What the patient wants: Addressing patients' treatment targets in an integrative group psychotherapy programme.

PubMed

Kealy, David; Joyce, Anthony S; Weber, Rainer; Ehrenthal, Johannes C; Ogrodniczuk, John S

2018-02-13

Limited empirical attention has been devoted to individualized treatment objectives in intensive group therapy for personality dysfunction. This study investigated patients' ratings of distress associated with individual therapy goals - referred to as target object severity - in an intensive Evening Treatment Programme for patients with personality dysfunction. Change in target objective severity was examined in a sample of 81 patients who completed treatment in an intensive, integrative group therapy programme. Correlation and regression analyses were used to examine associations between change in target object severity and patients' pre-treatment diagnosis, symptom distress, and treatment outcome expectancy, and between change in target objective severity and patients' ratings of group therapy process (group climate, therapeutic alliance, group cohesion). The relationship between change in target objective severity and longer-range life satisfaction was also examined in a subsample of patients who rated life satisfaction at follow-up. While change in target objective severity was not significantly related to pre-treatment variables, significant associations were found with several aspects of group therapy process. Patients' experience of a highly engaged group climate was uniquely associated with improvement in target object severity. Such improvement was significantly related to longer-term life satisfaction after controlling for general symptom change. The working atmosphere in group therapy contributes to patients' progress regarding individual treatment targets, and such progress is an important factor in later satisfaction. Attention to individualized treatment targets deserves further clinical and research attention in the context of integrative group therapy for personality dysfunction. This study found that patients attending an integrative group treatment programme for personality dysfunction experienced significant improvement in severity of distress related to individual treatment objectives. Improvement in severity of distress related to individual treatment objectives was uniquely associated with patients' experience of an engaged, collaborative working atmosphere. Improvement in individual target objective severity was associated with patients' ratings of overall life satisfaction, rated an average of 9 months following termination, after controlling for change in general symptom severity. © 2018 The British Psychological Society.

Contextual cost: when a visual-search target is not where it should be.

PubMed

Makovski, Tal; Jiang, Yuhong V

2010-02-01

Visual search is often facilitated when the search display occasionally repeats, revealing a contextual-cueing effect. According to the associative-learning account, contextual cueing arises from associating the display configuration with the target location. However, recent findings emphasizing the importance of local context near the target have given rise to the possibility that low-level repetition priming may account for the contextual-cueing effect. This study distinguishes associative learning from local repetition priming by testing whether search is directed toward a target's expected location, even when the target is relocated. After participants searched for a T among Ls in displays that repeated 24 times, they completed a transfer session where the target was relocated locally to a previously blank location (Experiment 1) or to an adjacent distractor location (Experiment 2). Results revealed that contextual cueing decreased as the target appeared farther away from its expected location, ultimately resulting in a contextual cost when the target swapped locations with a local distractor. We conclude that target predictability is a key factor in contextual cueing.

Visual attention to features by associative learning.

PubMed

Gozli, Davood G; Moskowitz, Joshua B; Pratt, Jay

2014-11-01

Expecting a particular stimulus can facilitate processing of that stimulus over others, but what is the fate of other stimuli that are known to co-occur with the expected stimulus? This study examined the impact of learned association on feature-based attention. The findings show that the effectiveness of an uninformative color transient in orienting attention can change by learned associations between colors and the expected target shape. In an initial acquisition phase, participants learned two distinct sequences of stimulus-response-outcome, where stimuli were defined by shape ('S' vs. 'H'), responses were localized key-presses (left vs. right), and outcomes were colors (red vs. green). Next, in a test phase, while expecting a target shape (80% probable), participants showed reliable attentional orienting to the color transient associated with the target shape, and showed no attentional orienting with the color associated with the alternative target shape. This bias seemed to be driven by learned association between shapes and colors, and not modulated by the response. In addition, the bias seemed to depend on observing target-color conjunctions, since encountering the two features disjunctively (without spatiotemporal overlap) did not replicate the findings. We conclude that associative learning - likely mediated by mechanisms underlying visual object representation - can extend the impact of goal-driven attention to features associated with a target stimulus. Copyright © 2014 Elsevier B.V. All rights reserved.

Epidermal growth factor receptor and variant III targeted immunotherapy

PubMed Central

Congdon, Kendra L.; Gedeon, Patrick C.; Suryadevara, Carter M.; Caruso, Hillary G.; Cooper, Laurence J.N.; Heimberger, Amy B.; Sampson, John H.

2014-01-01

Immunotherapeutic approaches to cancer have shown remarkable promise. A critical barrier to successfully executing such immune-mediated interventions is the selection of safe yet immunogenic targets. As patient deaths have occurred when tumor-associated antigens shared by normal tissue have been targeted by strong cellular immunotherapeutic platforms, route of delivery, target selection and the immune-mediated approach undertaken must work together to maximize efficacy with safety. Selected tumor-specific targets can spare potential toxicity to normal tissue; however, they are far less common than tumor-associated antigens and may not be present on all patients. In the context of immunotherapy for high-grade glioma, 2 of the most prominently studied antigens are the tumor-associated epidermal growth factor receptor and its tumor-specific genetic deletion variant III. In this review, we will summarize the immune-mediated strategies employed against these targets as well as the caveats particular to these approaches. PMID:25342601

Multi-voxel pattern analysis reveals increased memory targeting and reduced use of retrieved details during single-agenda source monitoring

PubMed Central

McDuff, Susan G. R.; Frankel, Hillary C.; Norman, Kenneth A.

2009-01-01

We used multi-voxel pattern analysis (MVPA) of fMRI data to gain insight into how subjects’ retrieval agendas influence source memory judgments (was item X studied using source Y?). In Experiment 1, we used a single-agenda test where subjects judged whether items were studied with the targeted source or not. In Experiment 2, we used a multi-agenda test where subjects judged whether items were studied using the targeted source, studied using a different source, or nonstudied. To evaluate the differences between single- and multi-agenda source monitoring, we trained a classifier to detect source-specific fMRI activity at study, and then we applied the classifier to data from the test phase. We focused on trials where the targeted source and the actual source differed, so we could use MVPA to track neural activity associated with both the targeted source and the actual source. Our results indicate that single-agenda monitoring was associated with increased focus on the targeted source (as evidenced by increased targeted-source activity, relative to baseline) and reduced use of information relating to the actual, non-target source. In the multi-agenda experiment, high-levels of actual-source activity were associated with increased correct rejections, suggesting that subjects were using recollection of actual-source information to avoid source memory errors. In the single-agenda experiment, there were comparable levels of actual-source activity (suggesting that recollection was taking place), but the relationship between actual-source activity and behavior was absent (suggesting that subjects were failing to make proper use of this information). PMID:19144851

Reward-associated features capture attention in the absence of awareness: Evidence from object-substitution masking.

PubMed

Harris, Joseph A; Donohue, Sarah E; Schoenfeld, Mircea A; Hopf, Jens-Max; Heinze, Hans-Jochen; Woldorff, Marty G

2016-08-15

Reward-associated visual features have been shown to capture visual attention, evidenced in faster and more accurate behavioral performance, as well as in neural responses reflecting lateralized shifts of visual attention to those features. Specifically, the contralateral N2pc event-related-potential (ERP) component that reflects attentional shifting exhibits increased amplitude in response to task-relevant targets containing a reward-associated feature. In the present study, we examined the automaticity of such reward-association effects using object-substitution masking (OSM) in conjunction with MEG measures of visual attentional shifts. In OSM, a visual-search array is presented, with the target item to be detected indicated by a surrounding mask (here, four surrounding squares). Delaying the offset of the target-surrounding four-dot mask relative to the offset of the rest of the target/distracter array disrupts the viewer's awareness of the target (masked condition), whereas simultaneous offsets do not (unmasked condition). Here we manipulated whether the color of the OSM target was or was not of a previously reward-associated color. By tracking reward-associated enhancements of behavior and the N2pc in response to masked targets containing a previously rewarded or unrewarded feature, the automaticity of attentional capture by reward could be probed. We found an enhanced N2pc response to targets containing a previously reward-associated color feature. Moreover, this enhancement of the N2pc by reward did not differ between masking conditions, nor did it differ as a function of the apparent visibility of the target within the masked condition. Overall, these results underscore the automaticity of attentional capture by reward-associated features, and demonstrate the ability of feature-based reward associations to shape attentional capture and allocation outside of perceptual awareness. Copyright © 2016 Elsevier Inc. All rights reserved.

Financial relationships in economic analyses of targeted therapies in oncology.

PubMed

Valachis, Antonis; Polyzos, Nikolaos P; Nearchou, Andreas; Lind, Pehr; Mauri, Davide

2012-04-20

A potential financial relationship between investigators and pharmaceutical manufacturers has been associated with an increased likelihood of reporting favorable conclusions about a sponsor's proprietary agent in pharmacoeconomic studies. The purpose of this study is to investigate whether there is an association between financial relationships and outcome in economic analyses of new targeted therapies in oncology. We searched PubMed (last update June 2011) for economic analyses of targeted therapies (including monoclonal antibodies, tyrosine-kinase inhibitors, and mammalian target of rapamycin inhibitors) in oncology. The trials were qualitatively rated regarding the cost assessment as favorable, neutral, or unfavorable on the basis of prespecified criteria. Overall, 81 eligible studies were identified. Economic analyses that were funded by pharmaceutical companies were more likely to report favorable qualitative cost estimates (28 [82%] of 34 v 21 [45%] of 47; P = .003). The presence of an author affiliated with manufacturer was not associated with study outcome. Furthermore, if only studies including a conflict of interest statement were included (66 of 81), studies that reported any financial relationship with manufacturers (author affiliation and/or funding and/or other financial relationship) were more likely to report favorable results of targeted therapies compared with studies without financial relationship (32 [71%] of 45 v nine [43%] of 21; P = .025). Our study reveals a potential threat for industry-related bias in economic analyses of targeted therapies in oncology in favor of analyses with financial relationships between authors and manufacturers. A more balanced funding of economic analyses from other sources may allow greater confidence in the interpretation of their results.

Combinatorial Targeting of Prostate Carcinoma Cells and Tumor Associated Pericytes with Antibody-Based Immunotherapy and Metronomic Chemotherapy

DTIC Science & Technology

2011-03-01

Carcinoma Cells and Tumor Associated Pericytes with Antibody-Based Immunotherapy and Metronomic Chemotherapy. PRINCIPAL INVESTIGATOR: Soldano...Combinatorial Targeting of Prostate Carcinoma Cells and Tumor Associated Pericytes with Antibody-Based Immunotherapy and Metronomic Chemotherapy. 5b. GRANT...SUPPLEMENTARY NOTES 14. ABSTRACT Seventy seven 10 week old TRAMP mice were enrolled in the study. Administration of metronomic chemotherapy with

From Agents to Objects: Sexist Attitudes and Neural Responses to Sexualized Targets

PubMed Central

Cikara, Mina; Eberhardt, Jennifer L.; Fiske, Susan T.

