b), S52 (3a), and SA13 (5a......-specific patterns in HCV disease and control....

  14. Principles of human subjects protections applied in an opt-out, de-identified biobank.

    Science.gov (United States)

    Pulley, Jill; Clayton, Ellen; Bernard, Gordon R; Roden, Dan M; Masys, Daniel R

    2010-02-01

    BioVU, the Vanderbilt DNA Databank, is one of few biobanks that qualifies as non-human subjects research as determined by the local IRB and the federal Office of Human Research Protections (OHRP). BioVU accrues DNA samples extracted from leftover blood remaining from routine clinical testing. The resource is linked to a de-identified version of data extracted from an Electronic Medical Record (EMR) system, termed the Synthetic Device (SD), in which all personal identifiers have been removed. Thus, there is no identifiable private information attached to the records. The Belmont Report enumerates the importance of the boundary between practice and research, and three principles: Respect for Persons, Beneficence, and Justice, which constitute the essential ethical framework by which IRBs and ethics committees judge the risks and benefits of research involving human subjects. BioVU was developed by designing and implementing new procedures, for which there were no previously established methods, which are consistent with the principles of the Belmont Report. These included special oversight and governance, new informatics technologies, provisions to accommodate patients' preferences, as well as an extensive public education and communications component. Considerations of core principles and protections in the practical implementation of BioVU is the focus of this paper.

  15. Principles of Human Subjects Protections Applied in an Opt‐Out, De‐identified Biobank

    Science.gov (United States)

    Pulley, Jill; Clayton, Ellen; Bernard, Gordon R.; Roden, Dan M.; Masys, Daniel R.

    2010-01-01

    Abstract BioVU, the Vanderbilt DNA Databank, is one of few biobanks that qualifies as non‐human subjects research as determined by the local IRB and the federal Office of Human Research Protections (OHRP). BioVU accrues DNA samples extracted from leftover blood remaining from routine clinical testing. The resource is linked to a de‐identified version of data extracted from an Electronic Medical Record (EMR) system, termed the Synthetic Device (SD), in which all personal identifiers have been removed. Thus, there is no identifiable private information attached to the records. The Belmont Report enumerates the importance of the boundary between practice and research, and three principles: Respect for Persons, Beneficence, and Justice, which constitute the essential ethical framework by which IRBs and ethics committees judge the risks and benefi ts of research involving human subjects. BioVU was developed by designing and implementing new procedures, for which there were no previously established methods, which are consistent with the principles of the Belmont Report. These included special oversight and governance, new informatics technologies, provisions to accommodate patients’ preferences, as well as an extensive public education and communications component. Considerations of core principles and protections in the practical implementation of BioVU is the focus of this paper. Clin Trans Sci 2010; Volume #: 1–7 PMID:20443953

  16. Quantitative analysis of previously identified propionate-oxidizing bacteria and methanogens at different temperatures in an UASB reactor containing propionate as a sole carbon source.

    Science.gov (United States)

    Ban, Qiaoying; Li, Jianzheng; Zhang, Liguo; Jha, Ajay Kumar; Zhang, Yupeng

    2013-12-01

    Propionate degradation is crucial for maintaining the efficiency and stability of an anaerobic reactor. However, there was little information about the effects of ecological factor on propionate-oxidizing bacteria (POB). In current research, quantitative real-time fluorescence polymerase chain reaction (QPCR) of some identified POB and methanogens with a decrease in temperature in an upflow anaerobic sludge bed (UASB) reactor containing propionate as sole carbon source was investigated. The results showed that there were at least four identified POB, including Pelotomaculum schinkii, Pelotomaculum propionicum, Syntrophobacter fumaroxidans, and Syntrophobacter sulfatireducens, observed in this UASB reactor. Among them, P. schinkii was dominated during the whole operational period. Its quantity was 1.2 × 10(4) 16S rRNA gene copies per nanogram of DNA at 35 °C. A decrease in temperature from 35 to 30 °C led to P. schinkii to be increased by 1.8 times and then it was gradually reduced with a decrease in temperature from 30 to 25, 20, and 18 °C stepwise. A decrease in temperature from 35 to 20 °C did not make the amount of methanogens markedly changed, but hydrogenotrophic methanogens (Methanospirillum) and acetotrophic methanogens (Methanosaeta) at 18 °C were increased by an order of magnitude and 1.0 time, respectively, compared with other experimental conditions.

  17. Identifying novel components of human tumour suppressor networks

    NARCIS (Netherlands)

    J. Drost (Jarno)

    2012-01-01

    textabstractThe p53 pathway plays a central role in protecting cells from becoming tumorigenic. Reactivation of the pathway is under extensive study in the development of anti-cancer drugs. Although a lot is known about the pathway, the way it is inactivated in human tumours harbouring the wild-type

  18. Selection of bacteria originating from a human intestinal microbiota in the gut of previously germ-free rats.

    Science.gov (United States)

    Licht, Tine Rask; Madsen, Bodil; Wilcks, Andrea

    2007-12-01

    Denaturing gradient gel electrophoresis (DGGE) was applied to separate PCR-amplified 16S rRNA genes originating from human microbiota associated (HMA) rat faeces as well as from the human faecal sample used for inoculation of the animals. Subsequently, a total of 15 dominant bands were excised from the DGGE gels, cloned and sequenced. Comparison of the obtained sequences with the Ribosomal Database revealed that species of Bacteroides/Prevotella and Faecalibacterium gave rise to the majority of the dominant bands in the human sample and in the HMA rats. In the HMA rats, two dominant bands, which were not present in the human DGGE profile, originated from species of Ruminococcus. With the exception of the Ruminococcus sequences, sequences originating from both rats and human samples were represented in all major branches of a maximum parsimony tree, indicating that the rat feed and gut environment allows colonization of the dominant taxonomic units from the human microbiota, but additionally selects for Ruminococci. Bands representing Prevotella and Faecalibacterium, which were found in identical positions of the DGGE gels originating from human and HMA rat faecal samples, originated from completely identical sequences, indicating that the same strains of these species were dominating in the human and rat samples.

  19. Selection of bacteria originating from a human intestinal microbiota in the gut of previously germ-free rats

    DEFF Research Database (Denmark)

    Licht, Tine Rask; Madsen, Bodil; Wilcks, Andrea

    2007-01-01

    colonization of the dominant taxonomic units from the human microbiota, but additionally selects for Ruminococci. Bands representing Prevotella and Faecalibacterium, which were found in identical positions of the DGGE gels originating from human and HMA rat faecal samples, originated from completely identical...

  20. Circulating levels of endocannabinoids and oxylipins altered by dietary lipids in older women are likely associated with previously identified gene targets.

    Science.gov (United States)

    Watkins, Bruce A; Kim, Jeffrey; Kenny, Anne; Pedersen, Theresa L; Pappan, Kirk L; Newman, John W

    2016-11-01

    Postmenopausal women (PMW) report marginal n-3 PUFA intakes and are at risk of chronic diseases associated with the skeletal, muscular, neuroendocrine, and cardiovascular systems. How n-3 PUFA affect the amounts of endocannabinoids (ECs) and oxylipins (OLs) of metabolic and physiologic importance in PMW is not clear. Based on our recent findings that dietary n-3 PUFA alter gene targets of the EC system and lower pro-inflammatory OL we proceeded to characterize these actions in blood of PMW. Our aim was to determine levels of the ECs, OLs, and global metabolites (GM) in white PMW (75±7y), randomized in a double-masked manner, from baseline to 6mo after receiving a fish oil supplement of n-3 PUFA (720mg 20:5n3+480mg 22:6n3/d, n=20) or placebo (1.8g oleic acid/d, n=20). ECs and OLs in serum were determined by UPLC-MS/MS and GM by GC-MS and LC-MS/MS. Plasma 20:5n3 and 22:6n3 levels increased in PMW given fish oil. EC n-6 acyl-ethanolamides, arachidonate-derived diols were decreased and 20:5n3 and 22:6n3 diols, epoxides, and alcohols were increased in PMW given fish oil. GM analysis revealed that n-3 PUFA supplementation increased renal steroid hormone and proteolytic metabolite levels in PMW. Herein, we confirm that gene targets of the EC system, previously found as modifiable by n-3 PUFA result in changes in the levels of ECs and OLs in PMW. This study shows phenotypic responses (in levels) to n-3 PUFA supplementation in PMW and increases of n-3 acyl-ethanolamide and n-3-derived OL of clinical considerations in aging. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Analysis of 24-h Rhythm in Ventricular Repolarization Identifies QT Diurnality As a Novel Clinical Parameter Associated with Previous Ventricular Arrhythmias in Heart Failure Patients

    Directory of Open Access Journals (Sweden)

    Bastiaan C. Du Pre

    2017-08-01

    Full Text Available Introduction: Cardiac repolarization abnormalities are among the major causes of ventricular arrhythmias and sudden cardiac death. In humans, cardiac repolarization duration has a 24-h rhythm. Animal studies show that this rhythm is regulated by 24-h rhythms in ion channel function and that disruption of this rhythm leads to ventricular arrhythmias. We hypothesized that 24-h rhythms in QT duration can be used as a predictor for sudden cardiac death and are associated with ventricular arrhythmias. Secondly, we assessed a possible mechanistic explanation by studying the putative role of hERG channel dysfunction.Materials and Methods: In 2 retrospective studies, measures of the 24-h variation in the QT and QTc intervals (QT and QTc diurnality, QTd and QTcd, respectively have been derived from Holter analyses and compared between groups: 1 39 post-infarct patients with systolic heart failure (CHF: EF < 35%, of which 14 with, and 25 without a history of ventricular arrhythmias and 2 five patients with proven (LQTS2 and 16 with potential (Sotalol-induced hERG channel dysfunction vs. 22 controls.Results: QTd was two-fold higher in CHF patients with a history of ventricular arrhythmias (38 ± 15 ms compared to CHF patients without VT (16 ± 9 ms, p = 0.001. QTd was significantly increased in LQT2 patients (43 ± 24 ms or those treated with Sotalol (30 ± 10 ms compared to controls (21 ± 8 ms, p < 0.05 for both.Discussion: QT diurnality presents a novel clinical parameter of repolarization that can be derived from Holter registrations and may be useful for identification of patients at risk for ventricular arrhythmias.

  2. Updated canine infection rates for Dirofilaria immitis in areas of Brazil previously identified as having a high incidence of heartworm-infected dogs.

    Science.gov (United States)

    Labarthe, Norma Vollmer; Paiva, Jonimar Pereira; Reifur, Larissa; Mendes-de-Almeida, Flavya; Merlo, Alexandre; Carvalho Pinto, Carlos Jose; Juliani, Paulo Sérgio; de Almeida, Maria Angela Ornelas; Alves, Leucio Câmara

    2014-11-07

    Canine heartworm infections were frequently diagnosed in Brazil before the new millennium. After the year 2000, the frequency of diagnosis showed a sharp decline; however, a few years later, new evidence indicated that the parasite was still present and that canine infection rates seemed to be increasing. Therefore, an updated survey of canine heartworm prevalence was conducted in several locations in south, southeast, and northeast Brazil. Dogs from 15 locations having previously reported a high prevalence of heartworm infection were included in the survey according to defined criteria, including the absence of treatment with a macrocyclic lactone for at least 1 year. Blood samples from 1531 dogs were evaluated by an in-clinic immunochromatography test kit (Witness® Heartworm, Zoetis, USA) for detection of Dirofilaria immitis antigen. At each location, epidemiologic data, including physical characteristics and clinical signs reported by owners or observed by veterinarians, were recorded on prepared forms for tabulation of results by location, clinical signs, and physical characteristics. The overall prevalence of canine heartworm infection was 23.1%, with evidence of heartworm-infected dogs detected in all 15 locations studied. There was a tendency for higher prevalence rates in environmentally protected areas, despite some locations having less-than-ideal environmental temperatures for survival of vector mosquitoes. Among physical characteristics, it was noted that dogs with predominantly white hair coats and residing in areas with a high (≥20%) prevalence of heartworm were less likely to have heartworm infection detected by a commercial heartworm antigen test kit than were dogs with other coat colors. In general, dogs older than 2 years were more frequently positive for D. immitis antigen than were younger dogs. Clinical signs of heartworm infections were rare or owners were unable to detect them, and could not be used for reliable prediction of the

  3. Severe hypodontia: identifying patterns of human tooth agenesis

    NARCIS (Netherlands)

    Tan, S.P.K.; van Wijk, A.J.; Prahl-Andersen, B.

    2011-01-01

    Tooth agenesis is the most common dental anomaly. The aim of this retrospective study was to identify common patterns of tooth agenesis in a sample of 92 patients (55 females and 37 males; mean age 27.7 years) with non-syndromic severe hypodontia. The Tooth Agenesis Code (TAC) procedure was used for

  4. Human group C rotaviruses identified in Kenya | Mwenda | East ...

    African Journals Online (AJOL)

    Subjects and Methods:Faecal samples were collected from 119 infants and young children with diarrhoea and were analysed by commercial ELISA and polyacrylamide gel electrophoresis (SDS-PAGE) to identify possible non-group A rotaviruses. Extraction of any potential rrotavirus double-stranded RNA from faeces amd ...

  5. Identifying Patients Who May Be Candidates for a Clinical Trial of Salvage Accelerated Partial Breast Irradiation after Previous Whole Breast Irradiation

    Directory of Open Access Journals (Sweden)

    Linna Li

    2012-01-01

    Full Text Available Background and Objectives. Accelerated partial breast irradiation (APBI has been proposed as an alternative to salvage mastectomy for patients with ipsilateral breast tumor recurrence (IBTR after prior breast conservation. We studied factors that are associated with a more favorable local recurrence profile that could make certain patients eligible for APBI. Methods. Between 1980 and 2005, 157 Stage 0–II breast cancer patients had an IBTR treated by mastectomy. Clinical and pathological features were analyzed to identify factors associated with favorable IBTR defined as unifocal DCIS or T1 ≤ 2 cm, without skin involvement, and >2 year interval from initial treatment. Results. Median followup was 140 months and time to recurrence was 73 months. Clinical stage distribution at recurrence was DCIS in 32 pts (20%, T1 in 90 pts (57%, T2 in 14 pts (9%, T3 in 4 pts (3%, and T4 in 9 pts (6%. IBTR was classified as favorable in 71%. Clinical stage of IBTR predicted for pathologic stage –95% of patients with clinical T1 IBTR had pathologic T1 disease at salvage mastectomy . Conclusions. Clinical stage at presentation strongly correlated with pathologic stage at mastectomy. More than 70% of recurrences were favorable and may be appropriate candidates for salvage APBI trials.

  6. Nodule worm infection in humans and wild primates in Uganda: cryptic species in a newly identified region of human transmission.

    Directory of Open Access Journals (Sweden)

    Ria R Ghai

    Full Text Available Soil-transmitted helminths (STHs are a major health concern in tropical and sub-tropical countries. Oesophagostomum infection is considered endemic to West Africa but has also been identified in Uganda, East Africa, among primates (including humans. However, the taxonomy and ecology of Oesophagostomum in Uganda have not been studied, except for in chimpanzees (Pan troglodytes, which are infected by both O. bifurcum and O. stephanostomum.We studied Oesophagostomum in Uganda in a community of non-human primates that live in close proximity to humans. Prevalence estimates based on microscopy were lower than those based on polymerase chain reaction (PCR, indicating greater sensitivity of PCR. Prevalence varied among host species, with humans and red colobus (Procolobus rufomitratus infected at lowest prevalence (25% and 41% by PCR, respectively, and chimpanzees, olive baboons (Papio anubis, and l'hoest monkeys (Cercopithecus lhoesti infected at highest prevalence (100% by PCR in all three species. Phylogenetic regression showed that primates travelling further and in smaller groups are at greatest risk of infection. Molecular phylogenetic analyses revealed three cryptic clades of Oesophagostomum that were not distinguishable based on morphological characteristics of their eggs. Of these, the clade with the greatest host range had not previously been described genetically. This novel clade infects humans, as well as five other species of primates.Multiple cryptic forms of Oesophagostomum circulate in the people and primates of western Uganda, and parasite clades differ in host range and cross-species transmission potential. Our results expand knowledge about human Oesophagostomum infection beyond the West African countries of Togo and Ghana, where the parasite is a known public health concern. Oesophagostomum infection in humans may be common throughout Sub-Saharan Africa, and the transmission of this neglected STH among primates, including zoonotic

  7. Interaction of Proteins Identified in Human Thyroid Cells

    Science.gov (United States)

    Pietsch, Jessica; Riwaldt, Stefan; Bauer, Johann; Sickmann, Albert; Weber, Gerhard; Grosse, Jirka; Infanger, Manfred; Eilles, Christoph; Grimm, Daniela

    2013-01-01

    Influence of gravity forces on the regulation of protein expression by healthy and malignant thyroid cells was studied with the aim to identify protein interactions. Western blot analyses of a limited number of proteins suggested a time-dependent regulation of protein expression by simulated microgravity. After applying free flow isoelectric focusing and mass spectrometry to search for differently expressed proteins by thyroid cells exposed to simulated microgravity for three days, a considerable number of candidates for gravi-sensitive proteins were detected. In order to show how proteins sensitive to microgravity could directly influence other proteins, we investigated all polypeptide chains identified with Mascot scores above 100, looking for groups of interacting proteins. Hence, UniProtKB entry numbers of all detected proteins were entered into the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and processed. The program indicated that we had detected various groups of interacting proteins in each of the three cell lines studied. The major groups of interacting proteins play a role in pathways of carbohydrate and protein metabolism, regulation of cell growth and cell membrane structuring. Analyzing these groups, networks of interaction could be established which show how a punctual influence of simulated microgravity may propagate via various members of interaction chains. PMID:23303277

  8. A new imprinted cluster on the human chromosome 7q21-q31, identified by human-mouse monochromosomal hybrids.

    Science.gov (United States)

    Okita, Chiga; Meguro, Makiko; Hoshiya, Hidetoshi; Haruta, Masayuki; Sakamoto, Yu-ki; Oshimura, Mitsuo

    2003-06-01

    We have previously established a series of human monochromosomal hybrids containing a single human chromosome of defined parental origin as an in vitro resource for the investigation of human imprinted loci. Using the hybrids with a paternal or maternal human chromosome 7, we determined the allelic expression profiles of 76 ESTs mapped to the human chromosome 7q21-q31. Seven genes/transcripts, including PEG10 which has previously been reported to be imprinted, showed parent-of-origin-specific expression in monochromosomal hybrids. One of the 6 candidate genes/transcripts, i.e., DLX5 was confirmed to be imprinted in normal human lymphoblasts and brain tissues by a polymorphic analysis. Thus, an imprinted domain has been newly defined in the region of human chromosome 7q21-q31 using human-mouse monochromosomal hybrids.

  9. Biotin IgM Antibodies in Human Blood: A Previously Unknown Factor Eliciting False Results in Biotinylation-Based Immunoassays

    Science.gov (United States)

    Chen, Tingting; Hedman, Lea; Mattila, Petri S.; Jartti, Laura; Jartti, Tuomas; Ruuskanen, Olli; Söderlund-Venermo, Maria; Hedman, Klaus

    2012-01-01

    Biotin is an essential vitamin that binds streptavidin or avidin with high affinity and specificity. As biotin is a small molecule that can be linked to proteins without affecting their biological activity, biotinylation is applied widely in biochemical assays. In our laboratory, IgM enzyme immuno assays (EIAs) of µ-capture format have been set up against many viruses, using as antigen biotinylated virus like particles (VLPs) detected by horseradish peroxidase-conjugated streptavidin. We recently encountered one serum sample reacting with the biotinylated VLP but not with the unbiotinylated one, suggesting in human sera the occurrence of biotin-reactive antibodies. In the present study, we search the general population (612 serum samples from adults and 678 from children) for IgM antibodies reactive with biotin and develop an indirect EIA for quantification of their levels and assessment of their seroprevalence. These IgM antibodies were present in 3% adults regardless of age, but were rarely found in children. The adverse effects of the biotin IgM on biotinylation-based immunoassays were assessed, including four inhouse and one commercial virus IgM EIAs, showing that biotin IgM do cause false positivities. The biotin can not bind IgM and streptavidin or avidin simultaneously, suggesting that these biotin-interactive compounds compete for the common binding site. In competitive inhibition assays, the affinities of biotin IgM antibodies ranged from 2.1×10−3 to 1.7×10−4 mol/L. This is the first report on biotin antibodies found in humans, providing new information on biotinylation-based immunoassays as well as new insights into the biomedical effects of vitamins. PMID:22879954

  10. A Genome-Wide Association Study to Identify Diagnostic Markers for Human Pathogenic Campylobacter jejuni Strains

    Directory of Open Access Journals (Sweden)

    Cody J. Buchanan

    2017-06-01

    Full Text Available Campylobacter jejuni is a leading human enteric pathogen worldwide and despite an improved understanding of its biology, ecology, and epidemiology, limited tools exist for identifying strains that are likely to cause disease. In the current study, we used subtyping data in a database representing over 24,000 isolates collected through various surveillance projects in Canada to identify 166 representative genomes from prevalent C. jejuni subtypes for whole genome sequencing. The sequence data was used in a genome-wide association study (GWAS aimed at identifying accessory gene markers associated with clinically related C. jejuni subtypes. Prospective markers (n = 28 were then validated against a large number (n = 3,902 of clinically associated and non-clinically associated genomes from a variety of sources. A total of 25 genes, including six sets of genetically linked genes, were identified as robust putative diagnostic markers for clinically related C. jejuni subtypes. Although some of the genes identified in this study have been previously shown to play a role in important processes such as iron acquisition and vitamin B5 biosynthesis, others have unknown function or are unique to the current study and warrant further investigation. As few as four of these markers could be used in combination to detect up to 90% of clinically associated isolates in the validation dataset, and such markers could form the basis for a screening assay to rapidly identify strains that pose an increased risk to public health. The results of the current study are consistent with the notion that specific groups of C. jejuni strains of interest are defined by the presence of specific accessory genes.

  11. Effect of 30 mCi radioiodine on multinodular goiter previously treated with recombinant human thyroid-stimulating hormone

    Energy Technology Data Exchange (ETDEWEB)

    Paz-Filho, G.J.; Mesa-Junior, C.O.; Boguszewski, C.L.; Carvalho, G.A.; Graf, H. [Universidade Federal do Parana (UFPR), Curitiba, PR (Brazil). Hospital de Clinicas. Servico de Endocrinologia e Metabologia; Olandoski, M. [Pontificia Univ. Catolica do Parana, Curitiba, PR (Brazil). Nucleo de Bioestatistica; Woellner, L.C. [Centro de Medicina Nuclear, Curitiba, PR (Brazil); Goedert, C.A. [Centro de Tomografia Computadorizada, Curitiba, PR (Brazil)

    2007-12-15

    Recombinant human thyroid-stimulating hormone (rhTSH) enhances {sup 131}I uptake, permitting a decrease in radiation for the treatment of multinodular goiter (MNG). Our objective was to evaluate the safety and efficacy of a single 0.1-mg dose of rhTSH, followed by 30 mCi {sup 131}I, in patients with MNG. Seventeen patients (15 females, 59.0 {+-} 13.1 years), who had never been submitted to {sup 131}I therapy, received a single 0.1-mg injection of rhTSH followed by 30 mCi {sup 131}I on the next day. Mean basal thyroid volume measured by computed tomography was 106.1 {+-} 64.4 mL. {sup 131}I 24-h uptake, TSH, free-T4, T3, thyroglobulin, anti-thyroid antibodies, and thyroid volume were evaluated at regular intervals of 12 months. Mean {sup 131}I 24-h uptake increased from 18.1 {+-} 9.7 to 49.6 {+-} 13.4% (P < 0.001), a median 2.6-fold increase (1.2 to 9.2). Peak hormonal levels were 10.86 {+-} 5.44 mU/L for TSH (a median 15.5-fold increase), 1.80 {+-} 0.48 ng/dL for free-T4, 204.61 {+-} 58.37 ng/dL for T3, and a median of 557.0 ng/mL for thyroglobulin. The adverse effects observed were hyperthyroidism (17.6%), painful thyroiditis (29.4%) and hypothyroidism (52.9%). Thyroid volume was reduced by 34.3 {+-} 14.3% after 6 months (P < 0.001) and by 46.0 {+-} 14.6% after 1 year (P < 0.001). Treatment of MNG with a single 0.1-mg dose of rhTSH, followed by a fixed amount of radioactivity of {sup 131}I, leads to an efficacious decrease in thyroid volume for the majority of the patients, with a moderate incidence of non-serious and readily treatable adverse effects. (author)

  12. Transcriptome analysis of human brain tissue identifies reduced expression of complement complex C1Q Genes in Rett syndrome.

    Science.gov (United States)

    Lin, Peijie; Nicholls, Laura; Assareh, Hassan; Fang, Zhiming; Amos, Timothy G; Edwards, Richard J; Assareh, Amelia A; Voineagu, Irina

    2016-06-06

    MECP2, the gene mutated in the majority of Rett syndrome cases, is a transcriptional regulator that can activate or repress transcription. Although the transcription regulatory function of MECP2 has been known for over a decade, it remains unclear how transcriptional dysregulation leads to the neurodevelopmental disorder. Notably, little convergence was previously observed between the genes abnormally expressed in the brain of Rett syndrome mouse models and those identified in human studies. Here we carried out a comprehensive transcriptome analysis of human brain tissue from Rett syndrome brain using both RNA-seq and microarrays. We identified over two hundred differentially expressed genes, and identified the complement C1Q complex genes (C1QA, C1QB and C1QC) as a point of convergence between gene expression changes in human and mouse Rett syndrome brain. The results of our study support a role for alterations in the expression level of C1Q complex genes in RTT pathogenesis.

  13. Identifying Human Genome-Wide CNV, LOH and UPD by Targeted Sequencing of Selected Regions.

    Directory of Open Access Journals (Sweden)

    Wei Li

    Full Text Available Copy-number variations (CNV, loss of heterozygosity (LOH, and uniparental disomy (UPD are large genomic aberrations leading to many common inherited diseases, cancers, and other complex diseases. An integrated tool to identify these aberrations is essential in understanding diseases and in designing clinical interventions. Previous discovery methods based on whole-genome sequencing (WGS require very high depth of coverage on the whole genome scale, and are cost-wise inefficient. Another approach, whole exome genome sequencing (WEGS, is limited to discovering variations within exons. Thus, we are lacking efficient methods to detect genomic aberrations on the whole genome scale using next-generation sequencing technology. Here we present a method to identify genome-wide CNV, LOH and UPD for the human genome via selectively sequencing a small portion of genome termed Selected Target Regions (SeTRs. In our experiments, the SeTRs are covered by 99.73%~99.95% with sufficient depth. Our developed bioinformatics pipeline calls genome-wide CNVs with high confidence, revealing 8 credible events of LOH and 3 UPD events larger than 5M from 15 individual samples. We demonstrate that genome-wide CNV, LOH and UPD can be detected using a cost-effective SeTRs sequencing approach, and that LOH and UPD can be identified using just a sample grouping technique, without using a matched sample or familial information.

  14. Novel genetic loci underlying human intracranial volume identified through genome-wide association.

    Science.gov (United States)

    Adams, Hieab H H; Hibar, Derrek P; Chouraki, Vincent; Stein, Jason L; Nyquist, Paul A; Rentería, Miguel E; Trompet, Stella; Arias-Vasquez, Alejandro; Seshadri, Sudha; Desrivières, Sylvane; Beecham, Ashley H; Jahanshad, Neda; Wittfeld, Katharina; Van der Lee, Sven J; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S; Armstrong, Nicola J; Athanasiu, Lavinia; Axelsson, Tomas; Beiser, Alexa; Bernard, Manon; Bis, Joshua C; Blanken, Laura M E; Blanton, Susan H; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brickman, Adam M; Carmichael, Owen; Chakravarty, M Mallar; Chauhan, Ganesh; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; Braber, Anouk Den; Doan, Nhat Trung; Ehrlich, Stefan; Filippi, Irina; Ge, Tian; Giddaluru, Sudheer; Goldman, Aaron L; Gottesman, Rebecca F; Greven, Corina U; Grimm, Oliver; Griswold, Michael E; Guadalupe, Tulio; Hass, Johanna; Haukvik, Unn K; Hilal, Saima; Hofer, Edith; Hoehn, David; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Liao, Jiemin; Liewald, David C M; Lopez, Lorna M; Luciano, Michelle; Macare, Christine; Marquand, Andre; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; Mazoyer, Bernard; McKay, David R; McWhirter, Rebekah; Milaneschi, Yuri; Mirza-Schreiber, Nazanin; Muetzel, Ryan L; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C; Loohuis, Loes M Olde; Oosterlaan, Jaap; Papmeyer, Martina; Pappa, Irene; Pirpamer, Lukas; Pudas, Sara; Pütz, Benno; Rajan, Kumar B; Ramasamy, Adaikalavan; Richards, Jennifer S; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rommelse, Nanda; Rose, Emma J; Royle, Natalie A; Rundek, Tatjana; Sämann, Philipp G; Satizabal, Claudia L; Schmaal, Lianne; Schork, Andrew J; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V; Sprooten, Emma; Strike, Lachlan T; Teumer, Alexander; Thomson, Russell; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Meer, Dennis; Van Donkelaar, Marjolein M J; Van Eijk, Kristel R; Van Erp, Theo G M; Van Rooij, Daan; Walton, Esther; Westlye, Lars T; Whelan, Christopher D; Windham, Beverly G; Winkler, Anderson M; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Xu, Bing; Yanek, Lisa R; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P; Agartz, Ingrid; Aggarwal, Neelum T; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A; Arepalli, Sampath; Assareh, Amelia A; Barral, Sandra; Bastin, Mark E; Becker, Diane M; Becker, James T; Bennett, David A; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cahn, Wiepke; Calhoun, Vince D; Cannon, Dara M; Cavalleri, Gianpiero L; Chen, Christopher; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Dale, Anders M; Davies, Gareth E; De Geus, Eco J C; De Jager, Philip L; de Zubicaray, Greig I; Delanty, Norman; Depondt, Chantal; DeStefano, Anita L; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Espeseth, Thomas; Evans, Denis A; Fedko, Iryna O; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E; Fleischman, Debra A; Ford, Ian; Foroud, Tatiana M; Fox, Peter T; Francks, Clyde; Fukunaga, Masaki; Gibbs, J Raphael; Glahn, David C; Gollub, Randy L; Göring, Harald H H; Grabe, Hans J; Green, Robert C; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Hansell, Narelle K; Hardy, John; Hartman, Catharina A; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G; Heslenfeld, Dirk J; Ho, Beng-Choon; Hoekstra, Pieter J; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Ikram, M Kamran; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G; Jukema, J Wouter; Kahn, René S; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L; Longstreth, W T; Lopez, Oscar L; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S; McDonald, Colm; McIntosh, Andrew M; McMahon, Katie L; McMahon, Francis J; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W; Morris, Derek W; Mosley, Thomas H; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Nalls, Michael A; Nauck, Matthias; Nichols, Thomas E; Niessen, Wiro J; Nöthen, Markus M; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L; Ophoff, Roel A; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W J H; Pike, G Bruce; Potkin, Steven G; Psaty, Bruce M; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L; Romanczuk-Seiferth, Nina; Rotter, Jerome I; Ryten, Mina; Sacco, Ralph L; Sachdev, Perminder S; Saykin, Andrew J; Schmidt, Reinhold; Schofield, Peter R; Sigurdsson, Sigurdur; Simmons, Andy; Singleton, Andrew; Sisodiya, Sanjay M; Smith, Colin; Smoller, Jordan W; Soininen, Hilkka; Srikanth, Velandai; Steen, Vidar M; Stott, David J; Sussmann, Jessika E; Thalamuthu, Anbupalam; Tiemeier, Henning; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Tzourio, Christophe; Uitterlinden, Andre G; Hernández, Maria C Valdés; Van der Brug, Marcel; Van der Lugt, Aad; Van der Wee, Nic J A; Van Duijn, Cornelia M; Van Haren, Neeltje E M; Van T Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N; Veltman, Dick J; Vernooij, Meike W; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M; Wassink, Thomas H; Weale, Michael E; Weinberger, Daniel R; Weiner, Michael W; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y; Wright, Clinton B; Zielke, H Ronald; Zonderman, Alan B; Deary, Ian J; DeCarli, Charles; Schmidt, Helena; Martin, Nicholas G; De Craen, Anton J M; Wright, Margaret J; Launer, Lenore J; Schumann, Gunter; Fornage, Myriam; Franke, Barbara; Debette, Stéphanie; Medland, Sarah E; Ikram, M Arfan; Thompson, Paul M

    2016-12-01

    Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

  15. Altered endoribonuclease activity of apurinic/apyrimidinic endonuclease 1 variants identified in the human population.

    Directory of Open Access Journals (Sweden)

    Wan Cheol Kim

    Full Text Available Apurinic/apyrimidinic endonuclease 1 (APE1 is the major mammalian enzyme in the DNA base excision repair pathway and cleaves the DNA phosphodiester backbone immediately 5' to abasic sites. APE1 also has 3'-5' DNA exonuclease and 3' DNA phosphodiesterase activities, and regulates transcription factor DNA binding through its redox regulatory function. The human APE1 has recently been shown to endonucleolytically cleave single-stranded regions of RNA. Towards understanding the biological significance of the endoribonuclease activity of APE1, we examined eight different amino acid substitution variants of APE1 previously identified in the human population. Our study shows that six APE1 variants, D148E, Q51H, I64V, G241R, R237A, and G306A, exhibit a 76-85% reduction in endoribonuclease activity against a specific coding region of the c-myc RNA, yet fully retain the ability to cleave apurinic/apyrimidinic DNA. We found that two APE1 variants, L104R and E126D, exhibit a unique RNase inhibitor-resistant endoribonuclease activity, where the proteins cleave c-myc RNA 3' of specific single-stranded guanosine residues. Expression of L104R and E126D APE1 variants in bacterial Origami cells leads to a 60-80% reduction in colony formation and a 1.5-fold increase in cell doubling time, whereas the other variants, which exhibit diminished endoribonuclease activity, had no effect. These data indicate that two human APE1 variants exhibit a unique endoribonuclease activity, which correlates with their ability to induce cytotoxicity or slow down growth in bacterial cells and supports the notion of their biological functionality.

  16. Identifying areas of high risk of human exposure to coccidioidomycosis in Texas using serology data from dogs.

    Science.gov (United States)

    Gautam, R; Srinath, I; Clavijo, A; Szonyi, B; Bani-Yaghoub, M; Park, S; Ivanek, R

    2013-03-01

    Coccidioidomycosis or Valley Fever (VF) is an emerging soil-borne fungal zoonosis affecting humans and animals. Most non-human cases of VF are found in dogs, which we hypothesize may serve as sentinels for estimating the human exposure risk. The objective of this study is to use the spatial and temporal distribution and clusters of dogs seropositive for VF to define the geographic area in Texas where VF is endemic, and thus presents a higher risk of exposure to humans. The included specimens were seropositive dogs tested at a major diagnostic laboratory between 1999 and 2009. Data were aggregated by zip code and smoothed by empirical Bayesian estimation to develop an isopleth map of VF seropositive rates using kriging. Clusters of seropositive dogs were identified using the spatial scan test. Both the isopleth map and the scan test identified an area with a high rate of VF-seropositive dogs in the western and southwestern parts of Texas (relative risk = 31). This location overlapped an area that was previously identified as a potential endemic region based on human surveys. Together, these data suggest that dogs may serve as sentinels for estimating the risk of human exposure to VF. © 2012 Blackwell Verlag GmbH.

  17. Dynamics of co-existing Escherichia colilineages in situ of the infant gut and multiplex phenotypic targeted recovery of previously uncultivated bacteria from the human gut

    DEFF Research Database (Denmark)

    Gumpert, Heidi

    were selected due to an observed change in their antibiotic susceptibility profile. Via full genome sequencing, we identified that in both cases a conjugative plasmid harboring antibiotic resistance genes was transferred between co-existing E. coli lineages and is responsible for the change...... conditions. Antibiotictolerance phenotypes were determined, and this mapping was used to carefully tailor antibiotic combinations to specifically select for previously uncultivated bacteria. Usingthis method, four previously uncultivated species were successfully cultured andgenome sequenced, and two...... of which had 16S rRNA identities of less than 95% topreviously cultured bacteria. We assessed the genomic coverage and abundance ofthese sequenced isolates in the gut using publicly available metagenomes....

  18. Coexpression networks identify brain region-specific enhancer RNAs in the human brain.

    Science.gov (United States)

    Yao, Pu; Lin, Peijie; Gokoolparsadh, Akira; Assareh, Amelia; Thang, Mike W C; Voineagu, Irina

    2015-08-01

    Despite major progress in identifying enhancer regions on a genome-wide scale, the majority of available data are limited to model organisms and human transformed cell lines. We have identified a robust set of enhancer RNAs (eRNAs) expressed in the human brain and constructed networks assessing eRNA-gene coexpression interactions across human fetal brain and multiple adult brain regions. Our data identify brain region-specific eRNAs and show that enhancer regions expressing eRNAs are enriched for genetic variants associated with autism spectrum disorders.

  19. Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

    NARCIS (Netherlands)

    Barban, N.; Jansen, R.; de Vlaming, Ronald; Vaez, A.; Mandemakers, J.J.; Tropf, F.C.; Shen, X.; Wilson, J.F.; Chasman, D.I.; Nolte, I.M.; Mbarek, H.; Boomsma, D.I.; de Geus, E.J.C.; Penninx, B.W.J.H.; Willemsen, G.; Zondervan, K.T.; Stefansson, K.; Krueger, R.F.; Lee, J.J.; Benjamin, D.J.; Cesarini, D.; Koellinger, P.D.; den Hoed, M.A.H.; Snieder, H.; Mills, M.C.

    2016-01-01

    The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the

  20. Genome-wide analysis identifies 12 loci influencing human reproductive behavior

    NARCIS (Netherlands)

    Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J; Tropf, Felix C; Shen, Xia; Wilson, James F; Chasman, Daniel I; Nolte, Ilja M; Tragante, Vinicius; van der Laan, Sander W; Perry, John R B; Kong, Augustine; Ahluwalia, Tarunveer S; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J; Gieger, Christian; Gunderson, Erica P; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F; McMahon, George; Meddens, S Fleur W; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A; Monnereau, Claire; van der Most, Peter J; Myhre, Ronny; Nalls, Mike A; Nutile, Teresa; Kalafati, Ioanna Panagiota; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B; Rich-Edwards, Janet; Rietveld, Cornelius A; Robino, Antonietta; Rose, Lynda M; Rueedi, Rico; Ryan, Kathleen A; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A; Stolk, Lisette; Streeten, Elizabeth; Tönjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I; Buring, Julie E; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R; Cucca, Francesco; Toniolo, Daniela; Davey-Smith, George; Deary, Ian J; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M; de Geus, Eco J C; Eriksson, Johan G; Evans, Denis A; Faul, Jessica D; Sala, Cinzia Felicita; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J F; de Haan, Hugoline G; Haerting, Johannes; Harris, Tamara B; Heath, Andrew C; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G; Hopper, John; Hyppönen, Elina; Jacobsson, Bo; Jaddoe, Vincent W V; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L R; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William G; Lai, Sandra; Lehtimäki, Terho; Liewald, David C; Lindgren, Cecilia M; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; McQuillan, Ruth; Medland, Sarah E; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Traglia, Michela; Milani, Lili; Mitchell, Paul; Montgomery, Grant W; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda W J H; Perola, Markus; Peyser, Patricia A; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M; Ring, Susan M; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D; Starr, John M; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tung, Joyce Y; Uitterlinden, André G; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G; Wang, Jie Jin; Wareham, Nicholas J; Weir, David R; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F; Zondervan, Krina T; Stefansson, Kari; Krueger, Robert F; Lee, James J; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C

    2016-01-01

    The genetic architecture of human reproductive behavior age at first birth (AFB) and number of children ever born (NEB) has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the

  1. Genome-wide analysis identifies 12 loci influencing human reproductive behavior

    NARCIS (Netherlands)

    Barban, Nicola; Jansen, Rick; De Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J.; Tropf, Felix C.; Shen, Xia; Wilson, James F.; Chasman, Daniel I.; Nolte, Ilja M.; Tragante, Vinicius; Van Der Laan, Sander W.; Perry, John R B; Kong, Augustine; Ahluwalia, Tarunveer S.; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F.; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E.; Turman, Constance; Concas, Maria Pina; Cordell, Heather J.; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F.; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J.; Gieger, Christian; Gunderson, Erica P.; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K.; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A.; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F.; McMahon, George; Meddens, S. Fleur W; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A.; Monnereau, Claire; Van Der Most, Peter J.; Myhre, Ronny; Nalls, Mike A.; Nutile, Teresa; Kalafati, Ioanna Panagiota; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B.; Rich-Edwards, Janet; Rietveld, Cornelius A.; Robino, Antonietta; Rose, Lynda M.; Rueedi, Rico; Ryan, Kathleen A.; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A.; Stolk, Lisette; Streeten, Elizabeth; Tönjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V.; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I.; Buring, Julie E.; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R.; Cucca, Francesco; Toniolo, Daniela; Davey-Smith, George; Deary, Ian J.; Dedoussis, George; Deloukas, Panos; Van Duijn, Cornelia M.; De Geus, Eco J C; Eriksson, Johan G.; Evans, Denis A.; Faul, Jessica D.; Sala, Cinzia Felicita; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans Jörgen; Greiser, Karin Halina; Groenen, Patrick J F; De Haan, Hugoline G.; Haerting, Johannes; Harris, Tamara B.; Heath, Andrew C.; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G.; Hopper, John; Hyppönen, Elina; Jacobsson, Bo; Jaddoe, Vincent W V; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L R; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William G.; Lai, Sandra; Lehtimäki, Terho; Liewald, David C.; Lindgren, Cecilia M.; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrikke; Martin, Nicholas G.; McGue, Matt; McQuillan, Ruth; Medland, Sarah E.; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Traglia, Michela; Milani, Lili; Mitchell, Paul; Montgomery, Grant W.; Mook-Kanamori, Dennis; De Mutsert, Renée; Nohr, Ellen A.; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K.; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda W J H; Perola, Markus; Peyser, Patricia A.; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J.; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M.; Ring, Susan M.; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D.; Starr, John M.; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A.; Thorsteinsdottir, Unnur; Roy Thurik, A.; Timpson, Nicholas J.; Tung, Joyce Y.; Uitterlinden, André G.; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G.; Wang, Jie Jin; Wareham, Nicholas J.; Weir, David R.; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F.; Zondervan, Krina T.; Stefansson, Kari; Krueger, Robert F.; Lee, James J.; Benjamin, Daniel J.; Cesarini, David; Koellinger, Philipp D.; Den Hoed, Marcel; Snieder, Harold; Mills, Melinda C.

    2016-01-01

    The genetic architecture of human reproductive behavior - age at first birth (AFB) and number of children ever born (NEB) - has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the

  2. Genome-wide analysis identifies 12 loci influencing human reproductive behavior

    NARCIS (Netherlands)

    Barban, Nicola; Jansen, Rick; Vlaming, de Ronald; Vaez, Ahmad; Mandemakers, Jornt J.; Tropf, Felix C.; Shen, Xia; Wilson, James F.; Chasman, Daniel I.; Nolte, Ilja M.; Tragante, Vinicius; Laan, van der Sander W.; Perry, John R.B.; Kong, Augustine; Ahluwalia, Tarunveer S.; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F.; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E.; Turman, Constance; Concas, Maria Pina; Cordell, Heather J.; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F.; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J.; Gieger, Christian; Gunderson, Erica P.; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K.; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A.; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F.; McMahon, George; Meddens, S.F.W.; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A.; Monnereau, Claire; Most, van der Peter J.; Myhre, Ronny; Nalls, Mike A.; Nutile, Teresa; Kalafati, Ioanna Panagiota; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B.; Rich-Edwards, Janet; Rietveld, Cornelius A.; Robino, Antonietta; Rose, Lynda M.; Rueedi, Rico; Ryan, Kathleen A.; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A.; Stolk, Lisette; Streeten, Elizabeth; Tönjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V.; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I.; Buring, Julie E.; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R.; Cucca, Francesco; Toniolo, Daniela; Davey-Smith, George; Deary, Ian J.; Dedoussis, George; Deloukas, Panos; Duijn, van Cornelia M.; Geus, de Eco J.C.; Eriksson, Johan G.; Evans, Denis A.; Faul, Jessica D.; Sala, Cinzia Felicita; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J.F.; Haan, de Hugoline G.; Haerting, Johannes; Harris, Tamara B.; Heath, Andrew C.; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G.; Hopper, John; Hyppönen, Elina; Jacobsson, Bo; Jaddoe, Vincent W.V.; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L.R.; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; Bianca, la Martina; Lachance, Genevieve; Iacono, William G.; Lai, Sandra; Lehtimäki, Terho; Liewald, David C.; Lindgren, Cecilia M.; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; McQuillan, Ruth; Medland, Sarah E.; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Traglia, Michela; Milani, Lili; Mitchell, Paul; Montgomery, Grant W.; Mook-Kanamori, Dennis; Mutsert, de Renée; Nohr, Ellen A.; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K.; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda W.J.H.; Perola, Markus; Peyser, Patricia A.; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J.; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M.; Ring, Susan M.; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D.; Starr, John M.; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A.; Thorsteinsdottir, Unnur; Thurik, A.R.; Timpson, Nicholas J.; Tung, Joyce Y.; Uitterlinden, André G.; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G.; Wang, Jie Jin; Wareham, Nicholas J.; Weir, David R.; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F.; Zondervan, Krina T.; Stefansson, Kari; Krueger, Robert F.; Lee, James J.; Benjamin, Daniel J.; Cesarini, David; Koellinger, Philipp D.; Hoed, den Marcel; Snieder, Harold; Mills, Melinda C.

    2016-01-01

    The genetic architecture of human reproductive behavior—age at first birth (AFB) and number of children ever born (NEB)—has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the

  3. Identifying and managing conflicts between forest conservation and other human interests in Europe

    NARCIS (Netherlands)

    Niemela, J.; Young, J.; Alard, D.; Askasibar, M.; Henle, K.; Johnson, R.; Kurttila, M.; Larsson, T.B.; Matouch, S.; Nowicki, P.L.; Paiva, R.Q.; Portoghesi, L.; Smulders, M.J.M.; Stevenson, A.; Tartes, U.; Watt, A.

    2005-01-01

    In this paper, circumstances where various human activities and interests clash with the conservation of forest biodiversity are examined, with particular focus on the drivers behind the conflicts. After identifying past and current human-related threats potentially leading to conflicts in forests,

  4. Using a Functional Architecture to Identify Human-Automation Trust Needs and Design Requirements

    Science.gov (United States)

    2016-12-01

    placed in the Trustee’s information based on the Trustee’s voice or body language (perception of the Trustee). In human -automation relationships the...machine capabilities and the situation. Lyons (2013) identifies the same necessity in one of his three models for human - robot transparency factors...10.1518/hfes.46.1.50_30392. Lyons, Joseph B. 2013. “Being Transparent about Transparency: A model for Human - Robot Interaction.” AAAI Spring Symposium

  5. Multiple binding modes of ibuprofen in human serum albumin identified by absolute binding free energy calculations

    KAUST Repository

    Evoli, Stefania

    2016-11-10

    Human serum albumin possesses multiple binding sites and transports a wide range of ligands that include the anti-inflammatory drug ibuprofen. A complete map of the binding sites of ibuprofen in albumin is difficult to obtain in traditional experiments, because of the structural adaptability of this protein in accommodating small ligands. In this work, we provide a set of predictions covering the geometry, affinity of binding and protonation state for the pharmaceutically most active form (S-isomer) of ibuprofen to albumin, by using absolute binding free energy calculations in combination with classical molecular dynamics (MD) simulations and molecular docking. The most favorable binding modes correctly reproduce several experimentally identified binding locations, which include the two Sudlow\\'s drug sites (DS2 and DS1) and the fatty acid binding sites 6 and 2 (FA6 and FA2). Previously unknown details of the binding conformations were revealed for some of them, and formerly undetected binding modes were found in other protein sites. The calculated binding affinities exhibit trends which seem to agree with the available experimental data, and drastically degrade when the ligand is modeled in a protonated (neutral) state, indicating that ibuprofen associates with albumin preferentially in its charged form. These findings provide a detailed description of the binding of ibuprofen, help to explain a wide range of results reported in the literature in the last decades, and demonstrate the possibility of using simulation methods to predict ligand binding to albumin.

  6. Human immune responses to H. pylori HLA Class II epitopes identified by immunoinformatic methods.

    Directory of Open Access Journals (Sweden)

    Songhua Zhang

    Full Text Available H. pylori persists in the human stomach over decades and promotes several adverse clinical sequelae including gastritis, peptic ulcers and gastric cancer that are linked to the induction and subsequent evasion of chronic gastric inflammation. Emerging evidence indicates that H. pylori infection may also protect against asthma and some other immune-mediated conditions through regulatory T cell effects outside the stomach. To characterize the complexity of the CD4+ T cell response generated during H. pylori infection, computational methods were previously used to generate a panel of 90 predicted epitopes conserved among H. pylori genomes that broadly cover HLA Class II diversity for maximum population coverage. Here, these sequences were tested individually for their ability to induce in vitro responses in peripheral blood mononuclear cells by interferon-γ ELISpot assay. The average number of spot-forming cells/million PBMCs was significantly elevated in H. pylori-infected subjects over uninfected persons. Ten of the 90 peptides stimulated IFN-γ secretion in the H. pylori-infected group only, whereas two out of the 90 peptides elicited a detectable IFN-γ response in the H. pylori-uninfected subjects but no response in the H. pylori-infected group. Cytokine ELISA measurements performed using in vitro PBMC culture supernatants demonstrated significantly higher levels of TNF-α, IL-2, IL-4, IL-6, IL-10, and TGF-β1 in the H. pylori-infected subjects, whereas IL-17A expression was not related to the subjects H. pylori-infection status. Our results indicate that the human T cell responses to these 90 peptides are generally increased in actively H. pylori-infected, compared with H. pylori-naïve, subjects. This information will improve understanding of the complex immune response to H. pylori, aiding rational epitope-driven vaccine design as well as helping identify other H. pylori epitopes with potentially immunoregulatory effects.

  7. Structured methods for identifying and correcting potential human errors in aviation operations

    Energy Technology Data Exchange (ETDEWEB)

    Nelson, W.R.

    1997-10-01

    Human errors have been identified as the source of approximately 60% of the incidents and accidents that occur in commercial aviation. It can be assumed that a very large number of human errors occur in aviation operations, even though in most cases the redundancies and diversities built into the design of aircraft systems prevent the errors from leading to serious consequences. In addition, when it is acknowledged that many system failures have their roots in human errors that occur in the design phase, it becomes apparent that the identification and elimination of potential human errors could significantly decrease the risks of aviation operations. This will become even more critical during the design of advanced automation-based aircraft systems as well as next-generation systems for air traffic management. Structured methods to identify and correct potential human errors in aviation operations have been developed and are currently undergoing testing at the Idaho National Engineering and Environmental Laboratory (INEEL).

  8. Does correlated color temperature affect the ability of humans to identify veins?

    DEFF Research Database (Denmark)

    Argyraki, Aikaterini; Clemmensen, Line Katrine Harder; Petersen, Paul Michael

    2016-01-01

    In the present study we provide empirical evidence and demonstrate statistically that white illumination settings can affect the human ability to identify veins in the inner hand vasculature. A special light-emitting diode lamp with high color rendering index (CRI 84–95) was developed and the eff......In the present study we provide empirical evidence and demonstrate statistically that white illumination settings can affect the human ability to identify veins in the inner hand vasculature. A special light-emitting diode lamp with high color rendering index (CRI 84–95) was developed...... and the effect of correlated color temperature was evaluated, in the range between 2600 and 5700 K at an illuminance of 40 9 lx on the ability of adult humans to identify veins. It is shown that the ability to identify veins can, on average, be increased up to 24% when white illumination settings that do...

  9. Cross-comparison of the genome sequences from human, chimpanzee, Neanderthal and a Denisovan hominin identifies novel potentially compensated mutations

    Directory of Open Access Journals (Sweden)

    Zhang Guojie

    2011-07-01

    Full Text Available Abstract The recent publication of the draft genome sequences of the Neanderthal and a ~50,000-year-old archaic hominin from Denisova Cave in southern Siberia has ushered in a new age in molecular archaeology. We previously cross-compared the human, chimpanzee and Neanderthal genome sequences with respect to a set of disease-causing/disease-associated missense and regulatory mutations (Human Gene Mutation Database and succeeded in identifying genetic variants which, although apparently pathogenic in humans, may represent a 'compensated' wild-type state in at least one of the other two species. Here, in an attempt to identify further 'potentially compensated mutations' (PCMs of interest, we have compared our dataset of disease-causing/disease-associated mutations with their corresponding nucleotide positions in the Denisovan hominin, Neanderthal and chimpanzee genomes. Of the 15 human putatively disease-causing mutations that were found to be compensated in chimpanzee, Denisovan or Neanderthal, only a solitary F5 variant (Val1736Met was specific to the Denisovan. In humans, this missense mutation is associated with activated protein C resistance and an increased risk of thromboembolism and recurrent miscarriage. It is unclear at this juncture whether this variant was indeed a PCM in the Denisovan or whether it could instead have been associated with disease in this ancient hominin.

  10. Human and mouse ABCA1 comparative sequencing and transgenesis studies identify regulatory elements

    Energy Technology Data Exchange (ETDEWEB)

    Qiu, Yang; Cavelier, L.; Chiu, Sally; Rubin, Edward; Cheng, Jan-Fang

    2000-08-01

    The expression of ABCA1, a major participant in apolipoprotein mediated cholesterol efflux is highly regulated by a variety of factors including intracellular cholesterol concentration. To analyze its genomic organization and identify those sequences involved in its regulation we sequenced and compared approximately 200 Kb of orthologous DNA from mice and humans containing the ABCA1 gene and significant flanking DNA. The comparison revealed a variety of mouse human conserved sequences including 50 conserved ABCA1 exons over 147Kb of human and 124Kb of mouse genomic DNA as well as multiple mouse human conserved noncoding sequences. Using as a criteria for identifying putative regulatory elements in non-coding sequence, human and mouse sequences that were &62;75% identical for over 120 bp were screened for resulting in the identification of 34 elements. The two most highly conserved human mouse noncoding elements (CNS1: 88% identity over 498 bp, CNS2: 81% identity over 214 bp)! were also highly conserved in the ABCA1 genes of rats, dogs, cows, rabbits and pigs. Two independent studies have demonstrated that the DNA segments containing CNS2 function in vitro as a sterol response promoter. Support for the inclusion of major ABCA1 regulatory elements in the human genomic sequence examined was the demonstration that mice containing a human BAC transgene containing sequences exclusively from the analyzed interval, expressed human ABCA1 in a tissue distribution mimicking expression of endogenous mouse ABC1. These studies using a comparative genomic approach has characterized the structure of the human and mouse ABCA1 genes and has helped identify sequences participating in its expression.

  11. Identifying pathogenicity of human variants via paralog-based yeast complementation.

    Directory of Open Access Journals (Sweden)

    Fan Yang

    2017-05-01

    Full Text Available To better understand the health implications of personal genomes, we now face a largely unmet challenge to identify functional variants within disease-associated genes. Functional variants can be identified by trans-species complementation, e.g., by failure to rescue a yeast strain bearing a mutation in an orthologous human gene. Although orthologous complementation assays are powerful predictors of pathogenic variation, they are available for only a few percent of human disease genes. Here we systematically examine the question of whether complementation assays based on paralogy relationships can expand the number of human disease genes with functional variant detection assays. We tested over 1,000 paralogous human-yeast gene pairs for complementation, yielding 34 complementation relationships, of which 33 (97% were novel. We found that paralog-based assays identified disease variants with success on par with that of orthology-based assays. Combining all homology-based assay results, we found that complementation can often identify pathogenic variants outside the homologous sequence region, presumably because of global effects on protein folding or stability. Within our search space, paralogy-based complementation more than doubled the number of human disease genes with a yeast-based complementation assay for disease variation.

  12. Proteomic profiling of human plasma exosomes identifies PPARγ as an exosome-associated protein

    International Nuclear Information System (INIS)

    Looze, Christopher; Yui, David; Leung, Lester; Ingham, Matthew; Kaler, Maryann; Yao, Xianglan; Wu, Wells W.; Shen Rongfong; Daniels, Mathew P.; Levine, Stewart J.

    2009-01-01

    Exosomes are nanovesicles that are released from cells as a mechanism of cell-free intercellular communication. Only a limited number of proteins have been identified from the plasma exosome proteome. Here, we developed a multi-step fractionation scheme incorporating gel exclusion chromatography, rate zonal centrifugation through continuous sucrose gradients, and high-speed centrifugation to purify exosomes from human plasma. Exosome-associated proteins were separated by SDS-PAGE and 66 proteins were identified by LC-MS/MS, which included both cellular and extracellular proteins. Furthermore, we identified and characterized peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor that regulates adipocyte differentiation and proliferation, as well as immune and inflammatory cell functions, as a novel component of plasma-derived exosomes. Given the important role of exosomes as intercellular messengers, the discovery of PPARγ as a component of human plasma exosomes identifies a potential new pathway for the paracrine transfer of nuclear receptors.

  13. Genome-wide analysis identifies 12 loci influencing human reproductive behavior

    DEFF Research Database (Denmark)

    Barban, Nicola; Jansen, Rick; de Vlaming, Ronald

    2016-01-01

    The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified......-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits....

  14. Genome-Wide Expression Profiling of Five Mouse Models Identifies Similarities and Differences with Human Psoriasis

    Science.gov (United States)

    Swindell, William R.; Johnston, Andrew; Carbajal, Steve; Han, Gangwen; Wohn, Christian; Lu, Jun; Xing, Xianying; Nair, Rajan P.; Voorhees, John J.; Elder, James T.; Wang, Xiao-Jing; Sano, Shigetoshi; Prens, Errol P.; DiGiovanni, John; Pittelkow, Mark R.; Ward, Nicole L.; Gudjonsson, Johann E.

    2011-01-01

    Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis. PMID:21483750

  15. Molecular analysis of clinical isolates previously diagnosed as Mycobacterium intracellulare reveals incidental findings of "Mycobacterium indicus pranii" genotypes in human lung infection.

    Science.gov (United States)

    Kim, Su-Young; Park, Hye Yun; Jeong, Byeong-Ho; Jeon, Kyeongman; Huh, Hee Jae; Ki, Chang-Seok; Lee, Nam Yong; Han, Seung-Jung; Shin, Sung Jae; Koh, Won-Jung

    2015-09-30

    Mycobacterium intracellulare is a major cause of Mycobacterium avium complex lung disease in many countries. Molecular studies have revealed several new Mycobacteria species that are closely related to M. intracellulare. The aim of this study was to re-identify and characterize clinical isolates from patients previously diagnosed with M. intracellulare lung disease at the molecular level. Mycobacterial isolates from 77 patients, initially diagnosed with M. intracellulare lung disease were re-analyzed by multi-locus sequencing and pattern of insertion sequences. Among the 77 isolates, 74 (96 %) isolates were designated as M. intracellulare based on multigene sequence-based analysis. Interestingly, the three remaining strains (4 %) were re-identified as "Mycobacterium indicus pranii" according to distinct molecular phylogenetic positions in rpoB and hsp65 sequence-based typing. In hsp65 sequevar analysis, code 13 was found in the majority of cases and three unreported codes were identified. In 16S-23S rRNA internal transcribed spacer (ITS) sequevar analysis, all isolates of both species were classified within the Min-A ITS sequevar. Interestingly, four of the M. intracellulare isolates harbored IS1311, a M. avium-specific element. Two of three patients infected with "M. indicus pranii" had persistent positive sputum cultures after antibiotic therapy, indicating the clinical relevance of this study. This analysis highlights the importance of precise identification of clinical isolates genetically close to Mycobacterium species, and suggests that greater attention should be paid to nontuberculous mycobacteria lung disease caused by "M. indicus pranii".

  16. Novel genetic loci underlying human intracranial volume identified through genome-wide association

    OpenAIRE

    Adams, Hieab HH; Hibar, Derrek P; Chouraki, Vincent; Stein, Jason L; Nyquist, Paul A; Renter��a, Miguel E; Trompet, Stella; Arias-Vasquez, Alejandro; Seshadri, Sudha; Desrivi��res, Sylvane; Beecham, Ashley H; Jahanshad, Neda; Wittfeld, Katharina; Van der Lee, Sven J; Abramovic, Lucija

    2016-01-01

    Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjus...

  17. Mirror activity in the human brain while observing hand movements: a comparison between EEG desynchronization in the mu-range and previous fMRI results.

    Science.gov (United States)

    Perry, Anat; Bentin, Shlomo

    2009-07-28

    Mu (mu) rhythms are EEG oscillations between 8-13 Hz distinguished from alpha by having more anterior distribution and being desynchronized by motor rather than visual activity. Evidence accumulating during the last decade suggests that the desynchronization of mu rhythms (mu suppression) might be also a manifestation of a human Mirror Neuron System (MNS). To further explore this hypothesis we used a paradigm that, in a previous fMRI study, successfully activated this putative MNS in humans. Our direct goal was to provide further support for a link between modulation of mu rhythms and the MNS, by finding parallels between the reported patterns of fMRI activations and patterns of mu suppression. The EEG power in the mu range has been recorded while participants passively observed either a left or a right hand, reaching to and grasping objects, and compared it with that recorded while participants observed the movement of a ball, and while observing static grasping scenes or still objects. Mirroring fMRI results (Shmuelof, L., Zohary, E., 2005. Dissociation between ventral and dorsal fMRI activation during object and action recognition. Neuron 47, 457-470), mu suppression was larger in the hemisphere contra-lateral to the moving hand and larger when the hands grasped different objects in different ways than when the movement was repetitive. No suppression was found while participants observed still objects but mu suppression was also found while seeing static grasping postures. These data are discussed in light of similar parallels between modulations of alpha waves and fMRI while recording EEG in the magnet. The present data support a link between mu suppression and a human MNS.

  18. The Human Genome Project and Eugenics: Identifying the Impact on Individuals with Mental Retardation.

    Science.gov (United States)

    Kuna, Jason

    2001-01-01

    This article explores the impact of the mapping work of the Human Genome Project on individuals with mental retardation and the negative effects of genetic testing. The potential to identify disabilities and the concept of eugenics are discussed, along with ethical issues surrounding potential genetic therapies. (Contains references.) (CR)

  19. Identifying the "Human Resource Enterprise": A South-east Asian Example.

    Science.gov (United States)

    Standing, Guy

    1992-01-01

    Data from a survey of over 1,300 Filipino enterprises are used to construct indices for measuring performance in recruitment, training, labor relations, and other personnel practices. The indices are proposed as a way to identify exemplary human resource practices in terms of equity and efficiency. (SK)

  20. Bioinformatics analysis identifies several intrinsically disordered human E3 ubiquitin-protein ligases

    DEFF Research Database (Denmark)

    Boomsma, Wouter Krogh; Nielsen, Sofie Vincents; Lindorff-Larsen, Kresten

    2016-01-01

    conduct a bioinformatics analysis to examine >600 human and S. cerevisiae E3 ligases to identify enzymes that are similar to San1 in terms of function and/or mechanism of substrate recognition. An initial sequence-based database search was found to detect candidates primarily based on the homology...

  1. Identifying Victims of Human Trafficking at Hotspots by Focusing on People Smuggled to Europe

    Directory of Open Access Journals (Sweden)

    Matilde Ventrella

    2017-06-01

    Full Text Available Research has shown that smuggling of migrants is associated with human trafficking. Hence, victims of human trafficking amongst smuggled migrants should be identified by EU Member States at hotspots established by the European Commission, to overcome the migrant and refugee crisis. Identified victims should be given a visa and a programme of protection to escape their traffickers. In order to achieve these objectives, research suggests that EU law on migrant smuggling should be amended and the Temporary Protection Directive should be applied to smuggled persons when there is an indication that they may be victims of human trafficking. This approach should be adopted by the EASO in cooperation with police forces investigating smuggling and trafficking at hotspots.

  2. Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

    Science.gov (United States)

    Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J; Tropf, Felix C; Shen, Xia; Wilson, James F; Chasman, Daniel I; Nolte, Ilja M; Tragante, Vinicius; van der Laan, Sander W; Perry, John R B; Kong, Augustine; Ahluwalia, Tarunveer S; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J; Gieger, Christian; Gunderson, Erica P; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F; McMahon, George; Meddens, S Fleur W; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A; Monnereau, Claire; van der Most, Peter J; Myhre, Ronny; Nalls, Mike A; Nutile, Teresa; Kalafati, Ioanna Panagiota; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B; Rich-Edwards, Janet; Rietveld, Cornelius A; Robino, Antonietta; Rose, Lynda M; Rueedi, Rico; Ryan, Kathleen A; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A; Stolk, Lisette; Streeten, Elizabeth; Tönjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I; Buring, Julie E; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R; Cucca, Francesco; Toniolo, Daniela; Davey-Smith, George; Deary, Ian J; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M; de Geus, Eco J C; Eriksson, Johan G; Evans, Denis A; Faul, Jessica D; Sala, Cinzia Felicita; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J F; de Haan, Hugoline G; Haerting, Johannes; Harris, Tamara B; Heath, Andrew C; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G; Hopper, John; Hyppönen, Elina; Jacobsson, Bo; Jaddoe, Vincent W V; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L R; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William G; Lai, Sandra; Lehtimäki, Terho; Liewald, David C; Lindgren, Cecilia M; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; McQuillan, Ruth; Medland, Sarah E; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Traglia, Michela; Milani, Lili; Mitchell, Paul; Montgomery, Grant W; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda W J H; Perola, Markus; Peyser, Patricia A; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M; Ring, Susan M; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D; Starr, John M; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tung, Joyce Y; Uitterlinden, André G; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G; Wang, Jie Jin; Wareham, Nicholas J; Weir, David R; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F; Zondervan, Krina T; Stefansson, Kari; Krueger, Robert F; Lee, James J; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C

    2016-12-01

    The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

  3. Genome-wide analysis identifies 12 loci influencing human reproductive behavior

    Science.gov (United States)

    Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J.; Tropf, Felix C.; Shen, Xia; Wilson, James F.; Chasman, Daniel I.; Nolte, Ilja M.; Tragante, Vinicius; van der Laan, Sander W.; Perry, John R. B.; Kong, Augustine; Ahluwalia, Tarunveer; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F.; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J.; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F.; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J.; Gieger, Christian; Gunderson, Erica P.; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K.; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A.; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F.; McMahon, George; Meddens, S. Fleur W.; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A.; Monnereau, Claire; van der Most, Peter J.; Myhre, Ronny; Nalls, Mike A.; Nutile, Teresa; Panagiota, Kalafati Ioanna; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B.; Rich-Edwards, Janet; Rietveld, Cornelius A.; Robino, Antonietta; Rose, Lynda M.; Rueedi, Rico; Ryan, Kathy; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A.; Stolk, Lisette; Streeten, Elizabeth; Tonjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V.; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I.; Buring, Julie E.; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R.; Cucca, Francesco; Daniela, Toniolo; Davey-Smith, George; Deary, Ian J.; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M.; de Geus, Eco JC.; Eriksson, Johan G.; Evans, Denis A.; Faul, Jessica D.; Felicita, Sala Cinzia; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J.F.; de Haan, Hugoline G.; Haerting, Johannes; Harris, Tamara B.; Heath, Andrew C.; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G; Hopper, John; Hypponen, Elina; Jacobsson, Bo; Jaddoe, Vincent W. V.; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L.R.; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William; Lai, Sandra; Lehtimäki, Terho; Liewald, David C; Lindgren, Cecilia; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; McQuillan, Ruth; Medland, Sarah E.; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Michela, Traglia; Milani, Lili; Mitchell, Paul; Montgomery, Grant W.; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K.; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda WJH; Perola, Markus; Peyser, Patricia A.; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J.; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M.; Ring, Susan M.; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D.; Starr, John M.; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A.; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tönjes, Anke; Tung, Joyce Y.; Uitterlinden, André G.; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G.; Wang, Jie Jin; Wareham, Nicholas J.; Weir, David R.; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F.; Zondervan, Krina T.; Stefansson, Kari; Krueger, Robert F.; Lee, James J.; Benjamin, Daniel J.; Cesarini, David; Koellinger, Philipp D.; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C.

    2017-01-01

    The genetic architecture of human reproductive behavior – age at first birth (AFB) and number of children ever born (NEB) – has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified and the underlying mechanisms of AFB and NEB are poorly understood. We report the largest genome-wide association study to date of both sexes including 251,151 individuals for AFB and 343,072 for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study, and four additional loci in a gene-based effort. These loci harbor genes that are likely to play a role – either directly or by affecting non-local gene expression – in human reproduction and infertility, thereby increasing our understanding of these complex traits. PMID:27798627

  4. An evolutionary genomic approach to identify genes involved in human birth timing.

    Directory of Open Access Journals (Sweden)

    Jevon Plunkett

    2011-04-01

    Full Text Available Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.

  5. Application of Whole Exome Sequencing to Identify Disease-Causing Variants in Inherited Human Diseases

    Directory of Open Access Journals (Sweden)

    Gerald Goh

    2012-12-01

    Full Text Available The recent advent of next-generation sequencing technologies has dramatically changed the nature of biomedical research. Human genetics is no exception-it has never been easier to interrogate human patient genomes at the nucleotide level to identify disease-associated variants. To further facilitate the efficiency of this approach, whole exome sequencing (WES was first developed in 2009. Over the past three years, multiple groups have demonstrated the power of WES through robust disease-associated variant discoveries across a diverse spectrum of human diseases. Here, we review the application of WES to different types of inherited human diseases and discuss analytical challenges and possible solutions, with the aim of providing a practical guide for the effective use of this technology.

  6. Functional metagenomics identifies novel genes ABCTPP, TMSRP1 and TLSRP1 among human gut enterotypes

    DEFF Research Database (Denmark)

    Verma, Manoj Kumar; Ahmed, Vasim; Gupta, Shashank

    2018-01-01

    gut microbiome to identify candidate genes responsible for the salt stress tolerance. A plasmid borne metagenomic library of Bacteroidetes enriched human fecal metagenomic DNA led to identification of unique salt osmotolerance clones SR6 and SR7. Subsequent gene analysis combined with functional...... groups in a North Indian population. This study unravels an alternative method for imparting ionic stress tolerance, which may be prevalent in the human gut microbiome....... is an important aspect of gut microbes for their survival and colonization. Identification of these survival mechanisms is a pivotal step towards understanding genomic suitability of a symbiont for successful human gut colonization. Here we highlight our recent work applying functional metagenomics to study human...

  7. Identifying human disease genes through cross-species gene mapping of evolutionary conserved processes.

    Directory of Open Access Journals (Sweden)

    Martin Poot

    2011-05-01

    Full Text Available Understanding complex networks that modulate development in humans is hampered by genetic and phenotypic heterogeneity within and between populations. Here we present a method that exploits natural variation in highly diverse mouse genetic reference panels in which genetic and environmental factors can be tightly controlled. The aim of our study is to test a cross-species genetic mapping strategy, which compares data of gene mapping in human patients with functional data obtained by QTL mapping in recombinant inbred mouse strains in order to prioritize human disease candidate genes.We exploit evolutionary conservation of developmental phenotypes to discover gene variants that influence brain development in humans. We studied corpus callosum volume in a recombinant inbred mouse panel (C57BL/6J×DBA/2J, BXD strains using high-field strength MRI technology. We aligned mouse mapping results for this neuro-anatomical phenotype with genetic data from patients with abnormal corpus callosum (ACC development.From the 61 syndromes which involve an ACC, 51 human candidate genes have been identified. Through interval mapping, we identified a single significant QTL on mouse chromosome 7 for corpus callosum volume with a QTL peak located between 25.5 and 26.7 Mb. Comparing the genes in this mouse QTL region with those associated with human syndromes (involving ACC and those covered by copy number variations (CNV yielded a single overlap, namely HNRPU in humans and Hnrpul1 in mice. Further analysis of corpus callosum volume in BXD strains revealed that the corpus callosum was significantly larger in BXD mice with a B genotype at the Hnrpul1 locus than in BXD mice with a D genotype at Hnrpul1 (F = 22.48, p<9.87*10(-5.This approach that exploits highly diverse mouse strains provides an efficient and effective translational bridge to study the etiology of human developmental disorders, such as autism and schizophrenia.

  8. A Systematic Approach to Identify Markers of Distinctly Activated Human Macrophages

    Directory of Open Access Journals (Sweden)

    Bayan eSudan

    2015-05-01

    Full Text Available Polarization has been a useful concept for describing activated macrophage phenotypes and gene expression profiles. However, macrophage activation status within tumors and other settings are often inferred based on only a few markers. Complicating matters for relevance to human biology, many of the best studied macrophage activation markers have been best characterized in mice and sometimes are not similarly regulated in human macrophages. To identify novel markers of activated human macrophages, gene expression profiles for human macrophages of a single donor subjected to 33 distinct activating conditions were obtained and a set of putative activation markers were subsequently evaluated in macrophages from multiple donors using integrated fluidic circuit (IFC-based RT-PCR. Using unsupervised hierarchical clustering of the microarray screen, highly-altered transcripts (>4-fold change in expression sorted the macrophage transcription profiles into two major and 13 minor clusters. Among the 1874 highly-altered transcripts, over 100 were uniquely altered in one major or two related minor clusters. IFC PCR-derived data confirmed the microarray results and to show the kinetics of expression of potential macrophage activation markers. Transcripts encoding chemokines, cytokines, and cell surface were prominent in our analyses. The activation markers identified by this study could be used to better characterize tumor-associated macrophages from biopsies as well as other macrophage populations collected from human clinical samples.

  9. Using BAC transgenesis in zebrafish to identify regulatory sequences of the amyloid precursor protein gene in humans

    Directory of Open Access Journals (Sweden)

    Shakes Leighcraft A

    2012-09-01

    Full Text Available Abstract Background Non-coding DNA in and around the human Amyloid Precursor Protein (APP gene that is central to Alzheimer’s disease (AD shares little sequence similarity with that of appb in zebrafish. Identifying DNA domains regulating expression of the gene in such situations becomes a challenge. Taking advantage of the zebrafish system that allows rapid functional analyses of gene regulatory sequences, we previously showed that two discontinuous DNA domains in zebrafish appb are important for expression of the gene in neurons: an enhancer in intron 1 and sequences 28–31 kb upstream of the gene. Here we identify the putative transcription factor binding sites responsible for this distal cis-acting regulation, and use that information to identify a regulatory region of the human APP gene. Results Functional analyses of intron 1 enhancer mutations in enhancer-trap BACs expressed as transgenes in zebrafish identified putative binding sites of two known transcription factor proteins, E4BP4/ NFIL3 and Forkhead, to be required for expression of appb. A cluster of three E4BP4 sites at −31 kb is also shown to be essential for neuron-specific expression, suggesting that the dependence of expression on upstream sequences is mediated by these E4BP4 sites. E4BP4/ NFIL3 and XFD1 sites in the intron enhancer and E4BP4/ NFIL3 sites at −31 kb specifically and efficiently bind the corresponding zebrafish proteins in vitro. These sites are statistically over-represented in both the zebrafish appb and the human APP genes, although their locations are different. Remarkably, a cluster of four E4BP4 sites in intron 4 of human APP exists in actively transcribing chromatin in a human neuroblastoma cell-line, SHSY5Y, expressing APP as shown using chromatin immunoprecipitation (ChIP experiments. Thus although the two genes share little sequence conservation, they appear to share the same regulatory logic and are regulated by a similar set of transcription

  10. Using BAC transgenesis in zebrafish to identify regulatory sequences of the amyloid precursor protein gene in humans.

    Science.gov (United States)

    Shakes, Leighcraft A; Du, Hansen; Wolf, Hope M; Hatcher, Charles; Norford, Derek C; Precht, Patricia; Sen, Ranjan; Chatterjee, Pradeep K

    2012-09-04

    Non-coding DNA in and around the human Amyloid Precursor Protein (APP) gene that is central to Alzheimer's disease (AD) shares little sequence similarity with that of appb in zebrafish. Identifying DNA domains regulating expression of the gene in such situations becomes a challenge. Taking advantage of the zebrafish system that allows rapid functional analyses of gene regulatory sequences, we previously showed that two discontinuous DNA domains in zebrafish appb are important for expression of the gene in neurons: an enhancer in intron 1 and sequences 28-31 kb upstream of the gene. Here we identify the putative transcription factor binding sites responsible for this distal cis-acting regulation, and use that information to identify a regulatory region of the human APP gene. Functional analyses of intron 1 enhancer mutations in enhancer-trap BACs expressed as transgenes in zebrafish identified putative binding sites of two known transcription factor proteins, E4BP4/ NFIL3 and Forkhead, to be required for expression of appb. A cluster of three E4BP4 sites at -31 kb is also shown to be essential for neuron-specific expression, suggesting that the dependence of expression on upstream sequences is mediated by these E4BP4 sites. E4BP4/ NFIL3 and XFD1 sites in the intron enhancer and E4BP4/ NFIL3 sites at -31 kb specifically and efficiently bind the corresponding zebrafish proteins in vitro. These sites are statistically over-represented in both the zebrafish appb and the human APP genes, although their locations are different. Remarkably, a cluster of four E4BP4 sites in intron 4 of human APP exists in actively transcribing chromatin in a human neuroblastoma cell-line, SHSY5Y, expressing APP as shown using chromatin immunoprecipitation (ChIP) experiments. Thus although the two genes share little sequence conservation, they appear to share the same regulatory logic and are regulated by a similar set of transcription factors. The results suggest that the clock

  11. Identifying Human Trafficking Victims on a Psychiatry Inpatient Service: a Case Series.

    Science.gov (United States)

    Nguyen, Phuong T; Lamkin, Joanna; Coverdale, John H; Scott, Samuel; Li, Karen; Gordon, Mollie R

    2017-10-02

    Human trafficking is a serious and prevalent human rights violation that closely intersects with mental health. Limited empirical attention has been paid to the presentations and identification of trafficking victims in psychiatric settings. The primary goal of this paper is to describe the varied presentations of trafficking victims on an urban inpatient psychiatric unit. A literature review was conducted to identify relevant empirical articles to inform our examination of cases. Adult inpatient cases meeting criteria for known or possible human trafficking were systematically identified and illustrative cases were described. Six cases were identified including one male and five females. Two had been labor trafficked and four were suspected or confirmed to have been sex trafficked. The cases demonstrated a tremendous diversity of demographic and psychiatric identifying factors. These cases indicate the importance of routinely screening for trafficking victims in inpatient psychiatry settings. Identification of cases is a requisite step in providing informed and evidence-based treatments and enabling the secondary prevention of re-exploitation. Additional research is warranted given the limited current empirical research on this topic area.

  12. Identifying transmission cycles at the human-animal interface: the role of animal reservoirs in maintaining gambiense human african trypanosomiasis.

    Directory of Open Access Journals (Sweden)

    Sebastian Funk

    Full Text Available Many infections can be transmitted between animals and humans. The epidemiological roles of different species can vary from important reservoirs to dead-end hosts. Here, we present a method to identify transmission cycles in different combinations of species from field data. We used this method to synthesise epidemiological and ecological data from Bipindi, Cameroon, a historical focus of gambiense Human African Trypanosomiasis (HAT, sleeping sickness, a disease that has often been considered to be maintained mainly by humans. We estimated the basic reproduction number [Formula: see text] of gambiense HAT in Bipindi and evaluated the potential for transmission in the absence of human cases. We found that under the assumption of random mixing between vectors and hosts, gambiense HAT could not be maintained in this focus without the contribution of animals. This result remains robust under extensive sensitivity analysis. When using the distributions of species among habitats to estimate the amount of mixing between those species, we found indications for an independent transmission cycle in wild animals. Stochastic simulation of the system confirmed that unless vectors moved between species very rarely, reintroduction would usually occur shortly after elimination of the infection from human populations. This suggests that elimination strategies may have to be reconsidered as targeting human cases alone would be insufficient for control, and reintroduction from animal reservoirs would remain a threat. Our approach is broadly applicable and could reveal animal reservoirs critical to the control of other infectious diseases.

  13. One Health approach to identify research needs in bovine and human babesioses: workshop report

    Directory of Open Access Journals (Sweden)

    McElwain Terry F

    2010-04-01

    Full Text Available Abstract Background Babesia are emerging health threats to humans and animals in the United States. A collaborative effort of multiple disciplines to attain optimal health for people, animals and our environment, otherwise known as the One Health concept, was taken during a research workshop held in April 2009 to identify gaps in scientific knowledge regarding babesioses. The impetus for this analysis was the increased risk for outbreaks of bovine babesiosis, also known as Texas cattle fever, associated with the re-infestation of the U.S. by cattle fever ticks. Results The involvement of wildlife in the ecology of cattle fever ticks jeopardizes the ability of state and federal agencies to keep the national herd free of Texas cattle fever. Similarly, there has been a progressive increase in the number of cases of human babesiosis over the past 25 years due to an increase in the white-tailed deer population. Human babesiosis due to cattle-associated Babesia divergens and Babesia divergens-like organisms have begun to appear in residents of the United States. Research needs for human and bovine babesioses were identified and are presented herein. Conclusions The translation of this research is expected to provide veterinary and public health systems with the tools to mitigate the impact of bovine and human babesioses. However, economic, political, and social commitments are urgently required, including increased national funding for animal and human Babesia research, to prevent the re-establishment of cattle fever ticks and the increasing problem of human babesiosis in the United States.

  14. Prevalence of high-risk human papillomavirus and cervical intraepithelial neoplasias in a previously unscreened population--a pooled analysis from three studies.

    Science.gov (United States)

    Basu, Partha; Mittal, Srabani; Bhaumik, Suchismita; Mandal, Shyam Sunder; Samaddar, Anusree; Ray, Chinmayi; Siddiqi, Maqsood; Biswas, Jaydip; Sankaranarayanan, Rengaswamy

    2013-04-01

    Population prevalence of human papillomavirus (HPV) and cervical intraepithelial neoplasias (CIN) is an important indicator to judge the disease burden in the community, to monitor the performance of cervical cancer screening program and to assess the impact of HPV vaccination program. India being a country without any cervical cancer screening program has no published data on the population prevalence of CIN and only a few large community-based studies to report the high-risk HPV prevalence. The objective of our study was to study HPV and CIN prevalence in a previously unscreened population. We pooled together the results of three research studies originally designed to assess the performance of visual inspection after acetic acid application and Hybrid Capture 2 (HC 2). Nearly 60% of the screened women had colposcopy irrespective of their screening test results. The diagnosis and grading of cervical neoplasias were based on histology. The age standardized prevalence of HPV by HC 2 test was 6.0%. Age-adjusted prevalence of CIN1 and CIN2 was 2.3% and 0.5%, respectively. The age-adjusted prevalence of CIN3 was 0.4% and that of invasive cancer was 0.2%. The prevalence of high-risk HPV was relatively low in the population we studied, which is reflected in the low prevalence of high-grade CIN. The prevalence of CIN3 remained constant across age groups due to absence of screening. Copyright © 2012 UICC.

  15. FINDSITE(X): a structure-based, small molecule virtual screening approach with application to all identified human GPCRs.

    Science.gov (United States)

    Zhou, Hongyi; Skolnick, Jeffrey

    2012-06-04

    We have developed FINDSITE(X), an extension of FINDSITE, a protein threading based algorithm for the inference of protein binding sites, biochemical function and virtual ligand screening, that removes the limitation that holo protein structures (those containing bound ligands) of a sufficiently large set of distant evolutionarily related proteins to the target be solved; rather, predicted protein structures and experimental ligand binding information are employed. To provide the predicted protein structures, a fast and accurate version of our recently developed TASSER(VMT), TASSER(VMT)-lite, for template-based protein structural modeling applicable up to 1000 residues is developed and tested, with comparable performance to the top CASP9 servers. Then, a hybrid approach that combines structure alignments with an evolutionary similarity score for identifying functional relationships between target and proteins with binding data has been developed. By way of illustration, FINDSITE(X) is applied to 998 identified human G-protein coupled receptors (GPCRs). First, TASSER(VMT)-lite provides updates of all human GPCR structures previously modeled in our lab. We then use these structures and the new function similarity detection algorithm to screen all human GPCRs against the ZINC8 nonredundant (TC identity > 30% to the target from the binding data library) on a 168 human GPCR set with known binding data, the average enrichment factor in the top 1% of the compound library (EF(0.01)) is 22.7, whereas EF(0.01) by FINDSITE is 7.1. For virtual screening when just the target and its native ligands are excluded, the average EF(0.01) reaches 41.4. We also analyze off-target interactions for the 168 protein test set. All predicted structures, virtual screening data and off-target interactions for the 998 human GPCRs are available at http://cssb.biology.gatech.edu/skolnick/webservice/gpcr/index.html .

  16. Data sharing platforms for de-identified data from human clinical trials.

    Science.gov (United States)

    Huser, Vojtech; Shmueli-Blumberg, Dikla

    2018-04-01

    Data sharing of de-identified individual participant data is being adopted by an increasing number of sponsors of human clinical trials. In addition to standardizing data syntax for shared trial data, semantic integration of various data elements is the focus of several initiatives that define research common data elements. This perspective article, in the first part, compares several data sharing platforms for de-identified clinical research data in terms of their size, policies and supported features. In the second part, we use a case study approach to describe in greater detail one data sharing platform (Data Share from National Institute of Drug Abuse). We present data on the past use of the platform, data formats offered, data de-identification approaches and its use of research common data elements. We conclude with a summary of current and expected future trends that facilitate secondary research use of data from completed human clinical trials.

  17. New families of human regulatory RNA structures identified by comparative analysis of vertebrate genomes

    DEFF Research Database (Denmark)

    Parker, Brian John; Moltke, Ida; Roth, Adam

    2011-01-01

    a comparative method, EvoFam, for genome-wide identification of families of regulatory RNA structures, based on primary sequence and secondary structure similarity. We apply EvoFam to a 41-way genomic vertebrate alignment. Genome-wide, we identify 220 human, high-confidence families outside protein...... identify tens of new families supported by strong evolutionary evidence and other statistical evidence, such as GO term enrichments. For some of these, detailed analysis has led to the formulation of specific functional hypotheses. Examples include two hypothesized auto-regulatory feedback mechanisms: one...... involving six long hairpins in the 3'-UTR of MAT2A, a key metabolic gene that produces the primary human methyl donor S-adenosylmethionine; the other involving a tRNA-like structure in the intron of the tRNA maturation gene POP1. We experimentally validate the predicted MAT2A structures. Finally, we...

  18. A new hydroxytyrosol metabolite identified in human plasma: hydroxytyrosol acetate sulphate.

    Science.gov (United States)

    Rubió, Laura; Macià, Alba; Valls, Rosa M; Pedret, Anna; Romero, Maria-Paz; Solà, Rosa; Motilva, Maria-José

    2012-09-15

    We report progress in the study of olive oil phenolic metabolites in humans and identify a new hydroxytyrosol metabolite called hydroxytyrosol acetate sulphate, which was determined using tandem MS, after ingestion of 30 ml of olive oil with a high phenolic content (500 mg/kg oil), reaching a maximum concentration of 1.63 μM. In order to understand and explain the generation of this metabolite, two different pathways are proposed. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. A Human-Machine Collaborative System for Identifying Rumors on Twitter

    OpenAIRE

    Vosoughi, Soroush; Roy, Deb K.

    2015-01-01

    The spread of rumors on social media, especially in time-sensitive situations such as real-world emergencies, can have harmful effects on individuals and society. In this work, we developed a human-machine collaborative system on Twitter for fast identification of rumors about real-world events. The system reduces the amount of information that users have to sift through in order to identify rumors about real-world events by several orders of magnitude.

  20. HindIII identifies a two allele DNA polymorphism of the human cannabinoid receptor gene (CNR)

    Energy Technology Data Exchange (ETDEWEB)

    Caenazzo, L.; Hoehe, M.R.; Hsieh, W.T.; Berrettini, W.H.; Bonner, T.I.; Gershon, E.S. (National Inst. of Health, Bethesda, MD (United States))

    1991-09-11

    HCNR p5, a 0.9 kb BamHI/EcoRI fragment from the human cannabinoid receptor gene inserted into pUC19, was used as probe. The fragment is located in an intron approximately 14 kb 5{prime} of the initiation codon. This fragment is a clean single copy sequence by genomic blotting. Hybridization of human genomic DNA digested with HindIII identified a two allele RFLP with bands at 5.5 (A1) and 3.3 kb (A2). The human cannabinoid receptor gene has been genetically mapped in CEPH reference pedigrees to the centromeric/q region of chromosome 6. In situ hybridization localizes it to 6q14-q15. Codominant segregation has been observed in 26 informative two- and three-generation CEPH pedigrees and in 14 medium-sized disease families.

  1. Gene expression-based classifiers identify Staphylococcus aureus infection in mice and humans.

    Directory of Open Access Journals (Sweden)

    Sun Hee Ahn

    Full Text Available Staphylococcus aureus causes a spectrum of human infection. Diagnostic delays and uncertainty lead to treatment delays and inappropriate antibiotic use. A growing literature suggests the host's inflammatory response to the pathogen represents a potential tool to improve upon current diagnostics. The hypothesis of this study is that the host responds differently to S. aureus than to E. coli infection in a quantifiable way, providing a new diagnostic avenue. This study uses Bayesian sparse factor modeling and penalized binary regression to define peripheral blood gene-expression classifiers of murine and human S. aureus infection. The murine-derived classifier distinguished S. aureus infection from healthy controls and Escherichia coli-infected mice across a range of conditions (mouse and bacterial strain, time post infection and was validated in outbred mice (AUC>0.97. A S. aureus classifier derived from a cohort of 94 human subjects distinguished S. aureus blood stream infection (BSI from healthy subjects (AUC 0.99 and E. coli BSI (AUC 0.84. Murine and human responses to S. aureus infection share common biological pathways, allowing the murine model to classify S. aureus BSI in humans (AUC 0.84. Both murine and human S. aureus classifiers were validated in an independent human cohort (AUC 0.95 and 0.92, respectively. The approach described here lends insight into the conserved and disparate pathways utilized by mice and humans in response to these infections. Furthermore, this study advances our understanding of S. aureus infection; the host response to it; and identifies new diagnostic and therapeutic avenues.

  2. Gene expression-based classifiers identify Staphylococcus aureus infection in mice and humans.

    Science.gov (United States)

    Ahn, Sun Hee; Tsalik, Ephraim L; Cyr, Derek D; Zhang, Yurong; van Velkinburgh, Jennifer C; Langley, Raymond J; Glickman, Seth W; Cairns, Charles B; Zaas, Aimee K; Rivers, Emanuel P; Otero, Ronny M; Veldman, Tim; Kingsmore, Stephen F; Lucas, Joseph; Woods, Christopher W; Ginsburg, Geoffrey S; Fowler, Vance G

    2013-01-01

    Staphylococcus aureus causes a spectrum of human infection. Diagnostic delays and uncertainty lead to treatment delays and inappropriate antibiotic use. A growing literature suggests the host's inflammatory response to the pathogen represents a potential tool to improve upon current diagnostics. The hypothesis of this study is that the host responds differently to S. aureus than to E. coli infection in a quantifiable way, providing a new diagnostic avenue. This study uses Bayesian sparse factor modeling and penalized binary regression to define peripheral blood gene-expression classifiers of murine and human S. aureus infection. The murine-derived classifier distinguished S. aureus infection from healthy controls and Escherichia coli-infected mice across a range of conditions (mouse and bacterial strain, time post infection) and was validated in outbred mice (AUC>0.97). A S. aureus classifier derived from a cohort of 94 human subjects distinguished S. aureus blood stream infection (BSI) from healthy subjects (AUC 0.99) and E. coli BSI (AUC 0.84). Murine and human responses to S. aureus infection share common biological pathways, allowing the murine model to classify S. aureus BSI in humans (AUC 0.84). Both murine and human S. aureus classifiers were validated in an independent human cohort (AUC 0.95 and 0.92, respectively). The approach described here lends insight into the conserved and disparate pathways utilized by mice and humans in response to these infections. Furthermore, this study advances our understanding of S. aureus infection; the host response to it; and identifies new diagnostic and therapeutic avenues.

  3. Human Trafficking in Ethiopia: A Scoping Review to Identify Gaps in Service Delivery, Research, and Policy.

    Science.gov (United States)

    Beck, Dana C; Choi, Kristen R; Munro-Kramer, Michelle L; Lori, Jody R

    2017-12-01

    The purpose of this review is to integrate evidence on human trafficking in Ethiopia and identify gaps and recommendations for service delivery, research and training, and policy. A scoping literature review approach was used to systematically search nursing, medical, psychological, law, and international databases and synthesize information on a complex, understudied topic. The search yielded 826 articles, and 39 met the predetermined criteria for inclusion in the review. Trafficking in Ethiopia has occurred internally and externally in the form of adult and child labor and sex trafficking. There were also some reports of organ trafficking and other closely related human rights violations, such as child marriage, child soldiering, and exploitative intercountry adoption. Risk factors for trafficking included push factors (poverty, political instability, economic problems, and gender discrimination) and pull factors (demand for cheap labor). Trafficking was associated with poor health and economic outcomes for victims. Key recommendations for service delivery, research and training, and policy are identified, including establishing comprehensive services for survivor rehabilitation and reintegration, conducting quantitative health outcomes research, and reforming policy around migration and trafficking. Implementing the recommendations identified by this review will allow policy makers, researchers, and practitioners to take meaningful steps toward confronting human trafficking in Ethiopia.

  4. CDC25A Protein Stability Represents a Previously Unrecognized Target of HER2 Signaling in Human Breast Cancer: Implication for a Potential Clinical Relevance in Trastuzumab Treatment

    Directory of Open Access Journals (Sweden)

    Emanuela Brunetto

    2013-06-01

    Full Text Available The CDC25A-CDK2 pathway has been proposed as critical for the oncogenic action of human epidermal growth factor receptor 2 (HER2 in mammary epithelial cells. In particular, transgenic expression of CDC25A cooperates with HER2 in promoting mammary tumors, whereas CDC25A hemizygous loss attenuates the HER2-induced tumorigenesis penetrance. On the basis of this evidence of a synergism between HER2 and the cell cycle regulator CDC25A in a mouse model of mammary tumorigenesis, we investigated the role of CDC25A in human HER2-positive breast cancer and its possible implications in therapeutic response. HER2 status and CDC25A expression were assessed in 313 breast cancer patients and we found statistically significant correlation between HER2 and CDC25A (P = .007. Moreover, an HER2-positive breast cancer subgroup with high levels of CDC25A and very aggressive phenotype was identified (P = .005. Importantly, our in vitro studies on breast cancer cell lines showed that the HER2 inhibitor efficacy on cell growth and viability relied also on CDC25A expression and that such inhibition induces CDC25A down-regulation through phosphatidylinositol 3-kinase/protein kinase B pathway and DNA damage response activation. In line with this observation, we found a statistical significant association between CDC25A overexpression and trastuzumab-combined therapy response rate in two different HER2-positive cohorts of trastuzumab-treated patients in either metastatic or neoadjuvant setting (P = .018 for the metastatic cohort and P = .021 for the neoadjuvant cohort. Our findings highlight a link between HER2 and CDC25A that positively modulates HER2- targeted therapy response, suggesting that, in HER2-positive breast cancer patients, CDC25A overexpression affects trastuzumab sensitivity.

  5. Clonal analyses and gene profiling identify genetic biomarkers of human brown and white preadipocyte thermogenic potential

    Science.gov (United States)

    Xue, Ruidan; Lynes, Matthew D.; Dreyfuss, Jonathan M.; Shamsi, Farnaz; Schulz, Tim J.; Zhang, Hongbin; Huang, Tian Lian; Townsend, Kristy L.; Li, Yiming; Takahashi, Hirokazu; Weiner, Lauren S.; White, Andrew P.; Lynes, Maureen S.; Rubin, Lee L.; Goodyear, Laurie J.; Cypess, Aaron M.; Tseng, Yu-Hua

    2015-01-01

    Targeting brown adipose tissue (BAT) content or activity has therapeutic potential for treating obesity and the metabolic syndrome by increasing energy expenditure. Both inter- and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here, we demonstrated the generated clones of brown and white preadipocytes from human neck fat of four individuals and characterized their adipogenic differentiation and thermogenic function. Combining an uncoupling protein 1(UCP1) reporter system and expression profiling, we defined novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of the cells once they were maturated in culture. Knocking out the positive UCP1 regulators identified by this approach, PREX1 and EDNRB in brown preadipocytes using CRISPR/Cas9 markedly abolished the high level of UCP1 in brown adipocytes differentiated from the preadipocytes. Finally, we were able to prospectively isolate adipose progenitors with great thermogenic potential using cell surface marker CD29. These data provide new insights into the cellular heterogeneity in human fat and offer the identification of possible biomarkers of thermogenically competent preadipocytes. PMID:26076036

  6. Impact and Cost-effectiveness of 3 Doses of 9-Valent Human Papillomavirus (HPV) Vaccine Among US Females Previously Vaccinated With 4-Valent HPV Vaccine.

    Science.gov (United States)

    Chesson, Harrell W; Laprise, Jean-François; Brisson, Marc; Markowitz, Lauri E

    2016-06-01

    We estimated the potential impact and cost-effectiveness of providing 3-doses of nonavalent human papillomavirus (HPV) vaccine (9vHPV) to females aged 13-18 years who had previously completed a series of quadrivalent HPV vaccine (4vHPV), a strategy we refer to as "additional 9vHPV vaccination." We used 2 distinct models: (1) the simplified model, which is among the most basic of the published dynamic HPV models, and (2) the US HPV-ADVISE model, a complex, stochastic, individual-based transmission-dynamic model. When assuming no 4vHPV cross-protection, the incremental cost per quality-adjusted life-year (QALY) gained by additional 9vHPV vaccination was $146 200 in the simplified model and $108 200 in the US HPV-ADVISE model ($191 800 when assuming 4vHPV cross-protection). In 1-way sensitivity analyses in the scenario of no 4vHPV cross-protection, the simplified model results ranged from $70 300 to $182 000, and the US HPV-ADVISE model results ranged from $97 600 to $118 900. The average cost per QALY gained by additional 9vHPV vaccination exceeded $100 000 in both models. However, the results varied considerably in sensitivity and uncertainty analyses. Additional 9vHPV vaccination is likely not as efficient as many other potential HPV vaccination strategies, such as increasing primary 9vHPV vaccine coverage. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  7. An Exploration of Human Well-Being Bundles as Identifiers of Ecosystem Service Use Patterns.

    Science.gov (United States)

    Hamann, Maike; Biggs, Reinette; Reyers, Belinda

    2016-01-01

    We take a social-ecological systems perspective to investigate the linkages between ecosystem services and human well-being in South Africa. A recent paper identified different types of social-ecological systems in the country, based on distinct bundles of ecosystem service use. These system types were found to represent increasingly weak direct feedbacks between nature and people, from rural "green-loop" communities to urban "red-loop" societies. Here we construct human well-being bundles and explore whether the well-being bundles can be used to identify the same social-ecological system types that were identified using bundles of ecosystem service use. Based on national census data, we found three distinct well-being bundle types that are mainly characterized by differences in income, unemployment and property ownership. The distribution of these well-being bundles approximates the distribution of ecosystem service use bundles to a substantial degree: High levels of income and education generally coincided with areas characterised by low levels of direct ecosystem service use (or red-loop systems), while the majority of low well-being areas coincided with medium and high levels of direct ecosystem service use (or transition and green-loop systems). However, our results indicate that transformations from green-loop to red-loop systems do not always entail an immediate improvement in well-being, which we suggest may be due to a time lag between changes in the different system components. Using human well-being bundles as an indicator of social-ecological dynamics may be useful in other contexts since it is based on socio-economic data commonly collected by governments, and provides important insights into the connections between ecosystem services and human well-being at policy-relevant sub-national scales.

  8. An Exploration of Human Well-Being Bundles as Identifiers of Ecosystem Service Use Patterns.

    Directory of Open Access Journals (Sweden)

    Maike Hamann

    Full Text Available We take a social-ecological systems perspective to investigate the linkages between ecosystem services and human well-being in South Africa. A recent paper identified different types of social-ecological systems in the country, based on distinct bundles of ecosystem service use. These system types were found to represent increasingly weak direct feedbacks between nature and people, from rural "green-loop" communities to urban "red-loop" societies. Here we construct human well-being bundles and explore whether the well-being bundles can be used to identify the same social-ecological system types that were identified using bundles of ecosystem service use. Based on national census data, we found three distinct well-being bundle types that are mainly characterized by differences in income, unemployment and property ownership. The distribution of these well-being bundles approximates the distribution of ecosystem service use bundles to a substantial degree: High levels of income and education generally coincided with areas characterised by low levels of direct ecosystem service use (or red-loop systems, while the majority of low well-being areas coincided with medium and high levels of direct ecosystem service use (or transition and green-loop systems. However, our results indicate that transformations from green-loop to red-loop systems do not always entail an immediate improvement in well-being, which we suggest may be due to a time lag between changes in the different system components. Using human well-being bundles as an indicator of social-ecological dynamics may be useful in other contexts since it is based on socio-economic data commonly collected by governments, and provides important insights into the connections between ecosystem services and human well-being at policy-relevant sub-national scales.

  9. Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

    Science.gov (United States)

    Duffy, Supipi; Fam, Hok Khim; Wang, Yi Kan; Styles, Erin B.; Kim, Jung-Hyun; Ang, J. Sidney; Singh, Tejomayee; Larionov, Vladimir; Shah, Sohrab P.; Andrews, Brenda; Boerkoel, Cornelius F.; Hieter, Philip

    2016-01-01

    Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors. PMID:27551064

  10. Genetic Characterization of a Novel HIV-1 Circulating Recombinant Form (CRF74_01B) Identified among Intravenous Drug Users in Malaysia: Recombination History and Phylogenetic Linkage with Previously Defined Recombinant Lineages.

    Science.gov (United States)

    Cheong, Hui Ting; Chow, Wei Zhen; Takebe, Yutaka; Chook, Jack Bee; Chan, Kok Gan; Al-Darraji, Haider Abdulrazzaq Abed; Koh, Clayton; Kamarulzaman, Adeeba; Tee, Kok Keng

    2015-01-01

    In many parts of Southeast Asia, the HIV-1 epidemic has been driven by the sharing of needles and equipment among intravenous drug users (IDUs). Over the last few decades, many studies have proven time and again that the diversity of HIV-1 epidemics can often be linked to the route of infection transmission. That said, the diversity and complexity of HIV-1 molecular epidemics in the region have been increasing at an alarming rate, due in part to the high tendency of the viral RNA to recombine. This scenario was exemplified by the discovery of numerous circulating recombinant forms (CRFs), especially in Thailand and Malaysia. In this study, we characterized a novel CRF designated CRF74_01B, which was identified in six epidemiologically unlinked IDUs in Kuala Lumpur, Malaysia. The near-full length genomes were composed of CRF01_AE and subtype B', with eight breakpoints dispersed in the gag-pol and nef regions. Remarkably, this CRF shared four and two recombination hotspots with the previously described CRF33_01B and the less prevalent CRF53_01B, respectively. Genealogy-based Bayesian phylogenetic analysis of CRF74_01B genomic regions showed that it is closely related to both CRF33_01B and CRF53_01B. This observation suggests that CRF74_01B was probably a direct descendent from specific lineages of CRF33_01B, CRF53_01B and subtype B' that could have emerged in the mid-1990s. Additionally, it illustrated the active recombination processes between prevalent HIV-1 subtypes and recombinants in Malaysia. In summary, we report a novel HIV-1 genotype designated CRF74_01B among IDUs in Kuala Lumpur, Malaysia. The characterization of the novel CRF74_01B is of considerable significance towards the understanding of the genetic diversity and population dynamics of HIV-1 circulating in the region.

  11. Identifying environmental risk factors and mapping the risk of human West Nile virus in South Dakota.

    Science.gov (United States)

    Hess, A.; Davis, J. K.; Wimberly, M. C.

    2017-12-01

    Human West Nile virus (WNV) first arrived in the USA in 1999 and has since then spread across the country. Today, the highest incidence rates are found in the state of South Dakota. The disease occurrence depends on the complex interaction between the mosquito vector, the bird host and the dead-end human host. Understanding the spatial domain of this interaction and being able to identify disease transmission hotspots is crucial for effective disease prevention and mosquito control. In this study we use geospatial environmental information to understand what drives the spatial distribution of cases of human West Nile virus in South Dakota and to map relative infection risk across the state. To map the risk of human West Nile virus in South Dakota, we used geocoded human case data from the years 2004-2016. Satellite data from the Landsat ETM+ and MODIS for the years 2003 to 2016 were used to characterize environmental patterns. From these datasets we calculated indices, such as the normalized differenced vegetation index (NDVI) and the normalized differenced water index (NDWI). In addition, datasets such as the National Land Data Assimilation System (NLDAS), National Land Cover Dataset (NLCD), National Wetland inventory (NWI), National Elevation Dataset (NED) and Soil Survey Geographic Database (SSURGO) were utilized. Environmental variables were summarized for a buffer zone around the case and control points. We used a boosted regression tree model to identify the most important variables describing the risk of WNV infection. We generated a risk map by applying this model across the entire state. We found that the highest relative risk is present in the James River valley in northeastern South Dakota. Factors that were identified as influencing the transmission risk include inter-annual variability of vegetation cover, water availability and temperature. Land covers such as grasslands, low developed areas and wetlands were also found to be good predictors for human

  12. Using a Delphi Method to Identify Human Factors Contributing to Nursing Errors.

    Science.gov (United States)

    Roth, Cheryl; Brewer, Melanie; Wieck, K Lynn

    2017-07-01

    The purpose of this study was to identify human factors associated with nursing errors. Using a Delphi technique, this study used feedback from a panel of nurse experts (n = 25) on an initial qualitative survey questionnaire followed by summarizing the results with feedback and confirmation. Synthesized factors regarding causes of errors were incorporated into a quantitative Likert-type scale, and the original expert panel participants were queried a second time to validate responses. The list identified 24 items as most common causes of nursing errors, including swamping and errors made by others that nurses are expected to recognize and fix. The responses provided a consensus top 10 errors list based on means with heavy workload and fatigue at the top of the list. The use of the Delphi survey established consensus and developed a platform upon which future study of nursing errors can evolve as a link to future solutions. This list of human factors in nursing errors should serve to stimulate dialogue among nurses about how to prevent errors and improve outcomes. Human and system failures have been the subject of an abundance of research, yet nursing errors continue to occur. © 2016 Wiley Periodicals, Inc.

  13. A new peptide ligand for targeting human carbonic anhydrase IX, identified through the phage display technology.

    Directory of Open Access Journals (Sweden)

    Vasileios Askoxylakis

    2010-12-01

    Full Text Available Carbonic anhydrase IX (CAIX is a transmembrane enzyme found to be overexpressed in various tumors and associated with tumor hypoxia. Ligands binding this target may be used to visualize hypoxia, tumor manifestation or treat tumors by endoradiotherapy.Phage display was performed with a 12 amino acid phage display library by panning against a recombinant extracellular domain of human carbonic anhydrase IX. The identified peptide CaIX-P1 was chemically synthesized and tested in vitro on various cell lines and in vivo in Balb/c nu/nu mice carrying subcutaneously transplanted tumors. Binding, kinetic and competition studies were performed on the CAIX positive human renal cell carcinoma cell line SKRC 52, the CAIX negative human renal cell carcinoma cell line CaKi 2, the human colorectal carcinoma cell line HCT 116 and on human umbilical vein endothelial cells (HUVEC. Organ distribution studies were carried out in mice, carrying SKRC 52 tumors. RNA expression of CAIX in HCT 116 and HUVEC cells was investigated by quantitative real time PCR.In vitro binding experiments of (125I-labeled-CaIX-P1 revealed an increased uptake of the radioligand in the CAIX positive renal cell carcinoma cell line SKRC 52. Binding of the radioligand in the colorectal carcinoma cell line HCT 116 increased with increasing cell density and correlated with the mRNA expression of CAIX. Radioligand uptake was inhibited up to 90% by the unlabeled CaIX-P1 peptide, but not by the negative control peptide octreotide at the same concentration. No binding was demonstrated in CAIX negative CaKi 2 and HUVEC cells. Organ distribution studies revealed a higher accumulation in SKRC 52 tumors than in heart, spleen, liver, muscle, intestinum and brain, but a lower uptake compared to blood and kidney.These data indicate that CaIX-P1 is a promising candidate for the development of new ligands targeting human carbonic anhydrase IX.

  14. GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics.

    Science.gov (United States)

    Ledda, Mirko; Kutalik, Zoltán; Souza Destito, Maria C; Souza, Milena M; Cirillo, Cintia A; Zamboni, Amabilene; Martin, Nathalie; Morya, Edgard; Sameshima, Koichi; Beckmann, Jacques S; le Coutre, Johannes; Bergmann, Sven; Genick, Ulrich K

    2014-01-01

    Human perception of bitterness displays pronounced interindividual variation. This phenotypic variation is mirrored by equally pronounced genetic variation in the family of bitter taste receptor genes. To better understand the effects of common genetic variations on human bitter taste perception, we conducted a genome-wide association study on a discovery panel of 504 subjects and a validation panel of 104 subjects from the general population of São Paulo in Brazil. Correction for general taste-sensitivity allowed us to identify a SNP in the cluster of bitter taste receptors on chr12 (10.88- 11.24 Mb, build 36.1) significantly associated (best SNP: rs2708377, P = 5.31 × 10(-13), r(2) = 8.9%, β = -0.12, s.e. = 0.016) with the perceived bitterness of caffeine. This association overlaps with-but is statistically distinct from-the previously identified SNP rs10772420 influencing the perception of quinine bitterness that falls in the same bitter taste cluster. We replicated this association to quinine perception (P = 4.97 × 10(-37), r(2) = 23.2%, β = 0.25, s.e. = 0.020) and additionally found the effect of this genetic locus to be concentration specific with a strong impact on the perception of low, but no impact on the perception of high concentrations of quinine. Our study, thus, furthers our understanding of the complex genetic architecture of bitter taste perception.

  15. Pilot Critical Incident Reports as a Means to Identify Human Factors of Remotely Piloted Aircraft

    Science.gov (United States)

    Hobbs, Alan; Cardoza, Colleen; Null, Cynthia

    2016-01-01

    It has been estimated that aviation accidents are typically preceded by numerous minor incidents arising from the same causal factors that ultimately produced the accident. Accident databases provide in-depth information on a relatively small number of occurrences, however incident databases have the potential to provide insights into the human factors of Remotely Piloted Aircraft System (RPAS) operations based on a larger volume of less-detailed reports. Currently, there is a lack of incident data dealing with the human factors of unmanned aircraft systems. An exploratory study is being conducted to examine the feasibility of collecting voluntary critical incident reports from RPAS pilots. Twenty-three experienced RPAS pilots volunteered to participate in focus groups in which they described critical incidents from their own experience. Participants were asked to recall (1) incidents that revealed a system flaw, or (2) highlighted a case where the human operator contributed to system resilience or mission success. Participants were asked to only report incidents that could be included in a public document. During each focus group session, a note taker produced a de-identified written record of the incident narratives. At the end of the session, participants reviewed each written incident report, and made edits and corrections as necessary. The incidents were later analyzed to identify contributing factors, with a focus on design issues that either hindered or assisted the pilot during the events. A total of 90 incidents were reported. Human factor issues included the impact of reduced sensory cues, traffic separation in the absence of an out-the-window view, control latencies, vigilance during monotonous and ultra-long endurance flights, control station design considerations, transfer of control between control stations, the management of lost link procedures, and decision-making during emergencies. Pilots participated willingly and enthusiastically in the study

  16. Human Adenine Nucleotide Translocase (ANT) Modulators Identified by High-Throughput Screening of Transgenic Yeast.

    Science.gov (United States)

    Zhang, Yujian; Tian, Defeng; Matsuyama, Hironori; Hamazaki, Takashi; Shiratsuchi, Takayuki; Terada, Naohiro; Hook, Derek J; Walters, Michael A; Georg, Gunda I; Hawkinson, Jon E

    2016-04-01

    Transport of ADP and ATP across mitochondria is one of the primary points of regulation to maintain cellular energy homeostasis. This process is mainly mediated by adenine nucleotide translocase (ANT) located on the mitochondrial inner membrane. There are four human ANT isoforms, each having a unique tissue-specific expression pattern and biological function, highlighting their potential as drug targets for diverse clinical indications, including male contraception and cancer. In this study, we present a novel yeast-based high-throughput screening (HTS) strategy to identify compounds inhibiting the function of ANT. Yeast strains generated by deletion of endogenous proteins with ANT activity followed by insertion of individual human ANT isoforms are sensitive to cell-permeable ANT inhibitors, which reduce proliferation. Screening hits identified in the yeast proliferation assay were characterized in ADP/ATP exchange assays employing recombinant ANT isoforms expressed in isolated yeast mitochondria and Lactococcus lactis as well as by oxygen consumption rate in mammalian cells. Using this approach, closantel and CD437 were identified as broad-spectrum ANT inhibitors, whereas leelamine was found to be a modulator of ANT function. This yeast "knock-out/knock-in" screening strategy is applicable to a broad range of essential molecular targets that are required for yeast survival. © 2016 Society for Laboratory Automation and Screening.

  17. Using molecular tools to identify the geographical origin of a case of human brucellosis.

    Science.gov (United States)

    Muchowski, J K; Koylass, M S; Dainty, A C; Stack, J A; Perrett, L; Whatmore, A M; Perrier, C; Chircop, S; Demicoli, N; Gatt, A B; Caruana, P A; Gopaul, K K

    2015-10-01

    Although Malta is historically linked with the zoonosis brucellosis, there had not been a case of the disease in either the human or livestock population for several years. However, in July 2013 a case of human brucellosis was identified on the island. To determine whether this recent case originated in Malta, four isolates from this case were subjected to molecular analysis. Molecular profiles generated using multilocus sequence analysis and multilocus variable number tandem repeat for the recent human case isolates and 11 Brucella melitensis strains of known Maltese origin were compared with others held on in-house and global databases. While the 11 isolates of Maltese origin formed a distinct cluster, the recent human isolation was not associated with these strains but instead clustered with isolates originating from the Horn of Africa. These data was congruent with epidemiological trace-back showed that the individual had travelled to Malta from Eritrea. This work highlights the potential of using molecular typing data to aid in epidemiological trace-back of Brucella isolations and assist in monitoring of the effectiveness of brucellosis control schemes.

  18. The use of human factors methods to identify and mitigate safety issues in radiation therapy

    International Nuclear Information System (INIS)

    Chan, Alvita J.; Islam, Mohammad K.; Rosewall, Tara; Jaffray, David A.; Easty, Anthony C.; Cafazzo, Joseph A.

    2010-01-01

    Background and purpose: New radiation therapy technologies can enhance the quality of treatment and reduce error. However, the treatment process has become more complex, and radiation dose is not always delivered as intended. Using human factors methods, a radiotherapy treatment delivery process was evaluated, and a redesign was undertaken to determine the effect on system safety. Material and methods: An ethnographic field study and workflow analysis was conducted to identify human factors issues of the treatment delivery process. To address specific issues, components of the user interface were redesigned through a user-centered approach. Sixteen radiation therapy students were then used to experimentally evaluate the redesigned system through a usability test to determine the effectiveness in mitigating use errors. Results: According to findings from the usability test, the redesigned system successfully reduced the error rates of two common errors (p < .04 and p < .01). It also improved the mean task completion time by 5.5% (p < .02) and achieved a higher level of user satisfaction. Conclusions: These findings demonstrated the importance and benefits of applying human factors methods in the design of radiation therapy systems. Many other opportunities still exist to improve patient safety in this area using human factors methods.

  19. What's the risk? Identifying potential human pathogens within grey-headed flying foxes faeces.

    Science.gov (United States)

    Henry, Rebekah; Galbraith, Penelope; Coutts, Scott; Prosser, Toby; Boyce, John; McCarthy, David T

    2018-01-01

    Pteropus poliocephalus (grey-headed flying foxes) are recognised vectors for a range of potentially fatal human pathogens. However, to date research has primarily focused on viral disease carriage, overlooking bacterial pathogens, which also represent a significant human disease risk. The current study applied 16S rRNA amplicon sequencing, community analysis and a multi-tiered database OTU picking approach to identify faecal-derived zoonotic bacteria within two colonies of P. poliocephalus from Victoria, Australia. Our data show that sequences associated with Enterobacteriaceae (62.8% ± 24.7%), Pasteurellaceae (19.9% ± 25.7%) and Moraxellaceae (9.4% ± 11.8%) dominate flying fox faeces. Further colony specific differences in bacterial faecal colonisation patterns were also identified. In total, 34 potential pathogens, representing 15 genera, were identified. However, species level definition was only possible for Clostridium perfringens, which likely represents a low infectious risk due to the low proportion observed within the faeces and high infectious dose required for transmission. In contrast, sequences associated with other pathogenic species clusters such as Haemophilus haemolyticus-H. influenzae and Salmonella bongori-S. enterica, were present at high proportions in the faeces, and due to their relatively low infectious doses and modes of transmissions, represent a greater potential human disease risk. These analyses of the microbial community composition of Pteropus poliocephalus have significantly advanced our understanding of the potential bacterial disease risk associated with flying foxes and should direct future epidemiological and quantitative microbial risk assessments to further define the health risks presented by these animals.

  20. What’s the risk? Identifying potential human pathogens within grey-headed flying foxes faeces

    Science.gov (United States)

    Galbraith, Penelope; Coutts, Scott; Prosser, Toby; Boyce, John; McCarthy, David T.

    2018-01-01

    Pteropus poliocephalus (grey-headed flying foxes) are recognised vectors for a range of potentially fatal human pathogens. However, to date research has primarily focused on viral disease carriage, overlooking bacterial pathogens, which also represent a significant human disease risk. The current study applied 16S rRNA amplicon sequencing, community analysis and a multi-tiered database OTU picking approach to identify faecal-derived zoonotic bacteria within two colonies of P. poliocephalus from Victoria, Australia. Our data show that sequences associated with Enterobacteriaceae (62.8% ± 24.7%), Pasteurellaceae (19.9% ± 25.7%) and Moraxellaceae (9.4% ± 11.8%) dominate flying fox faeces. Further colony specific differences in bacterial faecal colonisation patterns were also identified. In total, 34 potential pathogens, representing 15 genera, were identified. However, species level definition was only possible for Clostridium perfringens, which likely represents a low infectious risk due to the low proportion observed within the faeces and high infectious dose required for transmission. In contrast, sequences associated with other pathogenic species clusters such as Haemophilus haemolyticus-H. influenzae and Salmonella bongori-S. enterica, were present at high proportions in the faeces, and due to their relatively low infectious doses and modes of transmissions, represent a greater potential human disease risk. These analyses of the microbial community composition of Pteropus poliocephalus have significantly advanced our understanding of the potential bacterial disease risk associated with flying foxes and should direct future epidemiological and quantitative microbial risk assessments to further define the health risks presented by these animals. PMID:29360880

  1. Strong memory in time series of human magnetoencephalograms can identify photosensitive epilepsy

    International Nuclear Information System (INIS)

    Yulmetyev, R. M.; Yulmetyeva, D. G.; Haenggi, P.; Shimojo, S.; Bhattacharya, J.

    2007-01-01

    To discuss the salient role of statistical memory effects in human brain functioning, we have analyzed a set of stochastic memory quantifiers that reflects the dynamical characteristics of neuromagnetic responses of magnetoencephalographic signals to a flickering stimulus of different color combinations from a group of control subjects, and compared them with those for a patient with photosensitive epilepsy. We have discovered that the emergence of strong memory and the accompanying transition to a regular and robust regime of chaotic behavior of signals in separate areas for a patient most likely identifies the regions where the protective mechanism against the occurrence of photosensitive epilepsy is located

  2. Phosphoproteomic Analysis Identifies Signaling Pathways Regulated by Curcumin in Human Colon Cancer Cells.

    Science.gov (United States)

    Sato, Tatsuhiro; Higuchi, Yutaka; Shibagaki, Yoshio; Hattori, Seisuke

    2017-09-01

    Curcumin, a major polyphenol of the spice turmeric, acts as a potent chemopreventive and chemotherapeutic agent in several cancer types, including colon cancer. Although various proteins have been shown to be affected by curcumin, how curcumin exerts its anticancer activity is not fully understood. Phosphoproteomic analyses were performed using SW480 and SW620 human colon cancer cells to identify curcumin-affected signaling pathways. Curcumin inhibited the growth of the two cell lines in a dose-dependent manner. Thirty-nine curcumin-regulated phosphoproteins were identified, five of which are involved in cancer signaling pathways. Detailed analyses revealed that the mTORC1 and p53 signaling pathways are main targets of curcumin. Our results provide insight into the molecular mechanisms of the anticancer activities of curcumin and future molecular targets for its clinical application. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  3. Identifying a guiding list of high involvement practices in human resource management

    Directory of Open Access Journals (Sweden)

    M Rosario Perello-Marin

    2014-07-01

    Full Text Available In today global competitiveness, it is becoming increasingly frequent, the introduction of new management practices to organizations, seeking to enhance performance as a form of Management Innovation (MI. This is so because such practices are usually difficult to replicate exactly from one company to another, provided they are well rooted in the daily work in the organization. The main purpose of this paper is, by reviewing the previous work done in this area, to present a general list of Human Resource Practices (HRM practices geared towards improving organizational effectiveness and hence better performance outcomes. Many work has been done to date within this topic, but it is difficult to find a consensus about the best way to address to this practices, and this fact makes difficult to compare different studies and their results. We present a detailed but synthesized list of those HR practices to be used as a starting point in any sector whether industrial or services

  4. PREVIOUS SECOND TRIMESTER ABORTION

    African Journals Online (AJOL)

    PNLC

    PREVIOUS SECOND TRIMESTER ABORTION: A risk factor for third trimester uterine rupture in three ... for accurate diagnosis of uterine rupture. KEY WORDS: Induced second trimester abortion - Previous uterine surgery - Uterine rupture. ..... scarred uterus during second trimester misoprostol- induced labour for a missed ...

  5. On the Use of Biomineral Oxygen Isotope Data to Identify Human Migrants in the Archaeological Record: Intra-Sample Variation, Statistical Methods and Geographical Considerations

    Science.gov (United States)

    Lightfoot, Emma; O’Connell, Tamsin C.

    2016-01-01

    Oxygen isotope analysis of archaeological skeletal remains is an increasingly popular tool to study past human migrations. It is based on the assumption that human body chemistry preserves the δ18O of precipitation in such a way as to be a useful technique for identifying migrants and, potentially, their homelands. In this study, the first such global survey, we draw on published human tooth enamel and bone bioapatite data to explore the validity of using oxygen isotope analyses to identify migrants in the archaeological record. We use human δ18O results to show that there are large variations in human oxygen isotope values within a population sample. This may relate to physiological factors influencing the preservation of the primary isotope signal, or due to human activities (such as brewing, boiling, stewing, differential access to water sources and so on) causing variation in ingested water and food isotope values. We compare the number of outliers identified using various statistical methods. We determine that the most appropriate method for identifying migrants is dependent on the data but is likely to be the IQR or median absolute deviation from the median under most archaeological circumstances. Finally, through a spatial assessment of the dataset, we show that the degree of overlap in human isotope values from different locations across Europe is such that identifying individuals’ homelands on the basis of oxygen isotope analysis alone is not possible for the regions analysed to date. Oxygen isotope analysis is a valid method for identifying first-generation migrants from an archaeological site when used appropriately, however it is difficult to identify migrants using statistical methods for a sample size of less than c. 25 individuals. In the absence of local previous analyses, each sample should be treated as an individual dataset and statistical techniques can be used to identify migrants, but in most cases pinpointing a specific homeland should

  6. On the Use of Biomineral Oxygen Isotope Data to Identify Human Migrants in the Archaeological Record: Intra-Sample Variation, Statistical Methods and Geographical Considerations.

    Directory of Open Access Journals (Sweden)

    Emma Lightfoot

    Full Text Available Oxygen isotope analysis of archaeological skeletal remains is an increasingly popular tool to study past human migrations. It is based on the assumption that human body chemistry preserves the δ18O of precipitation in such a way as to be a useful technique for identifying migrants and, potentially, their homelands. In this study, the first such global survey, we draw on published human tooth enamel and bone bioapatite data to explore the validity of using oxygen isotope analyses to identify migrants in the archaeological record. We use human δ18O results to show that there are large variations in human oxygen isotope values within a population sample. This may relate to physiological factors influencing the preservation of the primary isotope signal, or due to human activities (such as brewing, boiling, stewing, differential access to water sources and so on causing variation in ingested water and food isotope values. We compare the number of outliers identified using various statistical methods. We determine that the most appropriate method for identifying migrants is dependent on the data but is likely to be the IQR or median absolute deviation from the median under most archaeological circumstances. Finally, through a spatial assessment of the dataset, we show that the degree of overlap in human isotope values from different locations across Europe is such that identifying individuals' homelands on the basis of oxygen isotope analysis alone is not possible for the regions analysed to date. Oxygen isotope analysis is a valid method for identifying first-generation migrants from an archaeological site when used appropriately, however it is difficult to identify migrants using statistical methods for a sample size of less than c. 25 individuals. In the absence of local previous analyses, each sample should be treated as an individual dataset and statistical techniques can be used to identify migrants, but in most cases pinpointing a specific

  7. Predictive models for identifying the binding activity of structurally diverse chemicals to human pregnane X receptor.

    Science.gov (United States)

    Yin, Cen; Yang, Xianhai; Wei, Mengbi; Liu, Huihui

    2017-08-01

    Toxic chemicals entered into human body would undergo a series of metabolism, transport and excretion, and the key roles played in there processes were metabolizing enzymes, which was regulated by the pregnane X receptor (PXR). However, some chemicals in environment could activate or antagonize human pregnane X receptor, thereby leading to a disturbance of normal physiological systems. In this study, based on a larger number of 2724 structurally diverse chemicals, we developed qualitative classification models by the k-nearest neighbor method. Moreover, the logarithm of 20 and 50% effective concentrations (log EC 20 and log EC 50 ) was used to establish quantitative structure-activity relationship (QSAR) models. With the classification model, two descriptors were enough to establish acceptable models, with the sensitivity, specificity, and accuracy being larger than 0.7, highlighting a high classification performance of the models. With two QSAR models, the statistics parameters with the correlation coefficient (R 2 ) of 0.702-0.749 and the cross-validation and external validation coefficient (Q 2 ) of 0.643-0.712, this indicated that the models complied with the criteria proposed in previous studies, i.e., R 2  > 0.6, Q 2  > 0.5. The small root mean square error (RMSE) of 0.254-0.414 and the good consistency between observed and predicted values proved satisfactory goodness of fit, robustness, and predictive ability of the developed QSAR models. Additionally, the applicability domains were characterized by the Euclidean distance-based approach and Williams plot, and results indicated that the current models had a wide applicability domain, which especially included a few classes of environmental contaminant, those that were not included in the previous models.

  8. Identifying indicators of illegal behaviour: carnivore killing in human-managed landscapes.

    Science.gov (United States)

    St John, Freya A V; Keane, Aidan M; Edwards-Jones, Gareth; Jones, Lauren; Yarnell, Richard W; Jones, Julia P G

    2012-02-22

    Managing natural resources often depends on influencing people's behaviour, however effectively targeting interventions to discourage environmentally harmful behaviours is challenging because those involved may be unwilling to identify themselves. Non-sensitive indicators of sensitive behaviours are therefore needed. Previous studies have investigated people's attitudes, assuming attitudes reflect behaviour. There has also been interest in using people's estimates of the proportion of their peers involved in sensitive behaviours to identify those involved, since people tend to assume that others behave like themselves. However, there has been little attempt to test the potential of such indicators. We use the randomized response technique (RRT), designed for investigating sensitive behaviours, to estimate the proportion of farmers in north-eastern South Africa killing carnivores, and use a modified logistic regression model to explore relationships between our best estimates of true behaviour (from RRT) and our proposed non-sensitive indicators (including farmers' attitudes, and estimates of peer-behaviour). Farmers' attitudes towards carnivores, question sensitivity and estimates of peers' behaviour, predict the likelihood of farmers killing carnivores. Attitude and estimates of peer-behaviour are useful indicators of involvement in illicit behaviours and may be used to identify groups of people to engage in interventions aimed at changing behaviour.

  9. Identifying molecular subtypes in human colon cancer using gene expression and DNA methylation microarray data.

    Science.gov (United States)

    Ren, Zhonglu; Wang, Wenhui; Li, Jinming

    2016-02-01

    Identifying colon cancer subtypes based on molecular signatures may allow for a more rational, patient-specific approach to therapy in the future. Classifications using gene expression data have been attempted before with little concordance between the different studies carried out. In this study we aimed to uncover subtypes of colon cancer that have distinct biological characteristics and identify a set of novel biomarkers which could best reflect the clinical and/or biological characteristics of each subtype. Clustering analysis and discriminant analysis were utilized to discover the subtypes in two different molecular levels on 153 colon cancer samples from The Cancer Genome Atlas (TCGA) Data Portal. At gene expression level, we identified two major subtypes, ECL1 (expression cluster 1) and ECL2 (expression cluster 2) and a list of signature genes. Due to the heterogeneity of colon cancer, the subtype ECL1 can be further subdivided into three nested subclasses, and HOTAIR were found upregulated in subclass 2. At DNA methylation level, we uncovered three major subtypes, MCL1 (methylation cluster 1), MCL2 (methylation cluster 2) and MCL3 (methylation cluster 3). We found only three subtypes of CpG island methylator phenotype (CIMP) in colon cancer instead of the four subtypes in the previous reports, and we found no sufficient evidence to subdivide MCL3 into two distinct subgroups.

  10. Transcriptome Analysis Identifies the Dysregulation of Ultraviolet Target Genes in Human Skin Cancers.

    Directory of Open Access Journals (Sweden)

    Yao Shen

    Full Text Available Exposure to ultraviolet radiation (UVR is a major risk factor for both melanoma and non-melanoma skin cancers. In addition to its mutagenic effect, UVR can also induce substantial transcriptional instability in skin cells affecting thousands of genes, including many cancer genes, suggesting that transcriptional instability may be another important etiological factor in skin photocarcinogenesis. In this study, we performed detailed transcriptomic profiling studies to characterize the kinetic changes in global gene expression in human keratinocytes exposed to different UVR conditions. We identified a subset of UV-responsive genes as UV signature genes (UVSGs based on 1 conserved UV-responsiveness of this subset of genes among different keratinocyte lines; and 2 UV-induced persistent changes in their mRNA levels long after exposure. Interestingly, 11 of the UVSGs were shown to be critical to skin cancer cell proliferation and survival. Through computational Gene Set Enrichment Analysis, we demonstrated that a significant portion of the UVSGs were dysregulated in human skin squamous cell carcinomas, but not in other human malignancies. This highlights the potential and specificity of the UVSGs in clinical diagnosis of UV damage and stratification of skin cancer risk.

  11. Untargeted metabolomic analysis in naturally occurring canine diabetes mellitus identifies similarities to human Type 1 Diabetes.