2013-01-01

Agency attribution is a hallmark of mind perception; thus, diminished attributions of agency may disrupt social-cognition processes typically elicited by human targets. The current studies examine the effect of perceivers’ sexist attitudes on associations of agency with, and neural responses to, images of sexualized and clothed men and women. In study 1, male (but not female) participants with higher hostile sexism scores more quickly associated sexualized women with first-person action verbs (“handle”) and clothed women with third-person action verbs (“handles”) than the inverse, as compared to their less sexist peers. In study 2, hostile sexism correlated negatively with activation of regions associated with mental state attribution—mPFC, posterior cingulate, temporal poles—but only when viewing sexualized women. Heterosexual men best recognized images of sexualized female bodies (but not faces), as compared with other targets’ bodies; however, neither face nor body recognition were related to hostile sexism, suggesting the fMRI findings are not explained by more or less attention to sexualized female targets. Diminished mental-state attribution is not unique to targets that people prefer to avoid, as in dehumanization of stigmatized people. The current studies demonstrate that appetitive social targets may elicit a similar response depending on perceivers’ attitudes toward them. PMID:20350187

The influence of participation in target-shooting sport for children with inattentive, hyperactive and impulsive symptoms - A controlled study of best practice.

PubMed

Månsson, Annegrete Gohr; Elmose, Mette; Dalsgaard, Søren; Roessler, Kirsten K

2017-03-28

Practising target-shooting sport requires focused attention and motoric steadiness. A previous non-controlled pilot study suggests that children with impairing symptoms of attention-deficit/hyperactivity disorder (ADHD) benefit from participating in target-shooting sport in local shooting associations, as rated by parents and teachers. This study aims at examining if, and to which extent, target-shooting sport reduces parent- and teacher-reported severity of inattentiveness, hyperactivity, and impulsivity in children with attention difficulties, and if, and to which extend, target-shooting sport improves the children's wellbeing and quality of life. A mixed method approach is applied. A non-blinded, waiting list controlled study is combined with a case study, consisting of interviews and observations. The intervention consists of children practising target-shooting sport, by attending a local shooting association, once a week for six months, during regular school hours. Data from questionnaires (ADHD-RS, SDQ, Kidscreen-27), as well as a computerized continued performance test (Qb test), measure the children's activity and attention. The study includes 50 children in an intervention group and 50 children in a waiting list control group. The Qb test collects data from at least 20 children from the intervention group and at least 20 children from the waiting list control group. Data from the questionnaires and Qb-test is collected at baseline, and six months post intervention. In addition, a case study is carried out, consisting of interviews of at least five children from the intervention group, their parents, teachers and shooting instructors. Observations are carried out, when children are in school and while they are attending the local shooting association. The case study adds to an in-depth understanding of children's participation in target-shooting sports. At present, little is known about the effects and influence of practising target-shooting sport for children experiencing difficulties with inattentiveness, hyperactivity and impulsivity. This study is expected to contribute to an understanding of the influence of participating in target-shooting sports on inattentive, hyperactive and impulsive symptoms, and the effects on the children's psychological wellbeing and quality of life. Current Controlled Trials NCT02898532 . Retrospectively registered 14 September 2016.

Processing Lexical and Speaker Information in Repetition and Semantic/Associative Priming

ERIC Educational Resources Information Center

Lee, Chao-Yang; Zhang, Yu

2018-01-01

The purpose of this study is to investigate the interaction between processing lexical and speaker-specific information in spoken word recognition. The specific question is whether repetition and semantic/associative priming is reduced when the prime and target are produced by different speakers. In Experiment 1, the prime and target were repeated…

Clinical and Radiologic Follow-up Study for Biopsy Diagnosis of Radial Scar/Radial Sclerosing Lesion without Other Atypia.

PubMed

Kalife, Elizabeth Tágide; Lourenco, Ana P; Baird, Grayson L; Wang, Yihong

2016-11-01

To determine the incidence of malignancy for radial scars (RS)/radial sclerosing lesions (RSL) without associated atypia or malignancy identified at needle biopsy. Retrospective review of the pathology data base from January 2004 to July 2013 yielded 100 needle biopsies diagnosed as RS/RSL without associated atypia/malignancy. The RS/RSL was considered "incidental" if the target was calcifications and "targeted" if imaging revealed a mass, architectural distortion, or suspicious magnetic resonance imaging enhancement. The electronic medical record was used to identify surgical pathology, follow-up imaging, and clinical course; all pathology slides and imaging were reviewed by a board-certified pathologist and radiologist, respectively. Patient age, laterality, RS/RSL size, microcalcifications, and associated benign lesions were recorded. Among 100 cases, 54 were "incidental" and 46 were "targeted." In the incidental group, 14 underwent excision, 30 had imaging follow-up, and 10 were lost to follow-up. In the targeted group, 27 underwent excision, 11 had imaging follow-up, and 8 were lost to follow-up. Atypia was identified in four excisions: three from the incidental group and one from the targeted group. Among these, three had negative imaging follow-up (mean 45 months; range 15-60 months); the fourth patient (one of the incidental group) underwent excision alone. One of the 27 "targeted" patients who underwent excision developed ductal carcinoma in situ of the contralateral breast at 96 months. There have been no ipsilateral malignancies. We found no evidence of associated malignancy at excision for either incidental or targeted biopsies of RS/RSL without atypia. Our study suggests that close imaging follow-up is adequate for patients with RS/RSL without associated atypia/malignancy on needle biopsy. © 2016 Wiley Periodicals, Inc.

Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci.

PubMed

Kar, Siddhartha P; Adler, Emily; Tyrer, Jonathan; Hazelett, Dennis; Anton-Culver, Hoda; Bandera, Elisa V; Beckmann, Matthias W; Berchuck, Andrew; Bogdanova, Natalia; Brinton, Louise; Butzow, Ralf; Campbell, Ian; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Dansonka-Mieszkowska, Agnieszka; Doherty, Jennifer Anne; Dörk, Thilo; Dürst, Matthias; Eccles, Diana; Fasching, Peter A; Flanagan, James; Gentry-Maharaj, Aleksandra; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Gronwald, Jacek; Heitz, Florian; Hildebrandt, Michelle A T; Høgdall, Estrid; Høgdall, Claus K; Huntsman, David G; Jensen, Allan; Karlan, Beth Y; Kelemen, Linda E; Kiemeney, Lambertus A; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Lambrechts, Diether; Levine, Douglas A; Li, Qiyuan; Lissowska, Jolanta; Lu, Karen H; Lubiński, Jan; Massuger, Leon F A G; McGuire, Valerie; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Monteiro, Alvaro N; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Permuth, Jennifer B; Phelan, Catherine; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rossing, Mary Anne; Salvesen, Helga B; Schildkraut, Joellen M; Sellers, Thomas A; Sherman, Mark; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa; Terry, Kathryn L; Tworoger, Shelley S; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Freedman, Matthew L; Gayther, Simon A; Pharoah, Paul D P; Lawrenson, Kate

2017-02-14

Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). The PAX8-target gene set was ranked 1/615 in the discovery (P GSEA <0.001; FDR=0.21), 7/615 in the replication (P GSEA =0.004; FDR=0.37), and 1/615 in the combined (P GSEA <0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10 -5 (including six with P<5 × 10 -8 ). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (P GSEA =0.025) and IGROV1 (P GSEA =0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.

Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

PubMed Central

Kar, Siddhartha P; Adler, Emily; Tyrer, Jonathan; Hazelett, Dennis; Anton-Culver, Hoda; Bandera, Elisa V; Beckmann, Matthias W; Berchuck, Andrew; Bogdanova, Natalia; Brinton, Louise; Butzow, Ralf; Campbell, Ian; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Dansonka-Mieszkowska, Agnieszka; Doherty, Jennifer Anne; Dörk, Thilo; Dürst, Matthias; Eccles, Diana; Fasching, Peter A; Flanagan, James; Gentry-Maharaj, Aleksandra; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Gronwald, Jacek; Heitz, Florian; Hildebrandt, Michelle A T; Høgdall, Estrid; Høgdall, Claus K; Huntsman, David G; Jensen, Allan; Karlan, Beth Y; Kelemen, Linda E; Kiemeney, Lambertus A; Kjaer, Susanne K; Kupryjanczyk, Jolanta; Lambrechts, Diether; Levine, Douglas A; Li, Qiyuan; Lissowska, Jolanta; Lu, Karen H; Lubiński, Jan; Massuger, Leon F A G; McGuire, Valerie; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Monteiro, Alvaro N; Moysich, Kirsten B; Ness, Roberta B; Nevanlinna, Heli; Paul, James; Pearce, Celeste L; Pejovic, Tanja; Permuth, Jennifer B; Phelan, Catherine; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rossing, Mary Anne; Salvesen, Helga B; Schildkraut, Joellen M; Sellers, Thomas A; Sherman, Mark; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa; Terry, Kathryn L; Tworoger, Shelley S; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Freedman, Matthew L; Gayther, Simon A; Pharoah, Paul D P; Lawrenson, Kate

2017-01-01

Background: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. Methods: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). Results: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10−5 (including six with P<5 × 10−8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. Conclusions: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC. PMID:28103614

Features of Modularly Assembled Compounds That Impart Bioactivity Against an RNA Target

PubMed Central

Rzuczek, Suzanne G.; Gao, Yu; Tang, Zhen-Zhi; Thornton, Charles A.; Kodadek, Thomas; Disney, Matthew D.

2013-01-01

Transcriptomes provide a myriad of potential RNAs that could be the targets of therapeutics or chemical genetic probes of function. Cell permeable small molecules, however, generally do not exploit these targets, owing to the difficulty in the design of high affinity, specific small molecules targeting RNA. As part of a general program to study RNA function using small molecules, we designed bioactive, modularly assembled small molecules that target the non-coding expanded RNA repeat that causes myotonic dystrophy type 1 (DM1), r(CUG)exp. Herein, we present a rigorous study to elucidate features in modularly assembled compounds that afford bioactivity. Different modular assembly scaffolds were investigated including polyamines, α-peptides, β-peptides, and peptide tertiary amides (PTAs). Based on activity as assessed by improvement of DM1-associated defects, stability against proteases, cellular permeability, and toxicity, we discovered that constrained backbones, namely PTAs, are optimal. Notably, we determined that r(CUG)exp is the target of the optimal PTA in cellular models and that the optimal PTA improves DM1-associated defects in a mouse model. Biophysical analyses were employed to investigate potential sources of bioactivity. These investigations show that modularly assembled compounds have increased residence times on their targets and faster on rates than the RNA-binding modules from which they were derived and faster on rates than the protein that binds r(CUG)exp, the inactivation of which gives rise to DM1-associated defects. These studies provide information about features of small molecules that are programmable for targeting RNA, allowing for the facile optimization of therapeutics or chemical probes against other cellular RNA targets. PMID:24032410

Features of modularly assembled compounds that impart bioactivity against an RNA target.

PubMed

Rzuczek, Suzanne G; Gao, Yu; Tang, Zhen-Zhi; Thornton, Charles A; Kodadek, Thomas; Disney, Matthew D

2013-10-18

Transcriptomes provide a myriad of potential RNAs that could be the targets of therapeutics or chemical genetic probes of function. Cell-permeable small molecules, however, generally do not exploit these targets, owing to the difficulty in the design of high affinity, specific small molecules targeting RNA. As part of a general program to study RNA function using small molecules, we designed bioactive, modularly assembled small molecules that target the noncoding expanded RNA repeat that causes myotonic dystrophy type 1 (DM1), r(CUG)(exp). Herein, we present a rigorous study to elucidate features in modularly assembled compounds that afford bioactivity. Different modular assembly scaffolds were investigated, including polyamines, α-peptides, β-peptides, and peptide tertiary amides (PTAs). On the basis of activity as assessed by improvement of DM1-associated defects, stability against proteases, cellular permeability, and toxicity, we discovered that constrained backbones, namely, PTAs, are optimal. Notably, we determined that r(CUG)(exp) is the target of the optimal PTA in cellular models and that the optimal PTA improves DM1-associated defects in a mouse model. Biophysical analyses were employed to investigate potential sources of bioactivity. These investigations show that modularly assembled compounds have increased residence times on their targets and faster on rates than the RNA-binding modules from which they were derived. Moreover, they have faster on rates than the protein that binds r(CUG)(exp), the inactivation of which gives rise to DM1-associated defects. These studies provide information about features of small molecules that are programmable for targeting RNA, allowing for the facile optimization of therapeutics or chemical probes against other cellular RNA targets.