    Science.gov (United States)

    O'Kell, Allison L; Garrett, Timothy J; Wasserfall, Clive; Atkinson, Mark A

    2017-08-25

    While predominant as a disease entity, knowledge voids exist regarding the pathogenesis of canine diabetes. To test the hypothesis that diabetic dogs have similar metabolomic perturbations to humans with type 1 diabetes (T1D), we analyzed serum metabolomic profiles of breed- and body weight-matched, diabetic (n = 6) and healthy (n = 6) dogs by liquid chromatography-mass spectrometry (LC-MS) profiling. We report distinct clustering of diabetic and control groups based on heat map analysis of known and unknown metabolites. Random forest classification identified 5/6 dogs per group correctly with overall out of bag error rate = 16.7%. Diabetic dogs demonstrated significant upregulation of glycolysis/gluconeogenesis intermediates (e.g., glucose/fructose, C 6 H 12 O 6 , keto-hexose, deoxy-hexose, (P diabetic versus healthy dogs (P diabetic animals (P diabetic versus healthy dogs shared similarities with those reported in human T1D (e.g., alterations in glycolysis/gluconeogensis metabolites, bile acids, and elevated branched chain AA). Further studies are warranted to evaluate the utility of canine diabetes to provide novel mechanistic insights to the human disorder.

  12. NKp46 identifies an NKT cell subset susceptible to leukemic transformation in mouse and human

    Science.gov (United States)

    Yu, Jianhua; Mitsui, Takeki; Wei, Min; Mao, Hsiaoyin; Butchar, Jonathan P.; Shah, Mithun Vinod; Zhang, Jianying; Mishra, Anjali; Alvarez-Breckenridge, Christopher; Liu, Xingluo; Liu, Shujun; Yokohama, Akihiko; Trotta, Rossana; Marcucci, Guido; Benson, Don M.; Loughran, Thomas P.; Tridandapani, Susheela; Caligiuri, Michael A.

    2011-01-01

    IL-15 may have a role in the development of T cell large granular lymphocyte (T-LGL) or NKT leukemias. However, the mechanisms of action and the identity of the cell subset that undergoes leukemic transformation remain elusive. Here we show that in both mice and humans, NKp46 expression marks a minute population of WT NKT cells with higher activity and potency to become leukemic. Virtually 100% of T-LGL leukemias in IL-15 transgenic mice expressed NKp46, as did a majority of human T-LGL leukemias. The minute NKp46+ NKT population, but not the NKp46– NKT population, was selectively expanded by overexpression of endogenous IL-15. Importantly, IL-15 transgenic NKp46– NKT cells did not become NKp46+ in vivo, suggesting that NKp46+ T-LGL leukemia cells were the malignant counterpart of the minute WT NKp46+ NKT population. Mechanistically, NKp46+ NKT cells possessed higher responsiveness to IL-15 in vitro and in vivo compared with that of their NKp46– NKT counterparts. Furthermore, interruption of IL-15 signaling using a neutralizing antibody could prevent LGL leukemia in IL-15 transgenic mice. Collectively, our data demonstrate that NKp46 identifies a functionally distinct NKT subset in mice and humans that appears to be directly susceptible to leukemic transformation when IL-15 is overexpressed. Thus, IL-15 signaling and NKp46 may be useful targets in the treatment of patients with T-LGL or NKT leukemia. PMID:21364281

  13. Identifying the gaps: Armenian health care legislation and human rights in patient care protections.

    Science.gov (United States)

    Zopunyan, Violeta; Krmoyan, Suren; Quinn, Ryan

    2013-12-12

    Since the collapse of the Soviet Union, the Republic of Armenia has undergone an extensive legislative overhaul. Although a number of developments have aimed to improve the quality and accessibility of Armenia's health care system, a host of factors has prevented the country from fully introducing measures to ensure respect for human rights in patient care. In particular, inadequate health care financing continues to oblige patients to make both formal and informal payments to obtain basic medical care and services. More generally, a lack of oversight and monitoring mechanisms has obstructed the implementation of Armenia's commitments to human rights in several international agreements. Within the framework of a broader project on promoting human rights in patient care, research was carried out to examine Armenia’s health care legislation with the aim of identifying gaps in comparison with international and regional standards. This research was designed using the 14 rights enshrined in the European Charter on Patient Rights as guiding principles, along with domestic legal acts relevant to the rights of health care providers. The gaps analysis revealed numerous problems with Armenian legislation governing the relationships between stakeholders in health care service delivery. It also identified several practical inconsistencies with the international legal instruments ratified by the Armenian government. These legislative shortcomings are illustrated by highlighting key health-related rights violations experienced by patients and their health care providers, and by indicating opportunities for improved rights protections. A full list of human rights relevant to patient care and recommendations for promoting them in the Armenian context is provided in Tables 1 and 2. A number of initiatives must be undertaken in order to promote the full spectrum of human rights in patient care in Armenia. This section highlights certain recommendations flowing from the findings of

  14. Metrics for the Human Proteome Project 2016: Progress on Identifying and Characterizing the Human Proteome, Including Post-Translational Modifications.

    Science.gov (United States)

    Omenn, Gilbert S; Lane, Lydie; Lundberg, Emma K; Beavis, Ronald C; Overall, Christopher M; Deutsch, Eric W

    2016-11-04

    The HUPO Human Proteome Project (HPP) has two overall goals: (1) stepwise completion of the protein parts list-the draft human proteome including confidently identifying and characterizing at least one protein product from each protein-coding gene, with increasing emphasis on sequence variants, post-translational modifications (PTMs), and splice isoforms of those proteins; and (2) making proteomics an integrated counterpart to genomics throughout the biomedical and life sciences community. PeptideAtlas and GPMDB reanalyze all major human mass spectrometry data sets available through ProteomeXchange with standardized protocols and stringent quality filters; neXtProt curates and integrates mass spectrometry and other findings to present the most up to date authorative compendium of the human proteome. The HPP Guidelines for Mass Spectrometry Data Interpretation version 2.1 were applied to manuscripts submitted for this 2016 C-HPP-led special issue [ www.thehpp.org/guidelines ]. The Human Proteome presented as neXtProt version 2016-02 has 16,518 confident protein identifications (Protein Existence [PE] Level 1), up from 13,664 at 2012-12, 15,646 at 2013-09, and 16,491 at 2014-10. There are 485 proteins that would have been PE1 under the Guidelines v1.0 from 2012 but now have insufficient evidence due to the agreed-upon more stringent Guidelines v2.0 to reduce false positives. neXtProt and PeptideAtlas now both require two non-nested, uniquely mapping (proteotypic) peptides of at least 9 aa in length. There are 2,949 missing proteins (PE2+3+4) as the baseline for submissions for this fourth annual C-HPP special issue of Journal of Proteome Research. PeptideAtlas has 14,629 canonical (plus 1187 uncertain and 1755 redundant) entries. GPMDB has 16,190 EC4 entries, and the Human Protein Atlas has 10,475 entries with supportive evidence. neXtProt, PeptideAtlas, and GPMDB are rich resources of information about post-translational modifications (PTMs), single amino acid

  15. Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling.

    Directory of Open Access Journals (Sweden)

    Deborah C Mash

    2007-11-01

    Full Text Available The chronic effects of cocaine abuse on brain structure and function are blamed for the inability of most addicts to remain abstinent. Part of the difficulty in preventing relapse is the persisting memory of the intense euphoria or cocaine "rush". Most abused drugs and alcohol induce neuroplastic changes in brain pathways subserving emotion and cognition. Such changes may account for the consolidation and structural reconfiguration of synaptic connections with exposure to cocaine. Adaptive hippocampal plasticity could be related to specific patterns of gene expression with chronic cocaine abuse. Here, we compare gene expression profiles in the human hippocampus from cocaine addicts and age-matched drug-free control subjects. Cocaine abusers had 151 gene transcripts upregulated, while 91 gene transcripts were downregulated. Topping the list of cocaine-regulated transcripts was RECK in the human hippocampus (FC = 2.0; p<0.05. RECK is a membrane-anchored MMP inhibitor that is implicated in the coordinated regulation of extracellular matrix integrity and angiogenesis. In keeping with elevated RECK expression, active MMP9 protein levels were decreased in the hippocampus from cocaine abusers. Pathway analysis identified other genes regulated by cocaine that code for proteins involved in the remodeling of the cytomatrix and synaptic connections and the inhibition of blood vessel proliferation (PCDH8, LAMB1, ITGB6, CTGF and EphB4. The observed microarray phenotype in the human hippocampus identified RECK and other region-specific genes that may promote long-lasting structural changes with repeated cocaine abuse. Extracellular matrix remodeling in the hippocampus may be a persisting effect of chronic abuse that contributes to the compulsive and relapsing nature of cocaine addiction.

  16. Elevated osteopontin and thrombospondin expression identifies malignant human breast carcinoma but is not indicative of metastatic status

    International Nuclear Information System (INIS)

    Wang-Rodriguez, Jessica; Urquidi, Virginia; Rivard, Amber; Goodison, Steve

    2003-01-01

    Our previous characterization of a human breast tumor metastasis model identified several candidate metastasis genes. The expression of osteopontin (OPN) correlated with the metastatic phenotype, whereas thrombospondin-1 (TSP-1) and tyrosinase-related protein-1 (TYRP-1) correlated with the nonmetastatic phenotype of independent MDA-MB-435 cell lines implanted orthotopically into athymic mice. The aim of the present study was to examine the cellular distribution of these molecules in human breast tissue and to determine whether the relative expression level of these three genes is associated with human breast tumor metastasis. Sixty-eight fresh, frozen specimens including 31 primary infiltrating ductal carcinomas, 22 nodal metastases, 10 fibroadenomas, and five normal breast tissues were evaluated for OPN expression, TSP-1 expression and TYRP-1 expression. Immunohistochemistry was performed to monitor the cellular distribution and to qualitatively assess expression. Quantitative analysis was achieved by enrichment of breast epithelial cells using laser-capture microdissection and subsequent real-time, quantitative PCR. The epithelial components of the breast tissue were the source of OPN and TSP-1 expression, whereas TYRP-1 was present in both the epithelial and stromal components. Both OPN and TSP-1 expression were significantly higher in malignant epithelial sources over normal and benign epithelial sources, but no difference in expression levels was evident between primary tumors with or without metastases, nor between primary and metastatic carcinomas. Elevated expression of OPN and TSP-1 may play a role in the pathogenesis of breast cancer. The multiplex analysis of these molecules may enhance our ability to diagnose and/or prognosticate human breast malignancy

  17. Investigating Salmonella Eko from Various Sources in Nigeria by Whole Genome Sequencing to Identify the Source of Human Infections.

    Directory of Open Access Journals (Sweden)

    Pimlapas Leekitcharoenphon

    Full Text Available Twenty-six Salmonella enterica serovar Eko isolated from various sources in Nigeria were investigated by whole genome sequencing to identify the source of human infections. Diversity among the isolates was observed and camel and cattle were identified as the primary reservoirs and the most likely source of the human infections.

  18. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta.

    Science.gov (United States)

    Becker, Jutta; Semler, Oliver; Gilissen, Christian; Li, Yun; Bolz, Hanno Jörn; Giunta, Cecilia; Bergmann, Carsten; Rohrbach, Marianne; Koerber, Friederike; Zimmermann, Katharina; de Vries, Petra; Wirth, Brunhilde; Schoenau, Eckhard; Wollnik, Bernd; Veltman, Joris A; Hoischen, Alexander; Netzer, Christian

    2011-03-11

    Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion. SERPINF1 encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  19. Connecting the Persistent Identifier Ecosystem: Building the Technical and Human Infrastructure for Open Research

    Directory of Open Access Journals (Sweden)

    Angela Dappert

    2017-06-01

    Full Text Available The persistent identifier (PID landscape extends to cover objects, individuals and organisations engaged in the process of research. Established services such as DataCite, Crossref, ORCID and ISNI are providing a foundation for a trusted ecosystem and a new generation of services. Scalable identifier systems will support researchers and capture research activity in a holistic way, across the entire lifecycle. Challenges remain – siloed services are not interoperable; important types of objects are not adequately covered, many processes remain manual, and adoption, while strong, is not consistent across disciplines. This article draws on the work of the EU-funded THOR project to take stock of the current state of interoperability across the PID landscape and to discuss the next steps towards an integrated research record. Examples illustrate how this interconnectivity is facilitated technically, as well as social and human challenges in fostering adoption. User stories highlight how this network of persistent identifier services is facilitating good practice in open research and where its limitations lie.

  20. Combined Gene Expression and RNAi Screening to Identify Alkylation Damage Survival Pathways from Fly to Human.

    Science.gov (United States)

    Zanotto-Filho, Alfeu; Dashnamoorthy, Ravi; Loranc, Eva; de Souza, Luis H T; Moreira, José C F; Suresh, Uthra; Chen, Yidong; Bishop, Alexander J R

    2016-01-01

    Alkylating agents are a key component of cancer chemotherapy. Several cellular mechanisms are known to be important for its survival, particularly DNA repair and xenobiotic detoxification, yet genomic screens indicate that additional cellular components may be involved. Elucidating these components has value in either identifying key processes that can be modulated to improve chemotherapeutic efficacy or may be altered in some cancers to confer chemoresistance. We therefore set out to reevaluate our prior Drosophila RNAi screening data by comparison to gene expression arrays in order to determine if we could identify any novel processes in alkylation damage survival. We noted a consistent conservation of alkylation survival pathways across platforms and species when the analysis was conducted on a pathway/process level rather than at an individual gene level. Better results were obtained when combining gene lists from two datasets (RNAi screen plus microarray) prior to analysis. In addition to previously identified DNA damage responses (p53 signaling and Nucleotide Excision Repair), DNA-mRNA-protein metabolism (transcription/translation) and proteasome machinery, we also noted a highly conserved cross-species requirement for NRF2, glutathione (GSH)-mediated drug detoxification and Endoplasmic Reticulum stress (ER stress)/Unfolded Protein Responses (UPR) in cells exposed to alkylation. The requirement for GSH, NRF2 and UPR in alkylation survival was validated by metabolomics, protein studies and functional cell assays. From this we conclude that RNAi/gene expression fusion is a valid strategy to rapidly identify key processes that may be extendable to other contexts beyond damage survival.

  1. Combined Gene Expression and RNAi Screening to Identify Alkylation Damage Survival Pathways from Fly to Human.

    Directory of Open Access Journals (Sweden)

    Alfeu Zanotto-Filho

    Full Text Available Alkylating agents are a key component of cancer chemotherapy. Several cellular mechanisms are known to be important for its survival, particularly DNA repair and xenobiotic detoxification, yet genomic screens indicate that additional cellular components may be involved. Elucidating these components has value in either identifying key processes that can be modulated to improve chemotherapeutic efficacy or may be altered in some cancers to confer chemoresistance. We therefore set out to reevaluate our prior Drosophila RNAi screening data by comparison to gene expression arrays in order to determine if we could identify any novel processes in alkylation damage survival. We noted a consistent conservation of alkylation survival pathways across platforms and species when the analysis was conducted on a pathway/process level rather than at an individual gene level. Better results were obtained when combining gene lists from two datasets (RNAi screen plus microarray prior to analysis. In addition to previously identified DNA damage responses (p53 signaling and Nucleotide Excision Repair, DNA-mRNA-protein metabolism (transcription/translation and proteasome machinery, we also noted a highly conserved cross-species requirement for NRF2, glutathione (GSH-mediated drug detoxification and Endoplasmic Reticulum stress (ER stress/Unfolded Protein Responses (UPR in cells exposed to alkylation. The requirement for GSH, NRF2 and UPR in alkylation survival was validated by metabolomics, protein studies and functional cell assays. From this we conclude that RNAi/gene expression fusion is a valid strategy to rapidly identify key processes that may be extendable to other contexts beyond damage survival.

  2. Identifying colon cancer risk modules with better classification performance based on human signaling network.

    Science.gov (United States)

    Qu, Xiaoli; Xie, Ruiqiang; Chen, Lina; Feng, Chenchen; Zhou, Yanyan; Li, Wan; Huang, Hao; Jia, Xu; Lv, Junjie; He, Yuehan; Du, Youwen; Li, Weiguo; Shi, Yuchen; He, Weiming

    2014-10-01

    Identifying differences between normal and tumor samples from a modular perspective may help to improve our understanding of the mechanisms responsible for colon cancer. Many cancer studies have shown that signaling transduction and biological pathways are disturbed in disease states, and expression profiles can distinguish variations in diseases. In this study, we integrated a weighted human signaling network and gene expression profiles to select risk modules associated with tumor conditions. Risk modules as classification features by our method had a better classification performance than other methods, and one risk module for colon cancer had a good classification performance for distinguishing between normal/tumor samples and between tumor stages. All genes in the module were annotated to the biological process of positive regulation of cell proliferation, and were highly associated with colon cancer. These results suggested that these genes might be the potential risk genes for colon cancer. Copyright © 2013. Published by Elsevier Inc.

  3. Positive selection moments identify potential functional residues in human olfactory receptors

    Science.gov (United States)

    Singer, M. S.; Weisinger-Lewin, Y.; Lancet, D.; Shepherd, G. M.

    1996-01-01

    Correlated mutation analysis and molecular models of olfactory receptors have provided evidence that residues in the transmembrane domains form a binding pocket for odor ligands. As an independent test of these results, we have calculated positive selection moments for the alpha-helical sixth transmembrane domain (TM6) of human olfactory receptors. The moments can be used to identify residues that have been preferentially affected by positive selection and are thus likely to interact with odor ligands. The results suggest that residue 622, which is commonly a serine or threonine, could form critical H-bonds. In some receptors a dual-serine subsite, formed by residues 622 and 625, could bind hydroxyl determinants on odor ligands. The potential importance of these residues is further supported by site-directed mutagenesis in the beta-adrenergic receptor. The findings should be of practical value for future physiological studies, binding assays, and site-directed mutagenesis.

  4. Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity.

    Directory of Open Access Journals (Sweden)

    Kristen Fortney

    2015-12-01

    Full Text Available We developed a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS, takes advantage of knowledge from large studies of age-related disease in order to narrow the search for SNPs associated with longevity. To gain support for our approach, we first show there is an overlap between loci involved in disease and loci associated with extreme longevity. These results indicate that several disease variants may be depleted in centenarians versus the general population. Next, we used iGWAS to harness information from 14 meta-analyses of disease and trait GWAS to identify longevity loci in two studies of long-lived humans. In a standard GWAS analysis, only one locus in these studies is significant (APOE/TOMM40 when controlling the false discovery rate (FDR at 10%. With iGWAS, we identify eight genetic loci to associate significantly with exceptional human longevity at FDR < 10%. We followed up the eight lead SNPs in independent cohorts, and found replication evidence of four loci and suggestive evidence for one more with exceptional longevity. The loci that replicated (FDR < 5% included APOE/TOMM40 (associated with Alzheimer's disease, CDKN2B/ANRIL (implicated in the regulation of cellular senescence, ABO (tags the O blood group, and SH2B3/ATXN2 (a signaling gene that extends lifespan in Drosophila and a gene involved in neurological disease. Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits, including coronary artery disease and Alzheimer's disease. iGWAS provides a new analytical strategy for uncovering SNPs that influence extreme longevity, and can be applied more broadly to boost power in other studies of complex phenotypes.

  5. Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity.

    Science.gov (United States)

    Fortney, Kristen; Dobriban, Edgar; Garagnani, Paolo; Pirazzini, Chiara; Monti, Daniela; Mari, Daniela; Atzmon, Gil; Barzilai, Nir; Franceschi, Claudio; Owen, Art B; Kim, Stuart K

    2015-12-01

    We developed a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS), takes advantage of knowledge from large studies of age-related disease in order to narrow the search for SNPs associated with longevity. To gain support for our approach, we first show there is an overlap between loci involved in disease and loci associated with extreme longevity. These results indicate that several disease variants may be depleted in centenarians versus the general population. Next, we used iGWAS to harness information from 14 meta-analyses of disease and trait GWAS to identify longevity loci in two studies of long-lived humans. In a standard GWAS analysis, only one locus in these studies is significant (APOE/TOMM40) when controlling the false discovery rate (FDR) at 10%. With iGWAS, we identify eight genetic loci to associate significantly with exceptional human longevity at FDR Alzheimer's disease), CDKN2B/ANRIL (implicated in the regulation of cellular senescence), ABO (tags the O blood group), and SH2B3/ATXN2 (a signaling gene that extends lifespan in Drosophila and a gene involved in neurological disease). Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits, including coronary artery disease and Alzheimer's disease. iGWAS provides a new analytical strategy for uncovering SNPs that influence extreme longevity, and can be applied more broadly to boost power in other studies of complex phenotypes.

  6. A molecular systems approach to modelling human skin pigmentation: identifying underlying pathways and critical components.

    Science.gov (United States)

    Raghunath, Arathi; Sambarey, Awanti; Sharma, Neha; Mahadevan, Usha; Chandra, Nagasuma

    2015-04-29

    Ultraviolet radiations (UV) serve as an environmental stress for human skin, and result in melanogenesis, with the pigment melanin having protective effects against UV induced damage. This involves a dynamic and complex regulation of various biological processes that results in the expression of melanin in the outer most layers of the epidermis, where it can exert its protective effect. A comprehensive understanding of the underlying cross talk among different signalling molecules and cell types is only possible through a systems perspective. Increasing incidences of both melanoma and non-melanoma skin cancers necessitate the need to better comprehend UV mediated effects on skin pigmentation at a systems level, so as to ultimately evolve knowledge-based strategies for efficient protection and prevention of skin diseases. A network model for UV-mediated skin pigmentation in the epidermis was constructed and subjected to shortest path analysis. Virtual knock-outs were carried out to identify essential signalling components. We describe a network model for UV-mediated skin pigmentation in the epidermis. The model consists of 265 components (nodes) and 429 directed interactions among them, capturing the manner in which one component influences the other and channels information. Through shortest path analysis, we identify novel signalling pathways relevant to pigmentation. Virtual knock-outs or perturbations of specific nodes in the network have led to the identification of alternate modes of signalling as well as enabled determining essential nodes in the process. The model presented provides a comprehensive picture of UV mediated signalling manifesting in human skin pigmentation. A systems perspective helps provide a holistic purview of interconnections and complexity in the processes leading to pigmentation. The model described here is extensive yet amenable to expansion as new data is gathered. Through this study, we provide a list of important proteins essential

  7. Novel snail1 target proteins in human colon cancer identified by proteomic analysis.

    Directory of Open Access Journals (Sweden)

    María Jesús Larriba

    2010-04-01

    Full Text Available The transcription factor Snail1 induces epithelial-to-mesenchymal transition (EMT, a process responsible for the acquisition of invasiveness during tumorigenesis. Several transcriptomic studies have reported Snail1-regulated genes in different cell types, many of them involved in cell adhesion. However, only a few studies have used proteomics as a tool for the characterization of proteins mediating EMT.We identified by proteomic analysis using 2D-DIGE electrophoresis combined with MALDI-TOF-TOF and ESI-linear ion trap mass spectrometry a number of proteins with variable functions whose expression is modulated by Snail1 in SW480-ADH human colon cancer cells. Validation was performed by Western blot and immunofluorescence analyses. Snail1 repressed several members of the 14-3-3 family of phosphoserine/phosphothreonine binding proteins and also the expression of the Proliferation-associated protein 2G4 (PA2G4 that was mainly localized at the nuclear Cajal bodies. In contrast, the expression of two proteins involved in RNA processing, the Cleavage and polyadenylation specificity factor subunit 6 (CPSF6 and the Splicing factor proline/glutamine-rich (SFPQ, was higher in Snail1-expressing cells than in controls. The regulation of 14-3-3epsilon, 14-3-3tau, 14-3-3zeta and PA2G4 by Snail1 was reproduced in HT29 colon cancer cells. In addition, we found an inverse correlation between 14-3-3sigma and Snail1 expression in human colorectal tumors.We have identified a set of novel Snail1 target proteins in colon cancer that expand the cellular processes affected by Snail1 and thus its relevance for cell function and phenotype.

  8. Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity

    Science.gov (United States)

    Fortney, Kristen; Dobriban, Edgar; Garagnani, Paolo; Pirazzini, Chiara; Monti, Daniela; Mari, Daniela; Atzmon, Gil; Barzilai, Nir; Franceschi, Claudio; Owen, Art B.; Kim, Stuart K.

    2015-01-01

    We developed a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS), takes advantage of knowledge from large studies of age-related disease in order to narrow the search for SNPs associated with longevity. To gain support for our approach, we first show there is an overlap between loci involved in disease and loci associated with extreme longevity. These results indicate that several disease variants may be depleted in centenarians versus the general population. Next, we used iGWAS to harness information from 14 meta-analyses of disease and trait GWAS to identify longevity loci in two studies of long-lived humans. In a standard GWAS analysis, only one locus in these studies is significant (APOE/TOMM40) when controlling the false discovery rate (FDR) at 10%. With iGWAS, we identify eight genetic loci to associate significantly with exceptional human longevity at FDR Alzheimer’s disease), CDKN2B/ANRIL (implicated in the regulation of cellular senescence), ABO (tags the O blood group), and SH2B3/ATXN2 (a signaling gene that extends lifespan in Drosophila and a gene involved in neurological disease). Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits, including coronary artery disease and Alzheimer’s disease. iGWAS provides a new analytical strategy for uncovering SNPs that influence extreme longevity, and can be applied more broadly to boost power in other studies of complex phenotypes. PMID:26677855

  9. Fourier transform infrared microspectroscopy identifies early lineage commitment in differentiating human embryonic stem cells.

    Science.gov (United States)

    Heraud, Philip; Ng, Elizabeth S; Caine, Sally; Yu, Qing C; Hirst, Claire; Mayberry, Robyn; Bruce, Amanda; Wood, Bayden R; McNaughton, Don; Stanley, Edouard G; Elefanty, Andrew G

    2010-03-01

    Human ESCs (hESCs) are a valuable tool for the study of early human development and represent a source of normal differentiated cells for pharmaceutical and biotechnology applications and ultimately for cell replacement therapies. For all applications, it will be necessary to develop assays to validate the efficacy of hESC differentiation. We explored the capacity for FTIR spectroscopy, a technique that rapidly characterises cellular macromolecular composition, to discriminate mesendoderm or ectoderm committed cells from undifferentiated hESCs. Distinct infrared spectroscopic "signatures" readily distinguished hESCs from these early differentiated progeny, with bioinformatic models able to correctly classify over 97% of spectra. These data identify a role for FTIR spectroscopy as a new modality to complement conventional analyses of hESCs and their derivatives. FTIR spectroscopy has the potential to provide low-cost, automatable measurements for the quality control of stem and differentiated cells to be used in industry and regenerative medicine. Crown Copyright 2009. Published by Elsevier B.V. All rights reserved.

  10. Visual genome-wide RNAi screening to identify human host factors required for Trypanosoma cruzi infection.

    Directory of Open Access Journals (Sweden)

    Auguste Genovesio

    Full Text Available The protozoan parasite Trypanosoma cruzi is the etiologic agent of Chagas disease, a neglected tropical infection that affects millions of people in the Americas. Current chemotherapy relies on only two drugs that have limited efficacy and considerable side effects. Therefore, the development of new and more effective drugs is of paramount importance. Although some host cellular factors that play a role in T. cruzi infection have been uncovered, the molecular requirements for intracellular parasite growth and persistence are still not well understood. To further study these host-parasite interactions and identify human host factors required for T. cruzi infection, we performed a genome-wide RNAi screen using cellular microarrays of a printed siRNA library that spanned the whole human genome. The screening was reproduced 6 times and a customized algorithm was used to select as hits those genes whose silencing visually impaired parasite infection. The 162 strongest hits were subjected to a secondary screening and subsequently validated in two different cell lines. Among the fourteen hits confirmed, we recognized some cellular membrane proteins that might function as cell receptors for parasite entry and others that may be related to calcium release triggered by parasites during cell invasion. In addition, two of the hits are related to the TGF-beta signaling pathway, whose inhibition is already known to diminish levels of T. cruzi infection. This study represents a significant step toward unveiling the key molecular requirements for host cell invasion and revealing new potential targets for antiparasitic therapy.

  11. Human amniotic membrane as newly identified source of amniotic fluid pulmonary surfactant.

    Science.gov (United States)

    Lemke, Angela; Castillo-Sánchez, José Carlos; Prodinger, Florian; Ceranic, Asja; Hennerbichler-Lugscheider, Simone; Pérez-Gil, Jesús; Redl, Heinz; Wolbank, Susanne

    2017-07-25

    Pulmonary surfactant (PS) reduces surface tension at the air-liquid interface in the alveolar epithelium of the lung, which is required for breathing and for the pulmonary maturity of the developing foetus. However, the origin of PS had never been thoroughly investigated, although it was assumed to be secreted from the foetal developing lung. Human amniotic membrane (hAM), particularly its epithelial cell layer, composes the amniotic sac enclosing the amniotic fluid. In this study, we therefore aimed to investigate a potential contribution of the cellular components of the hAM to pulmonary surfactant found in amniotic fluid. We identified that cells within the native membrane contain lamellar bodies and express all four surfactant proteins as well as ABCA3. Lipidomic profiling by nanoESI - MS/MS revealed the presence of the essential lipid species as found in PS. Also, the biophysical activity of conditioned cell culture supernatant obtained from hAM was tested with captive bubble surfactometry. hAM supernatant showed the ability to reduce surface tension, similar to human PS obtained from bronchoalveolar lavage. This means that hAM produces the essential PS-associated components and can therefore contribute as second potential source of PS in amniotic fluid aside from the foetal lung.

  12. High throughput Screening to Identify Natural Human Monoamine Oxidase B Inhibitors

    Science.gov (United States)

    Mazzio, E; Deiab, S; Park, K; Soliman, KFA

    2012-01-01

    Age-related increase in monoamine oxidase B (MAO-B) may contribute to CNS neurodegenerative diseases. Moreover, MAO-B inhibitors are used in the treatment of idiopathic Parkinson disease as preliminary monotherapy or adjunct therapy with L-dopa. To date, meager natural sources of MAO-B inhibitors have been identified, and the relative strength, potency and rank of many plants relative to standard drugs such as Selegiline (L-deprenyl, Eldepryl) are not known. In this work, we developed and utilized a high throughput enzyme microarray format to screen and evaluate 905 natural product extracts (0.025–.7 mg/ml) to inhibit human MAO-B derived from BTI-TN-5B1-4 cells infected with recombinant baculovirus. The protein sequence of purified enzyme was confirmed using 1D gel electrophoresis-matrix assisted laser desorption ionization-time-of-flight-tandem mass spectroscopy, and enzyme activity was confirmed by [1] substrate conversion (3-mM benzylamine) to H202 and [2] benzaldehyde. Of the 905 natural extracts tested, the lowest IC50s [Comfrey, Bringraj, Skullcap, Kava-kava, Wild Indigo, Gentian and Green Tea. In conclusion, the data reflect relative potency information by rank of commonly used herbs and plants that contain human MAO-B inhibitory properties in their natural form. PMID:22887993

  13. Breast cancer resistance protein identifies clonogenic keratinocytes in human interfollicular epidermis.

    Science.gov (United States)

    Ma, Dongrui; Chua, Alvin Wen Choong; Yang, Ennan; Teo, Peiyun; Ting, Yixin; Song, Colin; Lane, Ellen Birgitte; Lee, Seng Teik

    2015-03-24

    There is a practical need for the identification of robust cell-surface markers that can be used to enrich for living keratinocyte progenitor cells. Breast cancer resistance protein (ABCG2), a member of the ATP binding cassette (ABC) transporter family, is known to be a marker for stem/progenitor cells in many tissues and organs. We investigated the expression of ABCG2 protein in normal human epidermis to evaluate its potential as a cell surface marker for identifying and enriching for clonogenic epidermal keratinocytes outside the pilosebaceous tract. Immunofluorescence and immunoblotting studies of human skin showed that ABCG2 is expressed in a subset of basal layer cells in the epidermis. Flow cytometry analysis showed approximately 2-3% of keratinocytes in non-hair-bearing epidermis expressing ABCG2; this population also expresses p63, β1 and α6 integrins and keratin 14, but not CD34, CD71, C-kit or involucrin. The ABCG2-positive keratinocytes showed significantly higher colony forming efficiency when co-cultured with mouse 3T3 feeder cells, and more extensive long-term proliferation capacity in vitro, than did ABCG2-negative keratinocytes. Upon clonal analysis, most of the freshly isolated ABCG2-positive keratinocytes formed holoclones and were capable of generating a stratified differentiating epidermis in organotypic culture models. These data indicate that in skin, expression of the ABCG2 transporter is a characteristic of interfollicular keratinocyte progentior cells and suggest that ABCG2 may be useful for enriching keratinocyte stem cells in human interfollicular epidermis.

  14. Bioinformatics analysis identifies several intrinsically disordered human E3 ubiquitin-protein ligases

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    Wouter Boomsma

    2016-02-01

    Full Text Available The ubiquitin-proteasome system targets misfolded proteins for degradation. Since the accumulation of such proteins is potentially harmful for the cell, their prompt removal is important. E3 ubiquitin-protein ligases mediate substrate ubiquitination by bringing together the substrate with an E2 ubiquitin-conjugating enzyme, which transfers ubiquitin to the substrate. For misfolded proteins, substrate recognition is generally delegated to molecular chaperones that subsequently interact with specific E3 ligases. An important exception is San1, a yeast E3 ligase. San1 harbors extensive regions of intrinsic disorder, which provide both conformational flexibility and sites for direct recognition of misfolded targets of vastly different conformations. So far, no mammalian ortholog of San1 is known, nor is it clear whether other E3 ligases utilize disordered regions for substrate recognition. Here, we conduct a bioinformatics analysis to examine >600 human and S. cerevisiae E3 ligases to identify enzymes that are similar to San1 in terms of function and/or mechanism of substrate recognition. An initial sequence-based database search was found to detect candidates primarily based on the homology of their ordered regions, and did not capture the unique disorder patterns that encode the functional mechanism of San1. However, by searching specifically for key features of the San1 sequence, such as long regions of intrinsic disorder embedded with short stretches predicted to be suitable for substrate interaction, we identified several E3 ligases with these characteristics. Our initial analysis revealed that another remarkable trait of San1 is shared with several candidate E3 ligases: long stretches of complete lysine suppression, which in San1 limits auto-ubiquitination. We encode these characteristic features into a San1 similarity-score, and present a set of proteins that are plausible candidates as San1 counterparts in humans. In conclusion, our work

  15. Evaluation of Stimulated Raman Scattering Microscopy for Identifying Squamous Cell Carcinoma in Human Skin

    Science.gov (United States)

    Mittal, Richa; Balu, Mihaela; Krasieva, Tatiana; Potma, Eric O.; Elkeeb, Laila; Zachary, Christopher B.; Wilder-Smith, Petra

    2014-01-01

    Background and Significance There is a need to develop non-invasive diagnostic tools to achieve early and accurate detection of skin cancer in a non-surgical manner. In this study, we evaluate the capability of stimulated Raman scattering (SRS) microscopy, a potentially noninvasive optical imaging technique, for identifying the pathological features of s squamous cell carcinoma (SCC) tissue. Study design We studied ex vivo SCC and healthy skin tissues using SRS microscopy, and compared the SRS contrast with the contrast obtained in reflectance confocal microscopy (RCM) and standard histology. Results and Conclusion SRS images obtained at the carbon-hydrogen stretching vibration at 2945 cm−1 exhibit contrast related protein density that clearly delineates the cell nucleus from the cell cytoplasm. The morphological features of SCC tumor seen in the SRS images show excellent correlation with the diagnostic features identified by histological examination. Additionally, SRS exhibits enhanced cellular contrast in comparison to that seen in confocal microscopy. In conclusion, SRS represents an attractive approach for generating protein density maps with contrast that closely resembles histopathological contrast of SCC in human skin. PMID:23996592

  16. Gene expression profiling to identify the toxicities and potentially relevant human disease outcomes associated with environmental heavy metal exposure.

    Science.gov (United States)

    Korashy, Hesham M; Attafi, Ibraheem M; Famulski, Konrad S; Bakheet, Saleh A; Hafez, Mohammed M; Alsaad, Abdulaziz M S; Al-Ghadeer, Abdul Rahman M

    2017-02-01

    Heavy metals are the most commonly encountered toxic substances that increase susceptibility to various diseases after prolonged exposure. We have previously shown that healthy volunteers living near a mining area had significant contamination with heavy metals associated with significant changes in the expression of some detoxifying genes, xenobiotic metabolizing enzymes, and DNA repair genes. However, alterations of most of the molecular target genes associated with diseases are still unknown. Thus, the aims of this study were to (a) evaluate the gene expression profile and (b) identify the toxicities and potentially relevant human disease outcomes associated with long-term human exposure to environmental heavy metals in mining area using microarray analysis. For this purpose, 40 healthy male volunteers who were residents of a heavy metal-polluted area (Mahd Al-Dhahab city, Saudi Arabia) and 20 healthy male volunteers who were residents of a non-heavy metal-polluted area were included in the study. Total RNA was isolated from whole blood using PAXgene Blood RNA tubes and then reversed transcribed and hybridized to the gene array using the Affymetrix U219 GeneChip. Microarray analysis showed about 2129 genes were identified and differentially altered, among which a shared set of 425 genes was differentially expressed in the heavy metal-exposed groups. Ingenuity pathway analysis revealed that the most altered gene-regulated diseases in heavy metal-exposed groups included hematological and developmental disorders and mostly renal and urological diseases. Quantitative real-time polymerase chain reaction closely matched the microarray data for some genes tested. Importantly, changes in gene-related diseases were attributed to alterations in the genes encoded for protein synthesis. Renal and urological diseases were the diseases that were most frequently associated with the heavy metal-exposed group. Therefore, there is a need for further studies to validate these

  17. Haemophilus influenzae: using comparative genomics to accurately identify a highly recombinogenic human pathogen.

    Science.gov (United States)

    Price, Erin P; Sarovich, Derek S; Nosworthy, Elizabeth; Beissbarth, Jemima; Marsh, Robyn L; Pickering, Janessa; Kirkham, Lea-Ann S; Keil, Anthony D; Chang, Anne B; Smith-Vaughan, Heidi C

    2015-08-27

    Haemophilus influenzae is an opportunistic bacterial pathogen that exclusively colonises humans and is associated with both acute and chronic disease. Despite its clinical significance, accurate identification of H. influenzae is a non-trivial endeavour. H. haemolyticus can be misidentified as H. influenzae from clinical specimens using selective culturing methods, reflecting both the shared environmental niche and phenotypic similarities of these species. On the molecular level, frequent genetic exchange amongst Haemophilus spp. has confounded accurate identification of H. influenzae, leading to both false-positive and false-negative results with existing speciation assays. Whole-genome single-nucleotide polymorphism data from 246 closely related global Haemophilus isolates, including 107 Australian isolate genomes generated in this study, were used to construct a whole-genome phylogeny. Based on this phylogeny, H. influenzae could be differentiated from closely related species. Next, a H. influenzae-specific locus, fucP, was identified, and a novel TaqMan real-time PCR assay targeting fucP was designed. PCR specificity screening across a panel of clinically relevant species, coupled with in silico analysis of all species within the order Pasteurellales, demonstrated that the fucP assay was 100 % specific for H. influenzae; all other examined species failed to amplify. This study is the first of its kind to use large-scale comparative genomic analysis of Haemophilus spp. to accurately delineate H. influenzae and to identify a species-specific molecular signature for this species. The fucP assay outperforms existing H. influenzae targets, most of which were identified prior to the next-generation genomics era and thus lack validation across a large number of Haemophilus spp. We recommend use of the fucP assay in clinical and research laboratories for the most accurate detection and diagnosis of H. influenzae infection and colonisation.

  18. Laparoscopy After Previous Laparotomy

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    Zulfo Godinjak

    2006-11-01

    Full Text Available Following the abdominal surgery, extensive adhesions often occur and they can cause difficulties during laparoscopic operations. However, previous laparotomy is not considered to be a contraindication for laparoscopy. The aim of this study is to present that an insertion of Veres needle in the region of umbilicus is a safe method for creating a pneumoperitoneum for laparoscopic operations after previous laparotomy. In the last three years, we have performed 144 laparoscopic operations in patients that previously underwent one or two laparotomies. Pathology of digestive system, genital organs, Cesarean Section or abdominal war injuries were the most common causes of previouslaparotomy. During those operations or during entering into abdominal cavity we have not experienced any complications, while in 7 patients we performed conversion to laparotomy following the diagnostic laparoscopy. In all patients an insertion of Veres needle and trocar insertion in the umbilical region was performed, namely a technique of closed laparoscopy. Not even in one patient adhesions in the region of umbilicus were found, and no abdominal organs were injured.

  19. Identifying Darwinian selection acting on different human APOL1 variants among diverse African populations.

    Science.gov (United States)

    Ko, Wen-Ya; Rajan, Prianka; Gomez, Felicia; Scheinfeldt, Laura; An, Ping; Winkler, Cheryl A; Froment, Alain; Nyambo, Thomas B; Omar, Sabah A; Wambebe, Charles; Ranciaro, Alessia; Hirbo, Jibril B; Tishkoff, Sarah A

    2013-07-11

    Disease susceptibility can arise as a consequence of adaptation to infectious disease. Recent findings have suggested that higher rates of chronic kidney disease (CKD) in individuals with recent African ancestry might be attributed to two risk alleles (G1 and G2) at the serum-resistance-associated (SRA)-interacting-domain-encoding region of APOL1. These two alleles appear to have arisen adaptively, possibly as a result of their protective effects against human African trypanosomiasis (HAT), or African sleeping sickness. In order to explore the distribution of potential functional variation at APOL1, we studied nucleotide variation in 187 individuals across ten geographically and genetically diverse African ethnic groups with exposure to two Trypanosoma brucei subspecies that cause HAT. We observed unusually high levels of nonsynonymous polymorphism in the regions encoding the functional domains that are required for lysing parasites. Whereas allele frequencies of G2 were similar across all populations (3%-8%), the G1 allele was only common in the Yoruba (39%). Additionally, we identified a haplotype (termed G3) that contains a nonsynonymous change at the membrane-addressing-domain-encoding region of APOL1 and is present in all populations except for the Yoruba. Analyses of long-range patterns of linkage disequilibrium indicate evidence of recent selection acting on the G3 haplotype in Fulani from Cameroon. Our results indicate that the G1 and G2 variants in APOL1 are geographically restricted and that there might be other functional variants that could play a role in HAT resistance and CKD risk in African populations. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  20. Application of diffusion maps to identify human factors of self-reported anomalies in aviation.

    Science.gov (United States)

    Andrzejczak, Chris; Karwowski, Waldemar; Mikusinski, Piotr

    2012-01-01

    A study investigating what factors are present leading to pilots submitting voluntary anomaly reports regarding their flight performance was conducted. Diffusion Maps (DM) were selected as the method of choice for performing dimensionality reduction on text records for this study. Diffusion Maps have seen successful use in other domains such as image classification and pattern recognition. High-dimensionality data in the form of narrative text reports from the NASA Aviation Safety Reporting System (ASRS) were clustered and categorized by way of dimensionality reduction. Supervised analyses were performed to create a baseline document clustering system. Dimensionality reduction techniques identified concepts or keywords within records, and allowed the creation of a framework for an unsupervised document classification system. Results from the unsupervised clustering algorithm performed similarly to the supervised methods outlined in the study. The dimensionality reduction was performed on 100 of the most commonly occurring words within 126,000 text records describing commercial aviation incidents. This study demonstrates that unsupervised machine clustering and organization of incident reports is possible based on unbiased inputs. Findings from this study reinforced traditional views on what factors contribute to civil aviation anomalies, however, new associations between previously unrelated factors and conditions were also found.

  1. Incidental Findings in the Use of DNA to Identify Human Remains: An Ethical Assessment

    Science.gov (United States)

    Parker, Lisa S.; Aronson, Jay D.

    2012-01-01

    DNA analysis is increasingly used to identify the remains of victims of conflicts and disasters. This is especially true in cases where remains are badly damaged and fragmented, or where antemortem records are unavailable. Incidental findings (IFs)—that is, genetics-related information for which investigators were not looking—may result from these identification efforts employing DNA analysis. Because of the critical role played by family members of the missing in identification efforts, as well as the familial nature of DNA, identification initiatives employing DNA analysis are particularly prone to reveal IFs about familial relationships, such as misattributed paternity or false beliefs about sibling relationships. Despite forensic scientists’ widespread awareness of the possibility of generating IFs, to date there has been relatively little explicit guidance about their management. This paper fills that gap. It offers substantive guidance about the ethical management of IFs in this context. To ensure that the analysis addresses actual needs and practices in the field, one author (JDA) conducted semi-structured interviews with key informants from six regionally diverse organizations involved in post-conflict or post-disaster identification efforts. The paper first describes how methods of DNA analysis give rise to IFs. Next, it explains the importance of developing an ethically justified general policy for managing IFs and discusses features of DNA identification efforts that are relevant to such a policy. Then it presents an argument in support of a general policy of nondisclosure—specifically, that considerations of fair access to the individual and social benefits of identification efforts, and the concern to minimize and fairly distribute the risks of participation, support a policy of nondisclosure. It concludes by considering some implications of this argument for the choice among scientific practices involved in using DNA analysis to identify human

  2. Metabolomics Identifies Multiple Candidate Biomarkers to Diagnose and Stage Human African Trypanosomiasis.

    Science.gov (United States)

    Vincent, Isabel M; Daly, Rónán; Courtioux, Bertrand; Cattanach, Amy M; Biéler, Sylvain; Ndung'u, Joseph M; Bisser, Sylvie; Barrett, Michael P

    2016-12-01

    Treatment for human African trypanosomiasis is dependent on the species of trypanosome causing the disease and the stage of the disease (stage 1 defined by parasites being present in blood and lymphatics whilst for stage 2, parasites are found beyond the blood-brain barrier in the cerebrospinal fluid (CSF)). Currently, staging relies upon detecting the very low number of parasites or elevated white blood cell numbers in CSF. Improved staging is desirable, as is the elimination of the need for lumbar puncture. Here we use metabolomics to probe samples of CSF, plasma and urine from 40 Angolan patients infected with Trypanosoma brucei gambiense, at different disease stages. Urine samples provided no robust markers indicative of infection or stage of infection due to inherent variability in urine concentrations. Biomarkers in CSF were able to distinguish patients at stage 1 or advanced stage 2 with absolute specificity. Eleven metabolites clearly distinguished the stage in most patients and two of these (neopterin and 5-hydroxytryptophan) showed 100% specificity and sensitivity between our stage 1 and advanced stage 2 samples. Neopterin is an inflammatory biomarker previously shown in CSF of stage 2 but not stage 1 patients. 5-hydroxytryptophan is an important metabolite in the serotonin synthetic pathway, the key pathway in determining somnolence, thus offering a possible link to the eponymous symptoms of "sleeping sickness". Plasma also yielded several biomarkers clearly indicative of the presence (87% sensitivity and 95% specificity) and stage of disease (92% sensitivity and 81% specificity). A logistic regression model including these metabolites showed clear separation of patients being either at stage 1 or advanced stage 2 or indeed diseased (both stages) versus control.

  3. Metabolomics Identifies Multiple Candidate Biomarkers to Diagnose and Stage Human African Trypanosomiasis.

    Directory of Open Access Journals (Sweden)

    Isabel M Vincent

    2016-12-01

    Full Text Available Treatment for human African trypanosomiasis is dependent on the species of trypanosome causing the disease and the stage of the disease (stage 1 defined by parasites being present in blood and lymphatics whilst for stage 2, parasites are found beyond the blood-brain barrier in the cerebrospinal fluid (CSF. Currently, staging relies upon detecting the very low number of parasites or elevated white blood cell numbers in CSF. Improved staging is desirable, as is the elimination of the need for lumbar puncture. Here we use metabolomics to probe samples of CSF, plasma and urine from 40 Angolan patients infected with Trypanosoma brucei gambiense, at different disease stages. Urine samples provided no robust markers indicative of infection or stage of infection due to inherent variability in urine concentrations. Biomarkers in CSF were able to distinguish patients at stage 1 or advanced stage 2 with absolute specificity. Eleven metabolites clearly distinguished the stage in most patients and two of these (neopterin and 5-hydroxytryptophan showed 100% specificity and sensitivity between our stage 1 and advanced stage 2 samples. Neopterin is an inflammatory biomarker previously shown in CSF of stage 2 but not stage 1 patients. 5-hydroxytryptophan is an important metabolite in the serotonin synthetic pathway, the key pathway in determining somnolence, thus offering a possible link to the eponymous symptoms of "sleeping sickness". Plasma also yielded several biomarkers clearly indicative of the presence (87% sensitivity and 95% specificity and stage of disease (92% sensitivity and 81% specificity. A logistic regression model including these metabolites showed clear separation of patients being either at stage 1 or advanced stage 2 or indeed diseased (both stages versus control.

  4. Resolving Anatomical and Functional Structure in Human Brain Organization: Identifying Mesoscale Organization in Weighted Network Representations

    Science.gov (United States)

    Lohse, Christian; Bassett, Danielle S.; Lim, Kelvin O.; Carlson, Jean M.

    2014-01-01

    Human brain anatomy and function display a combination of modular and hierarchical organization, suggesting the importance of both cohesive structures and variable resolutions in the facilitation of healthy cognitive processes. However, tools to simultaneously probe these features of brain architecture require further development. We propose and apply a set of methods to extract cohesive structures in network representations of brain connectivity using multi-resolution techniques. We employ a combination of soft thresholding, windowed thresholding, and resolution in community detection, that enable us to identify and isolate structures associated with different weights. One such mesoscale structure is bipartivity, which quantifies the extent to which the brain is divided into two partitions with high connectivity between partitions and low connectivity within partitions. A second, complementary mesoscale structure is modularity, which quantifies the extent to which the brain is divided into multiple communities with strong connectivity within each community and weak connectivity between communities. Our methods lead to multi-resolution curves of these network diagnostics over a range of spatial, geometric, and structural scales. For statistical comparison, we contrast our results with those obtained for several benchmark null models. Our work demonstrates that multi-resolution diagnostic curves capture complex organizational profiles in weighted graphs. We apply these methods to the identification of resolution-specific characteristics of healthy weighted graph architecture and altered connectivity profiles in psychiatric disease. PMID:25275860

  5. Identifying human diamine sensors for death related putrescine and cadaverine molecules.

    Directory of Open Access Journals (Sweden)

    Cristina Izquierdo

    2018-01-01

    Full Text Available Pungent chemical compounds originating from decaying tissue are strong drivers of animal behavior. Two of the best-characterized death smell components are putrescine (PUT and cadaverine (CAD, foul-smelling molecules produced by decarboxylation of amino acids during decomposition. These volatile polyamines act as 'necromones', triggering avoidance or attractive responses, which are fundamental for the survival of a wide range of species. The few studies that have attempted to identify the cognate receptors for these molecules have suggested the involvement of the seven-helix trace amine-associated receptors (TAARs, localized in the olfactory epithelium. However, very little is known about the precise chemosensory receptors that sense these compounds in the majority of organisms and the molecular basis of their interactions. In this work, we have used computational strategies to characterize the binding between PUT and CAD with the TAAR6 and TAAR8 human receptors. Sequence analysis, homology modeling, docking and molecular dynamics studies suggest a tandem of negatively charged aspartates in the binding pocket of these receptors which are likely to be involved in the recognition of these small biogenic diamines.

  6. Novel genetic loci underlying human intracranial volume identified through genome-wide association

    Science.gov (United States)

    Adams, Hieab HH; Hibar, Derrek P; Chouraki, Vincent; Stein, Jason L; Nyquist, Paul A; Rentería, Miguel E; Trompet, Stella; Arias-Vasquez, Alejandro; Seshadri, Sudha; Desrivières, Sylvane; Beecham, Ashley H; Jahanshad, Neda; Wittfeld, Katharina; Van der Lee, Sven J; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S; Armstrong, Nicola J; Athanasiu, Lavinia; Axelsson, Tomas; Beiser, Alexa; Bernard, Manon; Bis, Joshua C; Blanken, Laura ME; Blanton, Susan H; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brickman, Adam M; Carmichael, Owen; Chakravarty, M Mallar; Chauhan, Ganesh; Chen, Qiang; Ching, Christopher RK; Cuellar-Partida, Gabriel; Den Braber, Anouk; Doan, Nhat Trung; Ehrlich, Stefan; Filippi, Irina; Ge, Tian; Giddaluru, Sudheer; Goldman, Aaron L; Gottesman, Rebecca F; Greven, Corina U; Grimm, Oliver; Griswold, Michael E; Guadalupe, Tulio; Hass, Johanna; Haukvik, Unn K; Hilal, Saima; Hofer, Edith; Hoehn, David; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Liao, Jiemin; Liewald, David CM; Lopez, Lorna M; Luciano, Michelle; Macare, Christine; Marquand, Andre; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; Mazoyer, Bernard; McKay, David R; McWhirter, Rebekah; Milaneschi, Yuri; Mirza-Schreiber, Nazanin; Muetzel, Ryan L; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C; Olde Loohuis, Loes M; Oosterlaan, Jaap; Papmeyer, Martina; Pappa, Irene; Pirpamer, Lukas; Pudas, Sara; Pütz, Benno; Rajan, Kumar B; Ramasamy, Adaikalavan; Richards, Jennifer S; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rommelse, Nanda; Rose, Emma J; Royle, Natalie A; Rundek, Tatjana; Sämann, Philipp G; Satizabal, Claudia L; Schmaal, Lianne; Schork, Andrew J; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V; Sprooten, Emma; Strike, Lachlan T; Teumer, Alexander; Thomson, Russell; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Meer, Dennis; Van Donkelaar, Marjolein MJ; Van Eijk, Kristel R; Van Erp, Theo GM; Van Rooij, Daan; Walton, Esther; Westlye, Lars T; Whelan, Christopher D; Windham, Beverly G; Winkler, Anderson M; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Xu, Bing; Yanek, Lisa R; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P; Agartz, Ingrid; Aggarwal, Neelum T; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A; Arepalli, Sampath; Assareh, Amelia A; Barral, Sandra; Bastin, Mark E; Becker, Diane M; Becker, James T; Bennett, David A; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cahn, Wiepke; Calhoun, Vince D; Cannon, Dara M; Cavalleri, Gianpiero L; Chen, Christopher; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Dale, Anders M; Davies, Gareth E; De Geus, Eco JC; De Jager, Philip L; de Zubicaray, Greig I; Delanty, Norman; Depondt, Chantal; DeStefano, Anita L; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Espeseth, Thomas; Evans, Denis A; Fedko, Iryna O; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E; Fleischman, Debra A; Ford, Ian; Foroud, Tatiana M; Fox, Peter T; Francks, Clyde; Fukunaga, Masaki; Gibbs, J Raphael; Glahn, David C; Gollub, Randy L; Göring, Harald HH; Grabe, Hans J; Green, Robert C; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Hansell, Narelle K; Hardy, John; Hartman, Catharina A; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G; Heslenfeld, Dirk J; Ho, Beng-Choon; Hoekstra, Pieter J; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Ikram, M Kamran; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G; Jukema, J Wouter; Kahn, René S; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L; Longstreth, WT; Lopez, Oscar L; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S; McDonald, Colm; McIntosh, Andrew M; McMahon, Katie L; McMahon, Francis J; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W

    2016-01-01

    Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth. PMID:27694991

  7. Transcriptome analysis of Neisseria meningitidis in human whole blood and mutagenesis studies identify virulence factors involved in blood survival.

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    Hebert Echenique-Rivera

    2011-05-01

    Full Text Available During infection Neisseria meningitidis (Nm encounters multiple environments within the host, which makes rapid adaptation a crucial factor for meningococcal survival. Despite the importance of invasion into the bloodstream in the meningococcal disease process, little is known about how Nm adapts to permit survival and growth in blood. To address this, we performed a time-course transcriptome analysis using an ex vivo model of human whole blood infection. We observed that Nm alters the expression of ≈30% of ORFs of the genome and major dynamic changes were observed in the expression of transcriptional regulators, transport and binding proteins, energy metabolism, and surface-exposed virulence factors. In particular, we found that the gene encoding the regulator Fur, as well as all genes encoding iron uptake systems, were significantly up-regulated. Analysis of regulated genes encoding for surface-exposed proteins involved in Nm pathogenesis allowed us to better understand mechanisms used to circumvent host defenses. During blood infection, Nm activates genes encoding for the factor H binding proteins, fHbp and NspA, genes encoding for detoxifying enzymes such as SodC, Kat and AniA, as well as several less characterized surface-exposed proteins that might have a role in blood survival. Through mutagenesis studies of a subset of up-regulated genes we were able to identify new proteins important for survival in human blood and also to identify additional roles of previously known virulence factors in aiding survival in blood. Nm mutant strains lacking the genes encoding the hypothetical protein NMB1483 and the surface-exposed proteins NalP, Mip and NspA, the Fur regulator, the transferrin binding protein TbpB, and the L-lactate permease LctP were sensitive to killing by human blood. This increased knowledge of how Nm responds to adaptation in blood could also be helpful to develop diagnostic and therapeutic strategies to control the devastating

  8. Transcriptional profiling of human breast cancer cells cultured under microgravity conditions revealed the key role of genetic gravity sensors previously detected in Drosophila melanogaster

    Science.gov (United States)

    Valdivia-Silva, Julio E.; Lavan, David; Diego Orihuela-Tacuri, M.; Sanabria, Gabriela

    2016-07-01

    Currently, studies in Drosophila melanogaster has shown emerging evidence that microgravity stimuli can be detected at the genetic level. Analysis of the transcriptome in the pupal stage of the fruit flies under microgravity conditions versus ground controls has suggested the presence of a few candidate genes as "gravity sensors" which are experimentally validated. Additionally, several studies have shown that microgravity causes inhibitory effects in different types of cancer cells, although the genes involved and responsible for these effects are still unknown. Here, we demonstrate that the genes suggested as the sensors of gravitational waves in Drosophila melanogaster and their human counterpart (orthologous genes) are highly involved in carcinogenesis, proliferation, anti-apoptotic signals, invasiveness, and metastatic potential of breast cancer cell tumors. The transcriptome analyses suggested that the observed inhibitory effect in cancer cells could be due to changes in the genetic expression of these candidates. These results encourage the possibility of new therapeutic targets managed together and not in isolation.

  9. Investigating Salmonella Eko from Various Sources in Nigeria by Whole Genome Sequencing to Identify the Source of Human Infections

    DEFF Research Database (Denmark)

    Leekitcharoenphon, Pimlapas; Raufu, Ibrahim; Thorup Nielsen, Mette

    2016-01-01

    Twenty-six Salmonella enterica serovar Eko isolated from various sources in Nigeria were investigated by whole genome sequencing to identify the source of human infections. Diversity among the isolates was observed and camel and cattle were identified as the primary reservoirs and the most likely...

  10. A Humanized Mouse Identifies the Bone Marrow as a Niche with Low Therapeutic IgG Activity

    Directory of Open Access Journals (Sweden)

    Anja Lux

    2014-04-01

    Full Text Available Genetic differences between humans and in vivo model systems, including mice and nonhuman primates, make it difficult to predict the efficacy of immunoglobulin G (IgG activity in humans and understand the molecular and cellular mechanisms underlying that activity. To bridge this gap, we established a small-animal model system that allowed us to study human IgG effector functions in the context of an intact human immune system without the interference of murine Fcγ receptors expressed on mouse innate immune effector cells in vivo. Using a model of B cell depletion with different human IgG variants that recognize CD20, we show that this humanized mouse model can provide unique insights into the mechanism of human IgG activity in vivo. Importantly, these studies identify the bone marrow as a niche with low therapeutic IgG activity.

  11. Influence of previous provisional cementation on the bond strength between two definitive resin-based luting and dentin bonding agents and human dentin.

    Science.gov (United States)

    Erkut, Selim; Küçükesmen, Hakki Cenker; Eminkahyagil, Neslihan; Imirzalioglu, Pervin; Karabulut, Erdem

    2007-01-01

    This study evaluated the effect of two different types of provisional luting agents (RelyX Temp E, eugenol-based; RelyX Temp NE, eugenol-free) on the shear bond strengths between human dentin and two different resin-based luting systems (RelyXARC-Single Bond and Duo Link-One Step) after cementation with two different techniques (dual bonding and conventional technique). One hundred human molars were trimmed parallel to the original long axis, to expose flat dentin surfaces, and were divided into three groups. After related surface treatments for each specimen, the resin-based luting agent was applied in a silicone cylindrical mold (3.5 x 4 mm), placed on the bonding-agent-treated dentin surfaces and polymerized. In the control group (n = 20), the specimens were further divided into two groups (n = 10), and two different resin-based luting systems were immediately applied following the manufacturer's protocols: RelyX ARC-Single Bond (Group I C) and Duo Link-One Step (Group II C). In the provisionalization group (n = 40), the specimens were further divided into four subgroups of 10 specimens each (Group I N, I E and Group II N, II E). In Groups I N and II N, eugenol-free (RelyX NE), and in groups I E and II E, eugenol-based (RelyX E) provisional luting agents (PLA), were applied on the dentin surface. The dentin surfaces were cleaned with a flour-free pumice, and the resin-based luting systems RelyX ARC (Group I N and E) and Duo Link (Group II N and E) were applied. In the Dual bonding groups (n = 40), the specimens were divided into four subgroups of 10 specimens each (Group I ND, ED and Group II ND, ED). The specimens were treated with Single Bond (Groups I ND and ED) or One Step (Groups II ND and ED). After the dentin bonding agent treatment, RelyX Temp NE was applied to Groups I ND and II ND, and RelyX Temp E was applied to Groups I ED and II ED. The dentin surfaces were then cleaned as described in the provisionalization group, and the resin-based luting systems

  12. Conceptual aspects: analyses law, ethical, human, technical, social factors of development ICT, e-learning and intercultural development in different countries setting out the previous new theoretical model and preliminary findings

    NARCIS (Netherlands)

    Kommers, Petrus A.M.; Smyrnova-Trybulska, Eugenia; Morze, Natalia; Issa, Tomayess; Issa, Theodora

    2015-01-01

    This paper, prepared by an international team of authors focuses on the conceptual aspects: analyses law, ethical, human, technical, social factors of ICT development, e-learning and intercultural development in different countries, setting out the previous and new theoretical model and preliminary

  13. Testicular function in boys previously treated with recombinant-human growth hormone for non-growth hormone-deficient short stature.

    Science.gov (United States)

    Radicioni, A F; Paris, E; De Marco, E; Anzuini, A; Gandini, L; Lenzi, A

    2007-12-01

    Data on the effects of recombinant human GH (hGH) therapy during male puberty on future testis function are still inconclusive. The aim of this study was to investigate the long-term effects of recombinant hGH treatment on reproductive function in non-GH-deficient short stature boys. Eight boys with non-GH-deficient short stature, affected by constitutional delay of puberty or idiopathic short stature, were retrospectively studied after recombinant-hGH treatment to verify gonadal development, hormone production and semen quality. Auxological data, endocrinological/ andrological parameters and laboratory evaluation (GH, IGF-I, FSH, LH, testosterone, inhibin B) were assessed before treatment; after completion of pubertal development, the same parameters plus SHBG levels were evaluated and a seminal fluid examination was conducted (ejaculate volume, pH, sperm concentration, total sperm count, forward and total motility, morphology). All patients showed normal testicular volume at the final pubertal stage, with regular androgenization. Hormonal levels were within the normal adult range in all boys. Considering the immature reproductive system of these patients in comparison with adults, semen parameters (sperm count, motility, and morphology) were within almost normal limits, except in one patient. Although patients showed the wide fluctuation of semen values frequently observed at the end of puberty, the hypophysis-gonadal axis hormones were in the normal range in all adolescents. Pathological measurements of some seminal parameters were found in one patient only. This study suggests that recombinant hGH treatment has no detrimental effects on the development and maturation of male gonadal function in non- GH deficient short stature young patients.

  14. Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma

    Science.gov (United States)

    Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio

    2012-01-01

    The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth. PMID:22289125

  15. Detecting new microRNAs in human osteoarthritic chondrocytes identifies miR-3085 as a human, chondrocyte-selective, microRNA

    OpenAIRE

    Crowe, N.; Swingler, T.E.; Le, L.T.T.; Barter, M.J.; Wheeler, G.; Pais, H.; Donell, S.T.; Young, D.A.; Dalmay, T.; Clark, I.M.

    2016-01-01

    Summary Objective To use deep sequencing to identify novel microRNAs (miRNAs) in human osteoarthritic cartilage which have a functional role in chondrocyte phenotype or function. Design A small RNA library was prepared from human osteoarthritic primary chondrocytes using in-house adaptors and analysed by Illumina sequencing. Novel candidate miRNAs were validated by northern blot and qRT-PCR. Expression was measured in cartilage models. Targets of novel candidates were identified by microarray...

  16. A multi-sample based method for identifying common CNVs in normal human genomic structure using high-resolution aCGH data.

    Directory of Open Access Journals (Sweden)

    Chihyun Park

    Full Text Available BACKGROUND: It is difficult to identify copy number variations (CNV in normal human genomic data due to noise and non-linear relationships between different genomic regions and signal intensity. A high-resolution array comparative genomic hybridization (aCGH containing 42 million probes, which is very large compared to previous arrays, was recently published. Most existing CNV detection algorithms do not work well because of noise associated with the large amount of input data and because most of the current methods were not designed to analyze normal human samples. Normal human genome analysis often requires a joint approach across multiple samples. However, the majority of existing methods can only identify CNVs from a single sample. METHODOLOGY AND PRINCIPAL FINDINGS: We developed a multi-sample-based genomic variations detector (MGVD that uses segmentation to identify common breakpoints across multiple samples and a k-means-based clustering strategy. Unlike previous methods, MGVD simultaneously considers multiple samples with different genomic intensities and identifies CNVs and CNV zones (CNVZs; CNVZ is a more precise measure of the location of a genomic variant than the CNV region (CNVR. CONCLUSIONS AND SIGNIFICANCE: We designed a specialized algorithm to detect common CNVs from extremely high-resolution multi-sample aCGH data. MGVD showed high sensitivity and a low false discovery rate for a simulated data set, and outperformed most current methods when real, high-resolution HapMap datasets were analyzed. MGVD also had the fastest runtime compared to the other algorithms evaluated when actual, high-resolution aCGH data were analyzed. The CNVZs identified by MGVD can be used in association studies for revealing relationships between phenotypes and genomic aberrations. Our algorithm was developed with standard C++ and is available in Linux and MS Windows format in the STL library. It is freely available at: http://embio.yonsei.ac.kr/~Park/mgvd.php.