The likelihood of achieving quantified road safety targets: a binary logistic regression model for possible factors.

PubMed

Sze, N N; Wong, S C; Lee, C Y

2014-12-01

In past several decades, many countries have set quantified road safety targets to motivate transport authorities to develop systematic road safety strategies and measures and facilitate the achievement of continuous road safety improvement. Studies have been conducted to evaluate the association between the setting of quantified road safety targets and road fatality reduction, in both the short and long run, by comparing road fatalities before and after the implementation of a quantified road safety target. However, not much work has been done to evaluate whether the quantified road safety targets are actually achieved. In this study, we used a binary logistic regression model to examine the factors - including vehicle ownership, fatality rate, and national income, in addition to level of ambition and duration of target - that contribute to a target's success. We analyzed 55 quantified road safety targets set by 29 countries from 1981 to 2009, and the results indicate that targets that are in progress and with lower level of ambitions had a higher likelihood of eventually being achieved. Moreover, possible interaction effects on the association between level of ambition and the likelihood of success are also revealed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Interventions that involve parents to improve children's weight-related nutrition intake and activity patterns - what nutrition and activity targets and behaviour change techniques are associated with intervention effectiveness?

PubMed

Golley, R K; Hendrie, G A; Slater, A; Corsini, N

2011-02-01

Parent involvement is an important component of obesity prevention interventions. However, the best way to support parents remains unclear. This review identifies interventions targeting parents to improve children's weight status, dietary and/or activity patterns, examines whether intervention content and behaviour change techniques employed are associated with effectiveness. Seventeen studies, in English, 1998-2008, were included. Studies were evaluated by two reviewers for study quality, nutrition/activity content and behaviour change techniques using a validated quality assessment tool and behaviour change technique taxonomy. Study findings favoured intervention effectiveness in 11 of 17 studies. Interventions that were considered effective had similar features: better study quality, parents responsible for participation and implementation, greater parental involvement and inclusion of prompt barrier identification, restructure the home environment, prompt self-monitoring, prompt specific goal setting behaviour change techniques. Energy intake/density and food choices were more likely to be targeted in effective interventions. The number of lifestyle behaviours targeted did not appear to be associated with effectiveness. Intervention effectiveness was favoured when behaviour change techniques spanned the spectrum of behaviour change process. The review provides guidance for researchers to make informed decisions on how best to utilize resources in interventions to support and engage parents, and highlights a need for improvement in intervention content reporting practices. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity.

The FMRP regulon: from targets to disease convergence

PubMed Central

Fernández, Esperanza; Rajan, Nicholas; Bagni, Claudia

2013-01-01

The fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates mRNA metabolism. FMRP has been largely studied in the brain, where the absence of this protein leads to fragile X syndrome, the most frequent form of inherited intellectual disability. Since the identification of the FMRP gene in 1991, many studies have primarily focused on understanding the function/s of this protein. Hundreds of potential FMRP mRNA targets and several interacting proteins have been identified. Here, we report the identification of FMRP mRNA targets in the mammalian brain that support the key role of this protein during brain development and in regulating synaptic plasticity. We compared the genes from databases and genome-wide association studies with the brain FMRP transcriptome, and identified several FMRP mRNA targets associated with autism spectrum disorders, mood disorders and schizophrenia, showing a potential common pathway/s for these apparently different disorders. PMID:24167470

Targeted exercise therapy for voice and swallow in persons with Parkinson’s disease

PubMed Central

Russell, John A.; Ciucci, Michelle R.; Connor, Nadine P.; Schallert, Timothy

2010-01-01

Sensorimotor deficits affecting voice and swallowing ability can have a devastating impact on the quality of life of people with Parkinson disease (PD). Recent scientific findings in animal models of PD pinpoint targeted exercise therapy as a potential treatment to reduce neurochemical loss and decrease parkinsonian symptoms. Although there may be beneficial effects, targeted exercise therapy is not a standard component of therapy for the cranial sensiromotor deficits seen in PD. In this paper we review the scientific evidence for targeted training for voice and swallowing deficits. The literature search revealed 19 publications that included targeted training for voice and only one publication that included targeted training for swallowing. We summarize 3 main findings: 1) targeted training may be associated with lasting changes in voice behavior, 2) targeted training of sensorimotor actions with anatomical or functional overlap with voice and swallowing may improve voice and swallowing to some degree, but it is unknown whether these effects endure over time, and 3) evidence regarding cranial sensorimotor interventions for Parkinson disease is sparse. We concluded that targeted training for voice and swallow is a promising but under-studied intervention for cranial sensorimotor deficits associated with PD and posit that animal models can be useful in designing empirically based studies that further the science on targeted training. PMID:20233583

Lessons from ten years of genome-wide association studies of asthma

PubMed Central

Vicente, Cristina T; Revez, Joana A; Ferreira, Manuel A R

2017-01-01

Twenty-five genome-wide association studies (GWAS) of asthma were published between 2007 and 2016, the largest with a sample size of 157242 individuals. Across these studies, 39 genetic variants in low linkage disequilibrium (LD) with each other were reported to associate with disease risk at a significance threshold of P<5 × 10−8, including 31 in populations of European ancestry. Results from analyses of the UK Biobank data (n=380 503) indicate that at least 28 of the 31 associations reported in Europeans represent true-positive findings, collectively explaining 2.5% of the variation in disease liability (median of 0.06% per variant). We identified 49 transcripts as likely target genes of the published asthma risk variants, mostly based on LD with expression quantitative trait loci (eQTL). Of these genes, 16 were previously implicated in disease pathophysiology by functional studies, including TSLP, TNFSF4, ADORA1, CHIT1 and USF1. In contrast, at present, there is limited or no functional evidence directly implicating the remaining 33 likely target genes in asthma pathophysiology. Some of these genes have a known function that is relevant to allergic disease, including F11R, CD247, PGAP3, AAGAB, CAMK4 and PEX14, and so could be prioritized for functional follow-up. We conclude by highlighting three areas of research that are essential to help translate GWAS findings into clinical research or practice, namely validation of target gene predictions, understanding target gene function and their role in disease pathophysiology and genomics-guided prioritization of targets for drug development. PMID:29333270

Epigenetic Drug Repositioning for Alzheimer's Disease Based on Epigenetic Targets in Human Interactome.

PubMed

Chatterjee, Paulami; Roy, Debjani; Rathi, Nitin

2018-01-01

Epigenetics has emerged as an important field in drug discovery. Alzheimer's disease (AD), the leading neurodegenerative disorder throughout the world, is shown to have an epigenetic basis. Currently, there are very few effective epigenetic drugs available for AD. In this work, for the first time we have proposed 14 AD repositioning epigenetic drugs and identified their targets from extensive human interactome. Interacting partners of the AD epigenetic proteins were identified from the extensive human interactome to construct Epigenetic Protein-Protein Interaction Network (EP-PPIN). Epigenetic Drug-Target Network (EP-DTN) was constructed with the drugs associated with the proteins of EP-PPIN. Regulation of non-coding RNAs associated with the target proteins of these drugs was also studied. AD related target proteins, epigenetic targets, enriched pathways, and functional categories of the proposed repositioning drugs were also studied. The proposed 14 AD epigenetic repositioning drugs have overlapping targets and miRs with known AD epigenetic targets and miRs. Furthermore, several shared functional categories and enriched pathways were obtained for these drugs with FDA approved epigenetic drugs and known AD drugs. The findings of our work might provide insight into future AD epigenetic-therapeutics.

Associations among Life Events, Empathic Concern, and Adolescents' Prosocial and Aggressive Behaviors Toward Specific Targets.

PubMed

Davis, Alexandra N; Luce, Haley; Davalos, Natasha

2018-05-25

The goal of the present study was to examine the links between life events and adolescents' social behaviors (prosocial and aggressive behaviors) toward specific targets and to examine how empathic concern may play a role in these associations. The study examined two hypotheses: both the mediating role of empathic concern and the moderating role of empathic concern. The sample included 311 high school students from the Midwest (M age = 16.10 years; age range = 14-19 years; 58.7% girls; 82.7% White, 13.6% Latino). The results demonstrated support for the moderation model as well as complex links between life events and prosocial and aggressive behaviors toward specific targets. The discussion focuses on the role of empathic concern in understanding how life events are ultimately associated with adolescents' social development.

Trial-to-trial dynamics of selective long-term-memory retrieval with continuously changing retrieval targets.

PubMed

Kizilirmak, Jasmin M; Rösler, Frank; Khader, Patrick H

2014-10-01

How do we control the successive retrieval of behaviorally relevant information from long-term memory (LTM) without being distracted by other potential retrieval targets associated to the same retrieval cues? Here, we approach this question by investigating the nature of trial-by-trial dynamics of selective LTM retrieval, i.e., in how far retrieval in one trial has detrimental or facilitatory effects on selective retrieval in the following trial. Participants first learned associations between retrieval cues and targets, with one cue always being linked to three targets, forming small associative networks. In successive trials, participants had to access either the same or a different target belonging to either the same or a different cue. We found that retrieval times were faster for targets that had already been relevant in the previous trial, with this facilitatory effect being substantially weaker when the associative network changed in which the targets were embedded. Moreover, staying within the same network still had a facilitatory effect even if the target changed, which became evident in a relatively higher memory performance in comparison to a network change. Furthermore, event-related brain potentials (ERPs) showed topographically and temporally dissociable correlates of these effects, suggesting that they result from combined influences of distinct processes that aid memory retrieval when relevant and irrelevant targets change their status from trial to trial. Taken together, the present study provides insight into the different processing stages of memory retrieval when fast switches between retrieval targets are required. Copyright © 2014 Elsevier Inc. All rights reserved.

Quantitative and Systems Pharmacology 3. Network-Based Identification of New Targets for Natural Products Enables Potential Uses in Aging-Associated Disorders.

PubMed

Fang, Jiansong; Gao, Li; Ma, Huili; Wu, Qihui; Wu, Tian; Wu, Jun; Wang, Qi; Cheng, Feixiong

2017-01-01

Aging that refers the accumulation of genetic and physiology changes in cells and tissues over a lifetime has been shown a high risk of developing various complex diseases, such as neurodegenerative disease, cardiovascular disease and cancer. Over the past several decades, natural products have been demonstrated as anti-aging interveners via extending lifespan and preventing aging-associated disorders. In this study, we developed an integrated systems pharmacology infrastructure to uncover new indications for aging-associated disorders by natural products. Specifically, we incorporated 411 high-quality aging-associated human genes or human-orthologous genes from mus musculus (MM), saccharomyces cerevisiae (SC), c aenorhabditis elegans (CE), and drosophila melanogaster (DM). We constructed a global drug-target network of natural products by integrating both experimental and computationally predicted drug-target interactions (DTI). We further built the statistical network models for identification of new anti-aging indications of natural products through integration of the curated aging-associated genes and drug-target network of natural products. High accuracy was achieved on the network models. We showcased several network-predicted anti-aging indications of four typical natural products (caffeic acid, metformin, myricetin, and resveratrol) with new mechanism-of-actions. In summary, this study offers a powerful systems pharmacology infrastructure to identify natural products for treatment of aging-associated disorders.

Quantitative and Systems Pharmacology 3. Network-Based Identification of New Targets for Natural Products Enables Potential Uses in Aging-Associated Disorders

PubMed Central

Fang, Jiansong; Gao, Li; Ma, Huili; Wu, Qihui; Wu, Tian; Wu, Jun; Wang, Qi; Cheng, Feixiong

2017-01-01

Aging that refers the accumulation of genetic and physiology changes in cells and tissues over a lifetime has been shown a high risk of developing various complex diseases, such as neurodegenerative disease, cardiovascular disease and cancer. Over the past several decades, natural products have been demonstrated as anti-aging interveners via extending lifespan and preventing aging-associated disorders. In this study, we developed an integrated systems pharmacology infrastructure to uncover new indications for aging-associated disorders by natural products. Specifically, we incorporated 411 high-quality aging-associated human genes or human-orthologous genes from mus musculus (MM), saccharomyces cerevisiae (SC), caenorhabditis elegans (CE), and drosophila melanogaster (DM). We constructed a global drug-target network of natural products by integrating both experimental and computationally predicted drug-target interactions (DTI). We further built the statistical network models for identification of new anti-aging indications of natural products through integration of the curated aging-associated genes and drug-target network of natural products. High accuracy was achieved on the network models. We showcased several network-predicted anti-aging indications of four typical natural products (caffeic acid, metformin, myricetin, and resveratrol) with new mechanism-of-actions. In summary, this study offers a powerful systems pharmacology infrastructure to identify natural products for treatment of aging-associated disorders. PMID:29093681

Electrophysiological Activity Generated during the Implicit Association Test: A Study Using Event-Related Potentials

ERIC Educational Resources Information Center

O'Toole, Catriona; Barnes-Holmes, Dermot

2009-01-01

The Implicit Association Test (IAT) examines the differential association of 2 target concepts with 2 attribute concepts. Responding is predicted to be faster on consistent trials, when concepts that are associated in memory share a response key, than on inconsistent trials, when less associated items share a key. In the current study,…

Deep brain stimulation in uncommon tremor disorders: indications, targets, and programming.

PubMed

Artusi, Carlo Alberto; Farooqi, Ashar; Romagnolo, Alberto; Marsili, Luca; Balestrino, Roberta; Sokol, Leonard L; Wang, Lily L; Zibetti, Maurizio; Duker, Andrew P; Mandybur, George T; Lopiano, Leonardo; Merola, Aristide

2018-03-06

In uncommon tremor disorders, clinical efficacy and optimal anatomical targets for deep brain stimulation (DBS) remain inadequately studied and insufficiently quantified. We performed a systematic review of PubMed.gov and ClinicalTrials.gov. Relevant articles were identified using the following keywords: "tremor", "Holmes tremor", "orthostatic tremor", "multiple sclerosis", "multiple sclerosis tremor", "neuropathy", "neuropathic tremor", "fragile X-associated tremor/ataxia syndrome", and "fragile X." We identified a total of 263 cases treated with DBS for uncommon tremor disorders. Of these, 44 had Holmes tremor (HT), 18 orthostatic tremor (OT), 177 multiple sclerosis (MS)-associated tremor, 14 neuropathy-associated tremor, and 10 fragile X-associated tremor/ataxia syndrome (FXTAS). DBS resulted in favorable, albeit partial, clinical improvements in HT cases receiving Vim-DBS alone or in combination with additional targets. A sustained improvement was reported in OT cases treated with bilateral Vim-DBS, while the two cases treated with unilateral Vim-DBS demonstrated only a transient effect. MS-associated tremor responded to dual-target Vim-/VO-DBS, but the inability to account for the progression of MS-associated disability impeded the assessment of its long-term clinical efficacy. Neuropathy-associated tremor substantially improved with Vim-DBS. In FXTAS patients, while Vim-DBS was effective in improving tremor, equivocal results were observed in those with ataxia. DBS of select targets may represent an effective therapeutic strategy for uncommon tremor disorders, although the level of evidence is currently in its incipient form and based on single cases or limited case series. An international registry is, therefore, warranted to clarify selection criteria, long-term results, and optimal surgical targets.

Articulatory Placement for /t/, /d/, /k/ and /g/ Targets in School Age Children with Speech Disorders Associated with Cleft Palate

ERIC Educational Resources Information Center

Gibbon, Fiona; Ellis, Lucy; Crampin, Lisa

2004-01-01

This study used electropalatography (EPG) to identify place of articulation for lingual plosive targets /t/, /d/, /k/ and /g/ in the speech of 15 school age children with repaired cleft palate. Perceptual judgements indicated that all children had correct velar placement for /k/, /g/ targets, but /t/, /d/ targets were produced as errors involving…

Epidermal growth factor receptor and variant III targeted immunotherapy.

PubMed

Congdon, Kendra L; Gedeon, Patrick C; Suryadevara, Carter M; Caruso, Hillary G; Cooper, Laurence J N; Heimberger, Amy B; Sampson, John H

2014-10-01

Immunotherapeutic approaches to cancer have shown remarkable promise. A critical barrier to successfully executing such immune-mediated interventions is the selection of safe yet immunogenic targets. As patient deaths have occurred when tumor-associated antigens shared by normal tissue have been targeted by strong cellular immunotherapeutic platforms, route of delivery, target selection and the immune-mediated approach undertaken must work together to maximize efficacy with safety. Selected tumor-specific targets can spare potential toxicity to normal tissue; however, they are far less common than tumor-associated antigens and may not be present on all patients. In the context of immunotherapy for high-grade glioma, 2 of the most prominently studied antigens are the tumor-associated epidermal growth factor receptor and its tumor-specific genetic deletion variant III. In this review, we will summarize the immune-mediated strategies employed against these targets as well as the caveats particular to these approaches. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

KSHV Targeted Therapy: An Update on Inhibitors of Viral Lytic Replication

PubMed Central

Coen, Natacha; Duraffour, Sophie; Snoeck, Robert; Andrei, Graciela

2014-01-01

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma, primary effusion lymphoma and multicentric Castleman’s disease. Since the discovery of KSHV 20 years ago, there is still no standard treatment and the management of virus-associated malignancies remains toxic and incompletely efficacious. As the majority of tumor cells are latently infected with KSHV, currently marketed antivirals that target the virus lytic cycle have shown inconsistent results in clinic. Nevertheless, lytic replication plays a major role in disease progression and virus dissemination. Case reports and retrospective studies have pointed out the benefit of antiviral therapy in the treatment and prevention of KSHV-associated diseases. As a consequence, potent and selective antivirals are needed. This review focuses on the anti-KSHV activity, mode of action and current status of antiviral drugs targeting KSHV lytic cycle. Among these drugs, different subclasses of viral DNA polymerase inhibitors and compounds that do not target the viral DNA polymerase are being discussed. We also cover molecules that target cellular kinases, as well as the potential of new drug targets and animal models for antiviral testing. PMID:25421895

GWASeq: targeted re-sequencing follow up to GWAS.

PubMed

Salomon, Matthew P; Li, Wai Lok Sibon; Edlund, Christopher K; Morrison, John; Fortini, Barbara K; Win, Aung Ko; Conti, David V; Thomas, Duncan C; Duggan, David; Buchanan, Daniel D; Jenkins, Mark A; Hopper, John L; Gallinger, Steven; Le Marchand, Loïc; Newcomb, Polly A; Casey, Graham; Marjoram, Paul

2016-03-03

For the last decade the conceptual framework of the Genome-Wide Association Study (GWAS) has dominated the investigation of human disease and other complex traits. While GWAS have been successful in identifying a large number of variants associated with various phenotypes, the overall amount of heritability explained by these variants remains small. This raises the question of how best to follow up on a GWAS, localize causal variants accounting for GWAS hits, and as a consequence explain more of the so-called "missing" heritability. Advances in high throughput sequencing technologies now allow for the efficient and cost-effective collection of vast amounts of fine-scale genomic data to complement GWAS. We investigate these issues using a colon cancer dataset. After QC, our data consisted of 1993 cases, 899 controls. Using marginal tests of associations, we identify 10 variants distributed among six targeted regions that are significantly associated with colorectal cancer, with eight of the variants being novel to this study. Additionally, we perform so-called 'SNP-set' tests of association and identify two sets of variants that implicate both common and rare variants in the etiology of colorectal cancer. Here we present a large-scale targeted re-sequencing resource focusing on genomic regions implicated in colorectal cancer susceptibility previously identified in several GWAS, which aims to 1) provide fine-scale targeted sequencing data for fine-mapping and 2) provide data resources to address methodological questions regarding the design of sequencing-based follow-up studies to GWAS. Additionally, we show that this strategy successfully identifies novel variants associated with colorectal cancer susceptibility and can implicate both common and rare variants.

Emotion-induced blindness reflects competition at early and late processing stages: an ERP study.

PubMed

Kennedy, Briana L; Rawding, Jennifer; Most, Steven B; Hoffman, James E

2014-12-01

Emotion-induced blindness (EIB) refers to impaired awareness of items appearing soon after an irrelevant, emotionally arousing stimulus. Superficially, EIB appears to be similar to the attentional blink (AB), a failure to report a target that closely follows another relevant target. Previous studies of AB using event-related potentials suggest that the AB results from interference with selection (N2 component) and consolidation (P3b component) of the second target into working memory. The present study applied a similar analysis to EIB and, similarly, found that an irrelevant emotional distractor suppressed the N2 and P3b components associated with the following target at short lags. Emotional distractors also elicited a positive deflection that appeared to be similar to the PD component, which has been associated with attempts to suppress salient, irrelevant distractors (Kiss, Grubert, Petersen, & Eimer, 2012; Sawaki, Geng, & Luck, 2012; Sawaki & Luck, 2010). These results suggest that irrelevant emotional pictures gain access to working memory, even when observers are attempting to ignore them and, like the AB, prevent access of a closely following target.

Antitumor Effects of Chimeric Receptor Engineered Human T Cells Directed to Tumor Stroma

PubMed Central

Kakarla, Sunitha; Chow, Kevin KH; Mata, Melinda; Shaffer, Donald R; Song, Xiao-Tong; Wu, Meng-Fen; Liu, Hao; Wang, Lisa L; Rowley, David R; Pfizenmaier, Klaus; Gottschalk, Stephen

2013-01-01

Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors. PMID:23732988

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals.