  17. A multi-sample based method for identifying common CNVs in normal human genomic structure using high-resolution aCGH data.

    Science.gov (United States)

    Park, Chihyun; Ahn, Jaegyoon; Yoon, Youngmi; Park, Sanghyun

    2011-01-01

    It is difficult to identify copy number variations (CNV) in normal human genomic data due to noise and non-linear relationships between different genomic regions and signal intensity. A high-resolution array comparative genomic hybridization (aCGH) containing 42 million probes, which is very large compared to previous arrays, was recently published. Most existing CNV detection algorithms do not work well because of noise associated with the large amount of input data and because most of the current methods were not designed to analyze normal human samples. Normal human genome analysis often requires a joint approach across multiple samples. However, the majority of existing methods can only identify CNVs from a single sample. We developed a multi-sample-based genomic variations detector (MGVD) that uses segmentation to identify common breakpoints across multiple samples and a k-means-based clustering strategy. Unlike previous methods, MGVD simultaneously considers multiple samples with different genomic intensities and identifies CNVs and CNV zones (CNVZs); CNVZ is a more precise measure of the location of a genomic variant than the CNV region (CNVR). We designed a specialized algorithm to detect common CNVs from extremely high-resolution multi-sample aCGH data. MGVD showed high sensitivity and a low false discovery rate for a simulated data set, and outperformed most current methods when real, high-resolution HapMap datasets were analyzed. MGVD also had the fastest runtime compared to the other algorithms evaluated when actual, high-resolution aCGH data were analyzed. The CNVZs identified by MGVD can be used in association studies for revealing relationships between phenotypes and genomic aberrations. Our algorithm was developed with standard C++ and is available in Linux and MS Windows format in the STL library. It is freely available at: http://embio.yonsei.ac.kr/~Park/mgvd.php.

  18. Abundant human DNA contamination identified in non-primate genome databases.

    Directory of Open Access Journals (Sweden)

    Mark S Longo

    Full Text Available During routine screens of the NCBI databases using human repetitive elements we discovered an unlikely level of nucleotide identity across a broad range of phyla. To ascertain whether databases containing DNA sequences, genome assemblies and trace archive reads were contaminated with human sequences, we performed an in depth search for sequences of human origin in non-human species. Using a primate specific SINE, AluY, we screened 2,749 non-primate public databases from NCBI, Ensembl, JGI, and UCSC and have found 492 to be contaminated with human sequence. These represent species ranging from bacteria (B. cereus to plants (Z. mays to fish (D. rerio with examples found from most phyla. The identification of such extensive contamination of human sequence across databases and sequence types warrants caution among the sequencing community in future sequencing efforts, such as human re-sequencing. We discuss issues this may raise as well as present data that gives insight as to how this may be occurring.

  19. DNA typing of ancient parasite eggs from environmental samples identifies human and animal worm infections in Viking-age settlement

    DEFF Research Database (Denmark)

    Søe, Martin Jensen; Fredensborg, Brian Lund; Nejsum, Peter

    paleoparasitological techniques such as morphological examination and molecular identification. Hard-shelled parasite eggs can be recovered from the environment even after extended periods of time and they have shown to be excellent reservoirs of ancient DNA (aDNA). aDNA analysis has enabled identifying which species...... parasite eggs from environmental samples collected at a Viking-age settlement (1018-1030 A.D.) are DNA typed to the species level. The human whipworm (Trichuris trichiura) and the human roundworm (Ascaris lumbricoides) are identified indicating that these parasites were endemic in Denmark in the Viking...

  20. Genome-wide DNA methylation study in human placenta identifies novel loci associated with maternal smoking during pregnancy.

    Science.gov (United States)

    Morales, Eva; Vilahur, Nadia; Salas, Lucas A; Motta, Valeria; Fernandez, Mariana F; Murcia, Mario; Llop, Sabrina; Tardon, Adonina; Fernandez-Tardon, Guillermo; Santa-Marina, Loreto; Gallastegui, Mara; Bollati, Valentina; Estivill, Xavier; Olea, Nicolas; Sunyer, Jordi; Bustamante, Mariona

    2016-10-01

    We conducted an epigenome-wide association study (EWAS) of DNA methylation in placenta in relation to maternal tobacco smoking during pregnancy and examined whether smoking-induced changes lead to low birthweight. DNA methylation in placenta was measured using the Illumina HumanMethylation450 BeadChip in 179 participants from the INfancia y Medio Ambiente (INMA) birth cohort. Methylation levels across 431 311 CpGs were tested for differential methylation between smokers and non-smokers in pregnancy. We took forward three top-ranking loci for further validation and replication by bisulfite pyrosequencing using data of 248 additional participants of the INMA cohort. We examined the association of methylation at smoking-associated loci with birthweight by applying a mediation analysis and a two-sample Mendelian randomization approach. Fifty CpGs were differentially methylated in placenta between smokers and non-smokers during pregnancy [false discovery rate (FDR) < 0.05]. We validated and replicated differential methylation at three top-ranking loci: cg27402634 located between LINC00086 and LEKR1, a gene previously related to birthweight in genome-wide association studies; cg20340720 (WBP1L); and cg25585967 and cg12294026 (TRIO). Dose-response relationships with maternal urine cotinine concentration during pregnancy were confirmed. Differential methylation at cg27402634 explained up to 36% of the lower birthweight in the offspring of smokers (Sobel P-value < 0.05). A two-sample Mendelian randomization analysis provided evidence that decreases in methylation levels at cg27402634 lead to decreases in birthweight. We identified novel loci differentially methylated in placenta in relation to maternal smoking during pregnancy. Adverse effects of maternal smoking on birthweight of the offspring may be mediated by alterations in the placental methylome. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International

  1. Fine-mapping the human leukocyte antigen locus in rheumatoid arthritis and other rheumatic diseases: identifying causal amino acid variants?

    Science.gov (United States)

    van Heemst, Jurgen; Huizinga, Tom J W; van der Woude, Diane; Toes, René E M

    2015-05-01

    To provide an update on and the context of the recent findings obtained with novel statistical methods on the association of the human leukocyte antigen (HLA) locus with rheumatic diseases. Novel single nucleotide polymorphism fine-mapping data obtained for the HLA locus have indicated the strongest association with amino acid positions 11 and 13 of HLA-DRB1 molecule for several rheumatic diseases. On the basis of these data, a dominant role for position 11/13 in driving the association with these diseases is proposed and the identification of causal variants in the HLA region in relation to disease susceptibility implicated. The HLA class II locus is the most important risk factor for several rheumatic diseases. Recently, new statistical approaches have identified previously unrecognized amino acid positions in the HLA-DR molecule that associate with anticitrullinated protein antibody-negative and anticitrullinated protein antibody-positive rheumatoid arthritis. Likewise, similar findings have been made for other rheumatic conditions such as giant-cell arteritis and systemic lupus erythematosus. Interestingly, all these studies point toward an association with the same amino acid positions: amino acid positions 11 and 13 of the HLA-DR β chain. As both these positions influence peptide binding by HLA-DR and have been implicated in antigen presentation, the novel fine-mapping approach is proposed to map causal variants in the HLA region relevant to rheumatoid arthritis and several rheumatic diseases. If these interpretations are correct, they would direct the biological research aiming to address the explanation for the HLA-disease association. Here, we provide an overview of the recent findings and evidence from literature that, although relevant new insights have been obtained on HLA-disease associations, the interpretation of the biological role of these amino acids as causal variants explaining that such associations should be taken with caution.

  2. Novel genetic loci underlying human intracranial volume identified through genome-wide association

    NARCIS (Netherlands)

    Adams, Hieab H H; Hibar, Derrek P; Chouraki, Vincent; Stein, Jason L; Nyquist, Paul A; Rentería, Miguel E; Trompet, Stella; Arias-Vasquez, Alejandro; Seshadri, Sudha; Desrivières, Sylvane; Beecham, Ashley H; Jahanshad, Neda; Wittfeld, Katharina; Van der Lee, Sven J; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S; Armstrong, Nicola J; Athanasiu, Lavinia; Axelsson, Tomas; Beiser, Alexa; Bernard, Manon; Bis, Joshua C; Blanken, Laura M E; Blanton, Susan H; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brickman, Adam M; Carmichael, Owen; Chakravarty, M Mallar; Chauhan, Ganesh; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; Braber, Anouk Den; Doan, Nhat Trung; Ehrlich, Stefan; Filippi, Irina; Ge, Tian; Giddaluru, Sudheer; Goldman, Aaron L; Gottesman, Rebecca F; Greven, Corina U; Grimm, Oliver; Griswold, Michael E; Guadalupe, Tulio; Hass, Johanna; Haukvik, Unn K; Hilal, Saima; Hofer, Edith; Hoehn, David; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Liao, Jiemin; Liewald, David C M; Lopez, Lorna M; Luciano, Michelle; Macare, Christine; Marquand, Andre; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; Mazoyer, Bernard; McKay, David R; McWhirter, Rebekah; Milaneschi, Yuri; Mirza-Schreiber, Nazanin; Muetzel, Ryan L; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C; Loohuis, Loes M Olde; Oosterlaan, Jaap; Papmeyer, Martina; Pappa, Irene; Pirpamer, Lukas; Pudas, Sara; Pütz, Benno; Rajan, Kumar B; Ramasamy, Adaikalavan; Richards, Jennifer S; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rommelse, Nanda; Rose, Emma J; Royle, Natalie A; Rundek, Tatjana; Sämann, Philipp G; Satizabal, Claudia L; Schmaal, Lianne; Schork, Andrew J; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V; Sprooten, Emma; Strike, Lachlan T; Teumer, Alexander; Thomson, Russell; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Meer, Dennis; Van Donkelaar, Marjolein M J; Van Eijk, Kristel R; Van Erp, Theo G M; Van Rooij, Daan; Walton, Esther; Westlye, Lars T; Whelan, Christopher D; Windham, Beverly G; Winkler, Anderson M; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Xu, Bing; Yanek, Lisa R; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P; Agartz, Ingrid; Aggarwal, Neelum T; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A; Arepalli, Sampath; Assareh, Amelia A; Barral, Sandra; Bastin, Mark E; Becker, Diane M; Becker, James T; Bennett, David A; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cahn, Wiepke; Calhoun, Vince D; Cannon, Dara M; Cavalleri, Gianpiero L; Chen, Christopher; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Dale, Anders M; Davies, Gareth E; De Geus, Eco J C; De Jager, Philip L; de Zubicaray, Greig I; Delanty, Norman; Depondt, Chantal; DeStefano, Anita L; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Espeseth, Thomas; Evans, Denis A; Fedko, Iryna O; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E; Fleischman, Debra A; Ford, Ian; Foroud, Tatiana M; Fox, Peter T; Francks, Clyde; Fukunaga, Masaki; Gibbs, J Raphael; Glahn, David C; Gollub, Randy L; Göring, Harald H H; Grabe, Hans J; Green, Robert C; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Hansell, Narelle K; Hardy, John; Hartman, Catharina A; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G; Heslenfeld, Dirk J; Ho, Beng-Choon; Hoekstra, Pieter J; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Pol, Hilleke E Hulshoff; Ikeda, Masashi; Ikram, M Kamran; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G; Jukema, J Wouter; Kahn, René S; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L; Longstreth, W T; Lopez, Oscar L; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S; McDonald, Colm; McIntosh, Andrew M; McMahon, Katie L; McMahon, Francis J; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W; Morris, Derek W; Mosley, Thomas H; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Nalls, Michael A; Nauck, Matthias; Nichols, Thomas E; Niessen, Wiro J; Nöthen, Markus M; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L; Ophoff, Roel A; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W J H; Pike, G Bruce; Potkin, Steven G; Psaty, Bruce M; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L; Romanczuk-Seiferth, Nina; Rotter, Jerome I; Ryten, Mina; Sacco, Ralph L; Sachdev, Perminder S; Saykin, Andrew J; Schmidt, Reinhold; Schofield, Peter R; Sigurdsson, Sigurdur; Simmons, Andy; Singleton, Andrew; Sisodiya, Sanjay M; Smith, Colin; Smoller, Jordan W; Soininen, Hilkka; Srikanth, Velandai; Steen, Vidar M; Stott, David J; Sussmann, Jessika E; Thalamuthu, Anbupalam; Tiemeier, Henning; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Tzourio, Christophe; Uitterlinden, Andre G; Hernández, Maria C Valdés; Van der Brug, Marcel; Van der Lugt, Aad; Van der Wee, Nic J A; Van Duijn, Cornelia M; Van Haren, Neeltje E M; Van T Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N; Veltman, Dick J; Vernooij, Meike W; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M; Wassink, Thomas H; Weale, Michael E; Weinberger, Daniel R; Weiner, Michael W; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y; Wright, Clinton B; Zielke, H Ronald; Zonderman, Alan B; Deary, Ian J; DeCarli, Charles; Schmidt, Helena; Martin, Nicholas G; De Craen, Anton J M; Wright, Margaret J; Launer, Lenore J; Schumann, Gunter; Fornage, Myriam; Franke, Barbara; Debette, Stéphanie; Medland, Sarah E; Ikram, M Arfan; Thompson, Paul M

    2016-01-01

    Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously

  3. Concordance analysis of microarray studies identifies representative gene expression changes in Parkinson's disease: a comparison of 33 human and animal studies.

    Science.gov (United States)

    Oerton, Erin; Bender, Andreas

    2017-03-23

    As the popularity of transcriptomic analysis has grown, the reported lack of concordance between different studies of the same condition has become a growing concern, raising questions as to the representativeness of different study types, such as non-human disease models or studies of surrogate tissues, to gene expression in the human condition. In a comparison of 33 microarray studies of Parkinson's disease, correlation and clustering analyses were used to determine the factors influencing concordance between studies, including agreement between different tissue types, different microarray platforms, and between neurotoxic and genetic disease models and human Parkinson's disease. Concordance over all studies is low, with correlation of only 0.05 between differential gene expression signatures on average, but increases within human patients and studies of the same tissue type, rising to 0.38 for studies of human substantia nigra. Agreement of animal models, however, is dependent on model type. Studies of brain tissue from Parkinson's disease patients (specifically the substantia nigra) form a distinct group, showing patterns of differential gene expression noticeably different from that in non-brain tissues and animal models of Parkinson's disease; while comparison with other brain diseases (Alzheimer's disease and brain cancer) suggests that the mixed study types display a general signal of neurodegenerative disease. A meta-analysis of these 33 microarray studies demonstrates the greater ability of studies in humans and highly-affected tissues to identify genes previously known to be associated with Parkinson's disease. The observed clustering and concordance results suggest the existence of a 'characteristic' signal of Parkinson's disease found in significantly affected human tissues in humans. These results help to account for the consistency (or lack thereof) so far observed in microarray studies of Parkinson's disease, and act as a guide to the selection of

  4. Single-Cell Analysis Identifies Distinct Stages of Human Endothelial-to-Hematopoietic Transition

    Directory of Open Access Journals (Sweden)

    Carolina Guibentif

    2017-04-01

    Full Text Available During development, hematopoietic cells originate from endothelium in a process known as endothelial-to-hematopoietic transition (EHT. To study human EHT, we coupled flow cytometry and single-cell transcriptional analyses of human pluripotent stem cell-derived CD34+ cells. The resulting transcriptional hierarchy showed a continuum of endothelial and hematopoietic signatures. At the interface of these two signatures, a unique group of cells displayed both an endothelial signature and high levels of key hematopoietic stem cell-associated genes. This interphase group was validated via sort and subculture as an immediate precursor to hematopoietic cells. Differential expression analyses further divided this population into subgroups, which, upon subculture, showed distinct hematopoietic lineage differentiation potentials. We therefore propose that immediate precursors to hematopoietic cells already have their hematopoietic lineage restrictions defined prior to complete downregulation of the endothelial signature. These findings increase our understanding of the processes of de novo hematopoietic cell generation in the human developmental context.

  5. Unique features of a global human ectoparasite identified through sequencing of the bed bug genome.

    Science.gov (United States)

    Benoit, Joshua B; Adelman, Zach N; Reinhardt, Klaus; Dolan, Amanda; Poelchau, Monica; Jennings, Emily C; Szuter, Elise M; Hagan, Richard W; Gujar, Hemant; Shukla, Jayendra Nath; Zhu, Fang; Mohan, M; Nelson, David R; Rosendale, Andrew J; Derst, Christian; Resnik, Valentina; Wernig, Sebastian; Menegazzi, Pamela; Wegener, Christian; Peschel, Nicolai; Hendershot, Jacob M; Blenau, Wolfgang; Predel, Reinhard; Johnston, Paul R; Ioannidis, Panagiotis; Waterhouse, Robert M; Nauen, Ralf; Schorn, Corinna; Ott, Mark-Christoph; Maiwald, Frank; Johnston, J Spencer; Gondhalekar, Ameya D; Scharf, Michael E; Peterson, Brittany F; Raje, Kapil R; Hottel, Benjamin A; Armisén, David; Crumière, Antonin Jean Johan; Refki, Peter Nagui; Santos, Maria Emilia; Sghaier, Essia; Viala, Sèverine; Khila, Abderrahman; Ahn, Seung-Joon; Childers, Christopher; Lee, Chien-Yueh; Lin, Han; Hughes, Daniel S T; Duncan, Elizabeth J; Murali, Shwetha C; Qu, Jiaxin; Dugan, Shannon; Lee, Sandra L; Chao, Hsu; Dinh, Huyen; Han, Yi; Doddapaneni, Harshavardhan; Worley, Kim C; Muzny, Donna M; Wheeler, David; Panfilio, Kristen A; Vargas Jentzsch, Iris M; Vargo, Edward L; Booth, Warren; Friedrich, Markus; Weirauch, Matthew T; Anderson, Michelle A E; Jones, Jeffery W; Mittapalli, Omprakash; Zhao, Chaoyang; Zhou, Jing-Jiang; Evans, Jay D; Attardo, Geoffrey M; Robertson, Hugh M; Zdobnov, Evgeny M; Ribeiro, Jose M C; Gibbs, Richard A; Werren, John H; Palli, Subba R; Schal, Coby; Richards, Stephen

    2016-02-02

    The bed bug, Cimex lectularius, has re-established itself as a ubiquitous human ectoparasite throughout much of the world during the past two decades. This global resurgence is likely linked to increased international travel and commerce in addition to widespread insecticide resistance. Analyses of the C. lectularius sequenced genome (650 Mb) and 14,220 predicted protein-coding genes provide a comprehensive representation of genes that are linked to traumatic insemination, a reduced chemosensory repertoire of genes related to obligate hematophagy, host-symbiont interactions, and several mechanisms of insecticide resistance. In addition, we document the presence of multiple putative lateral gene transfer events. Genome sequencing and annotation establish a solid foundation for future research on mechanisms of insecticide resistance, human-bed bug and symbiont-bed bug associations, and unique features of bed bug biology that contribute to the unprecedented success of C. lectularius as a human ectoparasite.

  6. Identifying Creative Research Accomplishments: Methodology and Results for Nanotechnology and Human Genetics

    NARCIS (Netherlands)

    Heinze, Thomas; Shapira, Philip; Senker, Jacqueline; Kuhlmann, Stefan

    2007-01-01

    Motivated by concerns about the organizational and institutional conditions that foster research creativity in science, we focus on how creative research can be defined, operationalized, and empirically identified. A functional typology of research creativity is proposed encompassing theoretical,

  7. Identifying molecular subtypes in human colon cancer using gene expression and DNA methylation microarray data

    OpenAIRE

    REN, ZHONGLU; WANG, WENHUI; LI, JINMING

    2015-01-01

    Identifying colon cancer subtypes based on molecular signatures may allow for a more rational, patient-specific approach to therapy in the future. Classifications using gene expression data have been attempted before with little concordance between the different studies carried out. In this study we aimed to uncover subtypes of colon cancer that have distinct biological characteristics and identify a set of novel biomarkers which could best reflect the clinical and/or biological characteristi...

  8. Identifying the Learning Styles and Instructional Tool Preferences of Beginning Food Science and Human Nutrition Majors

    Science.gov (United States)

    Bohn, D. M.; Rasmussen, C. N.; Schmidt, S. J.

    2004-01-01

    Learning styles vary among individuals, and understanding which instructional tools certain learning styles prefer can be utilized to enhance student learning. Students in the introductory Food Science and Human Nutrition course (FSHN 101), taught at the Univ. of Illinois at Urbana-Champaign, were asked to complete Gregorc's Learning Style…

  9. Mining Human Biomonitoring Data to Identify Prevalent Chemical Mixtures (SOT abstract)

    Science.gov (United States)

    Through food, water, air, and consumer products, humans are exposed to tens of thousands of environmental chemicals, and most of these have not been evaluated to determine their potential toxicities. In recent years, high-throughput screening (HTS) methods have been developed tha...

  10. Not only states but traits - Humans can identify permanent altruistic dispositions in 20 s

    NARCIS (Netherlands)

    Fetchenhauer, Detlef; Groothuis, Ton; Pradel, Julia

    Humans behave altruistically in one-shot interactions under total anonymity. In search of explanations for such behavior, it has been argued that at least some individuals have a general tendency to behave altruistically independent of profitability. In fact, a stable altruistic trait would be

  11. Monitoring immune modulation by nutrition in the general population: identifying and substantiating effects on human health.

    NARCIS (Netherlands)

    Albers, R.; Bourdet-Sicard, R.; Braun, D.; Calder, P.C.; Herz, U.; Lambert, C.; Lenoir-Wijnkoop, I.; Meheust, A.; Ouwehand, A.; Phothirath, P.; Sako, T.; Salminen, S.; Siemensma, A.; Loveren, van H.; Sack, U.

    2013-01-01

    Optimal functioning of the immune system is crucial to human health, and nutrition is one of the major exogenous factors modulating different aspects of immune function. Currently, no single marker is available to predict the effect of a dietary intervention on different aspects of immune function.

  12. 20170313 - Mining Human Biomonitoring Data to Identify Prevalent Chemical Mixtures (SOT abstract)

    Science.gov (United States)

    Through food, water, air, and consumer products, humans are exposed to tens of thousands of environmental chemicals, and most of these have not been evaluated to determine their potential toxicities. In recent years, high-throughput screening (HTS) methods have been developed tha...

  13. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species

    Science.gov (United States)

    Semple, Bridgette D.; Blomgren, Klas; Gimlin, Kayleen; Ferriero, Donna M.; Noble-Haeusslein, Linda J.

    2013-01-01

    Hypoxic-ischemic and traumatic brain injuries are leading causes of long-term mortality and disability in infants and children. Although several preclinical models using rodents of different ages have been developed, species differences in the timing of key brain maturation events can render comparisons of vulnerability and regenerative capacities difficult to interpret. Traditional models of developmental brain injury have utilized rodents at postnatal day 7–10 as being roughly equivalent to a term human infant, based historically on the measurement of post-mortem brain weights during the 1970s. Here we will examine fundamental brain development processes that occur in both rodents and humans, to delineate a comparable time course of postnatal brain development across species. We consider the timing of neurogenesis, synaptogenesis, gliogenesis, oligodendrocyte maturation and age-dependent behaviors that coincide with developmentally regulated molecular and biochemical changes. In general, while the time scale is considerably different, the sequence of key events in brain maturation is largely consistent between humans and rodents. Further, there are distinct parallels in regional vulnerability as well as functional consequences in response to brain injuries. With a focus on developmental hypoxicischemic encephalopathy and traumatic brain injury, this review offers guidelines for researchers when considering the most appropriate rodent age for the developmental stage or process of interest to approximate human brain development. PMID:23583307

  14. Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage

    Czech Academy of Sciences Publication Activity Database

    Amps, K.; Andrews, P.W.; Anyfantis, G.; Armstrong, L.; Avery, S.; Baharvand, H.; Baker, J.; Baker, D.; Munoz, M. N.; Beil, S.; Benvenisty, N.; Ben-Yosef, D.; Biancotti, J. C.; Bosman, A.; Brena, R. M.; Brison, D.; Caisander, G.; Camarasa, M. V.; Chen, J. M.; Chiao, E.; Choi, Y. M.; Choo, E.; Collins, D.; Colman, A.; Crook, J. M.; Daley, G. Q.; Dalton, A.; De Sousa, P. A.; Denning, C.; Downie, J.; Dvořák, P.; Hampl, Aleš

    2011-01-01

    Roč. 29, č. 12 (2011), s. 1132-1144 ISSN 1087-0156 Institutional research plan: CEZ:AV0Z50390703 Keywords : comparative genomic hybridization * copy number variation * human es cells Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 23.268, year: 2011

  15. Proteomic profiling identifies an UV-induced activation of cofilin-1 and destrin in human epidermis

    NARCIS (Netherlands)

    Hensbergen, Paul J.; Alewijnse, Astrid E.; Kempenaar, Johanna; van der Schors, Roel C.; Balog, Crinai A.; Deelder, André M.; Beumer, Gerrit; Ponec, Maria; Tensen, Cornelis P.

    2005-01-01

    The human skin is the only line of defense against UV radiation. A series of responses to protect the skin are induced by UV radiation. In this study, a proteomic approach was used to study these responses. We have performed high-resolution two-dimensional polyacrylamide gel electrophoresis

  16. Use of Moraxella catarrhalis lipooligosaccharide mutants to identify specific oligosaccharide epitopes recognized by human serum antibodies.

    Science.gov (United States)

    Schwingel, Johanna M; Edwards, Katie J; Cox, Andrew D; Masoud, Hussein; Richards, James C; St Michael, Frank; Tekwe, Carmen D; Sethi, Sanjay; Murphy, Timothy F; Campagnari, Anthony A

    2009-10-01

    Moraxella catarrhalis is a causative agent of otitis media in children and lower respiratory tract infections in adults suffering from chronic obstructive pulmonary disease (COPD). This strict human pathogen continues to be a significant cause of disease in this broad spectrum of patients because there is no available vaccine. Although numerous putative vaccine antigens have been described, little is known about the human immune response to M. catarrhalis infection in vivo. Human serum antibodies are directed at a number of surface proteins, and lipooligosaccharides (LOS) and detoxified LOS may be an effective immunogen in mice. In this study, we used a specific LOS-based enzyme-linked immunosorbent assay (ELISA), containing the three major M. catarrhalis serotypes together with a complete series of truncated LOS mutants, to detect the development of new antibodies to specific regions of the oligosaccharide molecule. We compared serum samples from COPD patients who had recently cleared an M. catarrhalis infection to serum samples collected prior to their infection. Variability in the antibody response to LOS was observed, as some patients developed serotype-specific antibodies, others developed antibodies to the LOS of each serotype, others developed broadly cross-reactive antibodies, and some did not develop new antibodies. These newly developed human antibodies are directed at both side chains and core structures in the LOS molecule. This LOS-based ELISA can be used to dissect the human antibody response to both internal and external carbohydrate epitopes, thus providing a better understanding of the humoral immune response to M. catarrhalis LOS epitopes developed during natural infection.

  17. Human skin microbiota: high diversity of DNA viruses identified on the human skin by high throughput sequencing.

    Directory of Open Access Journals (Sweden)

    Vincent Foulongne

    Full Text Available The human skin is a complex ecosystem that hosts a heterogeneous flora. Until recently, the diversity of the cutaneous microbiota was mainly investigated for bacteria through culture based assays subsequently confirmed by molecular techniques. There are now many evidences that viruses represent a significant part of the cutaneous flora as demonstrated by the asymptomatic carriage of beta and gamma-human papillomaviruses on the healthy skin. Furthermore, it has been recently suggested that some representatives of the Polyomavirus genus might share a similar feature. In the present study, the cutaneous virome of the surface of the normal-appearing skin from five healthy individuals and one patient with Merkel cell carcinoma was investigated through a high throughput metagenomic sequencing approach in an attempt to provide a thorough description of the cutaneous flora, with a particular focus on its viral component. The results emphasize the high diversity of the viral cutaneous flora with multiple polyomaviruses, papillomaviruses and circoviruses being detected on normal-appearing skin. Moreover, this approach resulted in the identification of new Papillomavirus and Circovirus genomes and confirmed a very low level of genetic diversity within human polyomavirus species. Although viruses are generally considered as pathogen agents, our findings support the existence of a complex viral flora present at the surface of healthy-appearing human skin in various individuals. The dynamics and anatomical variations of this skin virome and its variations according to pathological conditions remain to be further studied. The potential involvement of these viruses, alone or in combination, in skin proliferative disorders and oncogenesis is another crucial issue to be elucidated.

  18. Phenotypic Screening Identifies Modulators of Amyloid Precursor Protein Processing in Human Stem Cell Models of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Philip W. Brownjohn

    2017-04-01

    Full Text Available Summary: Human stem cell models have the potential to provide platforms for phenotypic screens to identify candidate treatments and cellular pathways involved in the pathogenesis of neurodegenerative disorders. Amyloid precursor protein (APP processing and the accumulation of APP-derived amyloid β (Aβ peptides are key processes in Alzheimer's disease (AD. We designed a phenotypic small-molecule screen to identify modulators of APP processing in trisomy 21/Down syndrome neurons, a complex genetic model of AD. We identified the avermectins, commonly used as anthelmintics, as compounds that increase the relative production of short Aβ peptides at the expense of longer, potentially more toxic peptides. Further studies demonstrated that this effect is not due to an interaction with the core γ-secretase responsible for Aβ production. This study demonstrates the feasibility of phenotypic drug screening in human stem cell models of Alzheimer-type dementia, and points to possibilities for indirectly modulating APP processing, independently of γ-secretase modulation. : In this article, Livesey and colleagues perform a phenotypic drug screen in a human stem cell model of Alzheimer's disease. The anthelminthic avermectins are identified as a family of compounds that increase the production of short Aβ peptides over longer more toxic Aβ forms. The effect is analogous to existing γ-secretase modulators, but is independent of the core γ-secretase complex. Keywords: neural stem cells, Alzheimer's disease, phenotypic screening, iPSCs, human neurons, dementia, Down syndrome, amyloid beta, ivermectin, selamectin

  19. Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants

    DEFF Research Database (Denmark)

    Li, Yingrui; Vinckenbosch, Nicolas; Tian, Geng

    2010-01-01

    Targeted capture combined with massively parallel exome sequencing is a promising approach to identify genetic variants implicated in human traits. We report exome sequencing of 200 individuals from Denmark with targeted capture of 18,654 coding genes and sequence coverage of each individual exome...

  20. A biotin enrichment strategy identifies novel carbonylated amino acids in proteins from human plasma

    DEFF Research Database (Denmark)

    Havelund, Jesper F; Wojdyla, Katarzyna Iwona; Davies, Michael J

    2017-01-01

    preparation and chromatography. For the first time MS/MS data analysis utilising diagnostic biotin fragment ions is used to pinpoint sites of biotin labelling and improve the confidence of carbonyl peptide assignments. We identified a total of 125 carbonylated residues in bovine serum albumin after extensive...... at the protein level and help to understand how carbonylation affects protein structure and function. The challenge for future research is to identify the type and nature of oxidised residues to gain a deeper understanding of the mechanism(s) governing carbonylation in cells and organisms and assess their role...

  1. Identifying and analyzing bacteriophages in human fecal samples: what could we discover?

    Science.gov (United States)

    Muniesa, Maite; Jofre, Juan

    2014-01-01

    The human gut is a complex ecosystem, densely populated with microbes including enormous amounts of phages. Metagenomic studies indicate a great diversity of bacteriophages, and because of the variety of gut bacterial species, the human or animal gut is probably a perfect ecological niche for phages that can infect and propagate in their bacterial communities. In addition, some phages have the capacity to mobilize genes, as demonstrated by the enormous fraction of phage particles in feces that contain bacterial DNA. All these facts indicate that, through predation and horizontal gene transfer, bacteriophages play a key role in shaping the size, structure and function of intestinal microbiomes, although our understanding of their effects on gut bacterial populations is only just beginning.

  2. Exome Sequencing Identifies Truncating Mutations in Human SERPINF1 in Autosomal-Recessive Osteogenesis Imperfecta

    OpenAIRE

    Becker, Jutta; Semler, Oliver; Gilissen, Christian; Li, Yun; Bolz, Hanno Jörn; Giunta, Cecilia; Bergmann, Carsten; Rohrbach, Marianne; Koerber, Friederike; Zimmermann, Katharina; de Vries, Petra; Wirth, Brunhilde; Schoenau, Eckhard; Wollnik, Bernd; Veltman, Joris A.

    2011-01-01

    Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps...

  3. Untargeted metabolomic analysis in naturally occurring canine diabetes mellitus identifies similarities to human Type 1 Diabetes

    OpenAIRE

    O?Kell, Allison L.; Garrett, Timothy J.; Wasserfall, Clive; Atkinson, Mark A.

    2017-01-01

    While predominant as a disease entity, knowledge voids exist regarding the pathogenesis of canine diabetes. To test the hypothesis that diabetic dogs have similar metabolomic perturbations to humans with type 1 diabetes (T1D), we analyzed serum metabolomic profiles of breed- and body weight-matched, diabetic (n?=?6) and healthy (n?=?6) dogs by liquid chromatography-mass spectrometry (LC-MS) profiling. We report distinct clustering of diabetic and control groups based on heat map analysis of k...

  4. Tracking chromatid segregation to identify human cardiac stem cells that regenerate extensively the infarcted myocardium.

    Science.gov (United States)

    Kajstura, Jan; Bai, Yingnan; Cappetta, Donato; Kim, Junghyun; Arranto, Christian; Sanada, Fumihiro; D'Amario, Domenico; Matsuda, Alex; Bardelli, Silvana; Ferreira-Martins, João; Hosoda, Toru; Leri, Annarosa; Rota, Marcello; Loscalzo, Joseph; Anversa, Piero

    2012-09-14

    According to the immortal DNA strand hypothesis, dividing stem cells selectively segregate chromosomes carrying the old template DNA, opposing accumulation of mutations resulting from nonrepaired replication errors and attenuating telomere shortening. Based on the premise of the immortal DNA strand hypothesis, we propose that stem cells retaining the old DNA would represent the most powerful cells for myocardial regeneration. Division of human cardiac stem cells (hCSCs) by nonrandom and random segregation of chromatids was documented by clonal assay of bromodeoxyuridine-tagged hCSCs. Additionally, their growth properties were determined by a series of in vitro and in vivo studies. We report that a small class of hCSCs retain during replication the mother DNA and generate 2 daughter cells, which carry the old and new DNA, respectively. hCSCs with immortal DNA form a pool of nonsenescent cells with longer telomeres and higher proliferative capacity. The self-renewal and long-term repopulating ability of these cells was shown in serial-transplantation assays in the infarcted heart; these cells created a chimeric organ, composed of spared rat and regenerated human cardiomyocytes and coronary vessels, leading to a remarkable restoration of cardiac structure and function. The documentation that hCSCs divide by asymmetrical and symmetrical chromatid segregation supports the view that the human heart is a self-renewing organ regulated by a compartment of resident hCSCs. The impressive recovery in ventricular hemodynamics and anatomy mediated by clonal hCSCs carrying the "mother" DNA underscores the clinical relevance of this stem cell class for the management of heart failure in humans.

  5. Human amniotic membrane as newly identified source of amniotic fluid pulmonary surfactant

    OpenAIRE

    Lemke, Angela; Castillo-S?nchez, Jos? Carlos; Prodinger, Florian; Ceranic, Asja; Hennerbichler-Lugscheider, Simone; P?rez-Gil, Jes?s; Redl, Heinz; Wolbank, Susanne

    2017-01-01

    Pulmonary surfactant (PS) reduces surface tension at the air-liquid interface in the alveolar epithelium of the lung, which is required for breathing and for the pulmonary maturity of the developing foetus. However, the origin of PS had never been thoroughly investigated, although it was assumed to be secreted from the foetal developing lung. Human amniotic membrane (hAM), particularly its epithelial cell layer, composes the amniotic sac enclosing the amniotic fluid. In this study, we therefo...

  6. Human sewage identified as likely source of white pox disease of the threatened Caribbean elkhorn coral, Acropora palmata.

    Science.gov (United States)

    Sutherland, Kathryn Patterson; Porter, James W; Turner, Jeffrey W; Thomas, Brian J; Looney, Erin E; Luna, Trevor P; Meyers, Meredith K; Futch, J Carrie; Lipp, Erin K

    2010-05-01

    Caribbean elkhorn coral, Acropora palmata, has been decimated in recent years, resulting in the listing of this species as threatened under the United States Endangered Species Act. A major contributing factor in the decline of this iconic species is white pox disease. In 2002, we identified the faecal enterobacterium, Serratia marcescens, as an etiological agent for white pox. During outbreaks in 2003 a unique strain of S. marcescens was identified in both human sewage and white pox lesions. This strain (PDR60) was also identified from corallivorious snails (Coralliophila abbreviata), reef water, and two non-acroporid coral species, Siderastrea siderea and Solenastrea bournoni. Identification of PDR60 in sewage, diseased Acropora palmata and other reef invertebrates within a discrete time frame suggests a causal link between white pox and sewage contamination on reefs and supports the conclusion that humans are a likely source of this disease.

  7. Apolipoprotein A5: A newly identified gene impacting plasmatriglyceride levels in humans and mice

    Energy Technology Data Exchange (ETDEWEB)

    Pennacchio, Len A.; Rubin, Edward M.

    2002-09-15

    Apolipoprotein A5 (APOA5) is a newly described member of theapolipoprotein gene family whose initial discovery arose from comparativesequence analysis of the mammalian APOA1/C3/A4 gene cluster. Functionalstudies in mice indicated that alteration in the level of APOA5significantly impacted plasma triglyceride concentrations. Miceover-expressing human APOA5 displayed significantly reducedtriglycerides, while mice lacking apoA5 had a large increase in thislipid parameter. Studies in humans have also suggested an important rolefor APOA5 in determining plasma triglyceride concentrations. In theseexperiments, polymorphisms in the human gene were found to define severalcommon haplotypes that were associated with significant changes intriglyceride concentrations in multiple populations. Several separateclinical studies have provided consistent and strong support for theeffect with 24 percent of Caucasians, 35 percent of African-Americans and53 percent of Hispanics carrying APOA5 haplotypes associated withincreased plasma triglyceride levels. In summary, APOA5 represents anewly discovered gene involved in triglyceride metabolism in both humansand mice whose mechanism of action remains to be deciphered.

  8. An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion.

    Science.gov (United States)

    Shutova, Maria V; Surdina, Anastasia V; Ischenko, Dmitry S; Naumov, Vladimir A; Bogomazova, Alexandra N; Vassina, Ekaterina M; Alekseev, Dmitry G; Lagarkova, Maria A; Kiselev, Sergey L

    2016-01-01

    The pluripotency of newly developed human induced pluripotent stem cells (iPSCs) is usually characterized by physiological parameters; i.e., by their ability to maintain the undifferentiated state and to differentiate into derivatives of the 3 germ layers. Nevertheless, a molecular comparison of physiologically normal iPSCs to the "gold standard" of pluripotency, embryonic stem cells (ESCs), often reveals a set of genes with different expression and/or methylation patterns in iPSCs and ESCs. To evaluate the contribution of the reprogramming process, parental cell type, and fortuity in the signature of human iPSCs, we developed a complete isogenic reprogramming system. We performed a genome-wide comparison of the transcriptome and the methylome of human isogenic ESCs, 3 types of ESC-derived somatic cells (fibroblasts, retinal pigment epithelium and neural cells), and 3 pairs of iPSC lines derived from these somatic cells. Our analysis revealed a high input of stochasticity in the iPSC signature that does not retain specific traces of the parental cell type and reprogramming process. We showed that 5 iPSC clones are sufficient to find with 95% confidence at least one iPSC clone indistinguishable from their hypothetical isogenic ESC line. Additionally, on the basis of a small set of genes that are characteristic of all iPSC lines and isogenic ESCs, we formulated an approach of "the best iPSC line" selection and confirmed it on an independent dataset.

  9. An Internet-Accessible DNA Sequence Database for Identifying Fusaria from Human and Animal Infections

    Science.gov (United States)

    Because less than one-third of clinically relevant fusaria can be accurately identified to species level using phenotypic data (i.e., morphological species recognition), we constructed a three-locus DNA sequence database to facilitate molecular identification of the 69 Fusarium species associated wi...

  10. Genome wide association study identifies KCNMA1 contributing to human obesity

    DEFF Research Database (Denmark)

    Jiao, Hong; Arner, Peter; Hoffstedt, Johan

    2011-01-01

    Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population...

  11. Identifying keystone species in the human gut microbiome from metagenomic timeseries using sparse linear regression.

    Science.gov (United States)

    Fisher, Charles K; Mehta, Pankaj

    2014-01-01

    Human associated microbial communities exert tremendous influence over human health and disease. With modern metagenomic sequencing methods it is now possible to follow the relative abundance of microbes in a community over time. These microbial communities exhibit rich ecological dynamics and an important goal of microbial ecology is to infer the ecological interactions between species directly from sequence data. Any algorithm for inferring ecological interactions must overcome three major obstacles: 1) a correlation between the abundances of two species does not imply that those species are interacting, 2) the sum constraint on the relative abundances obtained from metagenomic studies makes it difficult to infer the parameters in timeseries models, and 3) errors due to experimental uncertainty, or mis-assignment of sequencing reads into operational taxonomic units, bias inferences of species interactions due to a statistical problem called "errors-in-variables". Here we introduce an approach, Learning Interactions from MIcrobial Time Series (LIMITS), that overcomes these obstacles. LIMITS uses sparse linear regression with boostrap aggregation to infer a discrete-time Lotka-Volterra model for microbial dynamics. We tested LIMITS on synthetic data and showed that it could reliably infer the topology of the inter-species ecological interactions. We then used LIMITS to characterize the species interactions in the gut microbiomes of two individuals and found that the interaction networks varied significantly between individuals. Furthermore, we found that the interaction networks of the two individuals are dominated by distinct "keystone species", Bacteroides fragilis and Bacteroided stercosis, that have a disproportionate influence on the structure of the gut microbiome even though they are only found in moderate abundance. Based on our results, we hypothesize that the abundances of certain keystone species may be responsible for individuality in the human gut

  12. Structure modeling of all identified G protein-coupled receptors in the human genome.

    Directory of Open Access Journals (Sweden)

    Yang Zhang

    2006-02-01

    Full Text Available G protein-coupled receptors (GPCRs, encoded by about 5% of human genes, comprise the largest family of integral membrane proteins and act as cell surface receptors responsible for the transduction of endogenous signal into a cellular response. Although tertiary structural information is crucial for function annotation and drug design, there are few experimentally determined GPCR structures. To address this issue, we employ the recently developed threading assembly refinement (TASSER method to generate structure predictions for all 907 putative GPCRs in the human genome. Unlike traditional homology modeling approaches, TASSER modeling does not require solved homologous template structures; moreover, it often refines the structures closer to native. These features are essential for the comprehensive modeling of all human GPCRs when close homologous templates are absent. Based on a benchmarked confidence score, approximately 820 predicted models should have the correct folds. The majority of GPCR models share the characteristic seven-transmembrane helix topology, but 45 ORFs are predicted to have different structures. This is due to GPCR fragments that are predominantly from extracellular or intracellular domains as well as database annotation errors. Our preliminary validation includes the automated modeling of bovine rhodopsin, the only solved GPCR in the Protein Data Bank. With homologous templates excluded, the final model built by TASSER has a global C(alpha root-mean-squared deviation from native of 4.6 angstroms, with a root-mean-squared deviation in the transmembrane helix region of 2.1 angstroms. Models of several representative GPCRs are compared with mutagenesis and affinity labeling data, and consistent agreement is demonstrated. Structure clustering of the predicted models shows that GPCRs with similar structures tend to belong to a similar functional class even when their sequences are diverse. These results demonstrate the usefulness

  13. Identifying keystone species in the human gut microbiome from metagenomic timeseries using sparse linear regression.

    Directory of Open Access Journals (Sweden)

    Charles K Fisher

    Full Text Available Human associated microbial communities exert tremendous influence over human health and disease. With modern metagenomic sequencing methods it is now possible to follow the relative abundance of microbes in a community over time. These microbial communities exhibit rich ecological dynamics and an important goal of microbial ecology is to infer the ecological interactions between species directly from sequence data. Any algorithm for inferring ecological interactions must overcome three major obstacles: 1 a correlation between the abundances of two species does not imply that those species are interacting, 2 the sum constraint on the relative abundances obtained from metagenomic studies makes it difficult to infer the parameters in timeseries models, and 3 errors due to experimental uncertainty, or mis-assignment of sequencing reads into operational taxonomic units, bias inferences of species interactions due to a statistical problem called "errors-in-variables". Here we introduce an approach, Learning Interactions from MIcrobial Time Series (LIMITS, that overcomes these obstacles. LIMITS uses sparse linear regression with boostrap aggregation to infer a discrete-time Lotka-Volterra model for microbial dynamics. We tested LIMITS on synthetic data and showed that it could reliably infer the topology of the inter-species ecological interactions. We then used LIMITS to characterize the species interactions in the gut microbiomes of two individuals and found that the interaction networks varied significantly between individuals. Furthermore, we found that the interaction networks of the two individuals are dominated by distinct "keystone species", Bacteroides fragilis and Bacteroided stercosis, that have a disproportionate influence on the structure of the gut microbiome even though they are only found in moderate abundance. Based on our results, we hypothesize that the abundances of certain keystone species may be responsible for individuality in

  14. Identifying the public's knowledge and intention to use human cloning in Greek urban areas.

    Science.gov (United States)

    Tzamalouka, Georgia; Soultatou, Pelagia; Papadakaki, Maria; Chatzifotiou, Sevasti; Tarlatzis, Basil; El Chliaoutakis, Joannes

    2005-02-01

    The understanding of the public's knowledge on human cloning (HC) and its acceptability are considered important for the development of evidence-based policy making. The aim of this research study was to investigate the demographic and socioeconomic variables that affect the public's knowledge and intention to use HC in urban areas of Greece. Additionally, the possible association of religiousness with the knowledge and the intention to use HC were also investigated. Individual interviews were conducted with 1020 men and women of urban areas in Greece. Stratified random sampling was performed to select the respondents. Several scientists, experts in HC, evaluated the content of the instrument initially developed. The final questionnaire was consequently the result of a pilot study. Almost half of the respondents (51.5%) believed that "HC is a sort of in vitro fertilization" and 42.9% that "it has already been applied to human being." They were not aware that "the cloned fetus grows in the woman's uterus" (41.5%) and that "HC could regenerate human organs" (41.7%). The acceptability of human cloning for the cure of terminal diseases and transplantation need is very high (70.7% and 58.6%, respectively). The public's intention to have recourse to cloning on the grounds of "bringing" back to life a loved person or because of reproductive disorders was reported as desire by 35% and 32.5%, respectively. The occupational category (scientists, self-employed, and artists), the Intention to use HC, and the number of children are highly significant predictors of valid knowledge about HC. Low rates of church attendance appeared to relate with high reported Intention to use HC, and increasing scores of valid knowledge about HC increased the public's Intention to use HC. A number of specific demographic and socioeconomic characteristics and high scores of knowledge provide a persuasive justification in demonstrating intention toward HC. The current study suggests that these

  15. Identifying anti-growth factors for human cancer cell lines through genome-scale metabolic modeling

    DEFF Research Database (Denmark)

    Ghaffari, Pouyan; Mardinoglu, Adil; Asplund, Anna

    2015-01-01

    Human cancer cell lines are used as important model systems to study molecular mechanisms associated with tumor growth, hereunder how genomic and biological heterogeneity found in primary tumors affect cellular phenotypes. We reconstructed Genome scale metabolic models (GEMs) for eleven cell lines...... based on RNA-Seq data and validated the functionality of these models with data from metabolite profiling. We used cell line-specific GEMs to analyze the differences in the metabolism of cancer cell lines, and to explore the heterogeneous expression of the metabolic subsystems. Furthermore, we predicted...... for inhibition of cell growth may provide leads for the development of efficient cancer treatment strategies....

  16. High-density polymer microarrays: identifying synthetic polymers that control human embryonic stem cell growth.

    Science.gov (United States)

    Hansen, Anne; Mjoseng, Heidi K; Zhang, Rong; Kalloudis, Michail; Koutsos, Vasileios; de Sousa, Paul A; Bradley, Mark

    2014-06-01

    The fabrication of high-density polymer microarray is described, allowing the simultaneous and efficient evaluation of more than 7000 different polymers in a single-cellular-based screen. These high-density polymer arrays are applied in the search for synthetic substrates for hESCs culture. Up-scaling of the identified hit polymers enables long-term cellular cultivation and promoted successful stem-cell maintenance. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Visual genome-wide RNAi screening to identify human host factors required for Trypanosoma cruzi infection

    CSIR Research Space (South Africa)

    Genovesio, A

    2011-05-01

    Full Text Available and the parasite likely plays key roles in the outcome of the disease, suggesting genetic individuality of parasite clones [13,14]. At least 6 different subgroups of T. cruzi have recently been recognized based on genetic, molecular or immunological markers [12... using individual siRNAs in two different cell lines. Overall, our screening strategy allowed us to identify and validate 14 genes whose silencing impaired T. cruzi infection, providing clues about the molecular mechanisms that guide the infection...

  18. Identifying serotonergic mechanisms underlying the corticolimbic response to threat in humans

    DEFF Research Database (Denmark)

    Fisher, Patrick M; Hariri, Ahmad R

    2013-01-01

    A corticolimbic circuit including the amygdala and medial prefrontal cortex (mPFC) plays an important role in regulating sensitivity to threat, which is heightened in mood and anxiety disorders. Serotonin is a potent neuromodulator of this circuit; however, specific serotonergic mechanisms....... Integrating these methodological approaches offers novel opportunities to identify mechanisms through which serotonin signalling contributes to differences in brain function and behaviour, which in turn can illuminate factors that confer risk for illness and inform the development of more effective treatment...

  19. Novel asymmetrically localizing components of human centrosomes identified by complementary proteomics methods

    DEFF Research Database (Denmark)

    Jakobsen, Lis; Vanselow, Katja; Skogs, Marie

    2011-01-01

    Centrosomes in animal cells are dynamic organelles with a proteinaceous matrix of pericentriolar material assembled around a pair of centrioles. They organize the microtubule cytoskeleton and the mitotic spindle apparatus. Mature centrioles are essential for biogenesis of primary cilia that mediate...... by identifying a novel set of five proteins preferentially associated with mother or daughter centrioles, comprising genes implicated in cell polarity. Pulsed labelling demonstrates a remarkable variation in the stability of centrosomal protein complexes. These spatiotemporal proteomics data provide leads...

  20. Identifying recombinants in human and primate immunodeficiency virus sequence alignments using quartet scanning

    Directory of Open Access Journals (Sweden)

    Martin Darren P

    2009-04-01

    Full Text Available Abstract Background Recombination has a profound impact on the evolution of viruses, but characterizing recombination patterns in molecular sequences remains a challenging endeavor. Despite its importance in molecular evolutionary studies, identifying the sequences that exhibit such patterns has received comparatively less attention in the recombination detection framework. Here, we extend a quartet-mapping based recombination detection method to enable identification of recombinant sequences without prior specifications of either query and reference sequences. Through simulations we evaluate different recombinant identification statistics and significance tests. We compare the quartet approach with triplet-based methods that employ additional heuristic tests to identify parental and recombinant sequences. Results Analysis of phylogenetic simulations reveal that identifying the descendents of relatively old recombination events is a challenging task for all methods available, and that quartet scanning performs relatively well compared to the triplet based methods. The use of quartet scanning is further demonstrated by analyzing both well-established and putative HIV-1 recombinant strains. In agreement with recent findings, we provide evidence that the presumed circulating recombinant CRF02_AG is a 'pure' lineage, whereas the presumed parental lineage subtype G has a recombinant origin. We also demonstrate HIV-1 intrasubtype recombination, confirm the hybrid origin of SIV in chimpanzees and further disentangle the recombinant history of SIV lineages in a primate immunodeficiency virus data set. Conclusion Quartet scanning makes a valuable addition to triplet-based methods for identifying recombinant sequences without prior specifications of either query and reference sequences. The new method is available in the VisRD v.3.0 package http://www.cmp.uea.ac.uk/~vlm/visrd.

  1. A review of current approaches to identifying human genes involved in myopia.

    Science.gov (United States)

    Tang, Wing Chun; Yap, Maurice K H; Yip, Shea Ping

    2008-01-01

    The prevalence of myopia is high in many parts of the world, particularly among the Orientals such as Chinese and Japanese. Like other complex diseases such as diabetes and hypertension, myopia is likely to be caused by both genetic and environmental factors, and possibly their interactions. Owing to multiple genes with small effects, genetic heterogeneity and phenotypic complexity, the study of the genetics of myopia poses a complex challenge. This paper reviews the current approaches to the genetic analysis of complex diseases and how these can be applied to the identification of genes that predispose humans to myopia. These approaches include parametric linkage analysis, non-parametric linkage analysis like allele-sharing methods and genetic association studies. Basic concepts, advantages and disadvantages of these approaches are discussed and explained using examples from the literature on myopia. Microsatellites and single nucleotide polymorphisms are common genetic markers in the human genome and are indispensable tools for gene mapping. High throughput genotyping of millions of such markers has become feasible and efficient with recent technological advances. In turn, this makes the identification of myopia susceptibility genes a reality.

  2. Comparative analysis of human reproductive proteomes identifies candidate proteins of sperm maturation.

    Science.gov (United States)

    Fu-Jun, Liu; Xiao-Fang, Shen

    2012-12-01

    Male reproductive proteomes provide basis for studying gene products and its involvement or regulation in sperm physiology. Here, a comparative study between these proteomes was performed to find potential proteins and functions associated with human sperm maturation. Seven reproductive proteomes associated with human sperm physiology were integrated. Gene ontology analysis were performed using DAVID and Panther tools to determine enriched functions. Total of 270 proteins overlapped between epididymal, prostatic milieu and sperm proteome were thought to be candidate proteins involved in sperm maturation, and they showed enriched functions of proteasomal protein catabolic process and protein folding. 34 epididymal milieu proteins and 274 prostatic milieu proteins were contributed to the composition of seminal fluids proteome. Literatures have confirmed the involvements in sperm maturation of many of these proteins The spatial expressions of 24 epididymal milieu proteins involved in chaperone and antioxidant activity were authenticated by real-time RT-PCR. These proteins may serve as candidate molecules for future studies of sperm maturation and male infertility.

  3. A Western diet ecological module identified from the 'humanized' mouse microbiota predicts diet in adults and formula feeding in children.

    Science.gov (United States)

    Siddharth, Jay; Holway, Nicholas; Parkinson, Scott J

    2013-01-01

    The interplay between diet and the microbiota has been implicated in the growing frequency of chronic diseases associated with the Western lifestyle. However, the complexity and variability of microbial ecology in humans and preclinical models has hampered identification of the molecular mechanisms underlying the association of the microbiota in this context. We sought to address two key questions. Can the microbial ecology of preclinical models predict human populations? And can we identify underlying principles that surpass the plasticity of microbial ecology in humans? To do this, we focused our study on diet; perhaps the most influential factor determining the composition of the gut microbiota. Beginning with a study in 'humanized' mice we identified an interactive module of 9 genera allied with Western diet intake. This module was applied to a controlled dietary study in humans. The abundance of the Western ecological module correctly predicted the dietary intake of 19/21 top and 21/21 of the bottom quartile samples inclusive of all 5 Western and 'low-fat' diet subjects, respectively. In 98 volunteers the abundance of the Western module correlated appropriately with dietary intake of saturated fatty acids, fat-soluble vitamins and fiber. Furthermore, it correlated with the geographical location and dietary habits of healthy adults from the Western, developing and third world. The module was also coupled to dietary intake in children (and piglets) correlating with formula (vs breast) feeding and associated with a precipitous development of the ecological module in young children. Our study provides a conceptual platform to translate microbial ecology from preclinical models to humans and identifies an ecological network module underlying the association of the gut microbiota with Western dietary habits.

  4. Molecular detection identified a type six secretion system in Campylobacter jejuni from various sources but not from human cases.

    Science.gov (United States)

    Siddiqui, F; Champion, O; Akram, M; Studholme, D; Eqani, S A M A S; Wren, B W; Titball, R; Bokhari, H

    2015-05-01

    To determine the presence of the T6SS in Campylobacter jejuni from diverse sources. The recently identified type VI secretion system (T6SS) is a bacterial injection machinery that plays a role in virulence, symbiosis, bacterial interactions and environmental stress responses. This system has been recently discovered in the major enteric pathogen Camp. jejuni. In this study, we used multiplex PCR (mPCR), based on conserved genetic markers of the T6SS, to screen 366 Pakistani Camp. jejuni isolates from humans, poultry, cattle, wildlife or waste-water sources. We identified the T6SS in isolates from all of these sources except humans. The overall prevalence of the T6SS among the isolates was 17/366 (4·6%) and the T6SS positive isolates clustered into four different groups. Transcription of the T6SS genes, determined using RT-PCR, was observed in bacteria cultured at 37 or 42°C but not in 37°C cultures adjusted to pH3. Campylobacter jejuni isolates harbouring T6SS markers genes were identified in livestock and non-livestock sources but in this study we did not identify human diarrhoeal isolates which possessed the T6SS. We demonstrated down-regulation of T6SS in an acidic environment. This study questions the role of the T6SS in human diarrhoeal disease. Moreover this study did not identify a clear association of Camp. jejuni isolates harbouring T6SS with any of the niches tested. Our study highlights the need to establish the role of the T6SS in environmental survival or virulence. © 2015 The Society for Applied Microbiology.

  5. Deep Coverage Proteomics Identifies More Low-Abundance Missing Proteins in Human Testis Tissue with Q-Exactive HF Mass Spectrometer.

    Science.gov (United States)

    Wei, Wei; Luo, Weijia; Wu, Feilin; Peng, Xuehui; Zhang, Yao; Zhang, Manli; Zhao, Yan; Su, Na; Qi, YingZi; Chen, Lingsheng; Zhang, Yangjun; Wen, Bo; He, Fuchu; Xu, Ping

    2016-11-04

    Since 2012, missing proteins (MPs) investigation has been one of the critical missions of Chromosome-Centric Human Proteome Project (C-HPP) through various biochemical strategies. On the basis of our previous testis MPs study, faster scanning and higher resolution mass-spectrometry-based proteomics might be conducive to MPs exploration, especially for low-abundance proteins. In this study, Q-Exactive HF (HF) was used to survey proteins from the same testis tissues separated by two separating methods (tricine- and glycine-SDS-PAGE), as previously described. A total of 8526 proteins were identified, of which more low-abundance proteins were uniquely detected in HF data but not in our previous LTQ Orbitrap Velos (Velos) reanalysis data. Further transcriptomics analysis showed that these uniquely identified proteins by HF also had lower expression at the mRNA level. Of the 81 total identified MPs, 74 and 39 proteins were listed as MPs in HF and Velos data sets, respectively. Among the above MPs, 47 proteins (43 neXtProt PE2 and 4 PE3) were ranked as confirmed MPs after verifying with the stringent spectra match and isobaric and single amino acid variants filtering. Functional investigation of these 47 MPs revealed that 11 MPs were testis-specific proteins and 7 MPs were involved in spermatogenesis process. Therefore, we concluded that higher scanning speed and resolution of HF might be factors for improving the low-abundance MP identification in future C-HPP studies. All mass-spectrometry data from this study have been deposited in the ProteomeXchange with identifier PXD004092.

  6. Identifying cytotoxic T cell epitopes from genomic and proteomic information: "The human MHC project."

    DEFF Research Database (Denmark)

    Lauemøller, S L; Kesmir, C; Corbet, S L

    2000-01-01

    discrimination, even at the peptide level. It is not surprising that peptides are key targets of the immune system. It follows that proteomes can be translated into immunogens once it is known how the immune system generates and handles peptides. Recent advances have identified many of the basic principles...... processing, as these become available. The ability to translate the accumulating primary sequence databases in terms of immune recognition should enable scientists and clinicians to analyze any protein of interest for the presence of potentially immunogenic epitopes. The computational tools to scan entire...

  7. Secondary uses and the governance of de-identified data: Lessons from the human genome diversity panel

    Directory of Open Access Journals (Sweden)

    Lee Sandra S-J

    2011-09-01

    Full Text Available Abstract Background Recent changes to regulatory guidance in the US and Europe have complicated oversight of secondary research by rendering most uses of de-identified data exempt from human subjects oversight. To identify the implications of such guidelines for harms to participants and communities, this paper explores the secondary uses of one de-identified DNA sample collection with limited oversight: the Human Genome Diversity Project (HGDP-Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset (CEPH Human Genome Diversity Panel. Methods Using a combination of keyword and cited reference search, we identified English-language scientific articles published between 2002 and 2009 that reported analysis of HGDP Diversity Panel samples and/or data. We then reviewed each article to identify the specific research use to which the samples and/or data was applied. Secondary uses were categorized according to the type and kind of research supported by the collection. Results A wide variety of secondary uses were identified from 148 peer-reviewed articles. While the vast majority of these uses were consistent with the original intent of the collection, a minority of published reports described research whose primary findings could be regarded as controversial, objectionable, or potentially stigmatizing in their interpretation. Conclusions We conclude that potential risks to participants and communities cannot be wholly eliminated by anonymization of individual data and suggest that explicit review of proposed secondary uses, by a Data Access Committee or similar internal oversight body with suitable stakeholder representation, should be a required component of the trustworthy governance of any repository of data or specimens.

  8. Preservation Analysis of Macrophage Gene Coexpression Between Human and Mouse Identifies PARK2 as a Genetically Controlled Master Regulator of Oxidative Phosphorylation in Humans

    Directory of Open Access Journals (Sweden)

    Veronica Codoni

    2016-10-01

    Full Text Available Macrophages are key players involved in numerous pathophysiological pathways and an in-depth characterization of their gene regulatory networks can help in better understanding how their dysfunction may impact on human diseases. We here conducted a cross-species network analysis of macrophage gene expression data between human and mouse to identify conserved networks across both species, and assessed whether such networks could reveal new disease-associated regulatory mechanisms. From a sample of 684 individuals processed for genome-wide macrophage gene expression profiling, we identified 27 groups of coexpressed genes (modules. Six modules were found preserved (P < 10−4 in macrophages from 86 mice of the Hybrid Mouse Diversity Panel. One of these modules was significantly [false discovery rate (FDR = 8.9 × 10−11] enriched for genes belonging to the oxidative phosphorylation (OXPHOS pathway. This pathway was also found significantly (FDR < 10−4 enriched in susceptibility genes for Alzheimer, Parkinson, and Huntington diseases. We further conducted an expression quantitative trait loci analysis to identify SNP that could regulate macrophage OXPHOS gene expression in humans. This analysis identified the PARK2 rs192804963 as a trans-acting variant influencing (minimal P-value = 4.3 × 10−8 the expression of most OXPHOS genes in humans. Further experimental work demonstrated that PARK2 knockdown expression was associated with increased OXPHOS gene expression in THP1 human macrophages. This work provided strong new evidence that PARK2 participates to the regulatory networks associated with oxidative phosphorylation and suggested that PARK2 genetic variations could act as a trans regulator of OXPHOS gene macrophage expression in humans.

  9. High Aldehyde Dehydrogenase Activity Identifies a Subset of Human Mesenchymal Stromal Cells with Vascular Regenerative Potential.

    Science.gov (United States)

    Sherman, Stephen E; Kuljanin, Miljan; Cooper, Tyler T; Putman, David M; Lajoie, Gilles A; Hess, David A

    2017-06-01

    During culture expansion, multipotent mesenchymal stromal cells (MSCs) differentially express aldehyde dehydrogenase (ALDH), an intracellular detoxification enzyme that protects long-lived cells against oxidative stress. Thus, MSC selection based on ALDH-activity may be used to reduce heterogeneity and distinguish MSC subsets with improved regenerative potency. After expansion of human bone marrow-derived MSCs, cell progeny was purified based on low versus high ALDH-activity (ALDH hi ) by fluorescence-activated cell sorting, and each subset was compared for multipotent stromal and provascular regenerative functions. Both ALDH l ° and ALDH hi MSC subsets demonstrated similar expression of stromal cell (>95% CD73 + , CD90 + , CD105 + ) and pericyte (>95% CD146 + ) surface markers and showed multipotent differentiation into bone, cartilage, and adipose cells in vitro. Conditioned media (CDM) generated by ALDH hi MSCs demonstrated a potent proliferative and prosurvival effect on human microvascular endothelial cells (HMVECs) under serum-free conditions and augmented HMVEC tube-forming capacity in growth factor-reduced matrices. After subcutaneous transplantation within directed in vivo angiogenesis assay implants into immunodeficient mice, ALDH hi MSC or CDM produced by ALDH hi MSC significantly augmented murine vascular cell recruitment and perfused vessel infiltration compared with ALDH l ° MSC. Although both subsets demonstrated strikingly similar mRNA expression patterns, quantitative proteomic analyses performed on subset-specific CDM revealed the ALDH hi MSC subset uniquely secreted multiple proangiogenic cytokines (vascular endothelial growth factor beta, platelet derived growth factor alpha, and angiogenin) and actively produced multiple factors with chemoattractant (transforming growth factor-β, C-X-C motif chemokine ligand 1, 2, and 3 (GRO), C-C motif chemokine ligand 5 (RANTES), monocyte chemotactic protein 1 (MCP-1), interleukin [IL]-6, IL-8) and matrix

  10. Chemicals identified in human biological media: a data base. Third annual report, October 1981

    Energy Technology Data Exchange (ETDEWEB)

    Cone, M.V.; Baldauf, M.F.; Martin, F.M. (comps.)

    1981-12-01

    Data from almost 1600 of the 3800 body-burden documents collected to date have been entered in the data base as of October 1981. The emphasis on including recent literature and significant research documents has resulted in a chronological mix of articles from 1974 to the present. When body-burden articles are identified, data are extracted and entered in the data base by chemical and tissue/body fluid. Each data entry comprises a single record (or line entry) and is assigned a record number. If a particular document deals with more than one chemical and/or tissue, there will be multiple records for that document. For example, a study of 5 chemicals in each of 3 tissues has 15 different records (or 15 line entries) in the data base with 15 record numbers. Record numbers are assigned consecutively throughout the entire data base and appear in the upper left corner of the first column for each record.

  11. Identifying cytotoxic T cell epitopes from genomic and proteomic information: "The human MHC project."

    DEFF Research Database (Denmark)

    Lauemøller, S L; Kesmir, C; Corbet, S L

    2000-01-01

    Complete genomes of many species including pathogenic microorganisms are rapidly becoming available and with them the encoded proteins, or proteomes. Proteomes are extremely diverse and constitute unique imprints of the originating organisms allowing positive identification and accurate discrimin......Complete genomes of many species including pathogenic microorganisms are rapidly becoming available and with them the encoded proteins, or proteomes. Proteomes are extremely diverse and constitute unique imprints of the originating organisms allowing positive identification and accurate...... discrimination, even at the peptide level. It is not surprising that peptides are key targets of the immune system. It follows that proteomes can be translated into immunogens once it is known how the immune system generates and handles peptides. Recent advances have identified many of the basic principles...

  12. Combination of Classifiers Identifies Fungal-Specific Activation of Lysosome Genes in Human Monocytes

    Directory of Open Access Journals (Sweden)

    João P. Leonor Fernandes Saraiva

    2017-11-01

    Full Text Available Blood stream infections can be caused by several pathogens such as viruses, fungi and bacteria and can cause severe clinical complications including sepsis. Delivery of appropriate and quick treatment is mandatory. However, it requires a rapid identification of the invading pathogen. The current gold standard for pathogen identification relies on blood cultures and these methods require a long time to gain the needed diagnosis. The use of in situ experiments attempts to identify pathogen specific immune responses but these often lead to heterogeneous biomarkers due to the high variability in methods and materials used. Using gene expression profiles for machine learning is a developing approach to discriminate between types of infection, but also shows a high degree of inconsistency. To produce consistent gene signatures, capable of discriminating fungal from bacterial infection, we have employed Support Vector Machines (SVMs based on Mixed Integer Linear Programming (MILP. Combining classifiers by joint optimization constraining them to the same set of discriminating features increased the consistency of our biomarker list independently of leukocyte-type or experimental setup. Our gene signature showed an enrichment of genes of the lysosome pathway which was not uncovered by the use of independent classifiers. Moreover, our results suggest that the lysosome genes are specifically induced in monocytes. Real time qPCR of the identified lysosome-related genes confirmed the distinct gene expression increase in monocytes during fungal infections. Concluding, our combined classifier approach presented increased consistency and was able to “unmask” signaling pathways of less-present immune cells in the used datasets.

  13. DNA typing of ancient parasite eggs from environmental samples identifies human and animal worm infections in Viking-age settlement

    DEFF Research Database (Denmark)

    Søe, Martin Jensen; Fredensborg, Brian Lund; Nejsum, Peter

    Human worm infections have, to a large extent, been eradicated in countries with high sanitary standards by preventing the fecal-oral transmission of infective eggs. It is possible to study parasite infections among past populations by retrieving and analyzing parasite eggs using paleoparasitolog......-age. Further, eggs of the Liver Fluke (Fasciola hepatica), whose primary hosts are cows and sheep, are identified indicating that grazing animals were kept in close proximity of the settlement....

  14. A functional screen identifies specific microRNAs capable of inhibiting human melanoma cell viability.

    Directory of Open Access Journals (Sweden)

    Jos B Poell

    Full Text Available Malignant melanoma is an aggressive form of skin cancer with poor prognosis. Despite improvements in awareness and prevention of this disease, its incidence is rapidly increasing. MicroRNAs (miRNAs are a class of small RNA molecules that regulate cellular processes by repressing messenger RNAs (mRNAs with partially complementary target sites. Several miRNAs have already been shown to attenuate cancer phenotypes, by limiting proliferation, invasiveness, tumor angiogenesis, and stemness. Here, we employed a genome-scale lentiviral human miRNA expression library to systematically survey which miRNAs are able to decrease A375 melanoma cell viability. We highlight the strongest inhibitors of melanoma cell proliferation, including the miR-15/16, miR-141/200a and miR-96/182 families of miRNAs and miR-203. Ectopic expression of these miRNAs resulted in long-term inhibition of melanoma cell expansion, both in vitro and in vivo. We show specifically miR-16, miR-497, miR-96 and miR-182 are efficient effectors when introduced as synthetic miRNAs in several melanoma cell lines. Our study provides a comprehensive interrogation of miRNAs that interfere with melanoma cell proliferation and viability, and offers a selection of miRNAs that are especially promising candidates for application in melanoma therapy.

  15. Random small interfering RNA library screen identifies siRNAs that induce human erythroleukemia cell differentiation.

    Science.gov (United States)

    Fan, Cuiqing; Xiong, Yuan; Zhu, Ning; Lu, Yabin; Zhang, Jiewen; Wang, Song; Liang, Zicai; Shen, Yan; Chen, Meihong

    2011-03-01

    Cancers are characterized by poor differentiation. Differentiation therapy is a strategy to alleviate malignant phenotypes by inducing cancer cell differentiation. Here we carried out a combinatorial high-throughput screen with a random siRNA library on human erythroleukemia K-562 cell differentiation. Two siRNAs screened from the library were validated to be able to induce erythroid differentiation to varying degrees, determined by CD235 and globin up-regulation, GATA-2 down-regulation, and cell growth inhibition. The screen we performed here is the first trial of screening cancer differentiation-inducing agents from a random siRNA library, demonstrating that a random siRNA library can be considered as a new resource in efforts to seek new therapeutic agents for cancers. As a random siRNA library has a broad coverage for the entire genome, including known/unknown genes and protein coding/non-coding sequences, screening using a random siRNA library can be expected to greatly augment the repertoire of therapeutic siRNAs for cancers.

  16. Transcriptome sequencing of a large human family identifies the impact of rare noncoding variants.

    Science.gov (United States)

    Li, Xin; Battle, Alexis; Karczewski, Konrad J; Zappala, Zach; Knowles, David A; Smith, Kevin S; Kukurba, Kim R; Wu, Eric; Simon, Noah; Montgomery, Stephen B

    2014-09-04

    Recent and rapid human population growth has led to an excess of rare genetic variants that are expected to contribute to an individual's genetic burden of disease risk. To date, much of the focus has been on rare protein-coding variants, for which potential impact can be estimated from the genetic code, but determining the impact of rare noncoding variants has been more challenging. To improve our understanding of such variants, we combined high-quality genome sequencing and RNA sequencing data from a 17-individual, three-generation family to contrast expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs) within this family to eQTLs and sQTLs within a population sample. Using this design, we found that eQTLs and sQTLs with large effects in the family were enriched with rare regulatory and splicing variants (minor allele frequency impact of rare noncoding variants. We found that distance to the transcription start site, evolutionary constraint, and epigenetic annotation were considerably more informative for predicting the impact of rare variants than for predicting the impact of common variants. These results highlight that rare noncoding variants are important contributors to individual gene-expression profiles and further demonstrate a significant capability for genomic annotation to predict the impact of rare noncoding variants. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Role of educational institutions in identifying and responding to emerging health human resources needs.

    Science.gov (United States)

    Tzountzouris, John-Paul; Gilbert, John H V

    2009-01-01

    The healthcare system continues to evolve, requiring innovation to promote patient-centred, fiscally responsible healthcare delivery. This evolution includes changes to the skills and competencies required of the health human resources (HHR), both regulated and unregulated, who are central supports to healthcare delivery. This has become a priority agenda item at the international, national, provincial, regional and local levels. This paper describes the system factors that drive the emergence of HHR skill and competency needs, and explores the roles of various institutions in the identification of and response to HHR needs. Educational institutions play an important role in responding to emerging HHR needs. Their actual response to HHR skill and competency needs will ultimately depend on the risk posed to the organizations of either addressing, or not addressing, these needs. These decisions are complex and are balanced against strategic, operational and educational risks, benefits and realities within each given educational institution. Educational institutions - through their linkages with the workplace, industry, professional organizations and government - have a unique view and understanding of many facets of the complexity of HHR planning. This paper proposes that educational institutions play a pivotal role as levers in a more coordinated response to emerging HHR needs and, as such, should be intimately involved in comprehensive HHR planning.

  18. The Post-Apoptotic Fate of RNAs Identified Through High-Throughput Sequencing of Human Hair

    Science.gov (United States)

    Lefkowitz, Gloria K.; Mukhopadhyay, Anandaroop; Cowing-Zitron, Christopher; Yu, Benjamin D.

    2011-01-01

    The hair of all mammals consists of terminally differentiated cells that undergo a specialized form of apoptosis called cornification. While DNA is destroyed during cornification, the extent to which RNA is lost is unknown. Here we find that multiple types of RNA are incompletely degraded after hair shaft formation in both mouse and human. Notably, mRNAs and short regulatory microRNAs (miRNAs) are stable in the hair as far as 10 cm from the scalp. To better characterize the post-apoptotic RNAs that escape degradation in the hair, we performed sequencing (RNA-seq) on RNA isolated from hair shafts pooled from several individuals. This hair shaft RNA library, which encompasses different hair types, genders, and populations, revealed 7,193 mRNAs, 449 miRNAs and thousands of unannotated transcripts that remain in the post-apoptotic hair. A comparison of the hair shaft RNA library to that of viable keratinocytes revealed surprisingly similar patterns of gene coverage and indicates that degradation of RNA is highly inefficient during apoptosis of hair lineages. The generation of a hair shaft RNA library could be used as months of accumulated transcriptional history useful for retrospective detection of disease, drug response and environmental exposure. PMID:22110684

  19. DNA typing of ancient parasite eggs from environmental samples identifies human and animal worm infections in viking-age settlement

    DEFF Research Database (Denmark)

    Søe, Martin Jensen; Nejsum, Peter; Fredensborg, Brian Lund

    2015-01-01

    selecting genetic markers, PCR amplification and sequencing of ancient DNA (aDNA) isolates resulted in identification of: the human whipworm, Trichuris trichiura, using SSUrRNA sequence homology; Ascaris sp. with 100% homology to cox1 haplotype 07; and Fasciola hepatica using ITS1 sequence homology......Ancient parasite eggs were recovered from environmental samples collected at a Viking-age settlement in Viborg, Denmark, dated 1018-1030 A.D. Morphological examination identified Ascaris sp., Trichuris sp., and Fasciola sp. eggs, but size and shape did not allow species identification. By carefully....... The identification of T. trichiura eggs indicates that human fecal material is present and, hence, that the Ascaris sp. haplotype 07 was most likely a human variant in Viking-age Denmark. The location of the F. hepatica finding suggests that sheep or cattle are the most likely hosts. Further, we sequenced...

  20. Genome scan identifies a locus affecting gamma-globin expression in human beta-cluster YAC transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Lin, S.D.; Cooper, P.; Fung, J.; Weier, H.U.G.; Rubin, E.M.

    2000-03-01

    Genetic factors affecting post-natal g-globin expression - a major modifier of the severity of both b-thalassemia and sickle cell anemia, have been difficult to study. This is especially so in mice, an organism lacking a globin gene with an expression pattern equivalent to that of human g-globin. To model the human b-cluster in mice, with the goal of screening for loci affecting human g-globin expression in vivo, we introduced a human b-globin cluster YAC transgene into the genome of FVB mice . The b-cluster contained a Greek hereditary persistence of fetal hemoglobin (HPFH) g allele resulting in postnatal expression of human g-globin in transgenic mice. The level of human g-globin for various F1 hybrids derived from crosses between the FVB transgenics and other inbred mouse strains was assessed. The g-globin level of the C3HeB/FVB transgenic mice was noted to be significantly elevated. To map genes affecting postnatal g-globin expression, a 20 centiMorgan (cM) genome scan of a C3HeB/F VB transgenics [prime] FVB backcross was performed, followed by high-resolution marker analysis of promising loci. From this analysis we mapped a locus within a 2.2 cM interval of mouse chromosome 1 at a LOD score of 4.2 that contributes 10.4% of variation in g-globin expression level. Combining transgenic modeling of the human b-globin gene cluster with quantitative trait analysis, we have identified and mapped a murine locus that impacts on human g-globin expression in vivo.

  1. Genome scan identifies a locus affecting gamma-globin level in human beta-cluster YAC transgenic mice.

    Science.gov (United States)

    Lin, S D; Cooper, P; Fung, J; Weier, H U; Rubin, E M

    2000-11-01

    Genetic factors affecting postnatal gamma-globin expression--a major modifier of the severity of both beta-thalassemia and sickle cell anemia--have been difficult to study. This is especially so in mice, an organism lacking a globin gene with an expression pattern equivalent to that of human gamma-globin. To model the human beta-cluster in mice, with the goal of screening for loci affecting human gamma-globin expression in vivo, we introduced a human beta-globin cluster YAC transgene into the genome of FVB/N mice. The beta-cluster contained a Greek hereditary persistence of fetal hemoglobin (HPFH) gamma allele, resulting in postnatal expression of human gamma-globin in transgenic mice. The level of human gamma-globin for various F1 hybrids derived from crosses between the FVB/N transgenics and other inbred mouse strains was assessed. The gamma-globin level of the (C3HeB/FeJ x FVB/N)F1 transgenic mice was noted to be significantly elevated. To map genes affecting postnatal y-globin expression, we performed a 20-centiMorgan (cM) genome scan of a (C3HeB/FeJ x FVB/N)F1 transgenics x FVB/N backcross, followed by high-resolution marker analysis of promising loci. From this analysis we mapped a locus within an 18-cM interval of mouse Chromosome (Chr) 1 (LOD = 4.3) that contributes 10.9% of variation in gamma-globin level. Combining transgenic modeling of the human beta-globin gene cluster with quantitative trait analysis, we have identified and mapped a murine locus that impacts on human gamma-globin level in vivo.

  2. The transcriptional profiling of human in vivo-generated plasma cells identifies selective imbalances in monoclonal gammopathies.

    Directory of Open Access Journals (Sweden)

    Luis M Valor

    Full Text Available Plasma cells (PC represent the heterogeneous final stage of the B cells (BC differentiation process. To characterize the transition of BC into PC, transcriptomes from human naïve BC were compared to those of three functionally-different subsets of human in vivo-generated PC: i tonsil PC, mainly consisting of early PC; ii PC released to the blood after a potent booster-immunization (mostly cycling plasmablasts; and, iii bone marrow CD138+ PC that represent highly mature PC and include the long-lived PC compartment. This transcriptional transition involves subsets of genes related to key processes for PC maturation: the already known protein processing, apoptosis and homeostasis, and of new discovery including histones, macromolecule assembly, zinc-finger transcription factors and neuromodulation. This human PC signature is partially reproduced in vitro and is conserved in mouse. Moreover, the present study identifies genes that define PC subtypes (e.g., proliferation-associated genes for circulating PC and transcriptional-related genes for tonsil and bone marrow PC and proposes some putative transcriptional regulators of the human PC signatures (e.g., OCT/POU, XBP1/CREB, E2F, among others. Finally, we also identified a restricted imbalance of the present PC transcriptional program in monoclonal gammopathies that correlated with PC malignancy.

  3. A familial study of azoospermic men identifies three novel causative mutations in three new human azoospermia genes.

    Science.gov (United States)

    Gershoni, Moran; Hauser, Ron; Yogev, Leah; Lehavi, Ofer; Azem, Foad; Yavetz, Haim; Pietrokovski, Shmuel; Kleiman, Sandra E

    2017-09-01

    Up to 1% of all men experience azoospermia, a condition of complete absence of sperm in the semen. The mechanisms and genes involved in spermatogenesis are mainly studied in model organisms, and their relevance to humans is unclear because human genetic studies are very scarce. Our objective was to uncover novel human mutations and genes causing azoospermia due to testicular meiotic maturation arrest. Affected and unaffected siblings from three families were subjected to whole-exome or whole-genome sequencing, followed by comprehensive bioinformatics analyses to identify mutations suspected to cause azoospermia. These likely mutations were further screened in azoospermic and normozoospermic men and in men proven to be fertile, as well as in a reference database of local populations. We identified three novel likely causative mutations of azoospermia in three genes: MEIOB, TEX14, and DNAH6. These genes are associated with different meiotic processes: meiotic crossovers, daughter cell abscission, and possibly rapid prophase movements. The genes and pathways we identified are fundamental for delineating common causes of azoospermia originating in mutations affecting diverse meiotic processes and have great potential for accelerating approaches to diagnose, treat, and prevent infertility.Genet Med advance online publication 16 February 2017.

  4. Whole genome analysis of selected human and animal rotaviruses identified in Uganda from 2012 to 2014 reveals complex genome reassortment events between human, bovine, caprine and porcine strains.

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    Josephine Bwogi

    Full Text Available Rotaviruses of species A (RVA are a common cause of diarrhoea in children and the young of various other mammals and birds worldwide. To investigate possible interspecies transmission of RVAs, whole genomes of 18 human and 6 domestic animal RVA strains identified in Uganda between 2012 and 2014 were sequenced using the Illumina HiSeq platform. The backbone of the human RVA strains had either a Wa- or a DS-1-like genetic constellation. One human strain was a Wa-like mono-reassortant containing a DS-1-like VP2 gene of possible animal origin. All eleven genes of one bovine RVA strain were closely related to those of human RVAs. One caprine strain had a mixed genotype backbone, suggesting that it emerged from multiple reassortment events involving different host species. The porcine RVA strains had mixed genotype backbones with possible multiple reassortant events with strains of human and bovine origin.Overall, whole genome characterisation of rotaviruses found in domestic animals in Uganda strongly suggested the presence of human-to animal RVA transmission, with concomitant circulation of multi-reassortant strains potentially derived from complex interspecies transmission events. However, whole genome data from the human RVA strains causing moderate and severe diarrhoea in under-fives in Uganda indicated that they were primarily transmitted from person-to-person.

  5. Whole genome analysis of selected human and animal rotaviruses identified in Uganda from 2012 to 2014 reveals complex genome reassortment events between human, bovine, caprine and porcine strains.

    Science.gov (United States)

    Bwogi, Josephine; Jere, Khuzwayo C; Karamagi, Charles; Byarugaba, Denis K; Namuwulya, Prossy; Baliraine, Frederick N; Desselberger, Ulrich; Iturriza-Gomara, Miren

    2017-01-01

    Rotaviruses of species A (RVA) are a common cause of diarrhoea in children and the young of various other mammals and birds worldwide. To investigate possible interspecies transmission of RVAs, whole genomes of 18 human and 6 domestic animal RVA strains identified in Uganda between 2012 and 2014 were sequenced using the Illumina HiSeq platform. The backbone of the human RVA strains had either a Wa- or a DS-1-like genetic constellation. One human strain was a Wa-like mono-reassortant containing a DS-1-like VP2 gene of possible animal origin. All eleven genes of one bovine RVA strain were closely related to those of human RVAs. One caprine strain had a mixed genotype backbone, suggesting that it emerged from multiple reassortment events involving different host species. The porcine RVA strains had mixed genotype backbones with possible multiple reassortant events with strains of human and bovine origin.Overall, whole genome characterisation of rotaviruses found in domestic animals in Uganda strongly suggested the presence of human-to animal RVA transmission, with concomitant circulation of multi-reassortant strains potentially derived from complex interspecies transmission events. However, whole genome data from the human RVA strains causing moderate and severe diarrhoea in under-fives in Uganda indicated that they were primarily transmitted from person-to-person.

  6. Leukocyte Populations in Human Preterm and Term Breast Milk Identified by Multicolour Flow Cytometry

    Science.gov (United States)

    Trend, Stephanie; de Jong, Emma; Lloyd, Megan L.; Kok, Chooi Heen; Richmond, Peter; Doherty, Dorota A.; Simmer, Karen; Kakulas, Foteini; Strunk, Tobias; Currie, Andrew

    2015-01-01

    Background Extremely preterm infants are highly susceptible to bacterial infections but breast milk provides some protection. It is unknown if leukocyte numbers and subsets in milk differ between term and preterm breast milk. This study serially characterised leukocyte populations in breast milk of mothers of preterm and term infants using multicolour flow cytometry methods for extended differential leukocyte counts in blood. Methods Sixty mothers of extremely preterm (leukocyte subsets analysed using flow cytometry. Results The major CD45+ leukocyte populations circulating in blood were also detectable in breast milk but at different frequencies. Progression of lactation was associated with decreasing CD45+ leukocyte concentration, as well as increases in the relative frequencies of neutrophils and immature granulocytes, and decreases in the relative frequencies of eosinophils, myeloid and B cell precursors, and CD16- monocytes. No differences were observed between preterm and term breast milk in leukocyte concentration, though minor differences between preterm groups in some leukocyte frequencies were observed. Conclusions Flow cytometry is a useful tool to identify and quantify leukocyte subsets in breast milk. The stage of lactation is associated with major changes in milk leukocyte composition in this population. Fresh preterm breast milk is not deficient in leukocytes, but shorter gestation may be associated with minor differences in leukocyte subset frequencies in preterm compared to term breast milk. PMID:26288195

  7. Identifying Human SIRT1 Substrates by Integrating Heterogeneous Information from Various Sources.

    Science.gov (United States)

    Zhai, Zichao; Tang, Ming; Yang, Yue; Lu, Ming; Zhu, Wei-Guo; Li, Tingting

    2017-07-04

    Most proteins undergo different kinds of modification after translation. Protein acetylation is one of the most crucial post-translational modifications, which causes direct or indirect impact on various biological activities in vivo. As a member of Class III HDACs, SIRT1 was the closest one to the yeast sir2 and drew most attention, while a small number of known SIRT1 substrates caused difficulties to clarify its function. In this work, we designed a novel computational method to screen SIRT1 substrates based on manually collected data and Support Vector Machines (SVMs). Unlike other approaches, we took both primary sequence and protein functional features into consideration. Through integrating functional features, the Matthews correlation coefficient (MCC) for the prediction increased from 0.10 to 0.65. The prediction results were verified by independent dataset and biological experiments. The validation results demostrated that our classifier could effectively identify SIRT1 substrates and filter appropriate candidates for further research. Furthermore, we provide online tool to support SIRT1 substrates prediction, which is freely available at http://bioinfo.bjmu.edu.cn/huac/ .

  8. Triple Staining Including FOXA2 Identifies Stem Cell Lineages Undergoing Hepatic and Biliary Differentiation in Cirrhotic Human Liver.

    Science.gov (United States)

    Rogler, Charles E; Bebawee, Remon; Matarlo, Joe; Locker, Joseph; Pattamanuch, Nicole; Gupta, Sanjeev; Rogler, Leslie E

    2017-01-01

    Recent investigations have reported many markers associated with human liver stem/progenitor cells, "oval cells," and identified "niches" in diseased livers where stem cells occur. However, there has remained a need to identify entire lineages of stem cells as they differentiate into bile ducts or hepatocytes. We have used combined immunohistochemical staining for a marker of hepatic commitment and specification (FOXA2 [Forkhead box A2]), hepatocyte maturation (Albumin and HepPar1), and features of bile ducts (CK19 [cytokeratin 19]) to identify lineages of stem cells differentiating toward the hepatocytic or bile ductular compartments of end-stage cirrhotic human liver. We identified large clusters of disorganized, FOXA2 expressing, oval cells in localized liver regions surrounded by fibrotic matrix, designated as "micro-niches." Specific FOXA2-positive cells within the micro-niches organize into primitive duct structures that support both hepatocytic and bile ductular differentiation enabling identification of entire lineages of cells forming the two types of structures. We also detected expression of hsa-miR-122 in primitive ductular reactions expected for hepatocytic differentiation and hsa-miR-23b cluster expression that drives liver cell fate decisions in cells undergoing lineage commitment. Our data establish the foundation for a mechanistic hypothesis on how stem cell lineages progress in specialized micro-niches in cirrhotic end-stage liver disease.

  9. A systems biology pipeline identifies new immune and disease related molecular signatures and networks in human cells during microgravity exposure.

    Science.gov (United States)

    Mukhopadhyay, Sayak; Saha, Rohini; Palanisamy, Anbarasi; Ghosh, Madhurima; Biswas, Anupriya; Roy, Saheli; Pal, Arijit; Sarkar, Kathakali; Bagh, Sangram

    2016-05-17

    Microgravity is a prominent health hazard for astronauts, yet we understand little about its effect at the molecular systems level. In this study, we have integrated a set of systems-biology tools and databases and have analysed more than 8000 molecular pathways on published global gene expression datasets of human cells in microgravity. Hundreds of new pathways have been identified with statistical confidence for each dataset and despite the difference in cell types and experiments, around 100 of the new pathways are appeared common across the datasets. They are related to reduced inflammation, autoimmunity, diabetes and asthma. We have identified downregulation of NfκB pathway via Notch1 signalling as new pathway for reduced immunity in microgravity. Induction of few cancer types including liver cancer and leukaemia and increased drug response to cancer in microgravity are also found. Increase in olfactory signal transduction is also identified. Genes, based on their expression pattern, are clustered and mathematically stable clusters are identified. The network mapping of genes within a cluster indicates the plausible functional connections in microgravity. This pipeline gives a new systems level picture of human cells under microgravity, generates testable hypothesis and may help estimating risk and developing medicine for space missions.

  10. A double-blind cross-over controlled study to evaluate the effect of human biosynthetic growth hormone on ovarian stimulation in previous poor responders to in-vitro fertilization.

    Science.gov (United States)

    Hughes, S M; Huang, Z H; Morris, I D; Matson, P L; Buck, P; Lieberman, B A

    1994-01-01

    The effect of exogenous human biosynthetic growth hormone (HGH; 12 IU/day; Norditropin, Novo-Nordisk) on the response to ovarian stimulation using a buserelin/human menopausal gonadotrophin (HMG) regimen was assessed in women who had previously shown a 'poor response' in spite of increasing doses of HMG. Forty patients were recruited into a prospective double-blind placebo-controlled study. The serum follicle stimulating hormone (FSH) on day 2-5 of a menstrual cycle (HGH compared to the placebo cycle resulted in increased serum concentrations of fasting insulin on the 8th (median 3.9 versus 5.8 mU/l; P HGH. After 8 days of co-treatment with HGH the number of cohort follicles (14-16.9 mm) was significantly increased, but this change was not sustained on the day of HCG administration. No statistical difference in the serum oestradiol on the 8th day of HMG or day of HCG, length of the follicular phase, total dose of HMG used, or the number of oocytes collected was seen between the placebo or HGH cycles. This study demonstrates that HGH does not improve the ovarian response to ovulation induction in previous poor responders.

  11. Transcriptome profiling of whole blood cells identifies PLEK2 and C1QB in human melanoma.

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    Yuchun Luo

    Full Text Available Developing analytical methodologies to identify biomarkers in easily accessible body fluids is highly valuable for the early diagnosis and management of cancer patients. Peripheral whole blood is a "nucleic acid-rich" and "inflammatory cell-rich" information reservoir and represents systemic processes altered by the presence of cancer cells.We conducted transcriptome profiling of whole blood cells from melanoma patients. To overcome challenges associated with blood-based transcriptome analysis, we used a PAXgene™ tube and NuGEN Ovation™ globin reduction system. The combined use of these systems in microarray resulted in the identification of 78 unique genes differentially expressed in the blood of melanoma patients. Of these, 68 genes were further analyzed by quantitative reverse transcriptase PCR using blood samples from 45 newly diagnosed melanoma patients (stage I to IV and 50 healthy control individuals. Thirty-nine genes were verified to be differentially expressed in blood samples from melanoma patients. A stepwise logit analysis selected eighteen 2-gene signatures that distinguish melanoma from healthy controls. Of these, a 2-gene signature consisting of PLEK2 and C1QB led to the best result that correctly classified 93.3% melanoma patients and 90% healthy controls. Both genes were upregulated in blood samples of melanoma patients from all stages. Further analysis using blood fractionation showed that CD45(- and CD45(+ populations were responsible for the altered expression levels of PLEK2 and C1QB, respectively.The current study provides the first analysis of whole blood-based transcriptome biomarkers for malignant melanoma. The expression of PLEK2, the strongest gene to classify melanoma patients, in CD45(- subsets illustrates the importance of analyzing whole blood cells for biomarker studies. The study suggests that transcriptome profiling of blood cells could be used for both early detection of melanoma and monitoring of patients

  12. A Potential New Human Pathogen Belonging to Helicobacter Genus, Identified in a Bloodstream Infection

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    Nathalie L. van der Mee-Marquet

    2017-12-01

    Full Text Available We isolated from aerobic and anaerobic blood culture bottles from a febrile patient, a Helicobacter-like Gram negative, rod-shaped bacterium that MALDI-TOF MS failed to identify. Blood agar cultures incubated in a microaerobic atmosphere revealed a motile Gram negative rod, which was oxidase, catalase, nitrate reductase, esterase, and alkaline phosphatase positive. It grew at 42°C with no detectable urease activity. Antimicrobial susceptibility testing showed that the organism was susceptible to beta-lactams, gentamicin, erythromycin, and tetracycline but resistant to ciprofloxacin. Electronic microscopy analysis revealed a 3 × 0.5 μm curved rod bacterium harboring two sheathed amphitrichous flagella. Whole genome sequencing revealed a genome 1,708,265 base-pairs long with a GC content of 37.80% and a total of 1,697 coding sequences. The genomic analyses using the nucleotide sequences of the 16S rRNA gene, hsp60 and gyrB genes, as well as the GyrA protein sequence, and the results of Average Nucleotide Identity and in silico DNA-DNA hybridization suggest evidence for a novel Helicobacter species close to Helicobacter equorum and belonging to the group of enterohepatic Helicobacter species. As soon as the particular peptide mass fingerprint of this pathogen is added to the spectral databases, MALDI-TOF MS technology will improve its identification from clinical specimens, especially in case of “sterile infection”. We propose to associate the present strain with the Latin name of the place of isolation; Caesarodunum (Tours, France and suggest “Helicobacter caesarodunensis” for further description of this new bacterium.

  13. Leukocyte Populations in Human Preterm and Term Breast Milk Identified by Multicolour Flow Cytometry.

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    Stephanie Trend

    Full Text Available Extremely preterm infants are highly susceptible to bacterial infections but breast milk provides some protection. It is unknown if leukocyte numbers and subsets in milk differ between term and preterm breast milk. This study serially characterised leukocyte populations in breast milk of mothers of preterm and term infants using multicolour flow cytometry methods for extended differential leukocyte counts in blood.Sixty mothers of extremely preterm (<28 weeks gestational age, very preterm (28-31 wk, and moderately preterm (32-36 wk, as well as term (37-41 wk infants were recruited. Colostrum (d2-5, transitional (d8-12 and mature milk (d26-30 samples were collected, cells isolated, and leukocyte subsets analysed using flow cytometry.The major CD45+ leukocyte populations circulating in blood were also detectable in breast milk but at different frequencies. Progression of lactation was associated with decreasing CD45+ leukocyte concentration, as well as increases in the relative frequencies of neutrophils and immature granulocytes, and decreases in the relative frequencies of eosinophils, myeloid and B cell precursors, and CD16- monocytes. No differences were observed between preterm and term breast milk in leukocyte concentration, though minor differences between preterm groups in some leukocyte frequencies were observed.Flow cytometry is a useful tool to identify and quantify leukocyte subsets in breast milk. The stage of lactation is associated with major changes in milk leukocyte composition in this population. Fresh preterm breast milk is not deficient in leukocytes, but shorter gestation may be associated with minor differences in leukocyte subset frequencies in preterm compared to term breast milk.

  14. Walking the interactome to identify human miRNA-disease associations through the functional link between miRNA targets and disease genes

    Science.gov (United States)

    2013-01-01

    Background MicroRNAs (miRNAs) are important post-transcriptional regulators that have been demonstrated to play an important role in human diseases. Elucidating the associations between miRNAs and diseases at the systematic level will deepen our understanding of the molecular mechanisms of diseases. However, miRNA-disease associations identified by previous computational methods are far from completeness and more effort is needed. Results We developed a computational framework to identify miRNA-disease associations by performing random walk analysis, and focused on the functional link between miRNA targets and disease genes in protein-protein interaction (PPI) networks. Furthermore, a bipartite miRNA-disease network was constructed, from which several miRNA-disease co-regulated modules were identified by hierarchical clustering analysis. Our approach achieved satisfactory performance in identifying known cancer-related miRNAs for nine human cancers with an area under the ROC curve (AUC) ranging from 71.3% to 91.3%. By systematically analyzing the global properties of the miRNA-disease network, we found that only a small number of miRNAs regulated genes involved in various diseases, genes associated with neurological diseases were preferentially regulated by miRNAs and some immunological diseases were associated with several specific miRNAs. We also observed that most diseases in the same co-regulated module tended to belong to the same disease category, indicating that these diseases might share similar miRNA regulatory mechanisms. Conclusions In this study, we present a computational framework to identify miRNA-disease associations, and further construct a bipartite miRNA-disease network for systematically analyzing the global properties of miRNA regulation of disease genes. Our findings provide a broad perspective on the relationships between miRNAs and diseases and could potentially aid future research efforts concerning miRNA involvement in disease pathogenesis

  15. Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes.

    Science.gov (United States)

    Xue, Ruidan; Lynes, Matthew D; Dreyfuss, Jonathan M; Shamsi, Farnaz; Schulz, Tim J; Zhang, Hongbin; Huang, Tian Lian; Townsend, Kristy L; Li, Yiming; Takahashi, Hirokazu; Weiner, Lauren S; White, Andrew P; Lynes, Maureen S; Rubin, Lee L; Goodyear, Laurie J; Cypess, Aaron M; Tseng, Yu-Hua

    2015-07-01

    Targeting brown adipose tissue (BAT) content or activity has therapeutic potential for treating obesity and the metabolic syndrome by increasing energy expenditure. However, both inter- and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here we generated clones of brown and white preadipocytes from human neck fat and characterized their adipogenic and thermogenic differentiation. We combined an uncoupling protein 1 (UCP1) reporter system and expression profiling to define novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of the cells once they were maturated. Knocking out the positive UCP1 regulators, PREX1 and EDNRB, in brown preadipocytes using CRISPR-Cas9 markedly abolished the high level of UCP1 in brown adipocytes differentiated from the preadipocytes. Finally, we were able to prospectively isolate adipose progenitors with great thermogenic potential using the cell surface marker CD29. These data provide new insights into the cellular heterogeneity in human fat and offer potential biomarkers for identifying thermogenically competent preadipocytes.

  16. CHARACTERIZATION OF ANTERIOR SEGMENT OPHTHALMOLOGIC LESIONS IDENTIFIED IN FREE-RANGING DOLPHINS AND THOSE UNDER HUMAN CARE.

    Science.gov (United States)

    Colitz, Carmen M H; Walsh, Michael T; McCulloch, Stephen D

    2016-03-01

    Cetaceans in the wild and under human care develop a variety of ocular lesions. Although they have echolocation, cetacean species have good sight, making ocular health an important part of overall health care. The cornea is the primary site of abnormalities in both populations. Typical lesions of cetaceans under human care are characterized in this retrospective review of cases. One hundred eighty animals (n = 360 eyes) were chosen from the author's ophthalmologic examination reports from different geographic areas; they included Atlantic bottlenose dolphins (Tursiops truncatus), Pacific bottle nose dolphins (Tursiopstruncatus gilli), Indopacific bottlenose dolphins (Steno bredanensis), Indopacific humpback dolphins (Sousa chinensis), and roughtooth dolphins (Steno bredanensis). These animals were examined at least once, although most were examined numerous times over many years; lesions were categorized and are described. Seventy-seven eyes from 47 animals were normal. Medial keratopathy was the most common lesion and identified in 180 eyes from 97 animals, with 83 affected bilaterally. Horizontal keratopathy was identified in 69 eyes from 41 animals, with 28 affected bilaterally. Axial keratopathy and nonspecific axial opacities were identified in 67 eyes from 44 animals, with 21 affected bilaterally. Seventy-eight eyes from 50 animals, with 28 affected bilaterally, had more than one type of corneal lesion. Cataracts were identified in 32 eyes from 19 animals, with 13 affected bilaterally. Traumatic injuries were also common and involved eyelids and cornea. Sixteen eyes from 11 animals were blind; five dolphins were blind bilaterally due to phthisis bulbi secondary to corneal perforation or severe trauma. None of the diseases had a sex predisposition; however, medial keratopathy was significantly more common as a bilateral presentation than as a unilateral presentation. Cetaceans under human care with impaired sight can use echolocation; however, ocular health

  17. CXCR6, a newly defined biomarker of tissue-specific stem cell asymmetric self-renewal, identifies more aggressive human melanoma cancer stem cells.

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    Rouzbeh Taghizadeh

    2010-12-01

    Full Text Available A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells. Recent investigations of a variety of tumor types have shown that phenotypically identifiable and isolable subfractions of cells possess the tumor-forming ability. In the present paper, using two lineage-related human melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative line IGR37, two main observations are reported. The first one is the first phenotypic evidence to support the origin of melanoma cancer stem cells (CSCs from mutated tissue-specific stem cells; and the second one is the identification of a more aggressive subpopulation of CSCs in melanoma that are CXCR6+.We defined CXCR6 as a new biomarker for tissue-specific stem cell asymmetric self-renewal. Thus, the relationship between melanoma formation and ABCG2 and CXCR6 expression was investigated. Consistent with their non-metastatic character, unsorted IGR39 cells formed significantly smaller tumors than unsorted IGR37 cells. In addition, ABCG2+ cells produced tumors that had a 2-fold greater mass than tumors produced by unsorted cells or ABCG2- cells. CXCR6+ cells produced more aggressive tumors. CXCR6 identifies a more discrete subpopulation of cultured human melanoma cells with a more aggressive MCSC phenotype than cells selected on the basis of the ABCG2+ phenotype alone.The association of a more aggressive tumor phenotype with asymmetric self-renewal phenotype reveals a previously unrecognized aspect of tumor cell physiology. Namely, the retention of some tissue-specific stem cell attributes, like the ability to asymmetrically self-renew, impacts the natural history of human tumor development. Knowledge of this new aspect of tumor development and progression may provide new targets for cancer prevention and treatment.

  18. A synthetic interaction screen identifies factors selectively required for proliferation and TERT transcription in p53-deficient human cancer cells.

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    Li Xie

    Full Text Available Numerous genetic and epigenetic alterations render cancer cells selectively dependent on specific genes and regulatory pathways, and represent potential vulnerabilities that can be therapeutically exploited. Here we describe an RNA interference (RNAi-based synthetic interaction screen to identify genes preferentially required for proliferation of p53-deficient (p53- human cancer cells. We find that compared to p53-competent (p53+ human cancer cell lines, diverse p53- human cancer cell lines are preferentially sensitive to loss of the transcription factor ETV1 and the DNA damage kinase ATR. In p53- cells, RNAi-mediated knockdown of ETV1 or ATR results in decreased expression of the telomerase catalytic subunit TERT leading to growth arrest, which can be reversed by ectopic TERT expression. Chromatin immunoprecipitation analysis reveals that ETV1 binds to a region downstream of the TERT transcriptional start-site in p53- but not p53+ cells. We find that the role of ATR is to phosphorylate and thereby stabilize ETV1. Our collective results identify a regulatory pathway involving ETV1, ATR, and TERT that is preferentially important for proliferation of diverse p53- cancer cells.

  19. Mutagenesis identifies the critical amino acid residues of human endonuclease G involved in catalysis, magnesium coordination, and substrate specificity

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    Wu Shih-Lu

    2009-01-01

    Full Text Available Abstract Background Endonuclease G (EndoG, a member of DNA/RNA nonspecific ββα-Me-finger nucleases, is involved in apoptosis and normal cellular proliferation. In this study, we analyzed the critical amino acid residues of EndoG and proposed the catalytic mechanism of EndoG. Methods To identify the critical amino acid residues of human EndoG, we replaced the conserved histidine, asparagine, and arginine residues with alanine. The catalytic efficacies of Escherichia coli-expressed EndoG variants were further analyzed by kinetic studies. Results Diethyl pyrocarbonate modification assay revealed that histidine residues were involved in EndoG activity. His-141, Asn-163, and Asn-172 in the H-N-H motif of EndoG were critical for catalysis and substrate specificity. H141A mutant required a higher magnesium concentration to achieve its activity, suggesting the unique role of His-141 in both catalysis and magnesium coordination. Furthermore, an additional catalytic residue (Asn-251 and an additional metal ion binding site (Glu-271 of human EndoG were identified. Conclusion Based on the mutational analysis and homology modeling, we proposed that human EndoG shared a similar catalytic mechanism with nuclease A from Anabaena.

  20. Geographically Modified PageRank Algorithms: Identifying the Spatial Concentration of Human Movement in a Geospatial Network.

    Science.gov (United States)

    Chin, Wei-Chien-Benny; Wen, Tzai-Hung

    2015-01-01

    A network approach, which simplifies geographic settings as a form of nodes and links, emphasizes the connectivity and relationships of spatial features. Topological networks of spatial features are used to explore geographical connectivity and structures. The PageRank algorithm, a network metric, is often used to help identify important locations where people or automobiles concentrate in the geographical literature. However, geographic considerations, including proximity and location attractiveness, are ignored in most network metrics. The objective of the present study is to propose two geographically modified PageRank algorithms-Distance-Decay PageRank (DDPR) and Geographical PageRank (GPR)-that incorporate geographic considerations into PageRank algorithms to identify the spatial concentration of human movement in a geospatial network. Our findings indicate that in both intercity and within-city settings the proposed algorithms more effectively capture the spatial locations where people reside than traditional commonly-used network metrics. In comparing location attractiveness and distance decay, we conclude that the concentration of human movement is largely determined by the distance decay. This implies that geographic proximity remains a key factor in human mobility.

  1. Geographically Modified PageRank Algorithms: Identifying the Spatial Concentration of Human Movement in a Geospatial Network.

    Directory of Open Access Journals (Sweden)

    Wei-Chien-Benny Chin

    Full Text Available A network approach, which simplifies geographic settings as a form of nodes and links, emphasizes the connectivity and relationships of spatial features. Topological networks of spatial features are used to explore geographical connectivity and structures. The PageRank algorithm, a network metric, is often used to help identify important locations where people or automobiles concentrate in the geographical literature. However, geographic considerations, including proximity and location attractiveness, are ignored in most network metrics. The objective of the present study is to propose two geographically modified PageRank algorithms-Distance-Decay PageRank (DDPR and Geographical PageRank (GPR-that incorporate geographic considerations into PageRank algorithms to identify the spatial concentration of human movement in a geospatial network. Our findings indicate that in both intercity and within-city settings the proposed algorithms more effectively capture the spatial locations where people reside than traditional commonly-used network metrics. In comparing location attractiveness and distance decay, we conclude that the concentration of human movement is largely determined by the distance decay. This implies that geographic proximity remains a key factor in human mobility.

  2. Functional Classification of the Gut Microbiota: The Key to Cracking the Microbiota Composition Code: Functional classifications of the gut microbiota reveal previously hidden contributions of indigenous gut bacteria to human health and disease.

    Science.gov (United States)

    Rosen, Connor E; Palm, Noah W

    2017-12-01

    The last decade has seen an explosion of research on the gut microbiota-the trillions of microorganisms that colonize the human gut. It is now clear that interindividual diversity in microbiota composition plays an important role in determining susceptibility to a wide variety of diseases. However, identifying the precise changes in microbiota composition that play causal roles has remained a largely unrealized goal. Here, we propose that functional classifications of microbes based on their interactions with and effects on the host-particularly the host immune system-will illuminate the role of the microbiota in shaping human physiology. We outline the benefits of "functional" classification compared to phylogenetic classifications, and review current efforts at functional classification of the microbiota. Finally, we outline a theoretical framework for classifying host-microbiota interactions. Future advances enabling broader functional classifications of the microbiota promise to revolutionize our understanding of the role of gut microbes in health and disease. © 2017 WILEY Periodicals, Inc.

  3. A panel of microsatellites to individually identify leopards and its application to leopard monitoring in human dominated landscapes

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    Selvaraj Velu

    2009-12-01

    Full Text Available Abstract Background Leopards are the most widely distributed of the large cats, ranging from Africa to the Russian Far East. Because of habitat fragmentation, high human population densities and the inherent adaptability of this species, they now occupy landscapes close to human settlements. As a result, they are the most common species involved in human wildlife conflict in India, necessitating their monitoring. However, their elusive nature makes such monitoring difficult. Recent advances in DNA methods along with non-invasive sampling techniques can be used to monitor populations and individuals across large landscapes including human dominated ones. In this paper, we describe a DNA-based method for leopard individual identification where we used fecal DNA samples to obtain genetic material. Further, we apply our methods to non-invasive samples collected in a human-dominated landscape to estimate the minimum number of leopards in this human-leopard conflict area in Western India. Results In this study, 25 of the 29 tested cross-specific microsatellite markers showed positive amplification in 37 wild-caught leopards. These loci revealed varied levels of polymorphism (four-12 alleles and heterozygosity (0.05-0.79. Combining data on amplification success (including non-invasive samples and locus specific polymorphisms, we showed that eight loci provide a sibling probability of identity of 0.0005, suggesting that this panel can be used to discriminate individuals in the wild. When this microsatellite panel was applied to fecal samples collected from a human-dominated landscape, we identified 7 individuals, with a sibling probability of identity of 0.001. Amplification success of field collected scats was up to 72%, and genotype error ranged from 0-7.4%. Conclusion Our results demonstrated that the selected panel of eight microsatellite loci can conclusively identify leopards from various kinds of biological samples. Our methods can be used to

  4. Genome-wide association study identifies single-nucleotide polymorphism in KCNB1 associated with left ventricular mass in humans: The HyperGEN Study

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    Kraemer Rachel

    2009-05-01

    Full Text Available Abstract Background We conducted a genome-wide association study (GWAS and validation study for left ventricular (LV mass in the Family Blood Pressure Program – HyperGEN population. LV mass is a sensitive predictor of cardiovascular mortality and morbidity in all genders, races, and ages. Polymorphisms of candidate genes in diverse pathways have been associated with LV mass. However, subsequent studies have often failed to replicate these associations. Genome-wide association studies have unprecedented power to identify potential genes with modest effects on left LV mass. We describe here a GWAS for LV mass in Caucasians using the Affymetrix GeneChip Human Mapping 100 k Set. Cases (N = 101 and controls (N = 101 were selected from extreme tails of the LV mass index distribution from 906 individuals in the HyperGEN study. Eleven of 12 promising (Q Results Despite the relatively small sample, we identified 12 promising SNPs in the GWAS. Eleven SNPs were successfully genotyped in the validation study of 704 Caucasians and 1467 African Americans; 5 SNPs on chromosomes 5, 12, and 20 were significantly (P ≤ 0.05 associated with LV mass after correction for multiple testing. One SNP (rs756529 is intragenic within KCNB1, which is dephosphorylated by calcineurin, a previously reported candidate gene for LV hypertrophy within this population. Conclusion These findings suggest KCNB1 may be involved in the development of LV hypertrophy in humans.

  5. Identifying Potential Areas of Human Zika Infection in the City of Los Angeles, California by Use of Remote Sensing Imagery

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    Lee, J.

    2017-12-01

    As of April 2017, California is the third most prevalent state on the United States for Zika Infection and Southern California has an ever growing population of Aedes mosquitos. Zika is a disease which poses a significant risk to humans and other mammals due to its effects on pregnancy. This emerging disease is highly contagious due to its spread of infection primarily by Aedes aegypti mosquitos. Aedes mosquitos are able to breed in small rain collecting containers which allow the species to persevere in urban and semi urban environments. We hope to identify potential areas with risk of human infection within Los Angeles and its surrounding areas. This study integrates remote sensing, GIS, statistical, and environmental techniques to study favorable habitats for this particular species of mosquitos and their larvae. The study of the geographic and landscape factors which promote the larvae development allow for the disease spread to be analyzed and modeled. There are several goals in the development of this study. These include the coordination of statistical data with local epidemiology departments, identify workflows to improve efficiency, create models which can be utilized for disease prevention, and identify geographic risk factors for the spread of Zika.

  6. Csa-19, a radiation-responsive human gene, identified by an unbiased two-gel cDNA library screening method in human cancer cells

    Science.gov (United States)

    Balcer-Kubiczek, E. K.; Meltzer, S. J.; Han, L. H.; Zhang, X. F.; Shi, Z. M.; Harrison, G. H.; Abraham, J. M.

    1997-01-01

    A novel polymerase chain reaction (PCR)-based method was used to identify candidate genes whose expression is altered in cancer cells by ionizing radiation. Transcriptional induction of randomly selected genes in control versus irradiated human HL60 cells was compared. Among several complementary DNA (cDNA) clones recovered by this approach, one cDNA clone (CL68-5) was downregulated in X-irradiated HL60 cells but unaffected by 12-O-tetradecanoyl phorbol-13-acetate, forskolin, or cyclosporin-A. DNA sequencing of the CL68-5 cDNA revealed 100% nucleotide sequence homology to the reported human Csa-19 gene. Northern blot analysis of RNA from control and irradiated cells revealed the expression of a single 0.7-kilobase (kb) messenger RNA (mRNA) transcript. This 0.7-kb Csa-19 mRNA transcript was also expressed in a variety of human adult and corresponding fetal normal tissues. Moreover, when the effect of X- or fission neutron-irradiation on Csa-19 mRNA was compared in cultured human cells differing in p53 gene status (p53-/- versus p53+/+), downregulation of Csa-19 by X-rays or fission neutrons was similar in p53-wild type and p53-null cell lines. Our results provide the first known example of a radiation-responsive gene in human cancer cells whose expression is not associated with p53, adenylate cyclase or protein kinase C.

  7. New STLV-3 strains and a divergent SIVmus strain identified in non-human primate bushmeat in Gabon

    Directory of Open Access Journals (Sweden)

    Liégeois Florian

    2012-03-01

    Full Text Available Abstract Background Human retroviral infections such as Human Immunodeficiency Virus (HIV or Human T-cell Lymphotropic Virus (HTLV are the result of simian zoonotic transmissions through handling and butchering of Non-Human Primates (NHP or by close contact with pet animals. Recent studies on retroviral infections in NHP bushmeat allowed for the identification of numerous Simian Immunodeficiency Viruses (SIV and Simian T-cell Lymphotropic Viruses (STLV to which humans are exposed. Nevertheless, today, data on simian retroviruses at the primate/hunter interface remain scarce. We conducted a pilot study on 63 blood and/or tissues samples derived from NHP bushmeat seized by the competent authorities in different locations across the country. Results SIV and STLV were detected by antibodies to HIV and HTLV antigens, and PCRs were performed on samples with an HIV or/and HTLV-like or indeterminate profile. Fourteen percent of the samples cross-reacted with HIV antigens and 44% with HTLV antigens. We reported STLV-1 infections in five of the seven species tested. STLV-3 infections, including a new STLV-3 subtype, STLV-1 and -3 co-infections, and triple SIV, STLV-1, STLV-3 infections were observed in red-capped mangabeys (C.torquatus. We confirmed SIV infections by PCR and sequence analyses in mandrills, red-capped mangabeys and showed that mustached monkeys in Gabon are infected with a new SIV strain basal to the SIVgsn/mus/mon lineage that did not fall into the previously described SIVmus lineages reported from the corresponding species in Cameroon. The same monkey (subspecies can thus be carrier of, at least, three distinct SIVs. Overall, the minimal prevalence observed for both STLV and SIV natural infections were 26.9% and 11.1% respectively. Conclusions Overall, these data, obtained from a restricted sampling, highlight the need for further studies on simian retroviruses in sub-Saharan Africa to better understand their evolutionary history and to

  8. Identification of Human Intestinal Microbiota of 92 Men by Data Mining for 5 Characteristics, i.e., Age, BMI, Smoking Habit, Cessation Period of Previous Smokers and Drinking Habit.

    Science.gov (United States)

    Kobayashi, Toshio; Jin, Jong-Sik; Kibe, Ryoko; Touyama, Mutsumi; Tanaka, Yoshiki; Benno, Yoshiko; Fujiwara, Kenji; Shimakawa, Masaki; Maruo, Toshiya; Toda, Toshiya; Matsuda, Isao; Tagami, Hiroyuki; Matsumoto, Mitsuharu; Seo, Genichirou; Sato, Naoki; Chounan, Osamu; Benno, Yoshimi

    2013-01-01

    The intestinal microbiota compositions of 92 men living in Japan were identified following consumption of identical meals for 3 days. Fecal samples were analyzed by terminal restriction fragment length polymorphism with 4 primer-restriction enzyme systems, and the 120 obtained operational taxonomic units (OTUs) were analyzed by Data mining software focusing on the following 5 characteristics, namely, age, body mass index, present smoking habit, cessation period of previous smokers and drinking habit, according to the answers of the subjects. After performing Data mining analyses with each characteristic, the details of the constructed Decision trees precisely identified the subjects or discriminated them into various suitable groups. Through the pathways to reach the groups, practical roles of the related OTUs and their quantities were clearly recognized. Compared with the other identification methods for OTUs such as bicluster analyses, correlation coefficients and principal component analyses, the clear difference of this Data mining technique was that it set aside most OTUs and emphasized only some closely related ones. For example for a selected characteristic, such as smoking habit, only 7 OTUs out of 120 were able to identify all smokers, and the remaining 113 OTUs were thought of as data noise for smoking. Data mining analyses were affirmed as an effective method of subject discrimination for various physiological constitutions. The species of bacteria that were closely related to heavy smokers, i.e., HaeIII-291, were also discussed.

  9. Diagnostic Accuracy of Periapical Radiography and Cone-beam Computed Tomography in Identifying Root Canal Configuration of Human Premolars.

    Science.gov (United States)

    Sousa, Thiago Oliveira; Haiter-Neto, Francisco; Nascimento, Eduarda Helena Leandro; Peroni, Leonardo Vieira; Freitas, Deborah Queiroz; Hassan, Bassam

    2017-07-01

    The aim of this study was to assess the diagnostic accuracy of periapical radiography (PR) and cone-beam computed tomographic (CBCT) imaging in the detection of the root canal configuration (RCC) of human premolars. PR and CBCT imaging of 114 extracted human premolars were evaluated by 2 oral radiologists. RCC was recorded according to Vertucci's classification. Micro-computed tomographic imaging served as the gold standard to determine RCC. Accuracy, sensitivity, specificity, and predictive values were calculated. The Friedman test compared both PR and CBCT imaging with the gold standard. CBCT imaging showed higher values for all diagnostic tests compared with PR. Accuracy was 0.55 and 0.89 for PR and CBCT imaging, respectively. There was no difference between CBCT imaging and the gold standard, whereas PR differed from both CBCT and micro-computed tomographic imaging (P < .0001). CBCT imaging was more accurate than PR for evaluating different types of RCC individually. Canal configuration types III, VII, and "other" were poorly identified on CBCT imaging with a detection accuracy of 50%, 0%, and 43%, respectively. With PR, all canal configurations except type I were poorly visible. PR presented low performance in the detection of RCC in premolars, whereas CBCT imaging showed no difference compared with the gold standard. Canals with complex configurations were less identifiable using both imaging methods, especially PR. Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  10. Transcriptional profiling of human monocytes identifies the inhibitory receptor CD300a as regulator of transendothelial migration.

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    Sharang Ghavampour

    Full Text Available Local inflammatory responses are characterized by the recruitment of circulating leukocytes from the blood to sites of inflammation, a process requiring the directed migration of leukocytes across the vessel wall and hence a penetration of the endothelial lining. To identify underlying signalling events and novel factors involved in these processes we screened for genes differentially expressed in human monocytes following their adhesion to and passage through an endothelial monolayer. Functional annotation clustering of the genes identified revealed an overrepresentation of those associated with inflammation/immune response, in particular early monocyte to macrophage differentiation. Among the gene products so far not implicated in monocyte transendothelial migration was the inhibitory immune receptor CD300a. CD300a mRNA and protein levels were upregulated following transmigration and engagement of the receptor by anti-CD300a antibodies markedly reduced monocyte transendothelial migration. In contrast, siRNA mediated downregulation of CD300a in human monocytes increased their rate of migration. CD300a colocalized and cosedimented with actin filaments and, when activated, caused F-actin cytoskeleton alterations. Thus, monocyte transendothelial migration is accompanied by an elevation of CD300a which serves an inhibitory function possibly required for termination of the actual transmigration.

  11. Signature pathways identified from gene expression profiles in the human uterine cervix before and after spontaneous term parturition

    Science.gov (United States)

    HASSAN, Sonia S.; ROMERO, Roberto; TARCA, Adi L.; DRAGHICI, Sorin; PINELES, Beth; BUGRIM, Andrej; KHALEK, Nahla; CAMACHO, Natalia; MITTAL, Pooja; YOON, Bo Hyun; ESPINOZA, Jimmy; KIM, Chong Jai; SOROKIN, Yoram; MALONE, John

    2008-01-01

    Objective This study aimed to discover ‘signature pathways’ characterizing biological processes based on genes differentially expressed in the uterine cervix before and after spontaneous labor. Study Design The cervical transcriptome was previously characterized from biopsies taken before and after term labor. Pathway analysis was used to study the differentially expressed genes based on two gene-to-pathway annotation databases (KEGG and Metacore™). Over-represented and highly impacted pathways and connectivity nodes were identified. Results Fifty-two pathways in the Metacore™ database were significantly enriched in differentially expressed genes. Three of the top 5 pathways were known to be involved in cervical remodeling.Two novel pathways were: plasmin signaling and plasminogen activator urokinase (PLAU) signaling. The same analysis in the KEGG database identified 4 significant pathways, of which impact analysis confirmed. Multiple nodes providing connectivity within the plasmin and PLAU signaling pathways were identified.. Conclusions Three strategies for pathway analysis were consistent in their identification of novel, unexpected as well as expected networks, suggesting that this approach is both valid and effective for the elucidation of biological mechanisms involved in cervical dilation and remodeling. PMID:17826407

  12. Tartrazine and sunset yellow are xenoestrogens in a new screening assay to identify modulators of human oestrogen receptor transcriptional activity

    International Nuclear Information System (INIS)

    Axon, Andrew; May, Felicity E.B.; Gaughan, Luke E.; Williams, Faith M.; Blain, Peter G.; Wright, Matthew C.

    2012-01-01

    Primary biliary cirrhosis (PBC) is a cholestatic liver disease of unknown cause that occurs most frequently in post-menopausal women. Since the female sex hormone oestrogen can be cholestatic, we hypothesised that PBC may be triggered in part by chronic exposure to xenoestrogens (which may be more active on a background of low endogenous oestrogen levels seen in post-menopausal women). A reporter gene construct employing a synthetic oestrogen response element predicted to specifically interact with oestrogen receptors (ER) was constructed. Co-transfection of this reporter into an ER null cell line with a variety of nuclear receptor expression constructs indicated that the reporter gene was trans-activated by ERα and ERβ, but not by the androgen, thyroid, progesterone, glucocorticoid or vitamin D receptors. Chemicals linked to PBC were then screened for xenoestrogen activity in the human ERα-positive MCF-7 breast cancer cell line. Using this assay, the coal-derived food and cosmetic colourings – sunset yellow and tartrazine – were identified as novel human ERα activators, activating the human ER with an EC 50% concentration of 220 and 160 nM, respectively.

  13. Tartrazine and sunset yellow are xenoestrogens in a new screening assay to identify modulators of human oestrogen receptor transcriptional activity.

    Science.gov (United States)

    Axon, Andrew; May, Felicity E B; Gaughan, Luke E; Williams, Faith M; Blain, Peter G; Wright, Matthew C

    2012-08-16

    Primary biliary cirrhosis (PBC) is a cholestatic liver disease of unknown cause that occurs most frequently in post-menopausal women. Since the female sex hormone oestrogen can be cholestatic, we hypothesised that PBC may be triggered in part by chronic exposure to xenoestrogens (which may be more active on a background of low endogenous oestrogen levels seen in post-menopausal women). A reporter gene construct employing a synthetic oestrogen response element predicted to specifically interact with oestrogen receptors (ER) was constructed. Co-transfection of this reporter into an ER null cell line with a variety of nuclear receptor expression constructs indicated that the reporter gene was trans-activated by ERα and ERβ, but not by the androgen, thyroid, progesterone, glucocorticoid or vitamin D receptors. Chemicals linked to PBC were then screened for xenoestrogen activity in the human ERα-positive MCF-7 breast cancer cell line. Using this assay, the coal-derived food and cosmetic colourings--sunset yellow and tartrazine--were identified as novel human ERα activators, activating the human ER with an EC(50%) concentration of 220 and 160 nM, respectively. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  14. Comprehensive metabolomics identified lipid peroxidation as a prominent feature in human plasma of patients with coronary heart diseases

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    Jianhong Lu

    2017-08-01

    Full Text Available Coronary heart disease (CHD is a complex human disease associated with inflammation and oxidative stress. The underlying mechanisms and diagnostic biomarkers for the different types of CHD remain poorly defined. Metabolomics has been increasingly recognized as an enabling technique with the potential to identify key metabolomic features in an attempt to understand the pathophysiology and differentiate different stages of CHD. We performed comprehensive metabolomic analysis in human plasma from 28 human subjects with stable angina (SA, myocardial infarction (MI, and healthy control (HC. Subsequent analysis demonstrated a uniquely altered metabolic profile in these CHD: a total of 18, 37 and 36 differential metabolites were identified to distinguish SA from HC, MI from SA, and MI from HC groups respectively. Among these metabolites, glycerophospholipid (GPL metabolism emerged as the most significantly disturbed pathway. Next, we used a targeted metabolomic approach to systematically analyze GPL, oxidized phospholipid (oxPL, and downstream metabolites derived from polyunsaturated fatty acids (PUFAs, such as arachidonic acid and linoleic acid. Surprisingly, lipids associated with lipid peroxidation (LPO pathways including oxidized PL and isoprostanes, isomers of prostaglandins, were significantly elevated in plasma of MI patients comparing to HC and SA, consistent with the notion that oxidative stress-induced LPO is a prominent feature in CHD. Our studies using the state-of-the-art metabolomics help to understand the underlying biological mechanisms involved in the pathogenesis of CHD; LPO metabolites may serve as potential biomarkers to differentiation MI from SA and HC. Keywords: Metabolomics, Lipid peroxidation, Lipidomics, Myocardial infarction, Isoprostanes, Coronary heart disease (CHD

  15. Special Experts Meeting: Identifying and Overcoming Barriers to the Effective Consideration of Human and Organizational Factors in Event Analysis and Root Cause Analysis. Nuclear Energy Agency / Working Group on Human and Organizational Factors

    International Nuclear Information System (INIS)

    2011-01-01

    The main mission of the Nuclear Energy Agency (NEA) Working Group on Human and Organisational Factors (WGHOF) is to improve the understanding and treatment of human and organisational factors (HOF) within the nuclear industry in order to support the continued safety performance of nuclear installations and improve the effectiveness of regulatory practices in member countries. WGHOF developed a CSNI (Committee on the Safety of Nuclear Installations) Activity Proposal Sheet (CAPS) outlining the work and milestones necessary towards achieving the following objectives: - Identify barriers to analyzing and correctly identifying the Human and Organisational Factors (HOF) causes of events; - Identify barriers to implementing lessons learned from these analyses; and - Develop recommendations for overcoming these barriers to: improve the identification of HOF causes of events and support the successful implementation of appropriate corrective actions The CAPS can be found in Appendix A. The first activity under the plan was the development of a questionnaire. This was distributed to WGHOF members and their counterparts from the Working Group on Operating Experience (WGOE). The questionnaire was comprised of 20 questions based on the objectives of the CSNI Activity Proposed Sheet. The intended survey participants were licensees with previous experience conducting root cause analyses. Responses were received from 26 respondents from 11 different countries. The results of the questionnaire were analyzed to identify themes for further discussion during a specialist meeting planned for September 2009. The following themes were presented during the WGHOF meeting in March of 2009 and endorsed for further work: - Roles and Influence of Senior Management, - Skills and Knowledge of the Investigators, - Qualitative Nature of HOF, - Influence of the Regulator, - Systematic Approach to Investigation. A summary of the questionnaire responses is provided in Appendix B

  16. Native human autoantibodies targeting GIPC1 identify differential expression in malignant tumors of the breast and ovary

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    Yavelsky Victoria

    2008-08-01

    Full Text Available Abstract Background We have been studying the native humoral immune response to cancer and have isolated a library of fully human autoantibodies to a variety of malignancies. We previously described the isolation and characterization of two fully human monoclonal antibodies, 27.F7 and 27.B1, from breast cancer patients that target the protein known as GIPC1, an accessory PDZ-domain binding protein involved in regulation of G-protein signaling. Human monoclonal antibodies, 27.F7 and 27.B1, to GIPC1 demonstrate specific binding to malignant breast cancer tissue with no reactivity with normal breast tissue. Methods The current study employs cELISA, flow cytometry, Western blot analysis as well as immunocytochemistry, and immunohistochemistry. Data is analyzed statistically with the Fisher one-tail and two-tail tests for two independent samples. Results By screening several other cancer cell lines with 27.F7 and 27.B1 we found consistently strong staining of other human cancer cell lines including SKOV-3 (an ovarian cancer cell line. To further clarify the association of GIPC1 with breast and ovarian cancer we carefully studied 27.F7 and 27.B1 using immunocytochemical and immunohistochemical techniques. An immunohistochemical study of normal ovarian tissue, benign, borderline and malignant ovarian serous tumors, and different types of breast cancer revealed high expression of GIPC1 protein in neoplastic cells. Interestingly, antibodies 27.F7 and 27.B1 demonstrate differential staining of borderline ovarian tumors. Examination of different types of breast cancer demonstrates that the level of GIPC1 expression depends on tumor invasiveness and displays a higher expression than in benign tumors. Conclusion The present pilot study demonstrates that the GIPC1 protein is overexpressed in ovarian and breast cancer, which may provide an important diagnostic and prognostic marker and will constitute the basis for further study of the role that this protein

  17. Antibody Epitopes Identified in Critical Regions of Dengue Virus Nonstructural 1 Protein in Mouse Vaccination and Natural Human Infections.