PubMed

Ehret, Georg B; Ferreira, Teresa; Chasman, Daniel I; Jackson, Anne U; Schmidt, Ellen M; Johnson, Toby; Thorleifsson, Gudmar; Luan, Jian'an; Donnelly, Lousie A; Kanoni, Stavroula; Petersen, Ann-Kristin; Pihur, Vasyl; Strawbridge, Rona J; Shungin, Dmitry; Hughes, Maria F; Meirelles, Osorio; Kaakinen, Marika; Bouatia-Naji, Nabila; Kristiansson, Kati; Shah, Sonia; Kleber, Marcus E; Guo, Xiuqing; Lyytikäinen, Leo-Pekka; Fava, Cristiano; Eriksson, Niclas; Nolte, Ilja M; Magnusson, Patrik K; Salfati, Elias L; Rallidis, Loukianos S; Theusch, Elizabeth; Smith, Andrew J P; Folkersen, Lasse; Witkowska, Kate; Pers, Tune H; Joehanes, Roby; Kim, Stuart K; Lataniotis, Lazaros; Jansen, Rick; Johnson, Andrew D; Warren, Helen; Kim, Young Jin; Zhao, Wei; Wu, Ying; Tayo, Bamidele O; Bochud, Murielle; Absher, Devin; Adair, Linda S; Amin, Najaf; Arking, Dan E; Axelsson, Tomas; Baldassarre, Damiano; Balkau, Beverley; Bandinelli, Stefania; Barnes, Michael R; Barroso, Inês; Bevan, Stephen; Bis, Joshua C; Bjornsdottir, Gyda; Boehnke, Michael; Boerwinkle, Eric; Bonnycastle, Lori L; Boomsma, Dorret I; Bornstein, Stefan R; Brown, Morris J; Burnier, Michel; Cabrera, Claudia P; Chambers, John C; Chang, I-Shou; Cheng, Ching-Yu; Chines, Peter S; Chung, Ren-Hua; Collins, Francis S; Connell, John M; Döring, Angela; Dallongeville, Jean; Danesh, John; de Faire, Ulf; Delgado, Graciela; Dominiczak, Anna F; Doney, Alex S F; Drenos, Fotios; Edkins, Sarah; Eicher, John D; Elosua, Roberto; Enroth, Stefan; Erdmann, Jeanette; Eriksson, Per; Esko, Tonu; Evangelou, Evangelos; Evans, Alun; Fall, Tove; Farrall, Martin; Felix, Janine F; Ferrières, Jean; Ferrucci, Luigi; Fornage, Myriam; Forrester, Terrence; Franceschini, Nora; Duran, Oscar H Franco; Franco-Cereceda, Anders; Fraser, Ross M; Ganesh, Santhi K; Gao, He; Gertow, Karl; Gianfagna, Francesco; Gigante, Bruna; Giulianini, Franco; Goel, Anuj; Goodall, Alison H; Goodarzi, Mark O; Gorski, Mathias; Gräßler, Jürgen; Groves, Christopher; Gudnason, Vilmundur; Gyllensten, Ulf; Hallmans, Göran; Hartikainen, Anna-Liisa; Hassinen, Maija; Havulinna, Aki S; Hayward, Caroline; Hercberg, Serge; Herzig, Karl-Heinz; Hicks, Andrew A; Hingorani, Aroon D; Hirschhorn, Joel N; Hofman, Albert; Holmen, Jostein; Holmen, Oddgeir Lingaas; Hottenga, Jouke-Jan; Howard, Phil; Hsiung, Chao A; Hunt, Steven C; Ikram, M Arfan; Illig, Thomas; Iribarren, Carlos; Jensen, Richard A; Kähönen, Mika; Kang, Hyun; Kathiresan, Sekar; Keating, Brendan J; Khaw, Kay-Tee; Kim, Yun Kyoung; Kim, Eric; Kivimaki, Mika; Klopp, Norman; Kolovou, Genovefa; Komulainen, Pirjo; Kooner, Jaspal S; Kosova, Gulum; Krauss, Ronald M; Kuh, Diana; Kutalik, Zoltan; Kuusisto, Johanna; Kvaløy, Kirsti; Lakka, Timo A; Lee, Nanette R; Lee, I-Te; Lee, Wen-Jane; Levy, Daniel; Li, Xiaohui; Liang, Kae-Woei; Lin, Honghuang; Lin, Li; Lindström, Jaana; Lobbens, Stéphane; Männistö, Satu; Müller, Gabriele; Müller-Nurasyid, Martina; Mach, François; Markus, Hugh S; Marouli, Eirini; McCarthy, Mark I; McKenzie, Colin A; Meneton, Pierre; Menni, Cristina; Metspalu, Andres; Mijatovic, Vladan; Moilanen, Leena; Montasser, May E; Morris, Andrew D; Morrison, Alanna C; Mulas, Antonella; Nagaraja, Ramaiah; Narisu, Narisu; Nikus, Kjell; O'Donnell, Christopher J; O'Reilly, Paul F; Ong, Ken K; Paccaud, Fred; Palmer, Cameron D; Parsa, Afshin; Pedersen, Nancy L; Penninx, Brenda W; Perola, Markus; Peters, Annette; Poulter, Neil; Pramstaller, Peter P; Psaty, Bruce M; Quertermous, Thomas; Rao, Dabeeru C; Rasheed, Asif; Rayner, N William N W R; Renström, Frida; Rettig, Rainer; Rice, Kenneth M; Roberts, Robert; Rose, Lynda M; Rossouw, Jacques; Samani, Nilesh J; Sanna, Serena; Saramies, Jouko; Schunkert, Heribert; Sebert, Sylvain; Sheu, Wayne H-H; Shin, Young-Ah; Sim, Xueling; Smit, Johannes H; Smith, Albert V; Sosa, Maria X; Spector, Tim D; Stančáková, Alena; Stanton, Alice; Stirrups, Kathleen E; Stringham, Heather M; Sundstrom, Johan; Swift, Amy J; Syvänen, Ann-Christine; Tai, E-Shyong; Tanaka, Toshiko; Tarasov, Kirill V; Teumer, Alexander; Thorsteinsdottir, Unnur; Tobin, Martin D; Tremoli, Elena; Uitterlinden, Andre G; Uusitupa, Matti; Vaez, Ahmad; Vaidya, Dhananjay; van Duijn, Cornelia M; van Iperen, Erik P A; Vasan, Ramachandran S; Verwoert, Germaine C; Virtamo, Jarmo; Vitart, Veronique; Voight, Benjamin F; Vollenweider, Peter; Wagner, Aline; Wain, Louise V; Wareham, Nicholas J; Watkins, Hugh; Weder, Alan B; Westra, Harm-Jan; Wilks, Rainford; Wilsgaard, Tom; Wilson, James F; Wong, Tien Y; Yang, Tsun-Po; Yao, Jie; Yengo, Loic; Zhang, Weihua; Zhao, Jing Hua; Zhu, Xiaofeng; Bovet, Pascal; Cooper, Richard S; Mohlke, Karen L; Saleheen, Danish; Lee, Jong-Young; Elliott, Paul; Gierman, Hinco J; Willer, Cristen J; Franke, Lude; Hovingh, G Kees; Taylor, Kent D; Dedoussis, George; Sever, Peter; Wong, Andrew; Lind, Lars; Assimes, Themistocles L; Njølstad, Inger; Schwarz, Peter Eh; Langenberg, Claudia; Snieder, Harold; Caulfield, Mark J; Melander, Olle; Laakso, Markku; Saltevo, Juha; Rauramaa, Rainer; Tuomilehto, Jaakko; Ingelsson, Erik; Lehtimäki, Terho; Hveem, Kristian; Palmas, Walter; März, Winfried; Kumari, Meena; Salomaa, Veikko; Chen, Yii-Der I; Rotter, Jerome I; Froguel, Philippe; Jarvelin, Marjo-Riitta; Lakatta, Edward G; Kuulasmaa, Kari; Franks, Paul W; Hamsten, Anders; Wichmann, H-Erich; Palmer, Colin N A; Stefansson, Kari; Ridker, Paul M; Loos, Ruth J F; Chakravarti, Aravinda; Deloukas, Panos; Morris, Andrew P; Newton-Cheh, Christopher; Munroe, Patricia B

2016-10-01

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

Influence of socioeconomic and demographic status on spirometry testing in patients initiating medication targeting obstructive lung disease: a population-based cohort study.

PubMed

Koefoed, Mette M; Søndergaard, Jens; Christensen, René dePont; Jarbøl, Dorte E

2013-06-14

Socioeconomic status is known to influence the prevalence, severity and mortality of obstructive lung diseases, but it is uncertain whether it affects the use of diagnostic spirometry in patients initiating treatment for these conditions. The objective of this paper was to examine a possible association between education, income, labour market affiliation, cohabitation status and having spirometry performed when initiating medication targeting obstructive pulmonary disease. We conducted a population-based cohort study. Danish national registers were linked, retrieving data on prescriptions, spirometry testing, socioeconomic and demographic variables in all first time users of medication targeting obstructive lung disease in 2008. A total of 37,734 persons were included and approximately half of the cohort had spirometry performed. Among medication users under 65 years of age, being unemployed was significantly associated with reduced odds of having spirometry performed, the strongest association was seen in men (OR = 0.82, CI = 0.73-0.91). Medium income was associated with increased odds of having spirometry performed in men (OR =1.18, CI = 1.06-1.30) and high educational level (>12 years) was associated with reduced odds of having spirometry performed in women (OR = 0.86, CI = 0.78-0.94). Cohabitation status was not associated with having spirometry performed. Among medication users over 65 years of age, living alone was associated with reduced odds of having spirometry performed among men (OR = 0.78, CI = 0.69-0.88). Social inequity in spirometry testing among patients initiating medication targeting obstructive lung disease was confirmed in this study. Increased focus on spirometry testing among elderly men living alone, among the unemployed and among women with higher education is required when initiating medication.

Geographic Variations and Time Trends in Cancer Treatments in Taiwan.

PubMed

Hsu, Jason C; Chang, Sheng-Mao; Lu, Christine Y

2017-08-02

Targeted therapies have become important treatment options for cancer care in many countries. This study aimed to examine recent trends in utilization of antineoplastic drugs, particularly the use of targeted therapies for treatment of cancer, by geographic region in Taiwan (northern, midwestern, southern, and eastern regions and the outer islands). This was a retrospective observational study of antineoplastic agents using 2009-2012 quarterly claims data from Taiwan's National Health Insurance Research Database. Yearly market shares by prescription volume and costs for targeted therapies among total antineoplastic agents by region were estimated. We used multivariate regression model and ANOVA to examine variations in utilization of targeted therapies between geographic regions and used ARIMA models to estimate longitudinal trends. Population-adjusted use and costs of antineoplastic drugs (including targeted therapies) were highest in the southern region of Taiwan and lowest in the outer islands. We found a 4-fold difference in use of antineoplastic drugs and a 49-fold difference in use of targeted therapies between regions if the outer islands were included. There were minimal differences in use of antineoplastic drugs between other regions with about a 2-fold difference in use of targeted therapies. Without considering the outer islands, the market share by prescription volume and costs of targeted therapies increased almost 2-fold (1.84-1.90) and 1.5-fold (1.26-1.61) respectively between 2009 and 2012. Furthermore, region was not significantly associated with use of antineoplastic agents or use of targeted therapies after adjusting for confounders. Region was associated with costs of antineoplastic agents but it was not associated with costs of targeted therapies after confounding adjustments. Use of antineoplastic drugs overall and use of targeted therapies for treatment of cancer varied somewhat between regions in Taiwan; use was notably low in the outer islands. Strategies might be needed to ensure access to cancer care in each region as economic burden of cancer care increase due to growing use of targeted therapies.

Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight

PubMed Central

Chéron, Jean-Baptiste; Triki, Dhoha; Senac, Caroline; Flatters, Delphine; Camproux, Anne-Claude

2017-01-01

Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http://www.mti.univ-paris-diderot.fr/recherche/plateformes/logiciels. PMID:28817602

Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight.

PubMed

Regad, Leslie; Chéron, Jean-Baptiste; Triki, Dhoha; Senac, Caroline; Flatters, Delphine; Camproux, Anne-Claude

2017-01-01

Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http://www.mti.univ-paris-diderot.fr/recherche/plateformes/logiciels.