    Science.gov (United States)

    Hertz, Tomer; Beatty, P Robert; MacMillen, Zachary; Killingbeck, Sarah S; Wang, Chunling; Harris, Eva

    2017-05-15

    Dengue is a global public health problem and is caused by four dengue virus (DENV) serotypes (DENV1-4). A major challenge in dengue vaccine development is that cross-reactive anti-DENV Abs can be protective or potentially increase disease via Ab-dependent enhancement. DENV nonstructural protein 1 (NS1) has long been considered a vaccine candidate as it avoids Ab-dependent enhancement. In this study, we evaluated survival to challenge in a lethal DENV vascular leak model in mice immunized with NS1 combined with aluminum and magnesium hydroxide, monophosphoryl lipid A + AddaVax, or Sigma adjuvant system+CpG DNA, compared with mice infected with a sublethal dose of DENV2 and mice immunized with OVA (negative control). We characterized Ab responses to DENV1, 2, and 3 NS1 using an Ag microarray tiled with 20-mer peptides overlapping by 15 aa and identified five regions of DENV NS1 with significant levels of Ab reactivity in the NS1 + monophosphoryl lipid A + AddaVax group. Additionally, we profiled the Ab responses to NS1 of humans naturally infected with DENV2 or DENV3 in serum samples from Nicaragua collected at acute, convalescent, and 12-mo timepoints. One region in the wing domain of NS1 was immunodominant in both mouse vaccination and human infection studies, and two regions were identified only in NS1-immunized mice; thus, vaccination can generate Abs to regions that are not targeted in natural infection and could provide additional protection against lethal DENV infection. Overall, we identified a small number of immunodominant regions, which were in functionally important locations on the DENV NS1 protein and are potential correlates of protection. Copyright © 2017 by The American Association of Immunologists, Inc.

  18. Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene.

    Science.gov (United States)

    Kayser, Manfred; Liu, Fan; Janssens, A Cecile J W; Rivadeneira, Fernando; Lao, Oscar; van Duijn, Kate; Vermeulen, Mark; Arp, Pascal; Jhamai, Mila M; van Ijcken, Wilfred F J; den Dunnen, Johan T; Heath, Simon; Zelenika, Diana; Despriet, Dominiek D G; Klaver, Caroline C W; Vingerling, Johannes R; de Jong, Paulus T V M; Hofman, Albert; Aulchenko, Yurii S; Uitterlinden, Andre G; Oostra, Ben A; van Duijn, Cornelia M

    2008-02-01

    Human iris color was one of the first traits for which Mendelian segregation was established. To date, the genetics of iris color is still not fully understood and is of interest, particularly in view of forensic applications. In three independent genome-wide association (GWA) studies of a total of 1406 persons and a genome-wide linkage study of 1292 relatives, all from the Netherlands, we found that the 15q13.1 region is the predominant region involved in human iris color. There were no other regions showing consistent genome-wide evidence for association and linkage to iris color. Single nucleotide polymorphisms (SNPs) in the HERC2 gene and, to a lesser extent, in the neighboring OCA2 gene were independently associated to iris color variation. OCA2 has been implicated in iris color previously. A replication study within two populations confirmed that the HERC2 gene is a new and significant determinant of human iris color variation, in addition to OCA2. Furthermore, HERC2 rs916977 showed a clinal allele distribution across 23 European populations, which was significantly correlated to iris color variation. We suggest that genetic variants regulating expression of the OCA2 gene exist in the HERC2 gene or, alternatively, within the 11.7 kb of sequence between OCA2 and HERC2, and that most iris color variation in Europeans is explained by those two genes. Testing markers in the HERC2-OCA2 region may be useful in forensic applications to predict eye color phenotypes of unknown persons of European genetic origin.

  19. Identifying Spatial Units of Human Occupation in the Brazilian Amazon Using Landsat and CBERS Multi-Resolution Imagery

    Directory of Open Access Journals (Sweden)

    Maria Isabel Sobral Escada

    2012-01-01

    Full Text Available Every spatial unit of human occupation is part of a network structuring an extensive process of urbanization in the Amazon territory. Multi-resolution remote sensing data were used to identify and map human presence and activities in the Sustainable Forest District of Cuiabá-Santarém highway (BR-163, west of Pará, Brazil. The limits of spatial units of human occupation were mapped based on digital classification of Landsat-TM5 (Thematic Mapper 5 image (30m spatial resolution. High-spatial-resolution CBERS-HRC (China-Brazil Earth Resources Satellite-High-Resolution Camera images (5 m merged with CBERS-CCD (Charge Coupled Device images (20 m were used to map spatial arrangements inside each populated unit, describing intra-urban characteristics. Fieldwork data validated and refined the classification maps that supported the categorization of the units. A total of 133 spatial units were individualized, comprising population centers as municipal seats, villages and communities, and units of human activities, such as sawmills, farmhouses, landing strips, etc. From the high-resolution analysis, 32 population centers were grouped in four categories, described according to their level of urbanization and spatial organization as: structured, recent, established and dependent on connectivity. This multi-resolution approach provided spatial information about the urbanization process and organization of the territory. It may be extended into other areas or be further used to devise a monitoring system, contributing to the discussion of public policy priorities for sustainable development in the Amazon.

  20. Identifying grade/stage-related active modules in human co-regulatory networks: a case study for breast cancer.

    Science.gov (United States)

    Feng, Chenchen; Chen, Lina; Li, Wan; Wang, Hong; Zhang, Liangcai; Jia, Xu; Miao, Zhengqiang; Qu, Xiaoli; Li, Weiguo; He, Weiming

    2012-12-01

    The histological grade/stage of tumor is widely acknowledged as an important clinical prognostic factor for cancer progression. Recent experimental studies have explored the following two topics at the molecular level: (1) whether or not gene expression levels vary by different degrees among different tumor grades/stages, and (2) whether some well-defined modules could distinguish one grade/stage from another. In this article, using breast cancer as an example, we investigated this topic and identified grade/stage-related active modules under the framework of a weighted network integrated from a human protein interaction network and a transcriptional regulatory network. Our results enabled us to draw the conclusion that the gene expression profile could provide more clues about tumor grade, but reveals less evidence about tumor stage. In addition, we found that our modular biomarker method had additional advantages in identifying some tumor grade/stage-related genes with slightly altered expression. According to our case study, the framework we introduced could be used for other cancers to identify their modules during grading or staging.

  1. Validation of case-finding algorithms derived from administrative data for identifying adults living with human immunodeficiency virus infection.

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    Tony Antoniou

    Full Text Available OBJECTIVE: We sought to validate a case-finding algorithm for human immunodeficiency virus (HIV infection using administrative health databases in Ontario, Canada. METHODS: We constructed 48 case-finding algorithms using combinations of physician billing claims, hospital and emergency room separations and prescription drug claims. We determined the test characteristics of each algorithm over various time frames for identifying HIV infection, using data abstracted from the charts of 2,040 randomly selected patients receiving care at two medical practices in Toronto, Ontario as the reference standard. RESULTS: With the exception of algorithms using only a single physician claim, the specificity of all algorithms exceeded 99%. An algorithm consisting of three physician claims over a three year period had a sensitivity and specificity of 96.2% (95% CI 95.2%-97.9% and 99.6% (95% CI 99.1%-99.8%, respectively. Application of the algorithm to the province of Ontario identified 12,179 HIV-infected patients in care for the period spanning April 1, 2007 to March 31, 2009. CONCLUSIONS: Case-finding algorithms generated from administrative data can accurately identify adults living with HIV. A relatively simple "3 claims in 3 years" definition can be used for assembling a population-based cohort and facilitating future research examining trends in health service use and outcomes among HIV-infected adults in Ontario.

  2. Who’s Who at the Border? A rights-based approach to identifying human trafficking at international borders

    Directory of Open Access Journals (Sweden)

    Marika McAdam

    2013-09-01

    Full Text Available International borders are widely touted as bastions in the fight against trafficking in persons. This article acknowledges the important role border officials play in preventing human trafficking, but calls for expectations to be tempered by deference to the conceptual complexity of cross-border trafficking and the migration processes involved. The fact that many trafficked victims begin their journeys as irregular or smuggled migrants highlights the challenge posed to border officials in identifying trafficked persons among the people they encounter. Indicators of trafficking generally relate to the exploitation phase, leaving border officials with little guidance as to how persons vulnerable to trafficking can be accurately identified before any exploitation has occurred. Ultimately, this paper advocates a pragmatic rights-based approach in designating anti-trafficking functions to border officials. A rights-based approach to border control acknowledges the core work of border officials as being to uphold border integrity, while ensuring that their performance of this role does not jeopardise the rights of those they intercept nor result in missed opportunities for specialists to identify trafficked persons and other vulnerable people among them.

  3. Meta-analysis of genome-wide association studies identifies 8 novel loci involved in shape variation of human head hair.

    Science.gov (United States)

    Liu, Fan; Chen, Yan; Zhu, Gu; Hysi, Pirro G; Wu, Sijie; Adhikari, Kaustubh; Breslin, Krystal; Pospiech, Ewelina; Hamer, Merel A; Peng, Fuduan; Muralidharan, Charanya; Acuna-Alonzo, Victor; Canizales-Quinteros, Samuel; Bedoya, Gabriel; Gallo, Carla; Poletti, Giovanni; Rothhammer, Francisco; Bortolini, Maria Catira; Gonzalez-Jose, Rolando; Zeng, Changqing; Xu, Shuhua; Jin, Li; Uitterlinden, André G; Ikram, M Arfan; van Duijn, Cornelia M; Nijsten, Tamar; Walsh, Susan; Branicki, Wojciech; Wang, Sijia; Ruiz-Linares, Andrés; Spector, Timothy D; Martin, Nicholas G; Medland, Sarah E; Kayser, Manfred

    2018-02-01

    Shape variation of human head hair shows striking variation within and between human populations, while its genetic basis is far from being understood. We performed a series of genome-wide association studies (GWASs) and replication studies in a total of 28 964 subjects from 9 cohorts from multiple geographic origins. A meta-analysis of three European GWASs identified 8 novel loci (1p36.23 ERRFI1/SLC45A1, 1p36.22 PEX14, 1p36.13 PADI3, 2p13.3 TGFA, 11p14.1 LGR4, 12q13.13 HOXC13, 17q21.2 KRTAP, and 20q13.33 PTK6), and confirmed 4 previously known ones (1q21.3 TCHH/TCHHL1/LCE3E, 2q35 WNT10A, 4q21.21 FRAS1, and 10p14 LINC00708/GATA3), all showing genome-wide significant association with hair shape (P < 5e-8). All except one (1p36.22 PEX14) were replicated with nominal significance in at least one of the 6 additional cohorts of European, Native American and East Asian origins. Three additional previously known genes (EDAR, OFCC1, and PRSS53) were confirmed at the nominal significance level. A multivariable regression model revealed that 14 SNPs from different genes significantly and independently contribute to hair shape variation, reaching a cross-validated AUC value of 0.66 (95% CI: 0.62-0.70) and an AUC value of 0.64 in an independent validation cohort, providing an improved accuracy compared with a previous model. Prediction outcomes of 2504 individuals from a multiethnic sample were largely consistent with general knowledge on the global distribution of hair shape variation. Our study thus delivers target genes and DNA variants for future functional studies to further evaluate the molecular basis of hair shape in humans. © The Author(s) 2017. Published by Oxford University Press.

  4. Meta-analysis of genome-wide association studies identifies 8 novel loci involved in shape variation of human head hair

    Science.gov (United States)

    Liu, Fan; Chen, Yan; Zhu, Gu; Hysi, Pirro G; Wu, Sijie; Adhikari, Kaustubh; Breslin, Krystal; Pośpiech, Ewelina; Hamer, Merel A; Peng, Fuduan; Muralidharan, Charanya; Acuna-Alonzo, Victor; Canizales-Quinteros, Samuel; Bedoya, Gabriel; Gallo, Carla; Poletti, Giovanni; Rothhammer, Francisco; Bortolini, Maria Catira; Gonzalez-Jose, Rolando; Zeng, Changqing; Xu, Shuhua; Jin, Li; Uitterlinden, André G; Ikram, M Arfan; van Duijn, Cornelia M; Nijsten, Tamar; Walsh, Susan; Branicki, Wojciech; Wang, Sijia; Ruiz-Linares, Andrés; Spector, Timothy D; Martin, Nicholas G; Medland, Sarah E; Kayser, Manfred

    2018-01-01

    Abstract Shape variation of human head hair shows striking variation within and between human populations, while its genetic basis is far from being understood. We performed a series of genome-wide association studies (GWASs) and replication studies in a total of 28 964 subjects from 9 cohorts from multiple geographic origins. A meta-analysis of three European GWASs identified 8 novel loci (1p36.23 ERRFI1/SLC45A1, 1p36.22 PEX14, 1p36.13 PADI3, 2p13.3 TGFA, 11p14.1 LGR4, 12q13.13 HOXC13, 17q21.2 KRTAP, and 20q13.33 PTK6), and confirmed 4 previously known ones (1q21.3 TCHH/TCHHL1/LCE3E, 2q35 WNT10A, 4q21.21 FRAS1, and 10p14 LINC00708/GATA3), all showing genome-wide significant association with hair shape (P < 5e-8). All except one (1p36.22 PEX14) were replicated with nominal significance in at least one of the 6 additional cohorts of European, Native American and East Asian origins. Three additional previously known genes (EDAR, OFCC1, and PRSS53) were confirmed at the nominal significance level. A multivariable regression model revealed that 14 SNPs from different genes significantly and independently contribute to hair shape variation, reaching a cross-validated AUC value of 0.66 (95% CI: 0.62–0.70) and an AUC value of 0.64 in an independent validation cohort, providing an improved accuracy compared with a previous model. Prediction outcomes of 2504 individuals from a multiethnic sample were largely consistent with general knowledge on the global distribution of hair shape variation. Our study thus delivers target genes and DNA variants for future functional studies to further evaluate the molecular basis of hair shape in humans. PMID:29220522

  5. Laboratory Grouping Based on Previous Courses.

    Science.gov (United States)

    Doemling, Donald B.; Bowman, Douglas C.

    1981-01-01

    In a five-year study, second-year human physiology students were grouped for laboratory according to previous physiology and laboratory experience. No significant differences in course or board examination performance were found, though correlations were found between predental grade-point averages and grouping. (MSE)

  6. Functional requirements for the man-vehicle systems research facility. [identifying and correcting human errors during flight simulation

    Science.gov (United States)

    Clement, W. F.; Allen, R. W.; Heffley, R. K.; Jewell, W. F.; Jex, H. R.; Mcruer, D. T.; Schulman, T. M.; Stapleford, R. L.

    1980-01-01

    The NASA Ames Research Center proposed a man-vehicle systems research facility to support flight simulation studies which are needed for identifying and correcting the sources of human error associated with current and future air carrier operations. The organization of research facility is reviewed and functional requirements and related priorities for the facility are recommended based on a review of potentially critical operational scenarios. Requirements are included for the experimenter's simulation control and data acquisition functions, as well as for the visual field, motion, sound, computation, crew station, and intercommunications subsystems. The related issues of functional fidelity and level of simulation are addressed, and specific criteria for quantitative assessment of various aspects of fidelity are offered. Recommendations for facility integration, checkout, and staffing are included.

  7. Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design.

    Directory of Open Access Journals (Sweden)

    Thomas S Peat

    Full Text Available A fragment-based screen against human immunodeficiency virus type 1 (HIV integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework for the development of a new series of HIV integrase inhibitors that do not bind to the catalytic site of the enzyme.

  8. Metastasis-related plasma membrane proteins of human breast cancer cells identified by comparative quantitative mass spectrometry

    DEFF Research Database (Denmark)

    Leth-Larsen, Rikke; Lund, Rikke; Hansen, Helle V

    2009-01-01

    The spread of cancer cells from a primary tumor to form metastasis at distant sites is a complex multi-step process. The cancer cell proteins, and plasma membrane proteins in particular, involved in this process are poorly defined and a study of the very early events of the metastatic process using...... clinical samples or in vitro assays is not feasible. We have used a unique model system consisting of two isogenic human breast cancer cell lines that are equally tumorigenic in mice, but while one gives rise to metastasis, the other disseminates single cells that remain dormant at distant organs. Membrane......'-nucleotidase (ecto-5'-NT, CD73), Ndrg1, integrin beta1, CD44, CD74 and MHC class II proteins. The altered expression levels of proteins identified by LC-MS/MS were validated using flow cytometry, Western blotting, immunocyto- and immunohisto-chemistry. Analysis of clinical breast cancer biopsies demonstrated...

  9. Qualitative modeling identifies IL-11 as a novel regulator in maintaining self-renewal in human pluripotent stem cells

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    Hedi ePeterson

    2013-10-01

    Full Text Available Pluripotency in human embryonic stem cells (hESCs and induced pluripotent stem cells (iPSCs is regulated by three transcription factors - OCT3/4, SOX2 and NANOG. To fully exploit the therapeutic potential of these cells it is essential to have a good mechanistic understanding of the maintenance of self-renewal and pluripotency. In this study, we demonstrate a powerful systems biology approach in which we first expand literature-based network encompassing the core regulators of pluripotency by assessing the behaviour of genes targeted by perturbation experiments. We focused our attention on highly regulated genes encoding cell surface and secreted proteins as these can be more easily manipulated by the use of inhibitors or recombinant proteins. Qualitative modeling based on combining boolean networks and in silico perturbation experiments were employed to identify novel pluripotency-regulating genes. We validated Interleukin-11 (IL-11 and demonstrate that this cytokine is a novel pluripotency-associated factor capable of supporting self-renewal in the absence of exogenously added bFGF in culture. To date, the various protocols for hESCs maintenance require supplementation with bFGF to activate the Activin/Nodal branch of the TGFβ signaling pathway. Additional evidence supporting our findings is that IL-11 belongs to the same protein family as LIF, which is known to be necessary for maintaining pluripotency in mouse but not in human ESCs. These cytokines operate through the same gp130 receptor which interacts with Janus kinases. Our finding might explain why mESCs are in a more naïve cell state compared to hESCs and how to convert primed hESCs back to the naïve state. Taken together, our integrative modeling approach has identified novel genes as putative candidates to be incorporated into the expansion of the current gene regulatory network responsible for inducing and maintaining pluripotency.

  10. Release of skeletal muscle peptide fragments identifies individual proteins degraded during insulin deprivation in type 1 diabetic humans and mice.

    Science.gov (United States)

    Robinson, Matthew M; Dasari, Surendra; Karakelides, Helen; Bergen, H Robert; Nair, K Sreekumaran

    2016-09-01

    Insulin regulates skeletal muscle protein degradation, but the types of proteins being degraded in vivo remain to be determined due to methodological limitations. We present a method to assess the types of skeletal muscle proteins that are degraded by extracting their degradation products as low-molecular weight (LMW) peptides from muscle samples. High-resolution mass spectrometry was used to identify the original intact proteins that generated the LMW peptides, which we validated in rodents and then applied to humans. We deprived insulin from insulin-treated streptozotocin (STZ) diabetic mice for 6 and 96 h and for 8 h in type 1 diabetic humans (T1D) for comparison with insulin-treated conditions. Protein degradation was measured using activation of autophagy and proteasome pathways, stable isotope tracers, and LMW approaches. In mice, insulin deprivation activated proteasome pathways and autophagy in muscle homogenates and isolated mitochondria. Reproducibility analysis of LMW extracts revealed that ∼80% of proteins were detected consistently. As expected, insulin deprivation increased whole body protein turnover in T1D. Individual protein degradation increased with insulin deprivation, including those involved in mitochondrial function, proteome homeostasis, nDNA support, and contractile/cytoskeleton. Individual mitochondrial proteins that generated more LMW fragment with insulin deprivation included ATP synthase subunit-γ (+0.5-fold, P = 0.007) and cytochrome c oxidase subunit 6 (+0.305-fold, P = 0.03). In conclusion, identifying LMW peptide fragments offers an approach to determine the degradation of individual proteins. Insulin deprivation increases degradation of select proteins and provides insight into the regulatory role of insulin in maintaining proteome homeostasis, especially of mitochondria. Copyright © 2016 the American Physiological Society.

  11. Metaproteomics of saliva identifies human protein markers specific for individuals with periodontitis and dental caries compared to orally healthy controls

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    Daniel Belstrøm

    2016-09-01

    Full Text Available Background The composition of the salivary microbiota has been reported to differentiate between patients with periodontitis, dental caries and orally healthy individuals. To identify characteristics of diseased and healthy saliva we thus wanted to compare saliva metaproteomes from patients with periodontitis and dental caries to healthy individuals. Methods Stimulated saliva samples were collected from 10 patients with periodontitis, 10 patients with dental caries and 10 orally healthy individuals. The proteins in the saliva samples were subjected to denaturing buffer and digested enzymatically with LysC and trypsin. The resulting peptide mixtures were cleaned up by solid-phase extraction and separated online with 2 h gradients by nano-scale C18 reversed-phase chromatography connected to a mass spectrometer through an electrospray source. The eluting peptides were analyzed on a tandem mass spectrometer operated in data-dependent acquisition mode. Results We identified a total of 35,664 unique peptides from 4,161 different proteins, of which 1,946 and 2,090 were of bacterial and human origin, respectively. The human protein profiles displayed significant overexpression of the complement system and inflammatory markers in periodontitis and dental caries compared to healthy controls. Bacterial proteome profiles and functional annotation were very similar in health and disease. Conclusions Overexpression of proteins related to the complement system and inflammation seems to correlate with oral disease status. Similar bacterial proteomes in healthy and diseased individuals suggests that the salivary microbiota predominantly thrives in a planktonic state expressing no disease-associated characteristics of metabolic activity.

  12. Comparative transcriptomic analysis identifies genes differentially expressed in human epicardial progenitors and hiPSC-derived cardiac progenitors.

    Science.gov (United States)

    Synnergren, Jane; Drowley, Lauren; Plowright, Alleyn T; Brolén, Gabriella; Goumans, Marie-José; Gittenberger-de Groot, Adriana C; Sartipy, Peter; Wang, Qing-Dong

    2016-11-01

    Regenerative therapies hold great potential to change the treatment paradigm for cardiac diseases. Human cardiac progenitor cells can be used for drug discovery in this area and also provide a renewable source of cardiomyocytes. However, a better understanding of their characteristics is critical for interpreting data obtained from drug screening using these cells. In the present study, we performed global transcriptional analysis of two important sources of cardiac progenitors, i.e., patient epicardium-derived cells (EPDCs) and cardiac progenitor cells (CPCs) derived from human induced pluripotent stem cells. In addition, we also compared the gene expression profiles of these cells when they were cultured under normoxic and hypoxic conditions. We identified 3,289 mRNAs that were differentially expressed between EPDCs and CPCs. Gene ontology annotation and pathway enrichment analyses further revealed possible unique functions of these two cell populations. Notably, the impact of hypoxia vs normoxia on gene expression was modest and only a few genes (e.g., AK4, ALDOC, BNIP3P1, PGK1, and SLC2A1) were upregulated in EPDCs and CPCs after the cells were exposed to low oxygen for 24 h. Finally, we also performed a focused analysis of the gene expression patterns of a predefined set of 92 paracrine factors. We identified 30 of these genes as differentially expressed, and 29 were expressed at higher levels in EPDCs compared with CPCs. Taken together, the results of the present study advance our understanding of the transcriptional programs in EPDCs and CPCs and highlights important differences and similarities between these cell populations. Copyright © 2016 the American Physiological Society.

  13. Identifying the effects of visceral interoception on human brain connectome: A multivariate analysis of covariance of fMRI data.

    Science.gov (United States)

    Jarrahi, Behnaz; Mantini, Dante

    2016-08-01

    Sources of variations in the neural circuitry of the human brain and interrelationship between intrinsic connectivity networks (ICNs) are still a matter of debate and ongoing research. Here, we applied a multivariate analysis of covariance (MANCOVA) based on high-dimensional independent component analysis (ICA) to identify the effects of interoception and related variables on human brain connectome. Fifteen healthy right-handed subjects (all females, age range 21 - 48 years; mean age = 30.3, SD = 8.7 years) underwent a blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) that included continuous intravesical saline infusion and drainage. The design matrix included the intravesical fullness, subject fullness rating, normalized right and left insula thickness, age, and neuropsychological assessments (Mini-Mental State Exam; MMSE, and Hospital Anxiety and Depression Scale; HADS) as covariates of interest. Univariate tests were also performed with a reduced design matrix (p effects of interoception (intravesical fullness) on spatial map intensity of the salience network (anchored by insula and anterior cingulate cortex) and the frontoparietal central executive network, The left and right insula thickness influenced the spatial map intensity of the subcortical network, and the attention/cognitive and default-mode networks, respectively. The intravesical fullness also showed an effect on the spectral power of the subcortical network. Further investigations of the effect of internal (bodily) sensations on the ICN properties can provide an invaluable tool for understanding the role of interoception in health and illness.

  14. A Cost Benefit Analysis Approach to Identify Improvements in Merchant Navy Deck Officers’ HELM (Human Element Leadership and Management Training

    Directory of Open Access Journals (Sweden)

    Farhan Saeed

    2016-12-01

    Full Text Available A review of maritime accidents conducted over the last decade confirms that human error is the main contributing factor in these incidents. Well-developed Non-Technical Skills (NTS can reduce the effects of human error. NTS include both interpersonal and cognitive skills such as situation awareness, teamwork, decision-making, leadership, managerial skills, communication and language skills. In a crisis situation good NTS allow a deck officer to recognise the problem quickly, take action to manage the situation, and utilise the available team members safely and effectively. This paper identifies the importance of NTS training for merchant navy deck officers. It also highlights room for improvement in the existing HELM training. Research has shown that at present the structure of HELM training is not very effective. The other safety critical domains’ efforts into NTS developments are investigated and examples of best practice are adapted into the maritime domain’s NTS training. Suggestions are given for improvements to the HELM course based on proven successful methods in other safety critical domains (aviation and anaesthesia. A subsequent Cost Benefit Analysis for improving deck officers’ NTS is also carried out through the use of Bayesian Networks and Decision Tree Modelling.

  15. A three-dimensional human model of the fibroblast activation that accompanies bronchopulmonary dysplasia identifies Notch-mediated pathophysiology.

    Science.gov (United States)

    Sucre, Jennifer M S; Wilkinson, Dan; Vijayaraj, Preethi; Paul, Manash; Dunn, Bruce; Alva-Ornelas, Jackelyn A; Gomperts, Brigitte N

    2016-05-15

    Bronchopulmonary dysplasia (BPD) is a leading complication of premature birth and occurs primarily in infants delivered during the saccular stage of lung development. Histopathology shows decreased alveolarization and a pattern of fibroblast proliferation and differentiation to the myofibroblast phenotype. Little is known about the molecular pathways and cellular mechanisms that define BPD pathophysiology and progression. We have developed a novel three-dimensional human model of the fibroblast activation associated with BPD, and using this model we have identified the Notch pathway as a key driver of fibroblast activation and proliferation in response to changes in oxygen. Fetal lung fibroblasts were cultured on sodium alginate beads to generate lung organoids. After exposure to alternating hypoxia and hyperoxia, the organoids developed a phenotypic response characterized by increased α-smooth muscle actin (α-SMA) expression and other genes known to be upregulated in BPD and also demonstrated increased expression of downstream effectors of the Notch pathway. Inhibition of Notch with a γ-secretase inhibitor prevented the development of the pattern of cellular proliferation and α-SMA expression in our model. Analysis of human autopsy tissue from the lungs of infants who expired with BPD demonstrated evidence of Notch activation within fibrotic areas of the alveolar septae, suggesting that Notch may be a key driver of BPD pathophysiology. Copyright © 2016 the American Physiological Society.

  16. Novel mitochondria-targeted heat-soluble proteins identified in the anhydrobiotic Tardigrade improve osmotic tolerance of human cells.

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    Sae Tanaka

    Full Text Available Tardigrades are able to tolerate almost complete dehydration through transition to a metabolically inactive state, called "anhydrobiosis". Late Embryogenesis Abundant (LEA proteins are heat-soluble proteins involved in the desiccation tolerance of many anhydrobiotic organisms. Tardigrades, Ramazzottius varieornatus, however, express predominantly tardigrade-unique heat-soluble proteins: CAHS (Cytoplasmic Abundant Heat Soluble and SAHS (Secretory Abundant Heat Soluble proteins, which are secreted or localized in most intracellular compartments, except the mitochondria. Although mitochondrial integrity is crucial to ensure cellular survival, protective molecules for mitochondria have remained elusive. Here, we identified two novel mitochondrial heat-soluble proteins, RvLEAM and MAHS (Mitochondrial Abundant Heat Soluble, as potent mitochondrial protectants from Ramazzottius varieornatus. RvLEAM is a group3 LEA protein and immunohistochemistry confirmed its mitochondrial localization in tardigrade cells. MAHS-green fluorescent protein fusion protein localized in human mitochondria and was heat-soluble in vitro, though no sequence similarity with other known proteins was found, and one region was conserved among tardigrades. Furthermore, we demonstrated that RvLEAM protein as well as MAHS protein improved the hyperosmotic tolerance of human cells. The findings of the present study revealed that tardigrade mitochondria contain at least two types of heat-soluble proteins that might have protective roles in water-deficient environments.

  17. Expression and function analysis of mitotic checkpoint genes identifies TTK as a potential therapeutic target for human hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Xiao-Dong Liang

    Full Text Available The mitotic spindle checkpoint (SAC genes have been considered targets of anticancer therapies. Here, we sought to identify the attractive mitotic spindle checkpoint genes appropriate for human hepatocellular carcinoma (HCC therapies. Through expression profile analysis of 137 selected mitotic spindle checkpoint genes in the publicly available microarray datasets, we showed that 13 genes were dramatically up-regulated in HCC tissues compared to normal livers and adjacent non-tumor tissues. A role of the 13 genes in proliferation was evaluated by knocking them down via small interfering RNA (siRNA in HCC cells. As a result, several mitotic spindle checkpoint genes were required for maintaining the proliferation of HCC cells, demonstrated by cell viability assay and soft agar colony formation assay. Then we established sorafenib-resistant sublines of HCC cell lines Huh7 and HepG2. Intriguingly, increased TTK expression was significantly associated with acquired sorafenib-resistance in Huh7, HepG2 cells. More importantly, TTK was observably up-regulated in 46 (86.8% of 53 HCC specimens. A series of in vitro and in vivo functional experiment assays showed that TTK overexpression promoted cell proliferation, anchor-dependent colony formation and resistance to sorafenib of HCC cells; TTK knockdown restrained cell growth, soft agar colony formation and resistance to sorafenib of HCC cells. Collectively, TTK plays an important role in proliferation and sorafenib resistance and could act as a potential therapeutic target for human hepatocellular carcinoma.

  18. Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling.

    Directory of Open Access Journals (Sweden)

    Wei Li

    2008-01-01

    Full Text Available Specificity of protein ubiquitylation is conferred by E3 ubiquitin (Ub ligases. We have annotated approximately 617 putative E3s and substrate-recognition subunits of E3 complexes encoded in the human genome. The limited knowledge of the function of members of the large E3 superfamily prompted us to generate genome-wide E3 cDNA and RNAi expression libraries designed for functional screening. An imaging-based screen using these libraries to identify E3s that regulate mitochondrial dynamics uncovered MULAN/FLJ12875, a RING finger protein whose ectopic expression and knockdown both interfered with mitochondrial trafficking and morphology. We found that MULAN is a mitochondrial protein - two transmembrane domains mediate its localization to the organelle's outer membrane. MULAN is oriented such that its E3-active, C-terminal RING finger is exposed to the cytosol, where it has access to other components of the Ub system. Both an intact RING finger and the correct subcellular localization were required for regulation of mitochondrial dynamics, suggesting that MULAN's downstream effectors are proteins that are either integral to, or associated with, mitochondria and that become modified with Ub. Interestingly, MULAN had previously been identified as an activator of NF-kappaB, thus providing a link between mitochondrial dynamics and mitochondria-to-nucleus signaling. These findings suggest the existence of a new, Ub-mediated mechanism responsible for integration of mitochondria into the cellular environment.

  19. Identifying selected regions from heterozygosity and divergence using a light-coverage genomic dataset from two human populations.

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    Taras K Oleksyk

    2008-03-01

    Full Text Available When a selective sweep occurs in the chromosomal region around a target gene in two populations that have recently separated, it produces three dramatic genomic consequences: 1 decreased multi-locus heterozygosity in the region; 2 elevated or diminished genetic divergence (F(ST of multiple polymorphic variants adjacent to the selected locus between the divergent populations, due to the alternative fixation of alleles; and 3 a consequent regional increase in the variance of F(ST (S(2F(ST for the same clustered variants, due to the increased alternative fixation of alleles in the loci surrounding the selection target. In the first part of our study, to search for potential targets of directional selection, we developed and validated a resampling-based computational approach; we then scanned an array of 31 different-sized moving windows of SNP variants (5-65 SNPs across the human genome in a set of European and African American population samples with 183,997 SNP loci after correcting for the recombination rate variation. The analysis revealed 180 regions of recent selection with very strong evidence in either population or both. In the second part of our study, we compared the newly discovered putative regions to those sites previously postulated in the literature, using methods based on inspecting patterns of linkage disequilibrium, population divergence and other methodologies. The newly found regions were cross-validated with those found in nine other studies that have searched for selection signals. Our study was replicated especially well in those regions confirmed by three or more studies. These validated regions were independently verified, using a combination of different methods and different databases in other studies, and should include fewer false positives. The main strength of our analysis method compared to others is that it does not require dense genotyping and therefore can be used with data from population-based genome SNP scans

  20. Human Leptospirosis Infection in Fiji: An Eco-epidemiological Approach to Identifying Risk Factors and Environmental Drivers for Transmission.

    Science.gov (United States)

    Lau, Colleen L; Watson, Conall H; Lowry, John H; David, Michael C; Craig, Scott B; Wynwood, Sarah J; Kama, Mike; Nilles, Eric J

    2016-01-01

    Leptospirosis is an important zoonotic disease in the Pacific Islands. In Fiji, two successive cyclones and severe flooding in 2012 resulted in outbreaks with 576 reported cases and 7% case-fatality. We conducted a cross-sectional seroprevalence study and used an eco-epidemiological approach to characterize risk factors and drivers for human leptospirosis infection in Fiji, and aimed to provide an evidence base for improving the effectiveness of public health mitigation and intervention strategies. Antibodies indicative of previous or recent infection were found in 19.4% of 2152 participants (81 communities on the 3 main islands). Questionnaires and geographic information systems data were used to assess variables related to demographics, individual behaviour, contact with animals, socioeconomics, living conditions, land use, and the natural environment. On multivariable logistic regression analysis, variables associated with the presence of Leptospira antibodies included male gender (OR 1.55), iTaukei ethnicity (OR 3.51), living in villages (OR 1.64), lack of treated water at home (OR 1.52), working outdoors (1.64), living in rural areas (OR 1.43), high poverty rate (OR 1.74), living district (OR 1.04 per head/sqkm), and high maximum rainfall in the wettest month (OR 1.003 per mm). Risk factors and drivers for human leptospirosis infection in Fiji are complex and multifactorial, with environmental factors playing crucial roles. With global climate change, severe weather events and flooding are expected to intensify in the South Pacific. Population growth could also lead to more intensive livestock farming; and urbanization in developing countries is often associated with urban and peri-urban slums where diseases of poverty proliferate. Climate change, flooding, population growth, urbanization, poverty and agricultural intensification are important drivers of zoonotic disease transmission; these factors may independently, or potentially synergistically, lead to

  1. Identifying and Measuring the Lifelong Human Capital of “Unskilled” Migrants in the Mexico-US Migratory Circuit

    Directory of Open Access Journals (Sweden)

    Jacqueline Hagan

    2014-05-01

    Full Text Available Most human capital and migration studies classify migrants with limited formal education as “unskilled,” despite substantial skills developed through job and life experiences.  Drawing on a binational multi-stage research project that involved interviews with 320 Mexican migrants and return migrants in North Carolina and Guanajuato, Mexico, we identify the lifelong human capital they acquired and transferred throughout their careers and discover that these include not only basic education and English, but also technical and social skills and competences acquired informally on and off the job throughout the course of one’s life.  We further find that the learning and transfer of skills is a lifelong, gendered process, reflecting the different social contexts and jobs in which men and women learn. In this paper we document several mobility pathways associated with the acquisition and transfer of skills across the migratory circuit, including reskilling, occupational mobility, job jumping, and entrepreneurship.Our study has broad implications for the migration policies of both the US and Mexico.  US immigration policy confers preference to “skilled” immigrants who rank high on traditional human capital characteristics, such as education levels and other formal credentials, but limits the entry of “unskilled” migrants, a categorization that ignores the substantial informal skills they bring to US labor markets.  Instead of focusing only on the continued expansion of immigration policy preferences for narrowly defined skilled migrants, the US government needs to consider more carefully what we mean by skilled workers and design fairer and more effective immigration policies that match their abilities to the specific needs of US industry and thereby recognize the economic contributions of all migrants within a lifelong human capital framework. Mexico can also learn from our findings. Between 2005 and 2010 an estimated 1.4 million

  2. Potential hazards to embryo implantation: A human endometrial in vitro model to identify unwanted antigestagenic actions of chemicals

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, L.; Deppert, W.R. [Department of Obstetrics and Gynecology, University Hospital Freiburg (Germany); Pfeifer, D. [Department of Hematology and Oncology, University Hospital Freiburg (Germany); Stanzel, S.; Weimer, M. [Department of Biostatistics, German Cancer Research Center, Heidelberg (Germany); Hanjalic-Beck, A.; Stein, A.; Straßer, M.; Zahradnik, H.P. [Department of Obstetrics and Gynecology, University Hospital Freiburg (Germany); Schaefer, W.R., E-mail: wolfgang.schaefer@uniklinik-freiburg.de [Department of Obstetrics and Gynecology, University Hospital Freiburg (Germany)

    2012-05-01

    Embryo implantation is a crucial step in human reproduction and depends on the timely development of a receptive endometrium. The human endometrium is unique among adult tissues due to its dynamic alterations during each menstrual cycle. It hosts the implantation process which is governed by progesterone, whereas 17β-estradiol regulates the preceding proliferation of the endometrium. The receptors for both steroids are targets for drugs and endocrine disrupting chemicals. Chemicals with unwanted antigestagenic actions are potentially hazardous to embryo implantation since many pharmaceutical antiprogestins adversely affect endometrial receptivity. This risk can be addressed by human tissue-specific in vitro assays. As working basis we compiled data on chemicals interacting with the PR. In our experimental work, we developed a flexible in vitro model based on human endometrial Ishikawa cells. Effects of antiprogestin compounds on pre-selected target genes were characterized by sigmoidal concentration–response curves obtained by RT-qPCR. The estrogen sulfotransferase (SULT1E1) was identified as the most responsive target gene by microarray analysis. The agonistic effect of progesterone on SULT1E1 mRNA was concentration-dependently antagonized by RU486 (mifepristone) and ZK137316 and, with lower potency, by 4-nonylphenol, bisphenol A and apigenin. The negative control methyl acetoacetate showed no effect. The effects of progesterone and RU486 were confirmed on the protein level by Western blotting. We demonstrated proof of principle that our Ishikawa model is suitable to study quantitatively effects of antiprogestin-like chemicals on endometrial target genes in comparison to pharmaceutical reference compounds. This test is useful for hazard identification and may contribute to reduce animal studies. -- Highlights: ► We compare progesterone receptor-mediated endometrial effects of chemicals and drugs. ► 4-Nonylphenol, bisphenol A and apigenin exert weak

  3. Uterine rupture without previous caesarean delivery

    DEFF Research Database (Denmark)

    Thisted, Dorthe L. A.; H. Mortensen, Laust; Krebs, Lone

    2015-01-01

    OBJECTIVE: To determine incidence and patient characteristics of women with uterine rupture during singleton births at term without a previous caesarean delivery. STUDY DESIGN: Population based cohort study. Women with term singleton birth, no record of previous caesarean delivery and planned...... vaginal delivery (n=611,803) were identified in the Danish Medical Birth Registry (1997-2008). Medical records from women recorded with uterine rupture during labour were reviewed to ascertain events of complete uterine rupture. Relative Risk (RR) and adjusted Relative Risk Ratio (aRR) of complete uterine...... rupture with 95% confidence intervals (95% CI) were ascertained according to characteristics of the women and of the delivery. RESULTS: We identified 20 cases with complete uterine rupture. The incidence of complete uterine rupture among women without previous caesarean delivery was about 3...

  4. Gene-expression Analysis Identifies Specific Patterns of Dysregulated Molecular Pathways and Genetic Subgroups of Human Hepatocellular Carcinoma.

    Science.gov (United States)

    Hass, Holger G; Vogel, Ulrich; Scheurlen, Michael; Jobst, Jürgen

    2016-10-01

    Hepatocellular carcinoma comprises of a group of heterogeneous tumors of different etiologies. The multistep process of liver carcinogenesis involves various genetic and phenotypic alterations. The molecular pathways and driver mutations involved are still under investigation. DNA micorarray technology was used to identify differentially expressed genes between human hepatocarcinoma and non-tumorous liver tissues to establish a unique specific gene-expression profile independent of the underlying liver disease. The validity of this global gene-expression profile was tested for its robustness against biopsies from other liver entities (cirrhotic and non-cirrhotic liver) by diagnosing HCC in blinded samples. Most of the consistently and strongly overexpressed genes were related to cell-cycle regulation and DNA replication [27 genes, e.g. cyclin B1, karyopherin alpha 2 (KPNA2), cyclin-dependent kinase 2 (CDC2)], G-protein depending signaling [e.g. Rac GTPase activating protein 1 (RACGAP1), Rab GTPase YPT1 homolog (RAB1), and ADP-ribosylation factor-like 2 (ARL2)] and extracellular matrix re-modelling or cytoskeleton structure [22 genes, e.g. serine proteinase inhibitor 1 kazal-type (SPINK1), osteopontin (OPN), secreted protein acidic and rich in cysteine (SPARC), collagen type 1 alpha2 (COL1A2), integrin alpha6 (ITGA6), and metalloproteinase 12 (MMP12)]. Furthermore, significantly differentially expressed genes (e.g. calcium-binding proteins, G-proteins, oncofetal proteins) in relation to tumor differentiation were detected using gene-expression analysis. It is suggested that these significantly dysregulated genes are highly specific and potentially utilizable as prognostic markers and may lead to a better understanding of human hepatocarcinogenesis. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  5. Laboratory and field experiments used to identify Canis lupus var. familiaris active odor signature chemicals from drugs, explosives, and humans.

    Science.gov (United States)

    Lorenzo, Norma; Wan, TianLang; Harper, Ross J; Hsu, Ya-Li; Chow, Michael; Rose, Stefan; Furton, Kenneth G

    2003-08-01

    This paper describes the use of headspace solid-phase microextraction (SPME) combined with gas chromatography to identify the signature odors that law enforcement-certified detector dogs alert to when searching for drugs, explosives, and humans. Background information is provided on the many types of detector dog available and specific samples highlighted in this paper are the drugs cocaine and 3,4-methylenedioxy- N-methylamphetamine (MDMA or Ecstasy), the explosives TNT and C4, and human remains. Studies include the analysis and identification of the headspace "fingerprint" of a variety of samples, followed by completion of double-blind dog trials of the individual components in an attempt to isolate and understand the target compounds that dogs alert to. SPME-GC/MS has been demonstrated to have a unique capability for the extraction of volatiles from the headspace of forensic specimens including drugs and explosives and shows great potential to aid in the investigation and understanding of the complicated process of canine odor detection. Major variables evaluated for the headspace SPME included fiber chemistry and a variety of sampling times ranging from several hours to several seconds and the resultant effect on ratios of isolated volatile components. For the drug odor studies, the CW/DVB and PDMS SPME fibers proved to be the optimal fiber types. For explosives, the results demonstrated that the best fibers in field and laboratory applications were PDMS and CW/DVB, respectively. Gas chromatography with electron capture detector (GC/ECD) and mass spectrometry (GC/MS) was better for analysis of nitromethane and TNT odors, and C-4 odors, respectively. Field studies with detector dogs have demonstrated possible candidates for new pseudo scents as well as the potential use of controlled permeation devices as non-hazardous training aids providing consistent permeation of target odors.

  6. Immunochip analysis identifies novel susceptibility loci in the human leukocyte antigen region for acquired thrombotic thrombocytopenic purpura.

    Science.gov (United States)

    Mancini, I; Ricaño-Ponce, I; Pappalardo, E; Cairo, A; Gorski, M M; Casoli, G; Ferrari, B; Alberti, M; Mikovic, D; Noris, M; Wijmenga, C; Peyvandi, F

    2016-12-01

    Essentials Genetic predisposition to acquired thrombotic thrombocytopenic purpura (aTTP) is mainly unknown. Genetic risk factors for aTTP were studied by Immunochip analysis and replication study. Human leukocyte antigen (HLA) variant rs6903608 conferred a 2.5-fold higher risk of developing aTTP. rs6903608 and HLA-DQB1*05:03 may explain most of the HLA association signal in aTTP. Click to hear Dr Cataland's presentation on acquired thrombotic thrombocytopenic purpura SUMMARY: Background Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy associated with the development of autoantibodies against the von Willebrand factor-cleaving protease ADAMTS-13. Similarly to what has been found for other autoimmune disorders, there is evidence of a genetic contribution, including the association of the human leukocyte antigen (HLA) class II complex with disease risk. Objective To identify novel genetic risk factors in acquired TTP. Patients/Methods We undertook a case-control genetic association study in 190 European-origin TTP patients and 1255 Italian healthy controls by using the Illumina Immunochip. Replication analysis in 88 Italian cases and 456 controls was performed with single-nucleotide polymorphism (SNP) TaqMan assays. Results and conclusion We identified one common variant (rs6903608) located within the HLA class II locus that was independently associated with acquired TTP at genome-wide significance and conferred a 2.6-fold increased risk of developing a TTP episode (95% confidence interval [CI] 2.02-3.27, P = 1.64 × 10 -14 ). We also found five non-HLA variants mapping to chromosomes 2, 6, 8 and X that were suggestively associated with the disease: rs9490550, rs115265285, rs5927472, rs7823314, and rs1334768 (nominal P-values ranging from 1.59 × 10 -5 to 7.60 × 10 -5 ). Replication analysis confirmed the association of HLA variant rs6903608 with acquired TTP (pooled P = 3.95 × 10 -19 ). Imputation of classic

  7. Network-based SNP meta-analysis identifies joint and disjoint genetic features across common human diseases

    Directory of Open Access Journals (Sweden)

    Arnold Matthias

    2012-09-01

    Full Text Available Abstract Background Genome-wide association studies (GWAS have provided a large set of genetic loci influencing the risk for many common diseases. Association studies typically analyze one specific trait in single populations in an isolated fashion without taking into account the potential phenotypic and genetic correlation between traits. However, GWA data can be efficiently used to identify overlapping loci with analogous or contrasting effects on different diseases. Results Here, we describe a new approach to systematically prioritize and interpret available GWA data. We focus on the analysis of joint and disjoint genetic determinants across diseases. Using network analysis, we show that variant-based approaches are superior to locus-based analyses. In addition, we provide a prioritization of disease loci based on network properties and discuss the roles of hub loci across several diseases. We demonstrate that, in general, agonistic associations appear to reflect current disease classifications, and present the potential use of effect sizes in refining and revising these agonistic signals. We further identify potential branching points in disease etiologies based on antagonistic variants and describe plausible small-scale models of the underlying molecular switches. Conclusions The observation that a surprisingly high fraction (>15% of the SNPs considered in our study are associated both agonistically and antagonistically with related as well as unrelated disorders indicates that the molecular mechanisms influencing causes and progress of human diseases are in part interrelated. Genetic overlaps between two diseases also suggest the importance of the affected entities in the specific pathogenic pathways and should be investigated further.

  8. Transcriptome profiling to identify ATRA-responsive genes in human iPSC-derived endoderm for high-throughput point of departure analysis (SOT Annual Meeting)

    Science.gov (United States)

    Toxicological tipping points occur at chemical concentrations that overwhelm a cell’s adaptive response leading to permanent effects. We focused on retinoid signaling in differentiating endoderm to identify developmental pathways for tipping point analysis. Human induced pluripot...

  9. HPLC-based metabolomics to identify cytotoxic compounds from Plectranthus amboinicus (Lour.) Spreng against human breast cancer MCF-7Cells.

    Science.gov (United States)

    Yulianto, Wahid; Andarwulan, Nuri; Giriwono, Puspo Edi; Pamungkas, Joko

    2016-12-15

    The objective of this study was to identify the active compounds in Plectranthus amboinicus (Lour.) Spreng which play a role to inhibit viability of breast cancer MCF-7 cells using HPLC-based metabolomics approach. Five fractions of the plant extract were observed including ethanol, hexane, chloroform, ethyl acetate and water fraction. There were 45 HPLC chromatograms resulted from 5 fractions with 3 replications and 3 wavelengths detection. The chromatograms were compared to the data of IC 50 from MTT assay of each fraction against human breast cancer MCF-7 cells using metabolomics. The OPLS analysis result promptly pointed towards a chloroform fraction at retention time of 40.16-41.28min that has the greatest contribution to the cytotoxic activity. The data of mass spectra indicated that an abietane diterpene namely 7-acetoxy-6-hydroxyroyleanone was the main compound that contributed to the cytotoxic activity. This metabolomics application method can be used as a quick preliminary guideline to uncover the most dominant compound related to the bioactivity. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Bridging the Gap between Sample Collection and Laboratory Analysis: Using Dried Blood Spots to Identify Human Exposure to Chemical Agents.

    Science.gov (United States)

    Hamelin, Elizabeth I; Blake, Thomas A; Perez, Jonas W; Crow, Brian S; Shaner, Rebecca L; Coleman, Rebecca M; Johnson, Rudolph C

    2016-05-13

    Public health response to large scale chemical emergencies presents logistical challenges for sample collection, transport, and analysis. Diagnostic methods used to identify and determine exposure to chemical warfare agents, toxins, and poisons traditionally involve blood collection by phlebotomists, cold transport of biomedical samples, and costly sample preparation techniques. Use of dried blood spots, which consist of dried blood on an FDA-approved substrate, can increase analyte stability, decrease infection hazard for those handling samples, greatly reduce the cost of shipping/storing samples by removing the need for refrigeration and cold chain transportation, and be self-prepared by potentially exposed individuals using a simple finger prick and blood spot compatible paper. Our laboratory has developed clinical assays to detect human exposures to nerve agents through the analysis of specific protein adducts and metabolites, for which a simple extraction from a dried blood spot is sufficient for removing matrix interferents and attaining sensitivities on par with traditional sampling methods. The use of dried blood spots can bridge the gap between the laboratory and the field allowing for large scale sample collection with minimal impact on hospital resources while maintaining sensitivity, specificity, traceability, and quality requirements for both clinical and forensic applications.

  11. Molecular analysis of expansion, differentiation, and growth factor treatment of human chondrocytes identifies differentiation markers and growth-related genes.

    Science.gov (United States)

    Benz, Karin; Breit, Stephen; Lukoschek, Martin; Mau, Hans; Richter, Wiltrud

    2002-04-26

    This study is intended to optimise expansion and differentiation of cultured human chondrocytes by growth factor application and to identify molecular markers to monitor their differentiation state. We dissected the molecular consequences of matrix release, monolayer, and 3D-alginate culture, growth factor optimised expansion, and re-differentiation protocols by gene expression analysis. Among 19 common cartilage molecules assessed by cDNA array, six proved best to monitor differentiation. Instant down-regulation at release of cells from the matrix was strongest for COL 2A1, fibromodulin, and PRELP while LUM, CHI3L1, and CHI3L2 were expansion-related. Both gene sets reflected the physiologic effects of the most potent growth-inducing (PDGF-BB) and proteoglycan-inducing (BMP-4) factors. Only CRTAC1 expression correlated with 2D/3D switches while the molecular phenotype of native chondrocytes was not restored. The markers and optimised protocols we suggest can help to improve cell therapy of cartilage defects and chondrocyte differentiation from stem cell sources.

  12. Genomic and transcriptome profiling identified both human and HBV genetic variations and their interactions in Chinese hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Hua Dong

    2015-12-01

    Full Text Available Interaction between HBV and host genome integrations in hepatocellular carcinoma (HCC development is a complex process and the mechanism is still unclear. Here we described in details the quality controls and data mining of aCGH and transcriptome sequencing data on 50 HCC samples from the Chinese patients, published by Dong et al. (2015 (GEO#: GSE65486. In additional to the HBV-MLL4 integration discovered, we also investigated the genetic aberrations of HBV and host genes as well as their genetic interactions. We reported human genome copy number changes and frequent transcriptome variations (e.g. TP53, CTNNB1 mutation, especially MLL family mutations in this cohort of the patients. For HBV genotype C, we identified a novel linkage disequilibrium region covering HBV replication regulatory elements, including basal core promoter, DR1, epsilon and poly-A regions, which is associated with HBV core antigen over-expression and almost exclusive to HBV-MLL4 integration.

  13. An heuristic filtering tool to identify phenotype-associated genetic variants applied to human intellectual disability and canine coat colors.

    Science.gov (United States)

    Broeckx, Bart J G; Coopman, Frank; Verhoeven, Geert; Bosmans, Tim; Gielen, Ingrid; Dingemanse, Walter; Saunders, Jimmy H; Deforce, Dieter; Van Nieuwerburgh, Filip

    2015-11-19

    Identification of one or several disease causing variant(s) from the large collection of variants present in an individual is often achieved by the sequential use of heuristic filters. The recent development of whole exome sequencing enrichment designs for several non-model species created the need for a species-independent, fast and versatile analysis tool, capable of tackling a wide variety of standard and more complex inheritance models. With this aim, we developed "Mendelian", an R-package that can be used for heuristic variant filtering. The R-package Mendelian offers fast and convenient filters to analyze putative variants for both recessive and dominant models of inheritance, with variable degrees of penetrance and detectance. Analysis of trios is supported. Filtering against variant databases and annotation of variants is also included. This package is not species specific and supports parallel computation. We validated this package by reanalyzing data from a whole exome sequencing experiment on intellectual disability in humans. In a second example, we identified the mutations responsible for coat color in the dog. This is the first example of whole exome sequencing without prior mapping in the dog. We developed an R-package that enables the identification of disease-causing variants from the long list of variants called in sequencing experiments. The software and a detailed manual are available at https://github.com/BartBroeckx/Mendelian.

  14. Bridging the gap between sample collection and laboratory analysis: using dried blood spots to identify human exposure to chemical agents

    Science.gov (United States)

    Hamelin, Elizabeth I.; Blake, Thomas A.; Perez, Jonas W.; Crow, Brian S.; Shaner, Rebecca L.; Coleman, Rebecca M.; Johnson, Rudolph C.

    2016-05-01

    Public health response to large scale chemical emergencies presents logistical challenges for sample collection, transport, and analysis. Diagnostic methods used to identify and determine exposure to chemical warfare agents, toxins, and poisons traditionally involve blood collection by phlebotomists, cold transport of biomedical samples, and costly sample preparation techniques. Use of dried blood spots, which consist of dried blood on an FDA-approved substrate, can increase analyte stability, decrease infection hazard for those handling samples, greatly reduce the cost of shipping/storing samples by removing the need for refrigeration and cold chain transportation, and be self-prepared by potentially exposed individuals using a simple finger prick and blood spot compatible paper. Our laboratory has developed clinical assays to detect human exposures to nerve agents through the analysis of specific protein adducts and metabolites, for which a simple extraction from a dried blood spot is sufficient for removing matrix interferents and attaining sensitivities on par with traditional sampling methods. The use of dried blood spots can bridge the gap between the laboratory and the field allowing for large scale sample collection with minimal impact on hospital resources while maintaining sensitivity, specificity, traceability, and quality requirements for both clinical and forensic applications.

  15. Metabolomic approach to human brain spectroscopy identifies associations between clinical features and the frontal lobe metabolome in multiple sclerosis

    Science.gov (United States)

    Vingara, Lisa K.; Yu, Hui Jing; Wagshul, Mark E.; Serafin, Dana; Christodoulou, Christopher; Pelczer, István; Krupp, Lauren B.; Maletić-Savatić, Mirjana

    2013-01-01

    Proton magnetic resonance spectroscopy (1H-MRS) is capable of noninvasively detecting metabolic changes that occur in the brain tissue in vivo. Its clinical utility has been limited so far, however, by analytic methods that focus on independently evaluated metabolites and require prior knowledge about which metabolites to examine. Here, we applied advanced computational methodologies from the field of metabolomics, specifically partial least squares discriminant analysis and orthogonal partial least squares, to in vivo 1H-MRS from frontal lobe white matter of 27 patients with relapsing–remitting multiple sclerosis (RRMS) and 14 healthy controls. We chose RRMS, a chronic demyelinating disorder of the central nervous system, because its complex pathology and variable disease course make the need for reliable biomarkers of disease progression more pressing. We show that in vivo MRS data, when analyzed by multivariate statistical methods, can provide reliable, distinct profiles of MRS-detectable metabolites in different patient populations. Specifically, we find that brain tissue in RRMS patients deviates significantly in its metabolic profile from that of healthy controls, even though it appears normal by standard MRI techniques. We also identify, using statistical means, the metabolic signatures of certain clinical features common in RRMS, such as disability score, cognitive impairments, and response to stress. This approach to human in vivo MRS data should promote understanding of the specific metabolic changes accompanying disease pathogenesis, and could provide biomarkers of disease progression that would be useful in clinical trials. PMID:23751863

  16. Selective growth-inhibiting effects of compounds identified in Tabebuia impetiginosa inner bark on human intestinal bacteria.

    Science.gov (United States)

    Park, Byeoung-Soo; Kim, Jun-Ran; Lee, Sung-Eun; Kim, Kyoung Soon; Takeoka, Gary R; Ahn, Young-Joon; Kim, Jeong-Han

    2005-02-23

    The growth-inhibiting activity of anthraquinone-2-carboxylic acid and lapachol identified in the inner bark of taheebo, Tabebuia impetiginosa, toward 10 human intestinal bacteria was evaluated by using a paper disk diffusion bioassay and compared to those of seven lapachol congeners (1,4-naphthoquinone, naphthazarin, menadione, lawsone, plumbagin, juglone, and dichlone) as well as two commercially available antibiotics, chloramphenicol and tetracycline. Anthraquinone-2-carboxylic acid exhibited very strong growth inhibition of Clostridium paraputrificum at 1 microg/disk while 100 microg/disk of lapachol was needed for moderate growth inhibition of the same organism. These two isolates exhibited weak inhibition of Clostridium perfringens and Escherichia coli at 100 microg/disk while no adverse effects were observed on the growth of Bifidobacterium adolescentis, Bifidobacterium bifidum, Bifidobacterium infantis, Lactobacillus acidophilus, and Lactobacillus casei at 1000 microg/disk. Structure-activity relationships indicate that a methyl group in the C-2 position of 1,4-naphthoquinone derivatives might play an important role in antibacterial activity.

  17. Genome characterization of Turkey Rotavirus G strains from the United States identifies potential recombination events with human Rotavirus B strains.

    Science.gov (United States)

    Chen, Fangzhou; Knutson, Todd P; Porter, Robert E; Ciarlet, Max; Mor, Sunil Kumar; Marthaler, Douglas G

    2017-12-01

    Rotavirus G (RVG) strains have been detected in a variety of avian species, but RVG genomes have been published from only a single pigeon and two chicken strains. Two turkey RVG strains were identified and characterized, one in a hatchery with no reported health issues and the other in a hatchery with high embryo/poult mortality. The two turkey RVG strains shared only an 85.3 % nucleotide sequence identity in the VP7 gene while the other genes possessed high nucleotide identity among them (96.3-99.9 %). Low nucleotide percentage identities (31.6-87.3 %) occurred among the pigeon and chicken RVG strains. Interestingly, potential recombination events were detected between our RVG strains and a human RVB strain, in the VP6 and NSP3 segments. The epidemiology of RVG in avian flocks and the pathogenicity of the two different RVG strains should be further investigated to understand the ecology and impact of RVG in commercial poultry flocks.

  18. A cultured strain of "Helicobacter heilmannii," a human gastric pathogen, identified as H-bizzozeronii: Evidence for zoonotic potential of Helicobacter

    DEFF Research Database (Denmark)

    Jalava, K.; On, Stephen L.W.; Harrington, Clare S.

    2001-01-01

    We compared the characteristics of a cultured human "Helicobacter heilmannii" isolate with those of other helicobacters found in animals. Phenotypic, protein profile, 16S rDNA sequence, and DNA-DNA hybridization analyses identified the human strain as H. bizzozeronii, a species frequently found...

  19. Direct whole-genome deep-sequencing of human respiratory syncytial virus A and B from Vietnamese children identifies distinct patterns of inter- and intra-host evolution

    Science.gov (United States)

    Wilm, Andreas; van Doorn, H. Rogier; Lam, Ha Minh; Sim, Shuzhen; Sukumaran, Rashmi; Tran, Anh Tuan; Nguyen, Bach Hue; Tran, Thi Thu Loan; Tran, Quynh Huong; Vo, Quoc Bao; Dac, Nguyen Anh Tran; Trinh, Hong Nhien; Nguyen, Thi Thanh Hai; Binh, Bao Tinh Le; Le, Khanh; Nguyen, Minh Tien; Thai, Quang Tung; Vo, Thanh Vu; Ngo, Ngoc Quang Minh; Dang, Thi Kim Huyen; Cao, Ngoc Huong; Tran, Thu Van; Ho, Lu Viet; Farrar, Jeremy; de Jong, Menno; Chen, Swaine; Nagarajan, Niranjan; Bryant, Juliet E.; Hibberd, Martin L.

    2015-01-01

    Human respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children < 2 years of age. Little is known about RSV intra-host genetic diversity over the course of infection or about the immune pressures that drive RSV molecular evolution. We performed whole-genome deep-sequencing on 53 RSV-positive samples (37 RSV subgroup A and 16 RSV subgroup B) collected from the upper airways of hospitalized children in southern Vietnam over two consecutive seasons. RSV A NA1 and RSV B BA9 were the predominant genotypes found in our samples, consistent with other reports on global RSV circulation during the same period. For both RSV A and B, the M gene was the most conserved, confirming its potential as a target for novel therapeutics. The G gene was the most variable and was the only gene under detectable positive selection. Further, positively selected sites in G were found in close proximity to and in some cases overlapped with predicted glycosylation motifs, suggesting that selection on amino acid glycosylation may drive viral genetic diversity. We further identified hotspots and coldspots of intra-host genetic diversity in the RSV genome, some of which may highlight previously unknown regions of functional importance. PMID:26407694

  20. Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation

    Science.gov (United States)

    Yang, Hung-Chih; Xing, Sifei; Shan, Liang; O’Connell, Karen; Dinoso, Jason; Shen, Anding; Zhou, Yan; Shrum, Cynthia K.; Han, Yefei; Liu, Jun O.; Zhang, Hao; Margolick, Joseph B.; Siliciano, Robert F.

    2009-01-01

    The development of highly active antiretroviral therapy (HAART) to treat individuals infected with HIV-1 has dramatically improved patient outcomes, but HAART still fails to cure the infection. The latent viral reservoir in resting CD4+ T cells is a major barrier to virus eradication. Elimination of this reservoir requires reactivation of the latent virus. However, strategies for reactivating HIV-1 through nonspecific T cell activation have clinically unacceptable toxicities. We describe here the development of what we believe to be a novel in vitro model of HIV-1 latency that we used to search for compounds that can reverse latency. Human primary CD4+ T cells were transduced with the prosurvival molecule Bcl-2, and the resulting cells were shown to recapitulate the quiescent state of resting CD4+ T cells in vivo. Using this model system, we screened small-molecule libraries and identified a compound that reactivated latent HIV-1 without inducing global T cell activation, 5-hydroxynaphthalene-1,4-dione (5HN). Unlike previously described latency-reversing agents, 5HN activated latent HIV-1 through ROS and NF-κB without affecting nuclear factor of activated T cells (NFAT) and PKC, demonstrating that TCR pathways can be dissected and utilized to purge latent virus. Our study expands the number of classes of latency-reversing therapeutics and demonstrates the utility of this in vitro model for finding strategies to eradicate HIV-1 infection. PMID:19805909

  1. Diverse patterns of T-cell response against multiple newly identified human Y chromosome-encoded minor histocompatibility epitopes.

    Science.gov (United States)

    Ofran, Yishai; Kim, Haesook T; Brusic, Vladimir; Blake, Loren; Mandrell, Michael; Wu, Catherine J; Sarantopoulos, Stefanie; Bellucci, Roberto; Keskin, Derin B; Soiffer, Robert J; Antin, Joseph H; Ritz, Jerome

    2010-03-01

    Donor T cells respond to minor histocompatibility antigens (mHA), resulting in both graft-versus-host disease and graft versus leukemia after allogeneic hematopoietic stem cell transplantation. Because relatively few mHAs are known, we developed a new approach to predict and subsequently validate candidate mHA. We developed an algorithm based on genetic disparities between Y chromosome-encoded and X chromosome-encoded proteins and known requirements for binding to HLA class I molecules to predict Y chromosome-derived, HLA A*0201-restricted peptides (HY) and ranked peptides based on potential immunogenicity. We evaluated T-cell responses to 41 candidate peptides in 28 male recipients with female donors (FM), 22 male recipients with male donors (MM), and 26 normal individuals. All patients and donors were HLA A*0201 positive. Thirteen peptides derived from five proteins elicited significantly greater T-cell responses in FM patients compared with MM patients and in normal females compared with normal males. Six peptides were more immunogenic than the only previously known HLA A*0201-restricted Y-encoded mHA. Twenty-seven of 28 FM patients responded to at least one HY peptide, but despite a common Y chromosome mismatch and expression of HLA A*0201, each patient responded to a unique set of peptides. Novel HLA A*0201-restricted HY epitopes can be predicted and validated in patients after allogeneic hematopoietic stem cell transplantation. Highly diverse patterns of T-cell response against these epitopes have been identified. Prospective monitoring of responses to large panels of immunogenic peptides can facilitate the identification of clinically relevant targets of graft-versus-host disease and graft versus leukemia.