Episodic, generalized, and semantic memory tests: switching and strength effects.

PubMed

Humphreys, Michael S; Murray, Krista L

2011-09-01

We continue the process of investigating the probabilistic paired associate paradigm in an effort to understand the memory access control processes involved and to determine whether the memory structure produced is in transition between episodic and semantic memory. In this paradigm two targets are probabilistically paired with a cue across a large number of short lists. Participants can recall the target paired with the cue in the most recent list (list specific test), produce the first of the two targets that have been paired with that cue to come to mind (generalised test), and produce a free association response (semantic test). Switching between a generalised test and a list specific test did not produce a switching cost indicating a general similarity in the control processes involved. In addition, there was evidence for a dissociation between two different strength manipulations (amount of study time and number of cue-target pairings) such that number of pairings influenced the list specific, generalised and the semantic test but amount of study time only influenced the list specific and generalised test. © 2011 Canadian Psychological Association

Dissecting the expression relationships between RNA-binding proteins and their cognate targets in eukaryotic post-transcriptional regulatory networks.

PubMed

Nishtala, Sneha; Neelamraju, Yaseswini; Janga, Sarath Chandra

2016-05-10

RNA-binding proteins (RBPs) are pivotal in orchestrating several steps in the metabolism of RNA in eukaryotes thereby controlling an extensive network of RBP-RNA interactions. Here, we employed CLIP (cross-linking immunoprecipitation)-seq datasets for 60 human RBPs and RIP-ChIP (RNP immunoprecipitation-microarray) data for 69 yeast RBPs to construct a network of genome-wide RBP- target RNA interactions for each RBP. We show in humans that majority (~78%) of the RBPs are strongly associated with their target transcripts at transcript level while ~95% of the studied RBPs were also found to be strongly associated with expression levels of target transcripts when protein expression levels of RBPs were employed. At transcript level, RBP - RNA interaction data for the yeast genome, exhibited a strong association for 63% of the RBPs, confirming the association to be conserved across large phylogenetic distances. Analysis to uncover the features contributing to these associations revealed the number of target transcripts and length of the selected protein-coding transcript of an RBP at the transcript level while intensity of the CLIP signal, number of RNA-Binding domains, location of the binding site on the transcript, to be significant at the protein level. Our analysis will contribute to improved modelling and prediction of post-transcriptional networks.

Dissecting the expression relationships between RNA-binding proteins and their cognate targets in eukaryotic post-transcriptional regulatory networks

NASA Astrophysics Data System (ADS)

Nishtala, Sneha; Neelamraju, Yaseswini; Janga, Sarath Chandra

2016-05-01

RNA-binding proteins (RBPs) are pivotal in orchestrating several steps in the metabolism of RNA in eukaryotes thereby controlling an extensive network of RBP-RNA interactions. Here, we employed CLIP (cross-linking immunoprecipitation)-seq datasets for 60 human RBPs and RIP-ChIP (RNP immunoprecipitation-microarray) data for 69 yeast RBPs to construct a network of genome-wide RBP- target RNA interactions for each RBP. We show in humans that majority (~78%) of the RBPs are strongly associated with their target transcripts at transcript level while ~95% of the studied RBPs were also found to be strongly associated with expression levels of target transcripts when protein expression levels of RBPs were employed. At transcript level, RBP - RNA interaction data for the yeast genome, exhibited a strong association for 63% of the RBPs, confirming the association to be conserved across large phylogenetic distances. Analysis to uncover the features contributing to these associations revealed the number of target transcripts and length of the selected protein-coding transcript of an RBP at the transcript level while intensity of the CLIP signal, number of RNA-Binding domains, location of the binding site on the transcript, to be significant at the protein level. Our analysis will contribute to improved modelling and prediction of post-transcriptional networks.

Characterization of cationic liposome formulations designed to exhibit extended plasma residence times and tumor vasculature targeting properties.

PubMed

Ho, Emmanuel A; Ramsay, Euan; Ginj, Mihaela; Anantha, Malathi; Bregman, Isaiah; Sy, Jonathan; Woo, Janet; Osooly-Talesh, Maryam; Yapp, Donald T; Bally, Marcel B

2010-06-01

Cationic liposomes exhibit a propensity to selectively target tumor-associated blood vessels demonstrating potential value as anti-cancer drug delivery vehicles. Their utility however, is hampered by their biological instability and rapid elimination following i.v. administration. Efforts to circumvent rapid plasma elimination have, to date, focused on decreasing cationic lipid content and incorporating polyethylene glycol (PEG)-modified lipids. In this study we wanted to determine whether highly charged cationic liposomes with surface-associated PEG could be designed to exhibit extended circulation lifetimes, while retaining tumor vascular targeting properties in an HT29 colorectal cancer xenograft model. Cationic liposomes prepared of DSPC, cationic lipids (DODAC, DOTAP, or DC-CHOL), and DSPE-PEG(2000) were studied. Our results demonstrate that formulations prepared with 50 mol% DODAC or DC-CHOL, and 20 mol% DSPE-PEG(2000) exhibited circulation half-lives ranging from 6.5 to 12.5 h. Biodistribution studies demonstrated that DC-CHOL formulations prepared with DSPE-PEG(2000) accumulated threefold higher in s.c. HT29 tumors than its PEG-free counterpart. Fluorescence microscopy studies suggested that the presence of DSPE-PEG(2000) did not adversely affect liposomal tumor vasculature targeting. We show for the first time that it is achievable to design highly charged, highly pegylated (20 mol% DSPE-PEG(2000)) cationic liposomes which exhibit both extended circulation lifetimes and tumor vascular targeting properties. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association

Impact of Clinical Factors on the Achievement of Target Blood Pressure in Hypertensive Patients from Ivanovo Region of Russia: Data of 2015.

PubMed

Kiselev, A R; Posnenkova, O M; Belova, O A; Romanchuk, S V; Popova, Y V; Prokhorov, M D; Gridnev, V I

2017-12-01

In Russia, blood pressure (BP) control is below the optimal. The little is known about regional features and barriers to adequate BP control in Russian primary care. To evaluate the impact of clinical factors on achieving the target BP in hypertensive patients in one region of Russia. Retrospective medical data of 2015 on 11,129 patients (31.4% male) with hypertension (Htn) from Ivanovo region of Russia were examined. Achievement of target BP was assessed in all patients. We study association between BP control and clinical factors. 45.9% of studied patients with Htn had controlled BP. The frequency of achieving the target BP in subsets of hypertensive patients was 37.8% in patients with diabetes, 39.5% in patients with coronary artery disease, and 29.9% in patients with chronic heart failure. The main clinical factors associated with achieving the target BP in studied hypertensive patients were the advice on alcohol consumption, advice on smoking cessation, and advice on weight reduction. Therapy with main antihypertensive drugs (in particular, beta-blockers and thiazide diuretics) were also factors of optimal BP control in these patients. Comorbidities (chronic heart failure and cardiovascular diseases requiring the prescription of aspirin and statins) and family history of coronary artery disease were associated with inadequate BP control. A negative effect of some antihypertensive drugs (potassium sparing diuretics, ARBs, ACE-Is, and dihydropyridine CCBs) on BP control that was found out in our study requires further investigation. Other studied factors had no influence on BP control in patients with Htn from Ivanovo region. We identified regional factors of BP control in hypertensive patients from Ivanovo region of Russia. It is shown that individual medical education (in particular, medical advices) is the most important factor of optimal BP control. The intervention with antihypertensive therapy (beta-blockers and thiazide diuretics) facilitates the achievement of target BP. Comorbidity and age reduce the frequency of achieving the target BP.

Optimization of cell receptor-specific targeting through multivalent surface decoration of polymeric nanocarriers

PubMed Central

D’Addio, Suzanne M.; Baldassano, Steven; Shi, Lei; Cheung, Lila; Adamson, Douglas H.; Bruzek, Matthew; Anthony, John E.; Laskin, Debra L.; Sinko, Patrick J.; Prud’homme, Robert K.

2013-01-01

Treatment of tuberculosis is impaired by poor drug bioavailability, systemic side effects, patient non-compliance, and pathogen resistance to existing therapies. The mannose receptor (MR) is known to be involved in the recognition and internalization of Mycobacterium tuberculosis. We present a new assembly process to produce nanocarriers with variable surface densities of mannose targeting ligands in a single step, using kinetically-controlled, block copolymer-directed assembly. Nanocarrier association with murine macrophage J774 cells expressing the MR is examined as a function of incubation time and temperature, nanocarrier size, dose, and PEG corona properties. Amphiphilic diblock copolymers are prepared with terminal hydroxyl, methoxy, or mannoside functionality and incorporated into nanocarrier formulations at specific ratios by Flash NanoPrecipitation. Association of nanocarriers protected by a hydroxyl-terminated PEG corona with J774 cells is size dependent, while nanocarriers with methoxy-terminated PEG coronas do not associate with cells, regardless of size. Specific targeting of the MR is investigated using nanocarriers having 0-75% mannoside-terminated PEG chains in the PEG corona. This is a wider range of mannose densities than has been previously studied. Maximum nanocarrier association is attained with 9% mannoside-terminated PEG chains, increasing uptake more than 3-fold compared to non-targeted nanocarriers with a 5 kg mol−1 methoxy-terminated PEG corona. While a 5 kg mol−1 methoxy-terminated PEG corona prevents non-specific uptake, a 1.8 kg mol−1 methoxy-terminated PEG corona does not sufficiently protect the nanocarriers from nonspecific association. There is continuous uptake of MR-targeted nanocarriers at 37°C, but a saturation of association at 4°C. The majority of targeted nanocarriers associate with J774E cells are internalized at 37°C and uptake is receptor-dependent, diminishing with competitive inhibition by dextran. This characterization of nanocarrier uptake and targeting provides promise for optimizing drug delivery to macrophages for TB treatment and establishes a general route for optimizing targeted formulations of nanocarriers for specific delivery at targeted sites. PMID:23419950

Lunar Orbit Insertion Targeting and Associated Outbound Mission Design for Lunar Sortie Missions

NASA Technical Reports Server (NTRS)

Condon, Gerald L.

2007-01-01

This report details the Lunar Orbit Insertion (LOI) arrival targeting and associated mission design philosophy for Lunar sortie missions with up to a 7-day surface stay and with global Lunar landing site access. It also documents the assumptions, methodology, and requirements validated by TDS-04-013, Integrated Transit Nominal and Abort Characterization and Sensitivity Study. This report examines the generation of the Lunar arrival parking orbit inclination and Longitude of the Ascending Node (LAN) targets supporting surface missions with global Lunar landing site access. These targets support the Constellation Program requirement for anytime abort (early return) by providing for a minimized worst-case wedge angle [and an associated minimum plane change delta-velocity (V) cost] between the Crew Exploration Vehicle (CEV) and the Lunar Surface Access Module (LSAM) for an LSAM launch anytime during the Lunar surface stay.

Precision-guided antimicrobial peptide as a targeted modulator of human microbial ecology.