  2. A quantitative comparison of human HT-1080 fibrosarcoma cells and primary human dermal fibroblasts identifies a 3D migration mechanism with properties unique to the transformed phenotype.

    Directory of Open Access Journals (Sweden)

    Michael P Schwartz

    Full Text Available Here, we describe an engineering approach to quantitatively compare migration, morphologies, and adhesion for tumorigenic human fibrosarcoma cells (HT-1080s and primary human dermal fibroblasts (hDFs with the aim of identifying distinguishing properties of the transformed phenotype. Relative adhesiveness was quantified using self-assembled monolayer (SAM arrays and proteolytic 3-dimensional (3D migration was investigated using matrix metalloproteinase (MMP-degradable poly(ethylene glycol (PEG hydrogels ("synthetic extracellular matrix" or "synthetic ECM". In synthetic ECM, hDFs were characterized by vinculin-containing features on the tips of protrusions, multipolar morphologies, and organized actomyosin filaments. In contrast, HT-1080s were characterized by diffuse vinculin expression, pronounced β1-integrin on the tips of protrusions, a cortically-organized F-actin cytoskeleton, and quantitatively more rounded morphologies, decreased adhesiveness, and increased directional motility compared to hDFs. Further, HT-1080s were characterized by contractility-dependent motility, pronounced blebbing, and cortical contraction waves or constriction rings, while quantified 3D motility was similar in matrices with a wide range of biochemical and biophysical properties (including collagen despite substantial morphological changes. While HT-1080s were distinct from hDFs for each of the 2D and 3D properties investigated, several features were similar to WM239a melanoma cells, including rounded, proteolytic migration modes, cortical F-actin organization, and prominent uropod-like structures enriched with β1-integrin, F-actin, and melanoma cell adhesion molecule (MCAM/CD146/MUC18. Importantly, many of the features observed for HT-1080s were analogous to cellular changes induced by transformation, including cell rounding, a disorganized F-actin cytoskeleton, altered organization of focal adhesion proteins, and a weakly adherent phenotype. Based on our results

  3. A review of the use of human factors classification frameworks that identify causal factors for adverse events in the hospital setting.

    Science.gov (United States)

    Mitchell, R J; Williamson, A M; Molesworth, B; Chung, A Z Q

    2014-01-01

    Various human factors classification frameworks have been used to identified causal factors for clinical adverse events. A systematic review was conducted to identify human factors classification frameworks that identified the causal factors (including human error) of adverse events in a hospital setting. Six electronic databases were searched, identifying 1997 articles and 38 of these met inclusion criteria. Most studies included causal contributing factors as well as error and error type, but the nature of coding varied considerably between studies. The ability of human factors classification frameworks to provide information on specific causal factors for an adverse event enables the focus of preventive attention on areas where improvements are most needed. This review highlighted some areas needing considerable improvement in order to meet this need, including better definition of terms, more emphasis on assessing reliability of coding and greater sophistication in analysis of results of the classification. Practitioner Summary: Human factors classification frameworks can be used to identify causal factors of clinical adverse events. However, this review suggests that existing frameworks are diverse, limited in their identification of the context of human error and have poor reliability when used by different individuals.

  4. Serotonin transporter, sex, and hypoxia: microarray analysis in the pulmonary arteries of mice identifies genes with relevance to human PAH

    Science.gov (United States)

    White, Kevin; Loughlin, Lynn; Maqbool, Zakia; Nilsen, Margaret; McClure, John; Dempsie, Yvonne; Baker, Andrew H.

    2011-01-01

    Pulmonary arterial hypertension (PAH) is up to threefold more prevalent in women than men. Female mice overexpressing the serotonin transporter (SERT; SERT+ mice) exhibit PAH and exaggerated hypoxia-induced PAH, whereas male SERT+ mice remain unaffected. To further investigate these sex differences, microarray analysis was performed in the pulmonary arteries of normoxic and chronically hypoxic female and male SERT+ mice. Quantitative RT-PCR analysis was employed for validation of the microarray data. In relevant groups, immunoblotting was performed for genes of interest (CEBPβ, CYP1B1, and FOS). To translate clinical relevance to our findings, CEBPβ, CYP1B1, and FOS mRNA and protein expression was assessed in pulmonary artery smooth muscle cells (PASMCs) derived from idiopathic PAH (IPAH) patients and controls. In female SERT+ mice, multiple pathways with relevance to PAH were altered. This was also observed in chronically hypoxic female SERT+ mice. We selected 10 genes of interest for qRT-PCR analysis (FOS, CEBPβ, CYP1B1, MYL3, HAMP2, LTF, PLN, NPPA, UCP1, and C1S), and 100% concordance was reported. Protein expression of three selected genes, CEBPβ, CYP1B1, FOS, was also upregulated in female SERT+ mice. Serotonin and 17β-estradiol increased CEBPβ, CYP1B1, and FOS protein expression in PASMCs. In addition, CEBPβ, CYP1B1, and FOS mRNA and protein expression was also increased in PASMCs derived from IPAH patients. Here, we have identified a number of genes that may predispose female SERT+ mice to PAH, and these findings may also be relevant to human PAH. PMID:21303932

  5. Global tyrosine kinome profiling of human thyroid tumors identifies Src as a promising target for invasive cancers

    International Nuclear Information System (INIS)

    Cho, Nancy L.; Lin, Chi-Iou; Du, Jinyan; Whang, Edward E.; Ito, Hiromichi; Moore, Francis D.; Ruan, Daniel T.

    2012-01-01

    Highlights: ► Kinome profiling is a novel technique for identifying activated kinases in human cancers. ► Src activity is increased in invasive thyroid cancers. ► Inhibition of Src activity decreased proliferation and invasion in vitro. ► Further investigation of Src targeted therapies in thyroid cancer is warranted. -- Abstract: Background: Novel therapies are needed for the treatment of invasive thyroid cancers. Aberrant activation of tyrosine kinases plays an important role in thyroid oncogenesis. Because current targeted therapies are biased toward a small subset of tyrosine kinases, we conducted a study to reveal novel therapeutic targets for thyroid cancer using a bead-based, high-throughput system. Methods: Thyroid tumors and matched normal tissues were harvested from twenty-six patients in the operating room. Protein lysates were analyzed using the Luminex immunosandwich, a bead-based kinase phosphorylation assay. Data was analyzed using GenePattern 3.0 software and clustered according to histology, demographic factors, and tumor status regarding capsular invasion, size, lymphovascular invasion, and extrathyroidal extension. Survival and invasion assays were performed to determine the effect of Src inhibition in papillary thyroid cancer (PTC) cells. Results: Tyrosine kinome profiling demonstrated upregulation of nine tyrosine kinases in tumors relative to matched normal thyroid tissue: EGFR, PTK6, BTK, HCK, ABL1, TNK1, GRB2, ERK, and SRC. Supervised clustering of well-differentiated tumors by histology, gender, age, or size did not reveal significant differences in tyrosine kinase activity. However, supervised clustering by the presence of invasive disease showed increased Src activity in invasive tumors relative to non-invasive tumors (60% v. 0%, p < 0.05). In vitro, we found that Src inhibition in PTC cells decreased cell invasion and proliferation. Conclusion: Global kinome analysis enables the discovery of novel targets for thyroid cancer

  6. Omics analysis of human bone to identify genes and molecular networks regulating skeletal remodeling in health and disease.

    Science.gov (United States)

    Reppe, Sjur; Datta, Harish K; Gautvik, Kaare M

    2017-08-01

    The skeleton is a metabolically active organ throughout life where specific bone cell activity and paracrine/endocrine factors regulate its morphogenesis and remodeling. In recent years, an increasing number of reports have used multi-omics technologies to characterize subsets of bone biological molecular networks. The skeleton is affected by primary and secondary disease, lifestyle and many drugs. Therefore, to obtain relevant and reliable data from well characterized patient and control cohorts are vital. Here we provide a brief overview of omics studies performed on human bone, of which our own studies performed on trans-iliacal bone biopsies from postmenopausal women with osteoporosis (OP) and healthy controls are among the first and largest. Most other studies have been performed on smaller groups of patients, undergoing hip replacement for osteoarthritis (OA) or fracture, and without healthy controls. The major findings emerging from the combined studies are: 1. Unstressed and stressed bone show profoundly different gene expression reflecting differences in bone turnover and remodeling and 2. Omics analyses comparing healthy/OP and control/OA cohorts reveal characteristic changes in transcriptomics, epigenomics (DNA methylation), proteomics and metabolomics. These studies, together with genome-wide association studies, in vitro observations and transgenic animal models have identified a number of genes and gene products that act via Wnt and other signaling systems and are highly associated to bone density and fracture. Future challenge is to understand the functional interactions between bone-related molecular networks and their significance in OP and OA pathogenesis, and also how the genomic architecture is affected in health and disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Fetal antigen 2: an amniotic protein identified as the aminopropeptide of the alpha 1 chain of human procollagen type I

    DEFF Research Database (Denmark)

    Teisner, B; Rasmussen, H B; Højrup, P

    1992-01-01

    with the aminopropeptide of the alpha 1 chain of human procollagen type I as determined by nucleotide sequences. After oxidative procedures normally employed for radio-iodination (iodogen and chloramine-T), FA2 lost its immunoreactivity. An antigen which cross-reacted with polyclonal rabbit anti-human FA2 was demonstrated...... to that of FA2 in human skin. FA2 is a circulating form of the aminopropeptide of the alpha 1 chain of procollagen type I, and this is the first description of its isolation and structural characterization in humans. Udgivelsesdato: 1992-Dec...

  8. Concomitant and previous osteoporotic vertebral fractures.

    Science.gov (United States)

    Lenski, Markus; Büser, Natalie; Scherer, Michael

    2017-04-01

    Background and purpose - Patients with osteoporosis who present with an acute onset of back pain often have multiple fractures on plain radiographs. Differentiation of an acute osteoporotic vertebral fracture (AOVF) from previous fractures is difficult. The aim of this study was to investigate the incidence of concomitant AOVFs and previous OVFs in patients with symptomatic AOVFs, and to identify risk factors for concomitant AOVFs. Patients and methods - This was a prospective epidemiological study based on the Registry of Pathological Osteoporotic Vertebral Fractures (REPAPORA) with 1,005 patients and 2,874 osteoporotic vertebral fractures, which has been running since February 1, 2006. Concomitant fractures are defined as at least 2 acute short-tau inversion recovery (STIR-) positive vertebral fractures that happen concomitantly. A previous fracture is a STIR-negative fracture at the time of initial diagnostics. Logistic regression was used to examine the influence of various variables on the incidence of concomitant fractures. Results - More than 99% of osteoporotic vertebral fractures occurred in the thoracic and lumbar spine. The incidence of concomitant fractures at the time of first patient contact was 26% and that of previous fractures was 60%. The odds ratio (OR) for concomitant fractures decreased with a higher number of previous fractures (OR =0.86; p = 0.03) and higher dual-energy X-ray absorptiometry T-score (OR =0.72; p = 0.003). Interpretation - Concomitant and previous osteoporotic vertebral fractures are common. Risk factors for concomitant fractures are a low T-score and a low number of previous vertebral fractures in cases of osteoporotic vertebral fracture. An MRI scan of the the complete thoracic and lumbar spine with STIR sequence reduces the risk of under-diagnosis and under-treatment.

  9. CD31, a Valuable Marker to Identify Early and Late Stages of T Cell Differentiation in the Human Thymus

    NARCIS (Netherlands)

    Douaisi, Marc; Resop, Rachel S.; Nagasawa, Maho; Craft, Joshua; Jamieson, Beth D.; Blom, Bianca; Uittenbogaart, Christel H.

    2017-01-01

    Although CD31 expression on human thymocytes has been reported, a detailed analysis of CD31 expression at various stages of T cell development in the human thymus is missing. In this study, we provide a global picture of the evolution of CD31 expression from the CD34(+) hematopoietic precursor to

  10. Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size.

    Directory of Open Access Journals (Sweden)

    Nicole Soranzo

    2009-04-01

    Full Text Available Recent genome-wide (GW scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GW-significant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1x10(-8 and rs910316 in TMED10, P-value = 1.4x10(-7 and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3x10(-7 and rs849141 in JAZF1, P-value = 3.2x10(-11. One locus (rs1182188 at GNA12 identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk and lower-body (hip axis and femur skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4x10(-5 and rs6817306 in LCORL, P-value = 4x10(-4, hip axis length (including rs6830062 at LCORL, P-value = 4.8x10(-4 and rs4911494 at UQCC, P-value = 1.9x10(-4, and femur length (including rs710841 at PRKG2, P-value = 2.4x10(-5 and rs10946808 at HIST1H1D, P-value = 6.4x10(-6. Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.

  11. Potassium as a pluripotency-associated element identified through inorganic element profiling in human pluripotent stem cells.

    Science.gov (United States)

    Lin, Victor J T; Zolekar, Ashwini; Shi, Yi; Koneru, Bhuvaneswari; Dimitrijevich, Slobodan; Di Pasqua, Anthony J; Wang, Yu-Chieh

    2017-07-10

    Despite their well-known function in maintaining normal cell physiology, how inorganic elements are relevant to cellular pluripotency and differentiation in human pluripotent stem cells (hPSCs) has yet to be systematically explored. Using total reflection X-ray fluorescence (TXRF) spectrometry and inductively coupled plasma mass spectrometry (ICP-MS), we analyzed the inorganic components of human cells with isogenic backgrounds in distinct states of cellular pluripotency. The elemental profiles revealed that the potassium content of human cells significantly differs when their cellular pluripotency changes. Pharmacological treatment that alters cell membrane permeability to potassium affected the maintenance and establishment of cellular pluripotency via multiple mechanisms in bona fide hPSCs and reprogrammed cells. Collectively, we report that potassium is a pluripotency-associated inorganic element in human cells and provide novel insights into the manipulation of cellular pluripotency in hPSCs by regulating intracellular potassium.

  12. Cell surface marker profiling of human tracheal basal cells reveals distinct subpopulations, identifies MST1/MSP as a mitogenic signal, and identifies new biomarkers for lung squamous cell carcinomas.

    Science.gov (United States)

    Van de Laar, Emily; Clifford, Monica; Hasenoeder, Stefan; Kim, Bo Ram; Wang, Dennis; Lee, Sharon; Paterson, Josh; Vu, Nancy M; Waddell, Thomas K; Keshavjee, Shaf; Tsao, Ming-Sound; Ailles, Laurie; Moghal, Nadeem

    2014-12-31

    The large airways of the lungs (trachea and bronchi) are lined with a pseudostratified mucociliary epithelium, which is maintained by stem cells/progenitors within the basal cell compartment. Alterations in basal cell behavior can contribute to large airway diseases including squamous cell carcinomas (SQCCs). Basal cells have traditionally been thought of as a uniform population defined by basolateral position, cuboidal cell shape, and expression of pan-basal cell lineage markers like KRT5 and TP63. While some evidence suggests that basal cells are not all functionally equivalent, few heterogeneously expressed markers have been identified to purify and study subpopulations. In addition, few signaling pathways have been identified that regulate their cell behavior. The goals of this work were to investigate tracheal basal cell diversity and to identify new signaling pathways that regulate basal cell behavior. We used flow cytometry (FACS) to profile cell surface marker expression at a single cell level in primary human tracheal basal cell cultures that maintain stem cell/progenitor activity. FACS results were validated with tissue staining, in silico comparisons with normal basal cell and lung cancer datasets, and an in vitro proliferation assay. We identified 105 surface markers, with 47 markers identifying potential subpopulations. These subpopulations generally fell into more (~ > 13%) or less abundant (~ < 6%) groups. Microarray gene expression profiling supported the heterogeneous expression of these markers in the total population, and immunostaining of large airway tissue suggested that some of these markers are relevant in vivo. 24 markers were enriched in lung SQCCs relative to adenocarcinomas, with four markers having prognostic significance in SQCCs. We also identified 33 signaling receptors, including the MST1R/RON growth factor receptor, whose ligand MST1/MSP was mitogenic for basal cells. This work provides the largest description to date of

  13. A novel muscle-specific enhancer identified within the deletion overlap region of two XLDC patients lacking muscle exon 1 of the human dystrophin gene

    NARCIS (Netherlands)

    Bastianutto, Carlo; de Visser, Marianne; Muntoni, Francesco; Klamut, Henry J.; Patarnello, Tomaso

    2002-01-01

    Previous studies point to the involvement of several discrete transcriptional enhancers in the modulation of dystrophin gene expression in skeletal and cardiac muscle. Analysis of deletion breakpoints in two X-linked dilated cardiomyopathy patients with mutations that remove muscle exon 1 identified

  14. Chemokine Receptor Expression Identifies Pre–T Helper (Th)1, Pre–Th2, and Nonpolarized Cells among Human CD4+ Central Memory T Cells

    Science.gov (United States)

    Rivino, Laura; Messi, Mara; Jarrossay, David; Lanzavecchia, Antonio; Sallusto, Federica; Geginat, Jens

    2004-01-01

    We previously reported that central–memory T cells (TCM cells), which express lymph node homing receptors CCR7 and CD62L, are largely devoid of effector functions but acquire characteristics of effector–memory T cells (TEM cells) (i.e., CCR7− T helper [Th]1 or Th2 cells) after stimulation with T cell receptor agonists or homeostatic cytokines. Here we show that three chemokine receptors identify functional subsets within the human CD4+ TCM cell pool. TCM cells expressing CXCR3 secreted low amounts of interferon γ, whereas CCR4+ TCM cells produced some interleukin (IL)-4, but not IL-5. In response to IL-7 and IL-15, CXCR3+ TCM and CCR4+ TCM cells invariably generated fully differentiated CCR7− Th1 and Th2 cells, respectively, suggesting that they represent pre-Th1 and pre-Th2 cells. Conversely, CXCR5+ TCM cells lacking CXCR3 and CCR4 remained nonpolarized and retained CCR7 and CD62L expression upon cytokine-driven expansion. Unlike naive cells, all memory subsets had a low T cell receptor rearrangement excision circle content, spontaneously incorporated bromodeoxyuridine ex vivo, and contained cells specific for tetanus toxoid. Conversely, recall responses to cytomegalovirus and vaccinia virus were largely restricted to CXCR3+ TCM and TEM cells. We conclude that antigen-specific memory T cells are distributed between TEM cells and different subsets of TCM cells. Our results also explain how the quality of primary T cell responses could be maintained by TCM cells in the absence of antigen. PMID:15381728

  15. The use of protective barriers to deter inadvertent human intrusion into a mined geologic facility for the disposal of radioactive waste: A review of previous investigations and potential concepts

    International Nuclear Information System (INIS)

    Tolan, T.L.

    1993-06-01

    Sandia National Laboratories is evaluating the feasibility of developing protective barrier system for the Waste Isolation Pilot Plant (WIPP) to thwart inadvertent human intrusion into this radioactive-waste disposal system for a period of 9,900 years after assumed loss of active institutional controls. The protective barrier system would be part of a series of enduring passive institutional controls whose long-term function will be to reduce the likelihood of inadvertent human activities (e.g., exploratory drilling for resources) that could disrupt the WIPP disposal system

  16. The use of protective barriers to deter inadvertent human intrusion into a mined geologic facility for the disposal of radioactive waste: A review of previous investigations and potential concepts

    Energy Technology Data Exchange (ETDEWEB)

    Tolan, T.L. [Tolan, Beeson and Associates, Kennewick, WA (United States)

    1993-06-01

    Sandia National Laboratories is evaluating the feasibility of developing protective barrier system for the Waste Isolation Pilot Plant (WIPP) to thwart inadvertent human intrusion into this radioactive-waste disposal system for a period of 9,900 years after assumed loss of active institutional controls. The protective barrier system would be part of a series of enduring passive institutional controls whose long-term function will be to reduce the likelihood of inadvertent human activities (e.g., exploratory drilling for resources) that could disrupt the WIPP disposal system.

  17. Significance of functional disease-causal/susceptible variants identified by whole-genome analyses for the understanding of human diseases.

    Science.gov (United States)

    Hitomi, Yuki; Tokunaga, Katsushi

    2017-01-01

    Human genome variation may cause differences in traits and disease risks. Disease-causal/susceptible genes and variants for both common and rare diseases can be detected by comprehensive whole-genome analyses, such as whole-genome sequencing (WGS), using next-generation sequencing (NGS) technology and genome-wide association studies (GWAS). Here, in addition to the application of an NGS as a whole-genome analysis method, we summarize approaches for the identification of functional disease-causal/susceptible variants from abundant genetic variants in the human genome and methods for evaluating their functional effects in human diseases, using an NGS and in silico and in vitro functional analyses. We also discuss the clinical applications of the functional disease causal/susceptible variants to personalized medicine.

  18. Low/Negative Expression of PDGFR-α Identifies the Candidate Primary Mesenchymal Stromal Cells in Adult Human Bone Marrow

    DEFF Research Database (Denmark)

    Li, Hongzhe; Ghazanfari, Roshanak; Zacharaki, Dimitra

    2014-01-01

    exhibited high levels of genes associated with mesenchymal lineages and HSC supportive function. Moreover, lin(-)/CD45(-)/CD271(+)/CD140a(low/-) cells effectively mediated the ex vivo expansion of transplantable CD34(+) hematopoietic stem cells. Taken together, these data indicate that CD140a is a key...... negative selection marker for adult human BM-MSCs, which enables to prospectively isolate a close to pure population of candidate human adult stroma stem/progenitor cells with potent hematopoiesis-supporting capacity.......Human bone marrow (BM) contains a rare population of nonhematopoietic mesenchymal stromal cells (MSCs), which are of central importance for the hematopoietic microenvironment. However, the precise phenotypic definition of these cells in adult BM has not yet been reported. In this study, we show...

  19. Proteomic analysis identifies mitochondrial metabolic enzymes as major discriminators between different stages of the failing human myocardium

    DEFF Research Database (Denmark)

    Urbonavicius, Sigitas; Wiggers, Henrik; Bøtker, Hans Erik

    2009-01-01

    Our aim was to identify patterns in differentially regulated proteins associated with the progression of chronic heart failure. We specifically studied proteomics in chronic reversibly (RDM) and irreversibly dysfunctional myocardium (IRDM), as well as end-stage failing myocardium (ESFM)....

  20. ERIC-PCR fingerprinting-based community DNA hybridization to pinpoint genome-specific fragments as molecular markers to identify and track populations common to healthy human guts.

    Science.gov (United States)

    Wei, Guifang; Pan, Li; Du, Huimin; Chen, Junyi; Zhao, Liping

    2004-10-01

    Bacterial populations common to healthy human guts may play important roles in human health. A new strategy for discovering genomic sequences as markers for these bacteria was developed using Enterobacterial Repetitive Intergenic Consensus (ERIC)-PCR fingerprinting. Structural features within microbial communities are compared with ERIC-PCR followed by DNA hybridization to identify genomic fragments shared by samples from healthy human individuals. ERIC-PCR profiles of fecal samples from 12 diseased or healthy human and piglet subjects demonstrated stable, unique banding patterns for each individual tested. Sequence homology of DNA fragments in bands of identical size was examined between samples by hybridization under high stringency conditions with DIG-labeled ERIC-PCR products derived from the fecal sample of one healthy child. Comparative analysis of the hybridization profiles with the original agarose fingerprints identified three predominant bands as signatures for populations associated with healthy human guts with sizes of 500, 800 and 1000 bp. Clone library profiling of the three bands produced 17 genome fragments, three of which showed high similarity only with regions of the Bacteroides thetaiotaomicron genome, while the remainder were orphan sequences. Association of these sequences with healthy guts was validated by sequence-selective PCR experiments, which showed that a single fragment was present in all 32 healthy humans and 13 healthy piglets tested. Two fragments were present in the healthy human group and in 18 children with non-infectious diarrhea but not in eight children with infectious diarrhea. Genome fragments identified with this novel strategy may be used as genome-specific markers for dynamic monitoring and sequence-guided isolation of functionally important bacterial populations in complex communities such as human gut microflora.

  1. A Human Error Analysis Procedure for Identifying Potential Error Modes and Influencing Factors for Test and Maintenance Activities

    International Nuclear Information System (INIS)

    Kim, Jae Whan; Park, Jin Kyun

    2010-01-01

    Periodic or non-periodic test and maintenance (T and M) activities in large, complex systems such as nuclear power plants (NPPs) are essential for sustaining stable and safe operation of the systems. On the other hand, it also has been raised that human erroneous actions that might occur during T and M activities has the possibility of incurring unplanned reactor trips (RTs) or power derate, making safety-related systems unavailable, or making the reliability of components degraded. Contribution of human errors during normal and abnormal activities of NPPs to the unplanned RTs is known to be about 20% of the total events. This paper introduces a procedure for predictively analyzing human error potentials when maintenance personnel perform T and M tasks based on a work procedure or their work plan. This procedure helps plant maintenance team prepare for plausible human errors. The procedure to be introduced is focusing on the recurrent error forms (or modes) in execution-based errors such as wrong object, omission, too little, and wrong action

  2. Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

    Science.gov (United States)

    Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast™ chemical screening and prioritization research project. Metabolites from hES cultur...

  3. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

    NARCIS (Netherlands)

    J. Deelen (Joris); M. Beekman (Marian); H.-W. Uh (Hae-Won); L. Broer (Linda); K.L. Ayers (Kristin); Q. Tan (Qihua); Y. Kamatani (Yoichiro); A.M. Bennet (Anna Michaela); R. Tamm (Riin); S. Trompet (Stella); D.F. Guobjartsson (Daníel); F. Flachsbart (Friederike); G. Rose (Giuseppina); A. Viktorin (Alexander); K. Fischer (Krista); M. Nygaard (Marianne); H.J. Cordell (Heather); P. Crocco (Paolina); E.B. van den Akker (Erik); S. Böhringer (Stefan); Q. Helmer (Quinta); C.P. Nelson (Christopher P.); G.I. Saunders (Gary); M. Alver (Maris); K. Andersen-Ranberg (Karen); G. Breen (Gerome); R. van der Breggen (Ruud); A. Caliebe (Amke); Y. Capri (Yline); E. Cevenini (Elisa); J.C. Collerton (Joanna); S. Dato (Serena); K. Davies (Karen); I. Ford (Ian); J. Gampe (Jutta); P. Garagnani (Paolo); E.J.C. de Geus (Eco); J. Harrow (Jennifer); D. van Heemst (Diana); B.T. Heijmans (Bastiaan); F.-A. Heinsen (Femke-Anouska); J.J. Hottenga (Jouke Jan); A. Hofman (Albert); B. Jeune (Bernard); P.V. Jonsson (Palmi); M. Lathrop (Mark); D. Lechner (Doris); C. Martin-Ruiz (Carmen); S.E. Mcnerlan (Susan); E. Mihailov (Evelin); A. Montesanto (Alberto); S.P. Mooijaart (Simon); A. Murphy (Anne); C. Nohr (Christian); L. Paternoster (Lavinia); D. Postmus (Douwe); F. Rivadeneira Ramirez (Fernando); O.A. Ross (Owen); S. Salvioli (Stefano); N. Sattar (Naveed); S. Schreiber (Stefan); H. Stefansson (Hreinn); D.J. Stott (David. J.); H.W. Tiemeier (Henning); A.G. Uitterlinden (André); R.G.J. Westendorp (Rudi); G.A.H.M. Willemsen (Gonneke); N.J. Samani (Nilesh); P. Galan (Pilar); H.G. Sorensen; D.I. Boomsma (Dorret); J.W. Jukema (Jan Wouter); D. Rea (Dan); G. Passarino (Giuseppe); A.J. de Craen (Anton); K. Christensen (Kaare); A. Nebel (Almut); J-A. Zwart (John-Anker); A. Metspalu (Andres); P.K. Magnusson (Patrik); H. Blanché (Hélène); L. Christiansen (Lene); J.M. Kirkwood (John); C.M. van Duijn (Cornelia); C. Franceschi (Claudio); J.J. Houwing-Duistermaat (Jeanine); P.E. Slagboom (Eline)

    2014-01-01

    textabstractThe genetic contribution to the variation in human lifespan is ~25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of

  4. Phosphoproteomics identified Endofin, DCBLD2, and KIAA0582 as novel tyrosine phosphorylation targets of EGF signaling and Iressa in human cancer cells

    DEFF Research Database (Denmark)

    Chen, Yunhao; Low, Teck-Yew; Choong, Lee-Yee

    2007-01-01

    With the completion of the human genome project, analysis of enriched phosphotyrosyl proteins from epidermal growth factor (EGF)-induced phosphotyrosine proteome permits the identification of novel downstream substrates of the EGF receptor (EGFR). Using cICAT-based LC-MS/MS method, we identified...

  5. Mass spectrometry profiling of oxysterols in human sperm identifies 25-hydroxycholesterol as a marker of sperm function

    Directory of Open Access Journals (Sweden)

    Chiara Zerbinati

    2017-04-01

    Full Text Available Cholesterol is a main lipid component of sperm cell that is essential for sperm membrane fluidity, capacitation, and acrosomal reaction. Recent data obtained in bovine sperm showed that sperm capacitation is associated to the formation of oxysterols, oxidized products of cholesterol. The aim of this study was to profile oxysterol content in human semen, and to investigate their potential role in sperm pathophysiology. Among the 12 oxysterols analyzed, 25-hydroxycholesterol (25-HC resulted the most represented in normozoospermic samples, and its concentration positively correlated with spermatozoa number. We detected Cholesterol 25-hydroxylase, the enzyme responsible for 25-HC production, in human spermatozoa at the level of the neck and the post acrosomal area. Upon incubation with spermatozoa, 25-HC induced calcium and cholesterol transients in connection with the acrosomal reaction. Our results support a role for 25-HC in sperm function.

  6. Partial digestion with restriction enzymes of ultraviolet-irradiated human genomic DNA: a method for identifying restriction site polymorphisms

    International Nuclear Information System (INIS)

    Nobile, C.; Romeo, G.

    1988-01-01

    A method for partial digestion of total human DNA with restriction enzymes has been developed on the basis of a principle already utilized by P.A. Whittaker and E. Southern for the analysis of phage lambda recombinants. Total human DNA irradiated with uv light of 254 nm is partially digested by restriction enzymes that recognize sequences containing adjacent thymidines because of TT dimer formation. The products resulting from partial digestion of specific genomic regions are detected in Southern blots by genomic-unique DNA probes with high reproducibility. This procedure is rapid and simple to perform because the same conditions of uv irradiation are used for different enzymes and probes. It is shown that restriction site polymorphisms occurring in the genomic regions analyzed are recognized by the allelic partial digest patterns they determine

  7. Mass spectrometry profiling of oxysterols in human sperm identifies 25-hydroxycholesterol as a marker of sperm function.

    Science.gov (United States)

    Zerbinati, Chiara; Caponecchia, Luisa; Puca, Rosa; Ciacciarelli, Marco; Salacone, Pietro; Sebastianelli, Annalisa; Pastore, Antonio; Palleschi, Giovanni; Petrozza, Vincenzo; Porta, Natale; Rago, Rocco; Carbone, Antonio; Iuliano, Luigi

    2017-04-01

    Cholesterol is a main lipid component of sperm cell that is essential for sperm membrane fluidity, capacitation, and acrosomal reaction. Recent data obtained in bovine sperm showed that sperm capacitation is associated to the formation of oxysterols, oxidized products of cholesterol. The aim of this study was to profile oxysterol content in human semen, and to investigate their potential role in sperm pathophysiology. Among the 12 oxysterols analyzed, 25-hydroxycholesterol (25-HC) resulted the most represented in normozoospermic samples, and its concentration positively correlated with spermatozoa number. We detected Cholesterol 25-hydroxylase, the enzyme responsible for 25-HC production, in human spermatozoa at the level of the neck and the post acrosomal area. Upon incubation with spermatozoa, 25-HC induced calcium and cholesterol transients in connection with the acrosomal reaction. Our results support a role for 25-HC in sperm function. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  8. In-depth analysis of the secretome identifies three major independent secretory pathways in differentiating human myoblasts

    DEFF Research Database (Denmark)

    Le Bihan, Marie-Catherine; Bigot, Anne; Jensen, Søren Skov

    2012-01-01

    Efficient muscle regeneration requires cross talk between multiple cell types via secreted signaling molecules. However, as yet there has been no comprehensive analysis of this secreted signaling network in order to understand how it regulates myogenesis in humans. Using integrated proteomic...... features and larger, morphologically distinct, microvesicles. While they share some common features, their distinct protein and RNA cargos suggest independent functions in myogenesis. We further demonstrate that both types of microvesicles can dock and fuse with adjacent muscle cells but also deliver...

  9. A study on a robot chasing a human using Kinect while identifying walking parameters using the back view

    Science.gov (United States)

    Konno, S.; Mita, A.

    2014-03-01

    Recently, the demand of the building spaces to respond to increase of single aged households and the diversification of life style is increasing. Smart house is one of them, but it is difficult for them to be changed and renovated. Therefore, we suggest Biofied builing. In biofied building, we use a mobile robot to get concious and unconcious information about residents and try to make it more secure and comfort builing spaces by realizing the intraction between residents and builing spaces. Walking parameters are one of the most important unconscious information about residents. They are an indicator of autonomy of elderly, and changes of stride length and walking speed may be pridictive of a future fall and a cognitive impairment. By observing their walking and informing residents their walking state, they can forestall such dangers and it helps them to live more securely and autonomously. Many methods to estimate walking parameters have been studied. The famous ones are to use accelerometers and a motion capture camera. Walking parameters estimated by them are high precise but the sensors are attached to a human body in these method and it can make human's walk different from the original walk. Furthermore, some elderly feel it to invade them. In this work, Kinect which can get information about human untouchably was used on the mobile robot. A stride time, stride length, and walking speed were estimated from the back view of human by following him or her. Evaluation was done for 10m, 5m, 4m, and 3m in whole walking. As a result, the proposal system can estimate walking parameters of the walk more than 3m.

  10. Who’s Who at the Border? A rights-based approach to identifying human trafficking at international borders

    OpenAIRE

    Marika McAdam

    2013-01-01

    International borders are widely touted as bastions in the fight against trafficking in persons. This article acknowledges the important role border officials play in preventing human trafficking, but calls for expectations to be tempered by deference to the conceptual complexity of cross-border trafficking and the migration processes involved. The fact that many trafficked victims begin their journeys as irregular or smuggled migrants highlights the challenge posed to border officials in ide...

  11. Comparative proteomics as a tool for identifying specific alterations within interferon response pathways in human glioblastoma multiforme cells

    DEFF Research Database (Denmark)

    Tarasova, Irina A; Tereshkova, Alesya V; Lobas, Anna A

    2018-01-01

    An acquisition of increased sensitivity of cancer cells to viruses is a common outcome of malignant progression that justifies the development of oncolytic viruses as anticancer therapeutics. Studying molecular changes that underlie the sensitivity to viruses would help to identify cases where on...

  12. Development of Normal Human Colon Cell Cultures to Identify Unregulated Disiinfection By-products (DBPs) with a Carcinogenic Potential - GEMS.

    Science.gov (United States)

    Epidemiological studies have linked the consumption of chlorinated surface waters to an increased risk of colorectal cancer. Approximately 600 DBPs, less that half of the total organic carbon in drinking water, have been identified of which 50 unregulated DBPs have received the ...

  13. Identifying the links between violence against women and HIV/AIDS: ecosocial and human rights frameworks offer insight into U.S. prevention policies.

    Science.gov (United States)

    Teti, Michelle; Chilton, Mariana; Lloyd, Linda; Rubinstein, Susan

    2006-01-01

    While US government-sponsored HIV prevention initiatives have achieved notable successes, challenges remain to serving women effectively. Intimate partner violence hinders women's efforts to decrease their HIV risk behaviors. The global HIV/AIDS epidemic is often viewed as a human rights crisis. An analysis of US HIV prevention strategies based on ecosocial and health and human rights frameworks clarifies women's HIV risk practices and suggests opportunities for progress. These two frameworks help to (1) demonstrate how HIV/AIDS is a clinical manifestation of violence against women, (2) identify safety from violence as a human right necessary for well-being, and (3) suggest ways in which HIV prevention initiatives can more effectively improve women's health and fulfill their basic human rights.

  14. Comparative two-dimensional gel analysis and microsequencing identifies gelsolin as one of the most prominent downregulated markers of transformed human fibroblast and epithelial cells

    DEFF Research Database (Denmark)

    Vandekerckhove, J; Bauw, G; Vancompernolle, K

    1990-01-01

    downregulated markers typical of the transformed state. Using the information stored in the comprehensive human cellular protein database, we found this protein strongly expressed in several fetal tissues and one of them, epidermis, served as a source for preparative two-dimensional gel electrophoresis. Partial......A systematic comparison of the protein synthesis patterns of cultured normal and transformed human fibroblasts and epithelial cells, using two-dimensional gel protein analysis combined with computerized imaging and data acquisition, identified a 90-kD protein (SSP 5714) as one of the most striking...... and by coelectrophoresis with purified human gelsolin. These results suggest that an important regulatory protein of the microfilament system may play a role in defining the phenotype of transformed human fibroblast and epithelial cells in culture. Udgivelsesdato: 1990-Jul...

  15. Massively Parallel Signature Sequencing and Bioinformatics Analysis Identifies Up-Regulation of TGFBI and SOX4 in Human Glioblastoma

    OpenAIRE

    Lin, Biaoyang; Madan, Anup; Yoon, Jae-Geun; Fang, Xuefeng; Yan, Xiaowei; Kim, Taek-Kyun; Hwang, Daehee; Hood, Leroy; Foltz, Gregory

    2010-01-01

    BACKGROUND: A comprehensive network-based understanding of molecular pathways abnormally altered in glioblastoma multiforme (GBM) is essential for developing effective therapeutic approaches for this deadly disease. METHODOLOGY/PRINCIPAL FINDINGS: Applying a next generation sequencing technology, massively parallel signature sequencing (MPSS), we identified a total of 4535 genes that are differentially expressed between normal brain and GBM tissue. The expression changes of three up-regulated...

  16. Novel exons and splice variants in the human antibody heavy chain identified by single cell and single molecule sequencing.

    Directory of Open Access Journals (Sweden)

    Christopher Vollmers

    Full Text Available Antibody heavy chains contain a variable and a constant region. The constant region of the antibody heavy chain is encoded by multiple groups of exons which define the isotype and therefore many functional characteristics of the antibody. We performed both single B cell RNAseq and long read single molecule sequencing of antibody heavy chain transcripts and were able to identify novel exons for IGHA1 and IGHA2 as well as novel isoforms for IGHM antibody heavy chain.

  17. An Efficient Stepwise Statistical Test to Identify Multiple Linked Human Genetic Variants Associated with Specific Phenotypic Traits.

    Directory of Open Access Journals (Sweden)

    Iksoo Huh

    Full Text Available Recent advances in genotyping methodologies have allowed genome-wide association studies (GWAS to accurately identify genetic variants that associate with common or pathological complex traits. Although most GWAS have focused on associations with single genetic variants, joint identification of multiple genetic variants, and how they interact, is essential for understanding the genetic architecture of complex phenotypic traits. Here, we propose an efficient stepwise method based on the Cochran-Mantel-Haenszel test (for stratified categorical data to identify causal joint multiple genetic variants in GWAS. This method combines the CMH statistic with a stepwise procedure to detect multiple genetic variants associated with specific categorical traits, using a series of associated I × J contingency tables and a null hypothesis of no phenotype association. Through a new stratification scheme based on the sum of minor allele count criteria, we make the method more feasible for GWAS data having sample sizes of several thousands. We also examine the properties of the proposed stepwise method via simulation studies, and show that the stepwise CMH test performs better than other existing methods (e.g., logistic regression and detection of associations by Markov blanket for identifying multiple genetic variants. Finally, we apply the proposed approach to two genomic sequencing datasets to detect linked genetic variants associated with bipolar disorder and obesity, respectively.

  18. A robust approach to identifying tissue-specific gene expression regulatory variants using personalized human induced pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Je-Hyuk Lee

    2009-11-01

    Full Text Available Normal variation in gene expression due to regulatory polymorphisms is often masked by biological and experimental noise. In addition, some regulatory polymorphisms may become apparent only in specific tissues. We derived human induced pluripotent stem (iPS cells from adult skin primary fibroblasts and attempted to detect tissue-specific cis-regulatory variants using in vitro cell differentiation. We used padlock probes and high-throughput sequencing for digital RNA allelotyping and measured allele-specific gene expression in primary fibroblasts, lymphoblastoid cells, iPS cells, and their differentiated derivatives. We show that allele-specific expression is both cell type and genotype-dependent, but the majority of detectable allele-specific expression loci remains consistent despite large changes in the cell type or the experimental condition following iPS reprogramming, except on the X-chromosome. We show that our approach to mapping cis-regulatory variants reduces in vitro experimental noise and reveals additional tissue-specific variants using skin-derived human iPS cells.

  19. A robust approach to identifying tissue-specific gene expression regulatory variants using personalized human induced pluripotent stem cells.

    Science.gov (United States)

    Lee, Je-Hyuk; Park, In-Hyun; Gao, Yuan; Li, Jin Billy; Li, Zhe; Daley, George Q; Zhang, Kun; Church, George M

    2009-11-01

    Normal variation in gene expression due to regulatory polymorphisms is often masked by biological and experimental noise. In addition, some regulatory polymorphisms may become apparent only in specific tissues. We derived human induced pluripotent stem (iPS) cells from adult skin primary fibroblasts and attempted to detect tissue-specific cis-regulatory variants using in vitro cell differentiation. We used padlock probes and high-throughput sequencing for digital RNA allelotyping and measured allele-specific gene expression in primary fibroblasts, lymphoblastoid cells, iPS cells, and their differentiated derivatives. We show that allele-specific expression is both cell type and genotype-dependent, but the majority of detectable allele-specific expression loci remains consistent despite large changes in the cell type or the experimental condition following iPS reprogramming, except on the X-chromosome. We show that our approach to mapping cis-regulatory variants reduces in vitro experimental noise and reveals additional tissue-specific variants using skin-derived human iPS cells.

  20. Malignancy-Associated Regions of Transcriptional Activation: Gene Expression Profiling Identifies Common Chromosomal Regions of a Recurrent Transcriptional Activation in Human Prostate, Breast, Ovarian, and Colon Cancers

    Directory of Open Access Journals (Sweden)

    Gennadi V. Glinsky

    2003-05-01

    Full Text Available Despite remarkable advances in our understanding of a genetic basis of cancer, the precise molecular definition of the phenotypically relevant genetic features associated with human epithelial malignancies remains a significant and highly relevant challenge. Here we performed a systematic analysis of the chromosomal positions of cancer-associated transcripts for prostate, breast, ovarian, and colon tumors, and identified short segments of human chromosomes that appear to represent a common target for transcriptional activation in major epithelial malignancies in human. These cancer-associated transcriptomeres correspond well to the regions of transient transcriptional activity on chromosomes 1q21-q23 (144-160 Mbp, 12q13 (52-63 Mbp, 17q21 (38-50 Mbp, 17q23-q25 (72-82 Mbp, 19p13 (1-16 Mbp, and Xq28 (132-142 Mbp during human cell cycle, suggesting a common epigenetic mechanism of transcriptional activation. Consistent with this idea, two of these transcriptomeres (12q13 and 17q21 seemed to be related to the p53regulated transcriptional clusters, and some of the cancer-associated transcriptomeres appeared to correspond well to the recently identified regions of increased gene expression on human chromosomes.

  1. Human Plasma Metabolomics Study across All Stages of Age-Related Macular Degeneration Identifies Potential Lipid Biomarkers.

    Science.gov (United States)

    Laíns, Inês; Kelly, Rachel S; Miller, John B; Silva, Rufino; Vavvas, Demetrios G; Kim, Ivana K; Murta, Joaquim N; Lasky-Su, Jessica; Miller, Joan W; Husain, Deeba

    2018-02-01

    To characterize the plasma metabolomic profile of patients with age-related macular degeneration (AMD) using mass spectrometry (MS). Cross-sectional observational study. We prospectively recruited participants with a diagnosis of AMD and a control group (>50 years of age) without any vitreoretinal disease. All participants underwent color fundus photography, used for AMD diagnosis and staging, according to the Age-Related Eye Disease Study classification scheme. Fasting blood samples were collected and plasma was analyzed by Metabolon, Inc. (Durham, NC), using ultrahigh-performance liquid chromatography (UPLC) and high-resolution MS. Metabolon's hardware and software were used to identify peaks and control quality. Principal component analysis and multivariate regression were performed to assess differences in the metabolomic profiles of AMD patients versus controls, while controlling for potential confounders. For biological interpretation, pathway enrichment analysis of significant metabolites was performed using MetaboAnalyst. The primary outcome measures were levels of plasma metabolites in participants with AMD compared with controls and among different AMD severity stages. We included 90 participants with AMD (30 with early AMD, 30 with intermediate AMD, and 30 with late AMD) and 30 controls. Using UPLC and MS, 878 biochemicals were identified. Multivariate logistic regression identified 87 metabolites with levels that differed significantly between AMD patients and controls. Most of these metabolites (82.8%; n = 72), including the most significant metabolites, belonged to the lipid pathways. Analysis of variance revealed that of the 87 metabolites, 48 (55.2%) also were significantly different across the different stages of AMD. A significant enrichment of the glycerophospholipids pathway was identified (P = 4.7 × 10 -9 ) among these metabolites. Participants with AMD have altered plasma metabolomic profiles compared with controls. Our data suggest

  2. Identifying a Human Right to Access Sustainable Energy Services in International Human Rights Law (SDG 7)? (LRN Law and Sustainability Conference)

    NARCIS (Netherlands)

    Hesselman, Marlies

    2017-01-01

    This paper assessed whether a right to sustainable energy services access can be found in international human rights law, possibly in support of achieving UN Sustainable Development Goal 7. According to SDG 7.1, States are expected to strive for the implementation of "universal access to modern,

  3. Genetic analysis of completely sequenced disease-associated MHC haplotypes identifies shuffling of segments in recent human history.

    Directory of Open Access Journals (Sweden)

    James A Traherne

    2006-01-01

    Full Text Available The major histocompatibility complex (MHC is recognised as one of the most important genetic regions in relation to common human disease. Advancement in identification of MHC genes that confer susceptibility to disease requires greater knowledge of sequence variation across the complex. Highly duplicated and polymorphic regions of the human genome such as the MHC are, however, somewhat refractory to some whole-genome analysis methods. To address this issue, we are employing a bacterial artificial chromosome (BAC cloning strategy to sequence entire MHC haplotypes from consanguineous cell lines as part of the MHC Haplotype Project. Here we present 4.25 Mb of the human haplotype QBL (HLA-A26-B18-Cw5-DR3-DQ2 and compare it with the MHC reference haplotype and with a second haplotype, COX (HLA-A1-B8-Cw7-DR3-DQ2, that shares the same HLA-DRB1, -DQA1, and -DQB1 alleles. We have defined the complete gene, splice variant, and sequence variation contents of all three haplotypes, comprising over 259 annotated loci and over 20,000 single nucleotide polymorphisms (SNPs. Certain coding sequences vary significantly between different haplotypes, making them candidates for functional and disease-association studies. Analysis of the two DR3 haplotypes allowed delineation of the shared sequence between two HLA class II-related haplotypes differing in disease associations and the identification of at least one of the sites that mediated the original recombination event. The levels of variation across the MHC were similar to those seen for other HLA-disparate haplotypes, except for a 158-kb segment that contained the HLA-DRB1, -DQA1, and -DQB1 genes and showed very limited polymorphism compatible with identity-by-descent and relatively recent common ancestry (<3,400 generations. These results indicate that the differential disease associations of these two DR3 haplotypes are due to sequence variation outside this central 158-kb segment, and that shuffling of

  4. Molecular Docking and Molecular Dynamics to Identify a Novel Human Immunodeficiency Virus Inhibitor from Alkaloids of Toddalia asiatica.

    Science.gov (United States)

    Priya, R; Sumitha, Rajendrarao; Doss, C George Priya; Rajasekaran, C; Babu, S; Seenivasan, R; Siva, R

    2015-10-01

    Acquired immunodeficiency syndrome caused by human immunodeficiency virus (HIV) is an immunosuppressive disease. Over the past decades, it has plagued human health due to the grave consequences in its harness. For this reason, anti-HIV agents are imperative, and the search for the same from natural resources would assure the safety. In this investigation we have performed molecular docking, molecular property prediction, drug-likeness score, and molecular dynamics (MD) simulation to develop a novel anti-HIV drug. We have screened 12 alkaloids from a medicinal plant Toddalia asiatica for its probabilistic binding with the active site of the HIV-1-reverse transcriptase (HIV-1-RT) domain (the major contributor to the onset of the disease). The docking results were evaluated based on free energies of binding (ΔG), and the results suggested toddanol, toddanone, and toddalenone to be potent inhibitors of HIV-1-RT. In addition, the alkaloids were subjected to molecular property prediction analysis. Toddanol and toddanone with more rotatable bonds were found to have a drug-likeness score of 0.23 and 0.11, respectively. These scores were comparable with the standard anti-HIV drug zidovudine with a model score 0.28. Finally, two characteristic protein-ligand complexes were exposed to MD simulation to determine the stability of the predicted conformations. The toddanol-RT complex showed higher stability and stronger H-bonds than toddanone-RT complex. Based on these observations, we firmly believe that the alkaloid toddanol could aid in efficient HIV-1 drug discovery. In the present study, the molecular docking and MD simulations are performed to explore the possible binding mode of HIV 1 RT with 12 alkaloids of T. asiatica. Molecular docking by AutoDock4 revealed three alkaloids toddanol, toddanone, and toddalenone with highest binding affinity towards HIV 1 RT. The drug likeness model score revealed a positive score for toddanol and toddanone which is comparable to the drug

  5. A human monoclonal autoantibody to breast cancer identifies the PDZ domain containing protein GIPC1 as a novel breast cancer-associated antigen

    International Nuclear Information System (INIS)

    Rudchenko, Sergei; Trakht, Ilya; Scanlan, Matthew; Kalantarov, Gavreel; Yavelsky, Victoria; Levy, Chen; Estabrook, Alison; Old, Lloyd; Chan, Gerald L; Lobel, Leslie

    2008-01-01

    We have been studying the native autoimmune response to cancer through the isolation of human monoclonal antibodies that are cancer specific from cancer patients. To facilitate this work we previously developed a fusion partner cell line for human lymphocytes, MFP-2, that fuses efficiently with both human lymph node lymphocytes and peripheral blood lymphocytes. Using this unique trioma fusion partner cell line we isolated a panel of autologous human monoclonal antibodies, from both peripheral blood and lymph node lymphocytes, which are representative of the native repertoire of anti-cancer specific antibodies from breast cancer patients. The current study employs immunocytochemistry, immunohistochemistry, Western blot analysis as well as Northern blots, Scatchard binding studies and finally SEREX analysis for target antigen identification. By application of an expression cloning technique known as SEREX, we determined that the target antigen for two monoclonal antibodies, 27.B1 and 27.F7, derived from lymph node B-cells of a breast cancer patient, is the PDZ domain-containing protein known as GIPC1. This protein is highly expressed not only in cultured human breast cancer cells, but also in primary and metastatic tumor tissues and its overexpression appears to be cancer cell specific. Confocal microscopy revealed cell membrane and cytoplasmic localization of the target protein, which is consistent with previous studies of this protein. We have determined that GIPC1 is a novel breast cancer-associated immunogenic antigen that is overexpressed in breast cancer. Its role, however, in the initiation and/or progression of breast cancer remains unclear and needs further clarification

  6. A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism.

    Science.gov (United States)

    Arnò, Barbara; Coletta, Andrea; Tesauro, Cinzia; Zuccaro, Laura; Fiorani, Paola; Lentini, Sara; Galloni, Pierluca; Conte, Valeria; Floris, Barbara; Desideri, Alessandro

    2013-03-07

    The different steps of the human Top1 (topoisomerase I) catalytic cycle have been analysed in the presence of a pentacyclic-diquinoid synthetic compound. The experiments indicate that it efficiently inhibits the cleavage step of the enzyme reaction, fitting well into the catalytic site. Surprisingly the compound, when incubated with the binary topoisomerase-DNA cleaved complex, helps the enzyme to remove itself from the cleaved DNA and close the DNA gap, increasing the religation rate. The compound also induces the religation of the stalled enzyme-CPT (camptothecin)-DNA ternary complex. Analysis of the molecule docked over the binary complex, together with its chemical properties, suggests that the religation enhancement is due to the presence on the compound of two oxygen atoms that act as hydrogen acceptors. This property facilitates the deprotonation of the 5' DNA end, suggesting that this is the limiting step in the topoisomerase religation mechanism.

  7. Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality.

    Directory of Open Access Journals (Sweden)

    Johannes Raffler

    2015-09-01

    Full Text Available Genome-wide association studies with metabolic traits (mGWAS uncovered many genetic variants that influence human metabolism. These genetically influenced metabotypes (GIMs contribute to our metabolic individuality, our capacity to respond to environmental challenges, and our susceptibility to specific diseases. While metabolic homeostasis in blood is a well investigated topic in large mGWAS with over 150 known loci, metabolic detoxification through urinary excretion has only been addressed by few small mGWAS with only 11 associated loci so far. Here we report the largest mGWAS to date, combining targeted and non-targeted 1H NMR analysis of urine samples from 3,861 participants of the SHIP-0 cohort and 1,691 subjects of the KORA F4 cohort. We identified and replicated 22 loci with significant associations with urinary traits, 15 of which are new (HIBCH, CPS1, AGXT, XYLB, TKT, ETNPPL, SLC6A19, DMGDH, SLC36A2, GLDC, SLC6A13, ACSM3, SLC5A11, PNMT, SLC13A3. Two-thirds of the urinary loci also have a metabolite association in blood. For all but one of the 6 loci where significant associations target the same metabolite in blood and urine, the genetic effects have the same direction in both fluids. In contrast, for the SLC5A11 locus, we found increased levels of myo-inositol in urine whereas mGWAS in blood reported decreased levels for the same genetic variant. This might indicate less effective re-absorption of myo-inositol in the kidneys of carriers. In summary, our study more than doubles the number of known loci that influence urinary phenotypes. It thus allows novel insights into the relationship between blood homeostasis and its regulation through excretion. The newly discovered loci also include variants previously linked to chronic kidney disease (CPS1, SLC6A13, pulmonary hypertension (CPS1, and ischemic stroke (XYLB. By establishing connections from gene to disease via metabolic traits our results provide novel hypotheses about molecular

  8. Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

    International Nuclear Information System (INIS)

    Kleinstreuer, N.C.; Smith, A.M.; West, P.R.; Conard, K.R.; Fontaine, B.R.; Weir-Hauptman, A.M.; Palmer, J.A.; Knudsen, T.B.; Dix, D.J.; Donley, E.L.R.; Cezar, G.G.

    2011-01-01

    Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast™ chemical screening and prioritization research project. Metabolites from hES cultures were evaluated for known and novel signatures that may be indicative of developmental toxicity. Significant fold changes in endogenous metabolites were detected for 83 putatively annotated mass features in response to the subset of ToxCast chemicals. The annotations were mapped to specific human metabolic pathways. This revealed strong effects on pathways for nicotinate and nicotinamide metabolism, pantothenate and CoA biosynthesis, glutathione metabolism, and arginine and proline metabolism pathways. Predictivity for adverse outcomes in mammalian prenatal developmental toxicity studies used ToxRefDB and other sources of information, including Stemina Biomarker Discovery's predictive DevTox® model trained on 23 pharmaceutical agents of known developmental toxicity and differing potency. The model initially predicted developmental toxicity from the blinded ToxCast compounds in concordance with animal data with 73% accuracy. Retraining the model with data from the unblinded test compounds at one concentration level increased the predictive accuracy for the remaining concentrations to 83%. These preliminary results on a 11-chemical subset of the ToxCast chemical library indicate that metabolomics analysis of the hES secretome provides information valuable for predictive modeling and mechanistic understanding of mammalian developmental toxicity. -- Highlights: ► We tested 11 environmental compounds in a hESC metabolomics platform. ► Significant changes in secreted small molecule metabolites were observed. ► Perturbed mass features map to pathways critical for normal development and pregnancy. ► Arginine, proline, nicotinate, nicotinamide and glutathione pathways were affected.

  9. Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

    Energy Technology Data Exchange (ETDEWEB)

    Kleinstreuer, N.C., E-mail: kleinstreuer.nicole@epa.gov [NCCT, US EPA, RTP, NC 27711 (United States); Smith, A.M.; West, P.R.; Conard, K.R.; Fontaine, B.R. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); Weir-Hauptman, A.M. [Covance, Inc., Madison, WI 53704 (United States); Palmer, J.A. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); Knudsen, T.B.; Dix, D.J. [NCCT, US EPA, RTP, NC 27711 (United States); Donley, E.L.R. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); Cezar, G.G. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); University of Wisconsin-Madison, Madison, WI 53706 (United States)

    2011-11-15

    Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast Trade-Mark-Sign chemical screening and prioritization research project. Metabolites from hES cultures were evaluated for known and novel signatures that may be indicative of developmental toxicity. Significant fold changes in endogenous metabolites were detected for 83 putatively annotated mass features in response to the subset of ToxCast chemicals. The annotations were mapped to specific human metabolic pathways. This revealed strong effects on pathways for nicotinate and nicotinamide metabolism, pantothenate and CoA biosynthesis, glutathione metabolism, and arginine and proline metabolism pathways. Predictivity for adverse outcomes in mammalian prenatal developmental toxicity studies used ToxRefDB and other sources of information, including Stemina Biomarker Discovery's predictive DevTox Registered-Sign model trained on 23 pharmaceutical agents of known developmental toxicity and differing potency. The model initially predicted developmental toxicity from the blinded ToxCast compounds in concordance with animal data with 73% accuracy. Retraining the model with data from the unblinded test compounds at one concentration level increased the predictive accuracy for the remaining concentrations to 83%. These preliminary results on a 11-chemical subset of the ToxCast chemical library indicate that metabolomics analysis of the hES secretome provides information valuable for predictive modeling and mechanistic understanding of mammalian developmental toxicity. -- Highlights: Black-Right-Pointing-Pointer We tested 11 environmental compounds in a hESC metabolomics platform. Black-Right-Pointing-Pointer Significant changes in secreted small molecule metabolites were observed. Black-Right-Pointing-Pointer Perturbed mass features map to pathways critical for normal

  10. Rabbit monoclonal antibodies directed at the T3SS effector protein YopM identify human pathogenic Yersinia isolates.

    Science.gov (United States)

    Rüter, Christian; Silva, Mariana Ruiz; Grabowski, Benjamin; Lubos, Marie-Luise; Scharnert, Julia; Poceva, Marija; von Tils, Dominik; Flieger, Antje; Heesemann, Jürgen; Bliska, James B; Schmidt, M Alexander

    2014-05-01

    The Yersinia outer protein M (YopM) is a type 3 secretion system (T3SS)-dependent effector protein of Yersinia enterocolitica, Yersinia pseudotuberculosis and Yersinia pestis. Although YopM is indispensable for full virulence, its molecular functions still remain largely elusive. Recently, we could identify the recombinant YopM (rYopM) protein derived from the Y. enterocolitica strain 8081 (JB580) as a cell-penetrating protein, which down-regulates the expression of various pro-inflammatory cytokines including TNFα. In this study, we have generated rabbit monoclonal anti-YopM antibodies (RabMabs). RabMabs were characterized by SDS-PAGE and Western blotting using various truncated versions of rYopM to identify epitope-containing domains. RabMabs recognizing either the N- or C-terminus of YopM were characterized further and validated using a collection of 61 pathogenic and non-pathogenic Yersinia strains as well as exemplary strains of major intestinal bacterial pathogens such as Salmonella enterica ssp. enterica, Shigella flexneri and intestinal pathogenic Escherichia coli. RabMab 41.3 directed at the N-terminus of YopM of Y. enterocolitica strain 8081 recognized all YopM-expressing pathogenic Yersinia strains analyzed in this study but failed to recognize non-pathogenic isolates. Thus, RabMab 41.3 might be applicable for the detection of pathogenic Yersinia strains. Copyright © 2014 Elsevier GmbH. All rights reserved.

  11. A proteomic study to identify soya allergens--the human response to transgenic versus non-transgenic soya samples.

    Science.gov (United States)

    Batista, Rita; Martins, Isabel; Jeno, Paul; Ricardo, Cândido Pinto; Oliveira, Maria Margarida

    2007-01-01

    In spite of being among the main foods responsible for allergic reactions worldwide, soybean (Glycine max)-derived products continue to be increasingly widespread in a variety of food products due to their well-documented health benefits. Soybean also continues to be one of the elected target crops for genetic modification. The aim of this study was to characterize the soya proteome and, specifically, IgE-reactive proteins as well as to compare the IgE response in soya-allergic individuals to genetically modified Roundup Ready soya versus its non-transgenic control. We performed two-dimensional gel electrophoresis of protein extracts from a 5% genetically modified Roundup Ready flour sample and its non-transgenic control followed by Western blotting with plasma from 5 soya-sensitive individuals. We used peptide tandem mass spectrometry to identify soya proteins (55 protein matches), specifically IgE-binding ones, and to evaluate differences between transgenic and non-transgenic samples. We identified 2 new potential soybean allergens--one is maturation associated and seems to be part of the late embryogenesis abundant proteins group and the other is a cysteine proteinase inhibitor. None of the individuals tested reacted differentially to the transgenic versus non-transgenic samples under study. Soybean endogenous allergen expression does not seem to be altered after genetic modification. Proteomics should be considered a powerful tool for functional characterization of plants and for food safety assessment. Copyright (c) 2007 S. Karger AG, Basel.

  12. TRIM28 and β-actin identified via nanobody-based reverse proteomics approach as possible human glioblastoma biomarkers.

    Directory of Open Access Journals (Sweden)

    Ivana Jovčevska

    Full Text Available Malignant gliomas are among the rarest brain tumours, and they have the worst prognosis. Grade IV astrocytoma, known as glioblastoma multiforme (GBM, is a highly lethal disease where the standard therapies of surgery, followed by radiation and chemotherapy, cannot significantly prolong the life expectancy of the patients. Tumour recurrence shows more aggressive form compared to the primary tumour, and results in patient survival from 12 to 15 months only. Although still controversial, the cancer stem cell hypothesis postulates that cancer stem cells are responsible for early relapse of the disease after surgical intervention due to their high resistance to therapy. Alternative strategies for GBM therapy are thus urgently needed. Nanobodies are single-domain antigen-binding fragments of heavy-chain antibodies, and together with classical antibodies, they are part of the camelid immune system. Nanobodies are small and stable, and they share a high degree of sequence identity to the human heavy chain variable domain, and these characteristics offer them advantages over classical antibodies or antibody fragments. We first immunised an alpaca with a human GBM stem-like cell line prepared from primary GBM cultures. Next, a nanobody library was constructed in a phage-display vector. Using nanobody phage-display technology, we selected specific GBM stem-like cell binders through a number of affinity selections, using whole cell protein extracts and membrane protein-enriched extracts from eight different GBM patients, and membrane protein-enriched extracts from two established GBM stem-like cell lines (NCH644 and NCH421K cells. After the enrichment, periplasmic extract ELISA was used to screen for specific clones. These nanobody clones were recloned into the pHEN6 vector, expressed in Escherichia coli WK6, and purified using immobilised metal affinity chromatography and size-exclusion chromatography. Specific nanobody:antigen pairs were obtained and mass

  13. TRIM28 and β-actin identified via nanobody-based reverse proteomics approach as possible human glioblastoma biomarkers.

    Science.gov (United States)

    Jovčevska, Ivana; Zupanec, Neja; Kočevar, Nina; Cesselli, Daniela; Podergajs, Neža; Stokin, Clara Limbaeck; Myers, Michael P; Muyldermans, Serge; Ghassabeh, Gholamreza Hassanzadeh; Motaln, Helena; Ruaro, Maria Elisabetta; Bourkoula, Evgenia; Turnšek, Tamara Lah; Komel, Radovan

    2014-01-01

    Malignant gliomas are among the rarest brain tumours, and they have the worst prognosis. Grade IV astrocytoma, known as glioblastoma multiforme (GBM), is a highly lethal disease where the standard therapies of surgery, followed by radiation and chemotherapy, cannot significantly prolong the life expectancy of the patients. Tumour recurrence shows more aggressive form compared to the primary tumour, and results in patient survival from 12 to 15 months only. Although still controversial, the cancer stem cell hypothesis postulates that cancer stem cells are responsible for early relapse of the disease after surgical intervention due to their high resistance to therapy. Alternative strategies for GBM therapy are thus urgently needed. Nanobodies are single-domain antigen-binding fragments of heavy-chain antibodies, and together with classical antibodies, they are part of the camelid immune system. Nanobodies are small and stable, and they share a high degree of sequence identity to the human heavy chain variable domain, and these characteristics offer them advantages over classical antibodies or antibody fragments. We first immunised an alpaca with a human GBM stem-like cell line prepared from primary GBM cultures. Next, a nanobody library was constructed in a phage-display vector. Using nanobody phage-display technology, we selected specific GBM stem-like cell binders through a number of affinity selections, using whole cell protein extracts and membrane protein-enriched extracts from eight different GBM patients, and membrane protein-enriched extracts from two established GBM stem-like cell lines (NCH644 and NCH421K cells). After the enrichment, periplasmic extract ELISA was used to screen for specific clones. These nanobody clones were recloned into the pHEN6 vector, expressed in Escherichia coli WK6, and purified using immobilised metal affinity chromatography and size-exclusion chromatography. Specific nanobody:antigen pairs were obtained and mass spectrometry

  14. Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence.