PubMed

Guo, Lihong; McLean, Jeffrey S; Yang, Youngik; Eckert, Randal; Kaplan, Christopher W; Kyme, Pierre; Sheikh, Omid; Varnum, Brian; Lux, Renate; Shi, Wenyuan; He, Xuesong

2015-06-16

One major challenge to studying human microbiome and its associated diseases is the lack of effective tools to achieve targeted modulation of individual species and study its ecological function within multispecies communities. Here, we show that C16G2, a specifically targeted antimicrobial peptide, was able to selectively kill cariogenic pathogen Streptococcus mutans with high efficacy within a human saliva-derived in vitro oral multispecies community. Importantly, a significant shift in the overall microbial structure of the C16G2-treated community was revealed after a 24-h recovery period: several bacterial species with metabolic dependency or physical interactions with S. mutans suffered drastic reduction in their abundance, whereas S. mutans' natural competitors, including health-associated Streptococci, became dominant. This study demonstrates the use of targeted antimicrobials to modulate the microbiome structure allowing insights into the key community role of specific bacterial species and also indicates the therapeutic potential of C16G2 to achieve a healthy oral microbiome.

Mining, identification and function analysis of microRNAs and target genes in peanut (Arachis hypogaea L.).

PubMed

Zhang, Tingting; Hu, Shuhao; Yan, Caixia; Li, Chunjuan; Zhao, Xiaobo; Wan, Shubo; Shan, Shihua

2017-02-01

In the present investigation, a total of 60 conserved peanut (Arachis hypogaea L.) microRNA (miRNA) sequences, belonging to 16 families, were identified using bioinformatics methods. There were 392 target gene sequences, identified from 58 miRNAs with Target-align software and BLASTx analyses. Gene Ontology (GO) functional analysis suggested that these target genes were involved in mediating peanut growth and development, signal transduction and stress resistance. There were 55 miRNA sequences, verified employing a poly (A) tailing test, with a success rate of up to 91.67%. Twenty peanut target gene sequences were randomly selected, and the 5' rapid amplification of the cDNA ends (5'-RACE) method were used to validate the cleavage sites of these target genes. Of these, 14 (70%) peanut miRNA targets were verified by means of gel electrophoresis, cloning and sequencing. Furthermore, functional analysis and homologous sequence retrieval were conducted for target gene sequences, and 26 target genes were chosen as the objects for stress resistance experimental study. Real-time fluorescence quantitative PCR (qRT-PCR) technology was applied to measure the expression level of resistance-associated miRNAs and their target genes in peanut exposed to Aspergillus flavus (A. flavus) infection and drought stress, respectively. In consequence, 5 groups of miRNAs & targets were found accorded with the mode of miRNA negatively controlling the expression of target genes. This study, preliminarily determined the biological functions of some resistance-associated miRNAs and their target genes in peanut. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Predicting Ideological Prejudice

PubMed Central

Brandt, Mark J.

2017-01-01

A major shortcoming of current models of ideological prejudice is that although they can anticipate the direction of the association between participants’ ideology and their prejudice against a range of target groups, they cannot predict the size of this association. I developed and tested models that can make specific size predictions for this association. A quantitative model that used the perceived ideology of the target group as the primary predictor of the ideology-prejudice relationship was developed with a representative sample of Americans (N = 4,940) and tested against models using the perceived status of and choice to belong to the target group as predictors. In four studies (total N = 2,093), ideology-prejudice associations were estimated, and these observed estimates were compared with the models’ predictions. The model that was based only on perceived ideology was the most parsimonious with the smallest errors. PMID:28394693

Management of rheumatoid arthritis in clinical practice using treat-to-target strategy: Where do we stand in the multi-ethnic Malaysia population?

PubMed

Tan, Bee Eng; Lim, Ai Lee; Kan, Sow Lai; Lim, Chong Hong; Ng, Ying Fun; Tng, Serene Li Ching; Hassin, Nur Syakirah; Chandran, Losshenee; Hamid, Norshahida Abdul; Lee, Yvonne Yin Leng

2017-06-01

To evaluate the achievement of treat-to-target (T2T) strategy in rheumatoid arthritis (RA) and identify factors associated with failed treatment target in a public rheumatology center. A cross-sectional study was conducted from June 2015 to February 2016. RA patients with disease duration greater than 2 years and under T2T for over a year were invited to the study. Demographic, clinical data, disease activity score of 28 joints (DAS28), and clinical disease activity index (CDAI) were collected in a single routine clinic visit. Treatment target was defined as DAS28 <3.2 or CDAI ≤10. Retrospective chart review was performed to determine reasons of failed treatment target. A total of 371 patients were recruited and 87.1% were female. Mean age and duration of RA were 53.5 years (SD 10.3) and 9.1 years (SD 6.6), respectively. Ethnic distribution was 49% Chinese, 27% Malay, and 24% Indian. T2T was achieved in 81.7% of the cohort. Non-Chinese ethnicity, positive rheumatoid factor, and treatment with three disease modifying anti-rheumatic drugs (DMARDs) were associated with failed treatment target. After controlling for covariates, Malay ethnicity (OR 2.96; 95% CI 1.47-5.96) and treatment with three DMARDs (OR 2.14; 95% CI 1.06-4.35) were associated with failed treatment target. There was no association between age, gender, duration of RA, BMI, smoking status, anti-citrulinated cyclic peptide, and achievement of T2T. The most common reasons of failed treatment target were inability to escalate DMARDs due to side effects (18.8%), lack of biologics fund (15.6%), and persistent disease despite optimum treatment (14.1%). T2T was successfully implemented. Malay patients need aggressive treatment adaptation to achieve optimal outcome.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors).

PubMed

Winthrop, K L; Mariette, X; Silva, J T; Benamu, E; Calabrese, L H; Dumusc, A; Smolen, J S; Aguado, J M; Fernández-Ruiz, M

2018-06-01

The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. To review, from an Infectious Diseases perspective, the safety profile of agents targeting interleukins, immunoglobulins and complement factors and to suggest preventive recommendations. Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. Patients receiving interleukin-1 (IL-1) -targeted (anakinra, canakinumab or rilonacept) or IL-5-targeted (mepolizumab) agents have a moderate risk of infection and no specific prevention strategies are recommended. The use of IL-6/IL-6 receptor-targeted agents (tocilizumab and siltuximab) is associated with a risk increase similar to that observed with anti-tumour necrosis factor-α agents. IL-12/23-targeted agents (ustekinumab) do not seem to pose a meaningful risk of infection, although screening for latent tuberculosis infection may be considered and antiviral prophylaxis should be given to hepatitis B surface antigen-positive patients. Therapy with IL-17-targeted agents (secukinumab, brodalumab and ixekizumab) may result in the development of mild-to-moderate mucocutaneous candidiasis. Pre-treatment screening for Strongyloides stercoralis and other geohelminths should be considered in patients who come from areas where these are endemic who are receiving IgE-targeted agents (omalizumab). C5-targeted agents (eculizumab) are associated with a markedly increased risk of infection due to encapsulated bacteria, particularly Neisseria spp. Meningococcal vaccination and chemoprophylaxis must be administered 2-4 weeks before initiating eculizumab. Patients with high-risk behaviours and their partners should also be screened for gonococcal infection. Preventive strategies are particularly encouraged to minimize the occurrence of neisserial infection associated with eculizumab. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

State policies targeting junk food in schools: racial/ethnic differences in the effect of policy change on soda consumption.

PubMed

Taber, Daniel R; Stevens, June; Evenson, Kelly R; Ward, Dianne S; Poole, Charles; Maciejewski, Matthew L; Murray, David M; Brownson, Ross C

2011-09-01

We estimated the association between state policy changes and adolescent soda consumption and body mass index (BMI) percentile, overall and by race/ethnicity. We obtained data on whether states required or recommended that schools prohibit junk food in vending machines, snack bars, concession stands, and parties from the 2000 and 2006 School Health Policies and Programs Study. We used linear mixed models to estimate the association between 2000-2006 policy changes and 2007 soda consumption and BMI percentile, as reported by 90 730 students in 33 states and the District of Columbia in the Youth Risk Behavior Survey, and to test for racial/ethnic differences in the associations. Policy changes targeting concession stands were associated with 0.09 fewer servings of soda per day among students (95% confidence interval [CI] = -0.17, -0.01); the association was more pronounced among non-Hispanic Blacks (0.19 fewer servings per day). Policy changes targeting parties were associated with 0.07 fewer servings per day (95% CI = -0.13, 0.00). Policy changes were not associated with BMI percentile in any group. State policies targeting junk food in schools may reduce racial/ethnic disparities in adolescent soda consumption, but their impact appears to be too weak to reduce adolescent BMI percentile.

Risk Assessment and Prevention of Hypertension in Filipino Americans.

PubMed

Ma, Grace X; Lee, Minsun; Bhimla, Aisha; Tan, Yin; Gadegbeku, Crystal A; Yeh, Ming Chin; Aczon, Hermie

2017-08-01

Despite that Filipino Americans represent an important target group for hypertension, health behaviors associated with hypertension in this population have not been well studied. Two hundred Filipino Americans from eight community-based organizations completed the study. Information was collected to determine whether modifiable behavioral factors, as well as acculturation and demographic characteristics, were associated with hypertension status in Filipino Americans. Approximately 67% of Filipino Americans were hypertensive. Logistic regression analysis showed that adding salt, physical inactivity, and old age were significantly associated with hypertension status after controlling for other covariates. The present study confirmed a high rate of hypertension among Filipino Americans and demonstrates the association of hypertension status with behavioral factors. These findings highlight the need for targeted interventions to prevent and manage hypertension in this high-risk community by facilitating health behaviors, particularly, salt reduction and physical activity.

Source Memory in the Absence of Successful Cued Recall

ERIC Educational Resources Information Center

Cook, Gabriel I.; Marsh, Richard L.; Hicks, Jason L.

2006-01-01

Five experiments were conducted to address the question of whether source information could be accessed in the absence of being able to recall an item. The authors used a paired-associate learning paradigm in which cue-target word pairs were studied, and target recall was requested in the presence of the cue. When target recall failed,…

Interaction Studies of Withania Somnifera's Key Metabolite Withaferin A with Different Receptors Assoociated with Cardiovascular Disease.

PubMed

Ravindran, Rekha; Sharma, Nitika; Roy, Sujata; Thakur, Ashoke R; Ganesh, Subhadra; Kumar, Sriram; Devi, Jamuna; Rajkumar, Johanna

2015-01-01

Withania somnifera commonly known as Ashwagandha in India is used in many herbal formulations to treat various cardiovascular diseases. The key metabolite of this plant, Withaferin A was analyzed for its molecular mechanism through docking studies on different targets of cardiovascular disease. Six receptor proteins associated with cardiovascular disease were selected and interaction studies were performed with Withaferin A using AutoDock Vina. CORINA was used to model the small molecules and HBAT to compute the hydrogen bonding. Among the six targets, β1- adrenergic receptors, HMG-CoA and Angiotensinogen-converting enzyme showed significant interaction with Withaferin A. Pharmacophore modeling was done using PharmaGist to understand the pharmacophoric potential of Withaferin A. Clustering of Withaferin A with different existing drug molecules for cardiovascular disease was performed with ChemMine based on structural similarity and physicochemical properties. The ability of natural active component, Withaferin A to interact with different receptors associated with cardiovascular disease was elucidated with various modeling techniques. These studies conclusively revealed Withaferin A as a potent lead compound against multiple targets associated with cardiovascular disease.

Influence of prime-target relationship on semantic priming effects from words in a lexical-decision task.