    Science.gov (United States)

    Sniekers, Suzanne; Stringer, Sven; Watanabe, Kyoko; Jansen, Philip R; Coleman, Jonathan R I; Krapohl, Eva; Taskesen, Erdogan; Hammerschlag, Anke R; Okbay, Aysu; Zabaneh, Delilah; Amin, Najaf; Breen, Gerome; Cesarini, David; Chabris, Christopher F; Iacono, William G; Ikram, M Arfan; Johannesson, Magnus; Koellinger, Philipp; Lee, James J; Magnusson, Patrik K E; McGue, Matt; Miller, Mike B; Ollier, William E R; Payton, Antony; Pendleton, Neil; Plomin, Robert; Rietveld, Cornelius A; Tiemeier, Henning; van Duijn, Cornelia M; Posthuma, Danielle

    2017-07-01

    Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10 -6 ). Despite the well-known difference in twin-based heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (r g = 0.89, LD score regression P = 5.4 × 10 -29 ). These findings provide new insight into the genetic architecture of intelligence.

  15. Massively parallel signature sequencing and bioinformatics analysis identifies up-regulation of TGFBI and SOX4 in human glioblastoma.

    Directory of Open Access Journals (Sweden)

    Biaoyang Lin

    Full Text Available BACKGROUND: A comprehensive network-based understanding of molecular pathways abnormally altered in glioblastoma multiforme (GBM is essential for developing effective therapeutic approaches for this deadly disease. METHODOLOGY/PRINCIPAL FINDINGS: Applying a next generation sequencing technology, massively parallel signature sequencing (MPSS, we identified a total of 4535 genes that are differentially expressed between normal brain and GBM tissue. The expression changes of three up-regulated genes, CHI3L1, CHI3L2, and FOXM1, and two down-regulated genes, neurogranin and L1CAM, were confirmed by quantitative PCR. Pathway analysis revealed that TGF- beta pathway related genes were significantly up-regulated in GBM tumor samples. An integrative pathway analysis of the TGF beta signaling network identified two alternative TGF-beta signaling pathways mediated by SOX4 (sex determining region Y-box 4 and TGFBI (Transforming growth factor beta induced. Quantitative RT-PCR and immunohistochemistry staining demonstrated that SOX4 and TGFBI expression is elevated in GBM tissues compared with normal brain tissues at both the RNA and protein levels. In vitro functional studies confirmed that TGFBI and SOX4 expression is increased by TGF-beta stimulation and decreased by a specific inhibitor of TGF-beta receptor 1 kinase. CONCLUSIONS/SIGNIFICANCE: Our MPSS database for GBM and normal brain tissues provides a useful resource for the scientific community. The identification of non-SMAD mediated TGF-beta signaling pathways acting through SOX4 and TGFBI (GENE ID:7045 in GBM indicates that these alternative pathways should be considered, in addition to the canonical SMAD mediated pathway, in the development of new therapeutic strategies targeting TGF-beta signaling in GBM. Finally, the construction of an extended TGF-beta signaling network with overlaid gene expression changes between GBM and normal brain extends our understanding of the biology of GBM.

  16. Massively parallel signature sequencing and bioinformatics analysis identifies up-regulation of TGFBI and SOX4 in human glioblastoma.

    Science.gov (United States)

    Lin, Biaoyang; Madan, Anup; Yoon, Jae-Geun; Fang, Xuefeng; Yan, Xiaowei; Kim, Taek-Kyun; Hwang, Daehee; Hood, Leroy; Foltz, Gregory

    2010-04-19

    A comprehensive network-based understanding of molecular pathways abnormally altered in glioblastoma multiforme (GBM) is essential for developing effective therapeutic approaches for this deadly disease. Applying a next generation sequencing technology, massively parallel signature sequencing (MPSS), we identified a total of 4535 genes that are differentially expressed between normal brain and GBM tissue. The expression changes of three up-regulated genes, CHI3L1, CHI3L2, and FOXM1, and two down-regulated genes, neurogranin and L1CAM, were confirmed by quantitative PCR. Pathway analysis revealed that TGF- beta pathway related genes were significantly up-regulated in GBM tumor samples. An integrative pathway analysis of the TGF beta signaling network identified two alternative TGF-beta signaling pathways mediated by SOX4 (sex determining region Y-box 4) and TGFBI (Transforming growth factor beta induced). Quantitative RT-PCR and immunohistochemistry staining demonstrated that SOX4 and TGFBI expression is elevated in GBM tissues compared with normal brain tissues at both the RNA and protein levels. In vitro functional studies confirmed that TGFBI and SOX4 expression is increased by TGF-beta stimulation and decreased by a specific inhibitor of TGF-beta receptor 1 kinase. Our MPSS database for GBM and normal brain tissues provides a useful resource for the scientific community. The identification of non-SMAD mediated TGF-beta signaling pathways acting through SOX4 and TGFBI (GENE ID:7045) in GBM indicates that these alternative pathways should be considered, in addition to the canonical SMAD mediated pathway, in the development of new therapeutic strategies targeting TGF-beta signaling in GBM. Finally, the construction of an extended TGF-beta signaling network with overlaid gene expression changes between GBM and normal brain extends our understanding of the biology of GBM.

  17. Undisclosed Human Immunodeficiency Virus Risk Factors Identified through a Computer-based Questionnaire Program among Blood Donors in Brazil

    Science.gov (United States)

    Blatyta, Paula Fraiman; Custer, Brian; Gonçalez, Thelma Terezinha; Birch, Rebecca; Lopes, Maria Esther; Ferreira, Maria Ines Lopes; Proietti, Anna Barbara Carneiro; Sabino, Ester Cerdeira; Page, Kimberly; de Almeida Neto, Cesar

    2013-01-01

    Background HIV risk factor screening among blood donors remains a cornerstone for the safety of blood supply and is dependent on prospective donor self-disclosure and an attentive predonation interview. Residual risk of HIV transmission through blood transfusion is higher in Brazil than in many other countries. Audio computer-assisted structured-interview (ACASI) has been shown to increase self-reporting of risk behaviors. Study design and methods This cross-sectional study was conducted between January 2009 and March 2011 at four Brazilian blood centers to identify the population of HIV-negative eligible blood donors that answered face-to-face interviews without disclosing risks, but subsequently disclosed deferrable risk factors by ACASI. Compared to the donor interview, the ACASI contained expanded content on demographics, sexual behavior and other HIV risk factors questions. Results 901 HIV-negative blood donors were interviewed. On the ACASI, 13% of donors (N=120) declared a risk factor that would have resulted in deferral that was not disclosed during the face-to-face assessment. The main risk factors identified were recent unprotected sex with an unknown or irregular partner (49 donors), sex with a person with exposure to blood/ fluids (26 donors), multiple sexual partners (19 donors), and male-male sexual behavior (10 donors). Independent factors associated with the disclosure of any risk factor for HIV were age (≥40 years vs. 18–25 years, AOR=0.45; 95% CI 0.23–0.88) and blood center (Hemope vs. Hemominas, AOR=2.51; 95% CI 1.42–4.44). Conclusion ACASI elicited increased disclosure of HIV risk factors among blood donors. ACASI may be a valuable modality of interview to be introduced in Brazilian blood banks. PMID:23521083

  18. Yeast two-hybrid analysis of a human trabecular meshwork cDNA library identified EFEMP2 as a novel PITX2 interacting protein.

    Science.gov (United States)

    Acharya, Moulinath; Sharp, Michael W; Mirzayans, Farideh; Footz, Tim; Huang, Lijia; Birdi, Chanchal; Walter, Michael A

    2012-01-01

    Mutations in the homeobox transcription factor paired-like homeodomain transcription factor 2 (PITX2) cause Axenfeld-Reiger syndrome (ARS), which is associated with anterior segment dysgenesis (ASD) and glaucoma. To understand ARS pathogenesis, it is essential to know the normal functions of PITX2 and the proteins with which PITX2 interacts in the eye. Therefore, we used a unique cDNA library that we created from human trabecular meshwork (TM) primary cells to discover PITX2-interacting proteins (PIPs). A human TM cDNA library was created from primary cells in the ProQuest Two-Hybrid prey vector: pEXP-AD502. Human PITX2A and PITX2C isoforms were used independently as "bait" to identify novel PIPs. A total of 1.25×10⁶ clones were screened by yeast two-hybrid (Y2H) analyses. PIPs obtained from each Y2H experiment were confirmed by yeast retransformation and mammalian co-immunoprecipitation assays. EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2) was identified by both PITX2A and PITX2C isoforms as a novel PIP from Y2H analyses. EFEMP2 is 443 amino acids long with six epidermal growth factor (EGF)-like modules and one fibulin-like module. The PITX2-interaction domain in EFEMP2 lies between the second EGF-like module and the COOH-terminal fibulin-like module. Co-immunoprecipitation assays in COS-7 cells confirmed the interaction between PITX2 and EFEMP2. We discovered EFEMP2 as a novel PITX2-interacting protein. Further, our cDNA library made from human TM primary cells is a unique and effective resource to identify novel interacting proteins for glaucoma and ASD candidates. This resource could be used both for discovery and validation of interactomes identified from in silico analysis.

  19. Signature MicroRNA expression patterns identified in humans with 22q11.2 deletion/DiGeorge syndrome

    Science.gov (United States)

    de la Morena, M. Teresa; Eitson, Jennifer L.; Dozmorov, Igor M.; Belkaya, Serkan; Hoover, Ashley R.; Anguiano, Esperanza; Pascual, M. Virginia; van Oers, Nicolai S.C.

    2013-01-01

    Patients with 22q11.2 deletion syndrome have heterogeneous clinical presentations including immunodeficiency, cardiac anomalies, and hypocalcemia. The syndrome arises from hemizygous deletions of up to 3 Mb on chromosome 22q11.2, a region that contains 60 genes and 4 microRNAs. MicroRNAs are important post-transcriptional regulators of gene expression, with mutations in several microRNAs causal to specific human diseases. We characterized the microRNA expression patterns in the peripheral blood of patients with 22q11.2 deletion syndrome (n=31) compared to normal controls (n=22). Eighteen microRNAs had a statistically significant differential expression (p22q11.2 deletion syndrome cohort exhibited microRNA expression hyper-variability and group dysregulation. Selected microRNAs distinguished patients with cardiac anomalies, hypocalcemia, and/or low circulating T cell counts. In summary, microRNA profiling of chromosome 22q11.2 deletion syndrome/DiGeorge patients revealed a signature microRNA expression pattern distinct from normal controls with clinical relevance. PMID:23454892

  20. Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes, prior to recruitment, and identified through conserved transcriptional responses in mice and humans

    Science.gov (United States)

    Ruparelia, Neil; Godec, Jernej; Lee, Regent; Chai, Joshua T.; Dall'Armellina, Erica; McAndrew, Debra; Digby, Janet E.; Forfar, J. Colin; Prendergast, Bernard D.; Kharbanda, Rajesh K.; Banning, Adrian P.; Neubauer, Stefan; Lygate, Craig A.; Channon, Keith M.; Haining, Nicholas W.; Choudhury, Robin P.

    2015-01-01

    Aims Monocytes play critical roles in tissue injury and repair following acute myocardial infarction (AMI). Specifically targeting inflammatory monocytes in experimental models leads to reduced infarct size and improved healing. However, data from humans are sparse, and it remains unclear whether monocytes play an equally important role in humans. The aim of this study was to investigate whether the monocyte response following AMI is conserved between humans and mice and interrogate patterns of gene expression to identify regulated functions. Methods and results Thirty patients (AMI) and 24 control patients (stable coronary atherosclerosis) were enrolled. Female C57BL/6J mice (n = 6/group) underwent AMI by surgical coronary ligation. Myocardial injury was quantified by magnetic resonance imaging (human) and echocardiography (mice). Peripheral monocytes were isolated at presentation and at 48 h. RNA from separated monocytes was hybridized to Illumina beadchips. Acute myocardial infarction resulted in a significant peripheral monocytosis in both species that positively correlated with the extent of myocardial injury. Analysis of the monocyte transcriptome following AMI demonstrated significant conservation and identified inflammation and mitosis as central processes to this response. These findings were validated in both species. Conclusions Our findings show that the monocyte transcriptome is conserved between mice and humans following AMI. Patterns of gene expression associated with inflammation and proliferation appear to be switched on prior to their infiltration of injured myocardium suggesting that the specific targeting of inflammatory and proliferative processes in these immune cells in humans are possible therapeutic strategies. Importantly, they could be effective in the hours after AMI. PMID:25982896

  1. Plasma membrane proteomics of human breast cancer cell lines identifies potential targets for breast cancer diagnosis and treatment.

    Directory of Open Access Journals (Sweden)

    Yvonne S Ziegler

    Full Text Available The use of broad spectrum chemotherapeutic agents to treat breast cancer results in substantial and debilitating side effects, necessitating the development of targeted therapies to limit tumor proliferation and prevent metastasis. In recent years, the list of approved targeted therapies has expanded, and it includes both monoclonal antibodies and small molecule inhibitors that interfere with key proteins involved in the uncontrolled growth and migration of cancer cells. The targeting of plasma membrane proteins has been most successful to date, and this is reflected in the large representation of these proteins as targets of newer therapies. In view of these facts, experiments were designed to investigate the plasma membrane proteome of a variety of human breast cancer cell lines representing hormone-responsive, ErbB2 over-expressing and triple negative cell types, as well as a benign control. Plasma membranes were isolated by using an aqueous two-phase system, and the resulting proteins were subjected to mass spectrometry analysis. Overall, each of the cell lines expressed some unique proteins, and a number of proteins were expressed in multiple cell lines, but in patterns that did not always follow traditional clinical definitions of breast cancer type. From our data, it can be deduced that most cancer cells possess multiple strategies to promote uncontrolled growth, reflected in aberrant expression of tyrosine kinases, cellular adhesion molecules, and structural proteins. Our data set provides a very rich and complex picture of plasma membrane proteins present on breast cancer cells, and the sorting and categorizing of this data provides interesting insights into the biology, classification, and potential treatment of this prevalent and debilitating disease.

  2. Multiple lineages of human breast cancer stem/progenitor cells identified by profiling with stem cell markers.

    Directory of Open Access Journals (Sweden)

    Wendy W Hwang-Verslues

    2009-12-01

    Full Text Available Heterogeneity of cancer stem/progenitor cells that give rise to different forms of cancer has been well demonstrated for leukemia. However, this fundamental concept has yet to be established for solid tumors including breast cancer. In this communication, we analyzed solid tumor cancer stem cell markers in human breast cancer cell lines and primary specimens using flow cytometry. The stem/progenitor cell properties of different marker expressing-cell populations were further assessed by in vitro soft agar colony formation assay and the ability to form tumors in NOD/SCID mice. We found that the expression of stem cell markers varied greatly among breast cancer cell lines. In MDA-MB-231 cells, PROCR and ESA, instead of the widely used breast cancer stem cell markers CD44(+/CD24(-/low and ALDH, could be used to highly enrich cancer stem/progenitor cell populations which exhibited the ability to self renew and divide asymmetrically. Furthermore, the PROCR(+/ESA(+ cells expressed epithelial-mesenchymal transition markers. PROCR could also be used to enrich cells with colony forming ability from MB-361 cells. Moreover, consistent with the marker profiling using cell lines, the expression of stem cell markers differed greatly among primary tumors. There was an association between metastasis status and a high prevalence of certain markers including CD44(+/CD24(-/low, ESA(+, CD133(+, CXCR4(+ and PROCR(+ in primary tumor cells. Taken together, these results suggest that similar to leukemia, several stem/progenitor cell-like subpopulations can exist in breast cancer.

  3. Proteomics Analysis Reveals Previously Uncharacterized Virulence Factors in Vibrio proteolyticus

    Directory of Open Access Journals (Sweden)

    Ann Ray

    2016-07-01

    Full Text Available Members of the genus Vibrio include many pathogens of humans and marine animals that share genetic information via horizontal gene transfer. Hence, the Vibrio pan-genome carries the potential to establish new pathogenic strains by sharing virulence determinants, many of which have yet to be characterized. Here, we investigated the virulence properties of Vibrio proteolyticus, a Gram-negative marine bacterium previously identified as part of the Vibrio consortium isolated from diseased corals. We found that V. proteolyticus causes actin cytoskeleton rearrangements followed by cell lysis in HeLa cells in a contact-independent manner. In search of the responsible virulence factor involved, we determined the V. proteolyticus secretome. This proteomics approach revealed various putative virulence factors, including active type VI secretion systems and effectors with virulence toxin domains; however, these type VI secretion systems were not responsible for the observed cytotoxic effects. Further examination of the V. proteolyticus secretome led us to hypothesize and subsequently demonstrate that a secreted hemolysin, belonging to a previously uncharacterized clan of the leukocidin superfamily, was the toxin responsible for the V. proteolyticus-mediated cytotoxicity in both HeLa cells and macrophages. Clearly, there remains an armory of yet-to-be-discovered virulence factors in the Vibrio pan-genome that will undoubtedly provide a wealth of knowledge on how a pathogen can manipulate host cells.

  4. Generating the Nighttime Light of the Human Settlements by Identifying Periodic Components from DMSP/OLS Satellite Imagery.

    Science.gov (United States)

    Letu, Husi; Hara, Masanao; Tana, Gegen; Bao, Yuhai; Nishio, Fumihiko

    2015-09-01

    Nighttime lights of the human settlements (hereafter, "stable lights") are seen as a valuable proxy of social economic activity and greenhouse gas emissions at the subnational level. In this study, we propose an improved method to generate the stable lights from Defense Meteorological Satellite Program/Operational Linescan System (DMSP/OLS) daily nighttime light data for 1999. The study area includes Japan, China, India, and other 10 countries in East Asia. A noise reduction filter (NRF) was employed to generate a stable light from DMSP/OLS time-series daily nighttime light data. It was found that noise from amplitude of the 1-year periodic component is included in the stable light. To remove the amplitude of the 1-year periodic component noise included in the stable light, the NRF method was improved to extract the periodic component. Then, new stable light was generated by removing the amplitude of the 1-year periodic component using the improved NRF method. The resulting stable light was evaluated by comparing it with the conventional nighttime stable light provided by the National Oceanic and Atmosphere Administration/National Geophysical Data Center (NOAA/NGDC). It is indicated that DNs of the NOAA stable light image are lower than those of the new stable light image. This might be attributable to the influence of attenuation effects from thin warm water clouds. However, due to overglow effect of the thin cloud, light area in new stable light is larger than NOAA stable light. Furthermore, the cumulative digital numbers (CDNs) and number of light area pixels (NLAP) of the generated stable light and NOAA/NGDC stable light were applied to estimate socioeconomic variables of population, electric power consumption, gross domestic product, and CO2 emissions from fossil fuel consumption. It is shown that the correlations of the population and CO2FF with new stable light data are higher than those in NOAA stable light data; correlations of the EPC and GDP with NOAA

  5. Decoding of Baby Calls: Can Adult Humans Identify the Eliciting Situation from Emotional Vocalizations of Preverbal Infants?

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    Jitka Lindová

    Full Text Available Preverbal infants often vocalize in emotionally loaded situations, yet the communicative potential of these vocalizations is not well understood. The aim of our study was to assess how accurately adult listeners extract information about the eliciting situation from infant preverbal vocalizations. Vocalizations of 19 infants aged 5-10 months were recorded in 3 negative (Pain, Isolation, Demand for Food and 3 positive (Play, Reunion, After Feeding situations. The recordings were later rated by 333 adult listeners on the scales of emotional valence and intensity. Subsequently, the listeners assigned the eliciting situations in a forced choice task. Listeners were almost perfectly able to discriminate whether a recording came from a negative or a positive situation. Their discrimination may have been based on perceived valence as they consistently assigned higher valence when listening to positive, and lower valence when listening to negative, recordings. Ability to identify the particular situation within the negative or positive realm was substantially weaker, with only three of the six situations being discriminated above chance. The best discriminated situation, Play, was associated with high perceived intensity. The weak qualitative discrimination of negative situations seemed to be based on graded perception of negative recordings, from the most intense and unpleasant (assigned to Pain to the least intense and least unpleasant (assigned to Demand for Food. Parenthood and younger age, but not gender of listeners, had weak positive effects on the accuracy of judgments. Our results indicate that adults almost flawlessly distinguish positive and negative infant sounds, but are rather inaccurate regarding identification of the specific needs of the infant and may normally employ other sensory channels to gain this information.

  6. CaMKII Phosphorylation of Na(V)1.5: Novel in Vitro Sites Identified by Mass Spectrometry and Reduced S516 Phosphorylation in Human Heart Failure.

    Science.gov (United States)

    Herren, Anthony W; Weber, Darren M; Rigor, Robert R; Margulies, Kenneth B; Phinney, Brett S; Bers, Donald M

    2015-05-01

    The cardiac voltage-gated sodium channel, Na(V)1.5, drives the upstroke of the cardiac action potential and is a critical determinant of myocyte excitability. Recently, calcium (Ca(2+))/calmodulin(CaM)-dependent protein kinase II (CaMKII) has emerged as a critical regulator of Na(V)1.5 function through phosphorylation of multiple residues including S516, T594, and S571, and these phosphorylation events may be important for the genesis of acquired arrhythmias, which occur in heart failure. However, phosphorylation of full-length human Na(V)1.5 has not been systematically analyzed and Na(V)1.5 phosphorylation in human heart failure is incompletely understood. In the present study, we used label-free mass spectrometry to assess phosphorylation of human Na(V)1.5 purified from HEK293 cells with full coverage of phosphorylatable sites and identified 23 sites that were phosphorylated by CaMKII in vitro. We confirmed phosphorylation of S516 and S571 by LC-MS/MS and found a decrease in S516 phosphorylation in human heart failure, using a novel phospho-specific antibody. This work furthers our understanding of the phosphorylation of Na(V)1.5 by CaMKII under normal and disease conditions, provides novel CaMKII target sites for functional validation, and provides the first phospho-proteomic map of full-length human Na(V)1.5.

  7. 5 CFR 9701.352 - Use of highest previous rate.

    Science.gov (United States)

    2010-01-01

    ... HUMAN RESOURCES MANAGEMENT SYSTEM Pay and Pay Administration Pay Administration § 9701.352 Use of... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Use of highest previous rate. 9701.352 Section 9701.352 Administrative Personnel DEPARTMENT OF HOMELAND SECURITY HUMAN RESOURCES MANAGEMENT...

  8. A possible allosteric communication pathway identified through a resonance Raman study of four beta37 mutants of human hemoglobin A.

    Science.gov (United States)

    Peterson, E S; Friedman, J M

    1998-03-31

    The highly conserved tryptophan at position beta37 occupies a key locus at the hinge region within the alpha1beta2 interface of the mammalian hemoglobins. This residue is thought to play an important role in mediating the heme-heme interaction associated with the cooperative binding of oxygen; however, its explicit function is unclear. In this study, the proximal heme environments of several beta37 mutants of adult human hemoglobin (HbA) are probed using visible (Soret band enhanced) resonance Raman spectroscopy. In the equilibrium deoxy derivatives of these mutants, a systematic variation in proximal strain, as reflected in the iron-proximal histidine (F8) stretching frequency, nu(Fe-His), is seen upon mutation of the beta37 residue. The variation in proximal strain correlates with both the ligand binding rates [Kwiatkowski et al. (1998) Biochemistry 37, 4325-4335] and conformational changes observed at the FG corner through X-ray crystallography [Kavanaugh et al. (1998) Biochemistry 37, 4358-4373]. The results from the deoxy samples indicate a plasticity of the tertiary structure within the T quaternary state. The correlation between the X-ray data and the Raman supports the idea that the proximal strain at the heme within the T state can be modulated by a combination of forces including those arising from the hinge region of the alpha1beta2 interface, from the binding of allosteric effectors, and from the degree of iron displacement from the heme plane. Each of these contributors appears to operate through a shifting of the F helix either away from or toward the FG corner. The Raman spectra obtained from the 10 ns CO photoproduct of the beta37 mutant Hb's indicate that these mutants contain an altered coupling between the R state alpha1beta2 interface and the proximal heme environment. This altered coupling could be due to either dissociation of the ligated mutant tetramers into dimers or the formation of an R state tetramer with significantly weakened hydrogen

  9. Genome-wide association studies in dogs and humans identify ADAMTS20 as a risk variant for cleft lip and palate.

    Directory of Open Access Journals (Sweden)

    Zena T Wolf

    2015-03-01

    Full Text Available Cleft lip with or without cleft palate (CL/P is the most commonly occurring craniofacial birth defect. We provide insight into the genetic etiology of this birth defect by performing genome-wide association studies in two species: dogs and humans. In the dog, a genome-wide association study of 7 CL/P cases and 112 controls from the Nova Scotia Duck Tolling Retriever (NSDTR breed identified a significantly associated region on canine chromosome 27 (unadjusted p=1.1 x 10(-13; adjusted p= 2.2 x 10(-3. Further analysis in NSDTR families and additional full sibling cases identified a 1.44 Mb homozygous haplotype (chromosome 27: 9.29 - 10.73 Mb segregating with a more complex phenotype of cleft lip, cleft palate, and syndactyly (CLPS in 13 cases. Whole-genome sequencing of 3 CLPS cases and 4 controls at 15X coverage led to the discovery of a frameshift mutation within ADAMTS20 (c.1360_1361delAA (p.Lys453Ilefs*3, which segregated concordant with the phenotype. In a parallel study in humans, a family-based association analysis (DFAM of 125 CL/P cases, 420 unaffected relatives, and 392 controls from a Guatemalan cohort, identified a suggestive association (rs10785430; p =2.67 x 10-6 with the same gene, ADAMTS20. Sequencing of cases from the Guatemalan cohort was unable to identify a causative mutation within the coding region of ADAMTS20, but four coding variants were found in additional cases of CL/P. In summary, this study provides genetic evidence for a role of ADAMTS20 in CL/P development in dogs and as a candidate gene for CL/P development in humans.

  10. Ratio of cathepsin B to stefin A identifies heterogeneity within Gleason histologic scores for human prostate cancer.

    Science.gov (United States)

    Sinha, A A; Quast, B J; Wilson, M J; Fernandes, E T; Reddy, P K; Ewing, S L; Sloane, B F; Gleason, D F

    2001-09-15

    Cathepsin B (CB), a lysosomal cysteine protease, is involved in degradation of extracellular matrix proteins and progression of tumor cells from one biological compartment to another in many solid organ cancers, including prostate cancer. Our objective was to identify patterns of distribution of CB and its endogenous cellular inhibitor stefin A in cryostat sections of frozen BPH and prostate cancer tissue samples and to define these patterns in relation to Gleason histologic scores, clinical stages, and serum total PSA levels. We localized CB and stefin A in the same sections using polyclonal and monoclonal antibody immunoglobulin G (IgGs) against CB and stefin A using immunofluorescence and confocal microscopic techniques. Only cryostat sections of frozen prostates were used in localizations of CB and stefin A. Benign prostatic hyperplasia (BPH) showed similar localization patterns for CB and stefin A and a ratio of 1 was indicated by CB = stefin A. Confocal studies indicated that most CB and stefin A sites in BPH glandular cells overlapped as shown by the yellow fluorescence of their co-localization. We found considerable variability in individual localization of CB and stefin A within and between Gleason histologic scores for prostate cancers. This variability was also found in Gleason score 6 tumors that are otherwise considered similar histologically and morphologically. Negative control sections did not show localization of CB by FITC, stefin A by Cy3 or yellow fluorescence for co-localization. Our analysis of the ratio of CB to stefin A showed three patterns, namely CB = stefin A, CB > stefin A, and CB showed more sites of yellow fluorescence when the ratio was CB = stefin A than those found in CB > stefin A or CB showed prostate cancer cases with ratios of CB > stefin A (P show any specific relationship between the ratio of CB to stefin A and Gleason scores, clinical stages, and serum total prostate specific antigen (PSA) levels in prostate cancers

  11. Proteomics Analysis Reveals Previously Uncharacterized Virulence Factors in Vibrio proteolyticus.

    Science.gov (United States)

    Ray, Ann; Kinch, Lisa N; de Souza Santos, Marcela; Grishin, Nick V; Orth, Kim; Salomon, Dor

    2016-07-26

    Members of the genus Vibrio include many pathogens of humans and marine animals that share genetic information via horizontal gene transfer. Hence, the Vibrio pan-genome carries the potential to establish new pathogenic strains by sharing virulence determinants, many of which have yet to be characterized. Here, we investigated the virulence properties of Vibrio proteolyticus, a Gram-negative marine bacterium previously identified as part of the Vibrio consortium isolated from diseased corals. We found that V. proteolyticus causes actin cytoskeleton rearrangements followed by cell lysis in HeLa cells in a contact-independent manner. In search of the responsible virulence factor involved, we determined the V. proteolyticus secretome. This proteomics approach revealed various putative virulence factors, including active type VI secretion systems and effectors with virulence toxin domains; however, these type VI secretion systems were not responsible for the observed cytotoxic effects. Further examination of the V. proteolyticus secretome led us to hypothesize and subsequently demonstrate that a secreted hemolysin, belonging to a previously uncharacterized clan of the leukocidin superfamily, was the toxin responsible for the V. proteolyticus-mediated cytotoxicity in both HeLa cells and macrophages. Clearly, there remains an armory of yet-to-be-discovered virulence factors in the Vibrio pan-genome that will undoubtedly provide a wealth of knowledge on how a pathogen can manipulate host cells. The pan-genome of the genus Vibrio is a potential reservoir of unidentified toxins that can provide insight into how members of this genus have successfully risen as emerging pathogens worldwide. We focused on Vibrio proteolyticus, a marine bacterium that was previously implicated in virulence toward marine animals, and characterized its interaction with eukaryotic cells. We found that this bacterium causes actin cytoskeleton rearrangements and leads to cell death. Using a

  12. Application of a human factors classification framework for patient safety to identify precursor and contributing factors to adverse clinical incidents in hospital.

    Science.gov (United States)

    Mitchell, Rebecca J; Williamson, Ann; Molesworth, Brett

    2016-01-01

    This study aimed to identify temporal precursor and associated contributing factors for adverse clinical incidents in a hospital setting using the Human Factors Classification Framework (HFCF) for patient safety. A random sample of 498 clinical incidents were reviewed. The framework identified key precursor events (PE), contributing factors (CF) and the prime causes of incidents. Descriptive statistics and correspondence analysis were used to examine incident characteristics. Staff action was the most common type of PE identified. Correspondence analysis for all PEs that involved staff action by error type showed that rule-based errors were strongly related to performing medical or monitoring tasks or the administration of medication. Skill-based errors were strongly related to misdiagnoses. Factors relating to the organisation (66.9%) or the patient (53.2%) were the most commonly identified CFs. The HFCF for patient safety was able to identify patterns of causation for the clinical incidents, highlighting the need for targeted preventive approaches, based on an understanding of how and why incidents occur. Copyright © 2015 Elsevier Ltd and The Ergonomics Society. All rights reserved.

  13. Integrin α6β4 identifies human distal lung epithelial progenitor cells with potential as a cell-based therapy for cystic fibrosis lung disease.

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    Xiaopeng Li

    Full Text Available To develop stem/progenitor cell-based therapy for cystic fibrosis (CF lung disease, it is first necessary to identify markers of human lung epithelial progenitor/stem cells and to better understand the potential for differentiation into distinct lineages. Here we investigated integrin α6β4 as an epithelial progenitor cell marker in the human distal lung. We identified a subpopulation of α6β4(+ cells that localized in distal small airways and alveolar walls and were devoid of pro-surfactant protein C expression. The α6β4(+ epithelial cells demonstrated key properties of stem cells ex vivo as compared to α6β4(- epithelial cells, including higher colony forming efficiency, expression of stem cell-specific transcription factor Nanog, and the potential to differentiate into multiple distinct lineages including basal and Clara cells. Co-culture of α6β4(+ epithelial cells with endothelial cells enhanced proliferation. We identified a subset of adeno-associated virus (AAVs serotypes, AAV2 and AAV8, capable of transducing α6β4(+ cells. In addition, reconstitution of bronchi epithelial cells from CF patients with only 5% normal α6β4(+ epithelial cells significantly rescued defects in Cl(- transport. Therefore, targeting the α6β4(+ epithelial population via either gene delivery or progenitor cell-based reconstitution represents a potential new strategy to treat CF lung disease.

  14. Therapeutic molecules for multiple human diseases identified from pigeon pea (Cajanus cajan L. Millsp. through GC–MS and molecular docking

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    Deepu Mathew

    2017-12-01

    Full Text Available Molecular mechanism behind the therapeutic potential of pigeon pea over the human diseases such as rheumatoid arthritis, breast cancer, type II diabetes, malaria, measles and sickle cell disease were revealed through docking of GC–MS identified phyto-compound ligands with candidate disease proteins. Of the 242 ligands, three dimensional structures of 47 compounds had to be drawn using ChemSketch and the remaining structures were retrieved from PubChem and docked with the active sites of candidate proteins. The molecules identified through docking were further subjected to ADMET analysis and promising drug candidates were identified for each disease. This paper presents a precise account of the chemoprofile of pigeon pea leaves, stems and seeds, interaction of these molecules with target proteins and suggests 26 highly potential molecules which are drug candidates for multiple human diseases. Pigeon pea seeds are especially proven as invaluable source for therapeutic molecules. Keywords: Breast cancer, Drug discovery, Herbal medicine, In silico, Malaria, Measles, Phyto-compounds, Rheumatoid arthritis, Sickle cell disease, Type II diabetes

  15. An expression screen for aged-dependent microRNAs identifies miR-30a as a key regulator of aging features in human epidermis.

    Science.gov (United States)

    Muther, Charlotte; Jobeili, Lara; Garion, Maëlle; Heraud, Sandrine; Thepot, Amélie; Damour, Odile; Lamartine, Jérôme

    2017-11-19

    The mechanisms affecting epidermal homeostasis during aging remain poorly understood. To identify age-related microRNAs, a class of non-coding RNAs known to play a key role in the regulation of epidermal homeostasis, an exhaustive miRNA expression screen was performed in human keratinocytes from young or elderly subjects. Many microRNAs modulated by aging were identified, including miR-30a, in which both strands were overexpressed in aged cells and epidermal tissue. Stable MiR-30a over-expression strongly impaired epidermal differentiation, inducing severe barrier function defects in an organotypic culture model. A significant increase was also observed in the level of apoptotic cells in epidermis over-expressing miR-30a. Several gene targets of miR-30a were identified in keratinocytes, including LOX (encoding lysyl oxidase, a regulator of the proliferation/differentiation balance of keratinocytes), IDH1 (encoding isocitrate dehydrogenase, an enzyme of cellular metabolism) and AVEN (encoding a caspase inhibitor). Direct regulation of LOX , IDH1 and AVEN by miR-30a was confirmed in human keratinocytes. They were, moreover, observed to be repressed in aged skin, suggesting a possible link between miR-30a induction and skin-aging phenotype. This study revealed a new miRNA actor and deciphered new molecular mechanisms to explain certain alterations observed in epidermis during aging and especially those concerning keratinocyte differentiation and apoptosis.

  16. Identification of Tenrec ecaudatus, a Wild Mammal Introduced to Mayotte Island, as a Reservoir of the Newly Identified Human Pathogenic Leptospira mayottensis.

    Directory of Open Access Journals (Sweden)

    Erwan Lagadec

    2016-08-01

    Full Text Available Leptospirosis is a bacterial zoonosis of major concern on tropical islands. Human populations on western Indian Ocean islands are strongly affected by the disease although each archipelago shows contrasting epidemiology. For instance, Mayotte, part of the Comoros Archipelago, differs from the other neighbouring islands by a high diversity of Leptospira species infecting humans that includes Leptospira mayottensis, a species thought to be unique to this island. Using bacterial culture, molecular detection and typing, the present study explored the wild and domestic local mammalian fauna for renal carriage of leptospires and addressed the genetic relationships of the infecting strains with local isolates obtained from acute human cases and with Leptospira strains hosted by mammal species endemic to nearby Madagascar. Tenrec (Tenrec ecaudatus, Family Tenrecidae, a terrestrial mammal introduced from Madagascar, is identified as a reservoir of L. mayottensis. All isolated L. mayottensis sequence types form a monophyletic clade that includes Leptospira strains infecting humans and tenrecs on Mayotte, as well as two other Malagasy endemic tenrecid species of the genus Microgale. The lower diversity of L. mayottensis in tenrecs from Mayotte, compared to that occurring in Madagascar, suggests that L. mayottensis has indeed a Malagasy origin. This study also showed that introduced rats (Rattus rattus and dogs are probably the main reservoirs of Leptospira borgpetersenii and Leptospira kirschneri, both bacteria being prevalent in local clinical cases. Data emphasize the epidemiological link between the two neighbouring islands and the role of introduced small mammals in shaping the local epidemiology of leptospirosis.

  17. Identification of Tenrec ecaudatus, a Wild Mammal Introduced to Mayotte Island, as a Reservoir of the Newly Identified Human Pathogenic Leptospira mayottensis.

    Science.gov (United States)

    Lagadec, Erwan; Gomard, Yann; Le Minter, Gildas; Cordonin, Colette; Cardinale, Eric; Ramasindrazana, Beza; Dietrich, Muriel; Goodman, Steven M; Tortosa, Pablo; Dellagi, Koussay

    2016-08-01

    Leptospirosis is a bacterial zoonosis of major concern on tropical islands. Human populations on western Indian Ocean islands are strongly affected by the disease although each archipelago shows contrasting epidemiology. For instance, Mayotte, part of the Comoros Archipelago, differs from the other neighbouring islands by a high diversity of Leptospira species infecting humans that includes Leptospira mayottensis, a species thought to be unique to this island. Using bacterial culture, molecular detection and typing, the present study explored the wild and domestic local mammalian fauna for renal carriage of leptospires and addressed the genetic relationships of the infecting strains with local isolates obtained from acute human cases and with Leptospira strains hosted by mammal species endemic to nearby Madagascar. Tenrec (Tenrec ecaudatus, Family Tenrecidae), a terrestrial mammal introduced from Madagascar, is identified as a reservoir of L. mayottensis. All isolated L. mayottensis sequence types form a monophyletic clade that includes Leptospira strains infecting humans and tenrecs on Mayotte, as well as two other Malagasy endemic tenrecid species of the genus Microgale. The lower diversity of L. mayottensis in tenrecs from Mayotte, compared to that occurring in Madagascar, suggests that L. mayottensis has indeed a Malagasy origin. This study also showed that introduced rats (Rattus rattus) and dogs are probably the main reservoirs of Leptospira borgpetersenii and Leptospira kirschneri, both bacteria being prevalent in local clinical cases. Data emphasize the epidemiological link between the two neighbouring islands and the role of introduced small mammals in shaping the local epidemiology of leptospirosis.

  18. The pathogenicity of genetic variants previously associated with left ventricular non-compaction

    DEFF Research Database (Denmark)

    Abbasi, Yeganeh; Jabbari, Javad; Jabbari, Reza

    2016-01-01

    an updated list of previously reported LVNC-associated variants with biologic description and investigate the prevalence of LVNC variants in healthy general population to find false-positive LVNC-associated variants. METHODS AND RESULTS: The Human Gene Mutation Database and PubMed were systematically...... searched to identify all previously reported LVNC-associated variants. Thereafter, the Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC), that both represent the background population, was searched for all variants. Four in silico prediction tools were assessed to determine...

  19. A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits

    DEFF Research Database (Denmark)

    Volkov, Petr; Olsson, Anders H; Gillberg, Linn

    2016-01-01

    mediate their effects on metabolic traits (e.g. BMI, cholesterol, high-density lipoprotein (HDL), hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR)) via altered DNA methylation in human adipose tissue. This study identifies genome-wide interactions between genetic......Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men...... CHRNA5, G6PC2, GPX7, RPL27A, THNSL2 and ZFP57. SNPs in significant mQTLs were also associated with body mass index (BMI), lipid traits and glucose and insulin levels in our study cohort and public available consortia data. Importantly, the Causal Inference Test (CIT) demonstrates how genetic variants...

  20. Systems biology combining human- and animal-data miRNA and mRNA data identifies new targets in ureteropelvic junction obstruction.

    Science.gov (United States)

    Papadopoulos, Theofilos; Casemayou, Audrey; Neau, Eric; Breuil, Benjamin; Caubet, Cécile; Calise, Denis; Thornhill, Barbara A; Bachvarova, Magdalena; Belliere, Julie; Chevalier, Robert L; Moulos, Panagiotis; Bachvarov, Dimcho; Buffin-Meyer, Benedicte; Decramer, Stéphane; Auriol, Françoise Conte; Bascands, Jean-Loup; Schanstra, Joost P; Klein, Julie

    2017-03-01

    Although renal fibrosis and inflammation have shown to be involved in the pathophysiology of obstructive nephropathies, molecular mechanisms underlying evolution of these processes remain undetermined. In an attempt towards improved understanding of obstructive nephropathy and improved translatability of the results to clinical practice we have developed a systems biology approach combining omics data of both human and mouse obstructive nephropathy. We have studied in parallel the urinary miRNome of infants with ureteropelvic junction obstruction and the kidney tissue miRNome and transcriptome of the corresponding neonatal partial unilateral ureteral obstruction (UUO) mouse model. Several hundreds of miRNAs and mRNAs displayed changed abundance during disease. Combination of miRNAs in both species and associated mRNAs let to the prioritization of five miRNAs and 35 mRNAs associated to disease. In vitro and in vivo validation identified consistent dysregulation of let-7a-5p and miR-29-3p and new potential targets, E3 ubiquitin-protein ligase (DTX4) and neuron navigator 1 (NAV1), potentially involved in fibrotic processes, in obstructive nephropathy in both human and mice that would not be identified otherwise. Our study is the first to correlate a mouse model of neonatal partial UUO with human UPJ obstruction in a comprehensive systems biology analysis. Our data revealed let-7a and miR-29b as molecules potentially involved in the development of fibrosis in UPJ obstruction via the control of DTX4 in both man and mice that would not be identified otherwise.

  1. Spatially conserved regulatory elements identified within human and mouse Cd247 gene using high-throughput sequencing data from the ENCODE project

    DEFF Research Database (Denmark)

    Pundhir, Sachin; Hannibal, Tine Dahlbæk; Bang-Berthelsen, Claus Heiner

    2014-01-01

    . In this study, we have utilized the wealth of high-throughput sequencing data produced during the Encyclopedia of DNA Elements (ENCODE) project to identify spatially conserved regulatory elements within the Cd247 gene from human and mouse. We show the presence of two transcription factor binding sites......The Cd247 gene encodes for a transmembrane protein important for the expression and assembly of TCR/CD3 complex on the surface of T lymphocytes. Down-regulation of CD247 has functional consequences in systemic autoimmunity and has been shown to be associated with Type 1 Diabetes in NOD mouse......, supported by histone marks and ChIP-seq data, that specifically have features of an enhancer and a promoter, respectively. We also identified a putative long non-coding RNA from the characteristically long first intron of the Cd247 gene. The long non-coding RNA annotation is supported by manual annotations...

  2. Oxyntomodulin Identified as a Marker of Type 2 Diabetes and Gastric Bypass Surgery by Mass-spectrometry Based Profiling of Human Plasma

    Directory of Open Access Journals (Sweden)

    Nicolai J. Wewer Albrechtsen

    2016-05-01

    Full Text Available Low-abundance regulatory peptides, including metabolically important gut hormones, have shown promising therapeutic potential. Here, we present a streamlined mass spectrometry-based platform for identifying and characterizing low-abundance regulatory peptides in humans. We demonstrate the clinical applicability of this platform by studying a hitherto neglected glucose- and appetite-regulating gut hormone, namely, oxyntomodulin. Our results show that the secretion of oxyntomodulin in patients with type 2 diabetes is significantly impaired, and that its level is increased by more than 10-fold after gastric bypass surgery. Furthermore, we report that oxyntomodulin is co-distributed and co-secreted with the insulin-stimulating and appetite-regulating gut hormone glucagon-like peptide-1 (GLP-1, is inactivated by the same protease (dipeptidyl peptidase-4 as GLP-1 and acts through its receptor. Thus, oxyntomodulin may participate with GLP-1 in the regulation of glucose metabolism and appetite in humans. In conclusion, this mass spectrometry-based platform is a powerful resource for identifying and characterizing metabolically active low-abundance peptides.

  3. A Novel Computational Strategy to Identify A-to-I RNA Editing Sites by RNA-Seq Data: De Novo Detection in Human Spinal Cord Tissue

    Science.gov (United States)

    Picardi, Ernesto; Gallo, Angela; Galeano, Federica; Tomaselli, Sara; Pesole, Graziano

    2012-01-01

    RNA editing is a post-transcriptional process occurring in a wide range of organisms. In human brain, the A-to-I RNA editing, in which individual adenosine (A) bases in pre-mRNA are modified to yield inosine (I), is the most frequent event. Modulating gene expression, RNA editing is essential for cellular homeostasis. Indeed, its deregulation has been linked to several neurological and neurodegenerative diseases. To date, many RNA editing sites have been identified by next generation sequencing technologies employing massive transcriptome sequencing together with whole genome or exome sequencing. While genome and transcriptome reads are not always available for single individuals, RNA-Seq data are widespread through public databases and represent a relevant source of yet unexplored RNA editing sites. In this context, we propose a simple computational strategy to identify genomic positions enriched in novel hypothetical RNA editing events by means of a new two-steps mapping procedure requiring only RNA-Seq data and no a priori knowledge of RNA editing characteristics and genomic reads. We assessed the suitability of our procedure by confirming A-to-I candidates using conventional Sanger sequencing and performing RNA-Seq as well as whole exome sequencing of human spinal cord tissue from a single individual. PMID:22957051

  4. Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.

    Science.gov (United States)

    Spielmann, Malte; Kakar, Naseebullah; Tayebi, Naeimeh; Leettola, Catherine; Nürnberg, Gudrun; Sowada, Nadine; Lupiáñez, Darío G; Harabula, Izabela; Flöttmann, Ricarda; Horn, Denise; Chan, Wing Lee; Wittler, Lars; Yilmaz, Rüstem; Altmüller, Janine; Thiele, Holger; van Bokhoven, Hans; Schwartz, Charles E; Nürnberg, Peter; Bowie, James U; Ahmad, Jamil; Kubisch, Christian; Mundlos, Stefan; Borck, Guntram

    2016-02-01

    The CRISPR/Cas technology enables targeted genome editing and the rapid generation of transgenic animal models for the study of human genetic disorders. Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK. ZAK is a member of the MAPKKK family with no known role in limb development. We show that Zak is expressed in the developing limbs and that a CRISPR/Cas-mediated knockout of the two Zak isoforms is embryonically lethal in mice. In contrast, a deletion of the SAM domain induces a complex hindlimb defect associated with down-regulation of Trp63, a known split-hand/split-foot malformation disease gene. Our results identify ZAK as a key player in mammalian limb patterning and demonstrate the rapid utility of CRISPR/Cas genome editing to assign causality to human mutations in the mouse in <10 wk. © 2016 Spielmann et al.; Published by Cold Spring Harbor Laboratory Press.

  5. Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion.

    Directory of Open Access Journals (Sweden)

    Tasnim Dayeh

    2014-03-01

    Full Text Available Impaired insulin secretion is a hallmark of type 2 diabetes (T2D. Epigenetics may affect disease susceptibility. To describe the human methylome in pancreatic islets and determine the epigenetic basis of T2D, we analyzed DNA methylation of 479,927 CpG sites and the transcriptome in pancreatic islets from T2D and non-diabetic donors. We provide a detailed map of the global DNA methylation pattern in human islets, β- and α-cells. Genomic regions close to the transcription start site showed low degrees of methylation and regions further away from the transcription start site such as the gene body, 3'UTR and intergenic regions showed a higher degree of methylation. While CpG islands were hypomethylated, the surrounding 2 kb shores showed an intermediate degree of methylation, whereas regions further away (shelves and open sea were hypermethylated in human islets, β- and α-cells. We identified 1,649 CpG sites and 853 genes, including TCF7L2, FTO and KCNQ1, with differential DNA methylation in T2D islets after correction for multiple testing. The majority of the differentially methylated CpG sites had an intermediate degree of methylation and were underrepresented in CpG islands (∼ 7% and overrepresented in the open sea (∼ 60%. 102 of the differentially methylated genes, including CDKN1A, PDE7B, SEPT9 and EXOC3L2, were differentially expressed in T2D islets. Methylation of CDKN1A and PDE7B promoters in vitro suppressed their transcriptional activity. Functional analyses demonstrated that identified candidate genes affect pancreatic β- and α-cells as Exoc3l silencing reduced exocytosis and overexpression of Cdkn1a, Pde7b and Sept9 perturbed insulin and glucagon secretion in clonal β- and α-cells, respectively. Together, our data can serve as a reference methylome in human islets. We provide new target genes with altered DNA methylation and expression in human T2D islets that contribute to perturbed insulin and glucagon secretion. These

  6. Genome-wide siRNA-based functional genomics of pigmentation identifies novel genes and pathways that impact melanogenesis in human cells.

    Directory of Open Access Journals (Sweden)

    Anand K Ganesan

    2008-12-01

    Full Text Available Melanin protects the skin and eyes from the harmful effects of UV irradiation, protects neural cells from toxic insults, and is required for sound conduction in the inner ear. Aberrant regulation of melanogenesis underlies skin disorders (melasma and vitiligo, neurologic disorders (Parkinson's disease, auditory disorders (Waardenburg's syndrome, and opthalmologic disorders (age related macular degeneration. Much of the core synthetic machinery driving melanin production has been identified; however, the spectrum of gene products participating in melanogenesis in different physiological niches is poorly understood. Functional genomics based on RNA-mediated interference (RNAi provides the opportunity to derive unbiased comprehensive collections of pharmaceutically tractable single gene targets supporting melanin production. In this study, we have combined a high-throughput, cell-based, one-well/one-gene screening platform with a genome-wide arrayed synthetic library of chemically synthesized, small interfering RNAs to identify novel biological pathways that govern melanin biogenesis in human melanocytes. Ninety-two novel genes that support pigment production were identified with a low false discovery rate. Secondary validation and preliminary mechanistic studies identified a large panel of targets that converge on tyrosinase expression and stability. Small molecule inhibition of a family of gene products in this class was sufficient to impair chronic tyrosinase expression in pigmented melanoma cells and UV-induced tyrosinase expression in primary melanocytes. Isolation of molecular machinery known to support autophagosome biosynthesis from this screen, together with in vitro and in vivo validation, exposed a close functional relationship between melanogenesis and autophagy. In summary, these studies illustrate the power of RNAi-based functional genomics to identify novel genes, pathways, and pharmacologic agents that impact a biological phenotype

  7. Placental complications after a previous cesarean section

    OpenAIRE

    Milošević Jelena; Lilić Vekoslav; Tasić Marija; Radović-Janošević Dragana; Stefanović Milan; Antić Vladimir

    2009-01-01

    Introduction The incidence of cesarean section has been rising in the past 50 years. With the increased number of cesarean sections, the number of pregnancies with the previous cesarean section rises as well. The aim of this study was to establish the influence of the previous cesarean section on the development of placental complications: placenta previa, placental abruption and placenta accreta, as well as to determine the influence of the number of previous cesarean sections on the complic...

  8. Diverse small molecule inhibitors of human apurinic/apyrimidinic endonuclease APE1 identified from a screen of a large public collection.

    Directory of Open Access Journals (Sweden)

    Dorjbal Dorjsuren

    Full Text Available The major human apurinic/apyrimidinic endonuclease APE1 plays a pivotal role in the repair of base damage via participation in the DNA base excision repair (BER pathway. Increased activity of APE1, often observed in tumor cells, is thought to contribute to resistance to various anticancer drugs, whereas down-regulation of APE1 sensitizes cells to DNA damaging agents. Thus, inhibiting APE1 repair endonuclease function in cancer cells is considered a promising strategy to overcome therapeutic agent resistance. Despite ongoing efforts, inhibitors of APE1 with adequate drug-like properties have yet to be discovered. Using a kinetic fluorescence assay, we conducted a fully-automated high-throughput screen (HTS of the NIH Molecular Libraries Small Molecule Repository (MLSMR, as well as additional public collections, with each compound tested as a 7-concentration series in a 4 µL reaction volume. Actives identified from the screen were subjected to a panel of confirmatory and counterscreen tests. Several active molecules were identified that inhibited APE1 in two independent assay formats and exhibited potentiation of the genotoxic effect of methyl methanesulfonate with a concomitant increase in AP sites, a hallmark of intracellular APE1 inhibition; a number of these chemotypes could be good starting points for further medicinal chemistry optimization. To our knowledge, this represents the largest-scale HTS to identify inhibitors of APE1, and provides a key first step in the development of novel agents targeting BER for cancer treatment.

  9. Small regions of overlapping deletions on 6q26 in human astrocytic tumours identified using chromosome 6 tile path array CGH

    Science.gov (United States)

    Ichimura, Koichi; Mungall, Andrew J; Fiegler, Heike; Pearson, Danita M.; Dunham, Ian; Carter, Nigel P; Collins, V. Peter

    2009-01-01

    Deletions of chromosome 6 are a common abnormality in diverse human malignancies including astrocytic tumours, suggesting the presence of tumour suppressor genes (TSG). In order to help identify candidate TSGs, we have constructed a chromosome 6 tile path microarray. The array contains 1780 clones (778 PACs and 1002 BACs) that cover 98.3% of the published chromosome 6 sequences. A total of 104 adult astrocytic tumours (10 diffuse astrocytomas, 30 anaplastic astrocytomas (AA), 64 glioblastomas (GB)) were analysed using this array. Single copy number change was successfully detected and the result was in general concordant with a microsatellite analysis. The pattern of copy number change was complex with multiple interstitial deletions/gains. However, a predominance of telomeric 6q deletions was seen. Two small common and overlapping regions of deletion at 6q26 were identified. One was 1002 kb in size and contained PACRG and QKI, while the second was 199 kb and harbours a single gene, ARID1B. The data show that the chromosome 6 tile path array is useful in mapping copy number changes with high resolution and accuracy. We confirmed the high frequency of chromosome 6 deletions in AA and GB, and identified two novel commonly deleted regions that may harbour TSGs. PMID:16205629

  10. A network analysis of the human T-cell activation gene network identifies JAGGED1 as a therapeutic target for autoimmune diseases.

    Directory of Open Access Journals (Sweden)

    Ricardo Palacios

    2007-11-01

    Full Text Available Understanding complex diseases will benefit the recognition of the properties of the gene networks that control biological functions. Here, we set out to model the gene network that controls T-cell activation in humans, which is critical for the development of autoimmune diseases such as Multiple Sclerosis (MS. The network was established on the basis of the quantitative expression from 104 individuals of 20 genes of the immune system, as well as on biological information from the Ingenuity database and Bayesian inference. Of the 31 links (gene interactions identified in the network, 18 were identified in the Ingenuity database and 13 were new and we validated 7 of 8 interactions experimentally. In the MS patients network, we found an increase in the weight of gene interactions related to Th1 function and a decrease in those related to Treg and Th2 function. Indeed, we found that IFN-ss therapy induces changes in gene interactions related to T cell proliferation and adhesion, although these gene interactions were not restored to levels similar to controls. Finally, we identify JAG1 as a new therapeutic target whose differential behaviour in the MS network was not modified by immunomodulatory therapy. In vitro treatment with a Jagged1 agonist peptide modulated the T-cell activation network in PBMCs from patients with MS. Moreover, treatment of mice with experimental autoimmune encephalomyelitis with the Jagged1 agonist ameliorated the disease course, and modulated Th2, Th1 and Treg function. This study illustrates how network analysis can predict therapeutic targets for immune intervention and identified the immunomodulatory properties of Jagged1 making it a new therapeutic target for MS and other autoimmune diseases.

  11. Adding biological meaning to human protein-protein interactions identified by yeast two-hybrid screenings: A guide through bioinformatics tools.

    Science.gov (United States)

    Felgueiras, Juliana; Silva, Joana Vieira; Fardilha, Margarida

    2018-01-16

    "A man is known by the company he keeps" is a popular expression that perfectly fits proteins. A common approach to characterize the function of a target protein is to identify its interacting partners and thus infer its roles based on the known functions of the interactors. Protein-protein interaction networks (PPINs) have been created for several organisms, including humans, primarily as results of high-throughput screenings, such as yeast two-hybrid (Y2H). Their unequivocal use to understand events underlying human pathophysiology is promising in identifying genes and proteins associated with diseases. Therefore, numerous opportunities have emerged for PPINs as tools for clinical management of diseases: network-based disease classification systems, discovery of biomarkers and identification of therapeutic targets. Despite the great advantages of PPINs, their use is still unrecognised by several researchers who generate high-throughput data to generally characterize interactions in a certain model or to select an interaction to study in detail. We strongly believe that both approaches are not exclusive and that we can use PPINs as a complementary methodology and rich-source of information to the initial study proposal. Here, we suggest a pipeline to deal with Y2H results using bioinformatics tools freely available for academics. Yeast two-hybrid is widely-used to identify protein-protein interactions. Conventionally, the positive clones that result from a yeast two-hybrid screening are sequenced to identify the interactors of the protein of interest (also known as bait protein), and few interactions, thought as potentially relevant for the model in study, are selected for further validation using biochemical methods (e.g. co-immunoprecipitation and co-localization). The huge amount of data that is potentially lost during this conservative approach motivated us to write this tutorial-like review, so that researchers feel encouraged to take advantage of

  12. A novel psittacine adenovirus identified during an outbreak of avian chlamydiosis and human psittacosis: zoonosis associated with virus-bacterium coinfection in birds.

    Directory of Open Access Journals (Sweden)

    Kelvin K W To

    2014-12-01

    Full Text Available Chlamydophila psittaci is found worldwide, but is particularly common among psittacine birds in tropical and subtropical regions. While investigating a human psittacosis outbreak that was associated with avian chlamydiosis in Hong Kong, we identified a novel adenovirus in epidemiologically linked Mealy Parrots, which was not present in healthy birds unrelated to the outbreak or in other animals. The novel adenovirus (tentatively named Psittacine adenovirus HKU1 was most closely related to Duck adenovirus A in the Atadenovirus genus. Sequencing showed that the Psittacine adenovirus HKU1 genome consists of 31,735 nucleotides. Comparative genome analysis showed that the Psittacine adenovirus HKU1 genome contains 23 open reading frames (ORFs with sequence similarity to known adenoviral genes, and six additional ORFs at the 3' end of the genome. Similar to Duck adenovirus A, the novel adenovirus lacks LH1, LH2 and LH3, which distinguishes it from other viruses in the Atadenovirus genus. Notably, fiber-2 protein, which is present in Aviadenovirus but not Atadenovirus, is also present in Psittacine adenovirus HKU1. Psittacine adenovirus HKU1 had pairwise amino acid sequence identities of 50.3-54.0% for the DNA polymerase, 64.6-70.7% for the penton protein, and 66.1-74.0% for the hexon protein with other Atadenovirus. The C. psittaci bacterial load was positively correlated with adenovirus viral load in the lung. Immunostaining for fiber protein expression was positive in lung and liver tissue cells of affected parrots, confirming active viral replication. No other viruses were found. This is the first documentation of an adenovirus-C. psittaci co-infection in an avian species that was associated with a human outbreak of psittacosis. Viral-bacterial co-infection often increases disease severity in both humans and animals. The role of viral-bacterial co-infection in animal-to-human transmission of infectious agents has not received sufficient attention

  13. A novel psittacine adenovirus identified during an outbreak of avian chlamydiosis and human psittacosis: zoonosis associated with virus-bacterium coinfection in birds.

    Science.gov (United States)

    To, Kelvin K W; Tse, Herman; Chan, Wan-Mui; Choi, Garnet K Y; Zhang, Anna J X; Sridhar, Siddharth; Wong, Sally C Y; Chan, Jasper F W; Chan, Andy S F; Woo, Patrick C Y; Lau, Susanna K P; Lo, Janice Y C; Chan, Kwok-Hung; Cheng, Vincent C C; Yuen, Kwok-Yung

    2014-12-01

    Chlamydophila psittaci is found worldwide, but is particularly common among psittacine birds in tropical and subtropical regions. While investigating a human psittacosis outbreak that was associated with avian chlamydiosis in Hong Kong, we identified a novel adenovirus in epidemiologically linked Mealy Parrots, which was not present in healthy birds unrelated to the outbreak or in other animals. The novel adenovirus (tentatively named Psittacine adenovirus HKU1) was most closely related to Duck adenovirus A in the Atadenovirus genus. Sequencing showed that the Psittacine adenovirus HKU1 genome consists of 31,735 nucleotides. Comparative genome analysis showed that the Psittacine adenovirus HKU1 genome contains 23 open reading frames (ORFs) with sequence similarity to known adenoviral genes, and six additional ORFs at the 3' end of the genome. Similar to Duck adenovirus A, the novel adenovirus lacks LH1, LH2 and LH3, which distinguishes it from other viruses in the Atadenovirus genus. Notably, fiber-2 protein, which is present in Aviadenovirus but not Atadenovirus, is also present in Psittacine adenovirus HKU1. Psittacine adenovirus HKU1 had pairwise amino acid sequence identities of 50.3-54.0% for the DNA polymerase, 64.6-70.7% for the penton protein, and 66.1-74.0% for the hexon protein with other Atadenovirus. The C. psittaci bacterial load was positively correlated with adenovirus viral load in the lung. Immunostaining for fiber protein expression was positive in lung and liver tissue cells of affected parrots, confirming active viral replication. No other viruses were found. This is the first documentation of an adenovirus-C. psittaci co-infection in an avian species that was associated with a human outbreak of psittacosis. Viral-bacterial co-infection often increases disease severity in both humans and animals. The role of viral-bacterial co-infection in animal-to-human transmission of infectious agents has not received sufficient attention and should be

  14. Pan-Genome Analysis of Human Gastric Pathogen H. pylori: Comparative Genomics and Pathogenomics Approaches to Identify Regions Associated with Pathogenicity and Prediction of Potential Core Therapeutic Targets

    DEFF Research Database (Denmark)

    Ali, Amjad; Naz, Anam; Soares, Siomar C.

    2015-01-01

    Helicobacter pylori is a human gastric pathogen implicated as the major cause of peptic ulcer and second leading cause of gastric cancer (similar to 70%) around the world. Conversely, an increased resistance to antibiotics and hindrances in the development of vaccines against H. pylori are observed......-genome approach; the predicted conserved gene families (1,193) constitute similar to 77% of the average H. pylori genome and 45% of the global gene repertoire of the species. Reverse vaccinology strategies have been adopted to identify and narrow down the potential core-immunogenic candidates. Total of 28 nonhost...... homolog proteins were characterized as universal therapeutic targets against H. pylori based on their functional annotation and protein-protein interaction. Finally, pathogenomics and genome plasticity analysis revealed 3 highly conserved and 2 highly variable putative pathogenicity islands in all...

  15. Preoperative screening: value of previous tests.

    Science.gov (United States)

    Macpherson, D S; Snow, R; Lofgren, R P

    1990-12-15

    To determine the frequency of tests done in the year before elective surgery that might substitute for preoperative screening tests and to determine the frequency of test results that change from a normal value to a value likely to alter perioperative management. Retrospective cohort analysis of computerized laboratory data (complete blood count, sodium, potassium, and creatinine levels, prothrombin time, and partial thromboplastin time). Urban tertiary care Veterans Affairs Hospital. Consecutive sample of 1109 patients who had elective surgery in 1988. At admission, 7549 preoperative tests were done, 47% of which duplicated tests performed in the previous year. Of 3096 previous results that were normal as defined by hospital reference range and done closest to the time of but before admission (median interval, 2 months), 13 (0.4%; 95% CI, 0.2% to 0.7%), repeat values were outside a range considered acceptable for surgery. Most of the abnormalities were predictable from the patient's history, and most were not noted in the medical record. Of 461 previous tests that were abnormal, 78 (17%; CI, 13% to 20%) repeat values at admission were outside a range considered acceptable for surgery (P less than 0.001, frequency of clinically important abnormalities of patients with normal previous results with those with abnormal previous results). Physicians evaluating patients preoperatively could safely substitute the previous test results analyzed in this study for preoperative screening tests if the previous tests are normal and no obvious indication for retesting is present.

  16. In-cell intrabody selection from a diverse human library identifies C12orf4 protein as a new player in rodent mast cell degranulation.

    Directory of Open Access Journals (Sweden)

    Elsa Mazuc

    Full Text Available The high specificity of antibodies for their antigen allows a fine discrimination of target conformations and post-translational modifications, making antibodies the first choice tool to interrogate the proteome. We describe here an approach based on a large-scale intracellular expression and selection of antibody fragments in eukaryotic cells, so-called intrabodies, and the subsequent identification of their natural target within living cell. Starting from a phenotypic trait, this integrated system allows the identification of new therapeutic targets together with their companion inhibitory intrabody. We applied this system in a model of allergy and inflammation. We first cloned a large and highly diverse intrabody library both in a plasmid and a retroviral eukaryotic expression vector. After transfection in the RBL-2H3 rat basophilic leukemia cell line, we performed seven rounds of selection to isolate cells displaying a defect in FcεRI-induced degranulation. We used high throughput sequencing to identify intrabody sequences enriched during the course of selection. Only one intrabody was common to both plasmid and retroviral selections, and was used to capture and identify its target from cell extracts. Mass spectrometry analysis identified protein RGD1311164 (C12orf4, with no previously described function. Our data demonstrate that RGD1311164 is a cytoplasmic protein implicated in the early signaling events following FcεRI-induced cell activation. This work illustrates the strength of the intrabody-based in-cell selection, which allowed the identification of a new player in mast cell activation together with its specific inhibitor intrabody.

  17. Multiplex polymerase chain reaction to identify and determine the toxigenicity of Corynebacterium spp with zoonotic potential and an overview of human and animal infections

    Directory of Open Access Journals (Sweden)

    Luciene de Fátima Costa Torres

    2013-05-01

    Full Text Available Corynebacterium diphtheriae, Corynebacterium ulcerans and Corynebacterium pseudotuberculosis constitute a group of potentially toxigenic microorganisms that are related to different infectious processes in animal and human hosts. Currently, there is a lack of information on the p