PubMed

Abad, María J F; Noguera, Carmen; Ortells, Juan J

2003-07-01

The present research examines the influence of prime-target relationship (associative and categorical versus categorical only) on priming effects from attended and ignored parafoveal words. Participants performed a lexical-decision task on a single central target, which was preceded by two parafoveal prime words, one of which (the attended prime) was spatially precued. The results showed reliable positive and negative priming effects from attended and ignored words, respectively. However, this priming pattern was observed only for the "associative and categorical", but not for the "categorical only" relationship condition. These results suggest that the lack of semantic priming effects from words in some prior studies may be attributed to the kind of material used (i.e. weakly-associated word pairs).

[Advances in nanoparticle-targeting tumor associated macrophages for cancer imaging and therapy].

PubMed

Fengliang, Guo; Guping, Tang; Qinglian, H U

2017-03-25

Tumor tissues are composed of tumor cells and complicate microenvironment. Tumor associated macrophages (TAMs) as an important component in tumor microenvironment, play fundamental roles in tumor progression, metastasis and microenvironment regulation. Recently, studies have found that nanotechnology, as an emerging platform, provides unique potential for cancer imaging and therapy. With the nanotechnology, TAMs imaging presents direct evidence for cancer development, progression, and the effectiveness of cancer treatments; it also can regulate the immunosuppression of tumor microenvironment and improve therapeutic efficiency through TAMs targeted killing or phenotypic transformation. In this article, we illustrate the function of TAMs and review the latest development in nano-carriers and their applications in tumor associated macrophage targeting cancer imaging and therapy.

Evaluative Priming in the Pronunciation Task.

PubMed

Klauer, Karl Christoph; Becker, Manuel; Spruyt, Adriaan

2016-01-01

We replicated and extended a study by Spruyt and Hermans (2008) in which picture primes engendered an evaluative-priming effect on the pronunciation of target words. As preliminary steps, we assessed data reproducibility of the original study, conducted Pilot Study I to identify highly semantically related prime-target pairs, reanalyzed the original data excluding such pairs, conducted Pilot Study II to demonstrate that we can replicate traditional associative priming effects in the pronunciation task, and conducted Pilot Study III to generate relatively unrelated sets of prime pictures and target words. The main study comprised three between-participants conditions: (1) a close replication of the original study, (2) the same condition excluding highly related prime-target pairs, and (3) a condition based on the relatively unrelated sets of prime pictures and target words developed in Pilot Study III. There was little evidence for an evaluative priming effect independent of semantic relatedness.

Recall of "The Real Cost" Anti-Smoking Campaign Is Specifically Associated With Endorsement of Campaign-Targeted Beliefs.

PubMed

Kranzler, Elissa C; Gibson, Laura A; Hornik, Robert C

2017-10-01

Though previous research suggests the FDA's "The Real Cost" anti-smoking campaign has reduced smoking initiation, the theorized pathway of effects (through targeted beliefs) has not been evaluated. This study assesses the relationship between recall of campaign television advertisements and ad-specific anti-smoking beliefs. Respondents in a nationally representative survey of nonsmoking youths age 13-17 (n = 4,831) reported exposure to four The Real Cost advertisements and a fake ad, smoking-relevant beliefs, and nonsmoking intentions. Analyses separately predicted each targeted belief from specific ad recall, adjusting for potential confounders and survey weights. Parallel analyses with non-targeted beliefs showed smaller effects, strengthening claims of campaign effects. Recall of four campaign ads (but not the fake ad) significantly predicted endorsement of the ad-targeted belief (Mean β = .13). Two-sided sign tests indicated stronger ad recall associations with the targeted belief relative to the non-targeted belief (p < .05). Logistic regression analyses indicated that respondents who endorsed campaign-targeted beliefs were more likely to have no intention to smoke (p < .01). This study is the first to demonstrate a relationship between recall of ads from The Real Cost campaign and the theorized pathway of effects (through targeted beliefs). These analyses also provide a methodological template for showing campaign effects despite limitations of available data.

Differences in spousal influence on smoking cessation by gender and education among Japanese couples.

PubMed

Takagi, Daisuke; Kondo, Naoki; Takada, Misato; Hashimoto, Hideki

2014-11-19

Previous studies have reported that spousal non-smoking has a spillover effect on the partner's cessation. However, discussion is lacking on the factors modifying that association. We examined whether the spillover effect of spousal non-smoking was associated with the couple's educational attainment. We used paired marital data from the Japanese Study on Stratification, Health, Income, and Neighborhood (J-SHINE), which targeted residents aged 25-50 years in four Japanese municipalities. We selected a spouse smoker at the time of marriage (target respondent), and set his/her smoking status change (continued or quit smoking after marriage) as an outcome, regressed on the counterpart's smoking status (continued smoking or non-smoking) and combinations of each couple's educational attainment as explanatory variables using log-binomial regression models (n =1001 targets; 708 men and 293 women). Regression results showed that a counterpart who previously quit smoking or was a never-smoker was associated with the target male spouse's subsequent cessation. However, for women, the association between husband's non-smoking and their own cessation was significant only for couples in which both spouses were highly educated. Our findings suggest that a spouse's smoking status is important for smoking cessation interventions in men. For women, however, a couple's combined educational attainment may matter in the interventions.

Design and Construction of a Single-Tube, LATE-PCR, Multiplex Endpoint Assay with Lights-On/Lights-Off Probes for the Detection of Pathogens Associated with Sepsis

PubMed Central

Carver-Brown, Rachel K.; Reis, Arthur H.; Rice, Lisa M.; Czajka, John W.; Wangh, Lawrence J.

2012-01-01

Aims. The goal of this study was to construct a single tube molecular diagnostic multiplex assay for the detection of microbial pathogens commonly associated with septicemia, using LATE-PCR and Lights-On/Lights-Off probe technology. Methods and Results. The assay described here identified pathogens associated with sepsis by amplification and analysis of the 16S ribosomal DNA gene sequence for bacteria and specific gene sequences for fungi. A sequence from an unidentified gene in Lactococcus lactis subsp. cremoris served as a positive control for assay function. LATE-PCR was used to generate single-stranded amplicons that were then analyzed at endpoint over a wide temperature range in a specific fluorescent color. Each bacterial target was identified by its pattern of hybridization to Lights-On/Lights-Off probes derived from molecular beacons. Complex mixtures of targets were also detected. Conclusions. All microbial targets were identified in samples containing low starting copy numbers of pathogen genomic DNA, both as individual targets and in complex mixtures. Significance and Impact of the Study. This assay uses new technology to achieve an advance in the field of molecular diagnostics: a single-tube multiplex assay for identification of pathogens commonly associated with sepsis. PMID:23326668

Does Discourse Congruence Influence Spoken Language Comprehension before Lexical Association? Evidence from Event-Related Potentials

PubMed Central

Boudewyn, Megan A.; Gordon, Peter C.; Long, Debra; Polse, Lara; Swaab, Tamara Y.

2011-01-01

The goal of this study was to examine how lexical association and discourse congruence affect the time course of processing incoming words in spoken discourse. In an ERP norming study, we presented prime-target pairs in the absence of a sentence context to obtain a baseline measure of lexical priming. We observed a typical N400 effect when participants heard critical associated and unassociated target words in word pairs. In a subsequent experiment, we presented the same word pairs in spoken discourse contexts. Target words were always consistent with the local sentence context, but were congruent or not with the global discourse (e.g., “Luckily Ben had picked up some salt and pepper/basil”, preceded by a context in which Ben was preparing marinara sauce (congruent) or dealing with an icy walkway (incongruent). ERP effects of global discourse congruence preceded those of local lexical association, suggesting an early influence of the global discourse representation on lexical processing, even in locally congruent contexts. Furthermore, effects of lexical association occurred earlier in the congruent than incongruent condition. These results differ from those that have been obtained in studies of reading, suggesting that the effects may be unique to spoken word recognition. PMID:23002319

Clinical and psychosocial predictors of exceeding target length of stay during inpatient stroke rehabilitation.

PubMed

Lai, Wesley; Buttineau, Mackenzie; Harvey, Jennifer K; Pucci, Rebecca A; Wong, Anna P M; Dell'Erario, Linda; Bosnyak, Stephanie; Reid, Shannon; Salbach, Nancy M

2017-10-01

In Ontario, Canada, patients admitted to inpatient rehabilitation hospitals post-stroke are classified into rehabilitation patient groups based on age and functional level. Clinical practice guidelines, called quality-based procedures, recommend a target length of stay (LOS) for each group. The study objective was to evaluate the extent to which patients post-stroke at an inpatient rehabilitation hospital are meeting LOS targets and to identify patient characteristics that predict exceeding target LOS. A quantitative, longitudinal study from an inpatient rehabilitation hospital was conducted. Participants included adult patients (≥18 years) with stroke, admitted to an inpatient rehabilitation hospital between 2014 and 2015. The percentage of patients exceeding the recommended target LOS was determined. Logistic regression was performed to identify clinical and psychosocial patient characteristics associated with exceeding target LOS after adjusting for stroke severity. Of 165 patients, 38.8% exceeded their target LOS. Presence of ataxia, recurrent stroke, living alone, absence of a caregiver at admission, and acquiring a caregiver during hospital LOS was each associated with significantly higher odds of exceeding target LOS in comparison to patients without these characteristics after adjusting for stroke severity (p < 0.05). Findings suggest that social and stroke-specific factors may be helpful to adjust LOS expectations and promote efficient resource allocation. This exploratory study was limited to findings from one inpatient rehabilitation hospital. Cross-validation of results using data-sets from multiple rehabilitation hospitals across Ontario is recommended.

The impact of severe haemophilia and the presence of target joints on health-related quality-of-life.

PubMed

O'Hara, Jamie; Walsh, Shaun; Camp, Charlotte; Mazza, Giuseppe; Carroll, Liz; Hoxer, Christina; Wilkinson, Lars

2018-05-02

Joint damage remains a major complication associated with haemophilia and is widely accepted as one of the most debilitating symptoms for persons with severe haemophilia. The aim of this study is to describe how complications of haemophilia such as target joints influence health-related quality of life (HRQOL). Data on hemophilia patients without inhibitors were drawn from the 'Cost of Haemophilia across Europe - a Socioeconomic Survey' (CHESS) study, a cost-of-illness assessment in severe haemophilia A and B across five European countries (France, Germany, Italy, Spain, and the UK). Physicians provided clinical and sociodemographic information for 1285 adult patients, 551 of whom completed corresponding questionnaires, including EQ-5D. A generalised linear model was developed to investigate the relationship between EQ-5D index score and target joint status (defined in the CHESS study as areas of chronic synovitis), adjusted for patient covariates including socio-demographic characteristics and comorbidities. Five hundred and fifteen patients (42% of the sample) provided an EQ-5D response; a total of 692 target joints were recorded across the sample. Mean EQ-5D index score for patients with no target joints was 0.875 (standard deviation [SD] 0.179); for patients with one or more target joints, mean index score was 0.731 (SD 0.285). Compared to having no target joints, having one or more target joints was associated with lower index scores (average marginal effect (AME) -0.120; SD 0.0262; p < 0.000). This study found that the presence of chronic synovitis has a significant negative impact on HRQOL for adults with severe haemophilia. Prevention, early diagnosis and treatment of target joints should be an important consideration for clinicians and patients when managing haemophilia.

Multitarget tracking in cluttered environment for a multistatic passive radar system under the DAB/DVB network

NASA Astrophysics Data System (ADS)

Shi, Yi Fang; Park, Seung Hyo; Song, Taek Lyul

2017-12-01

The target tracking using multistatic passive radar in a digital audio/video broadcast (DAB/DVB) network with illuminators of opportunity faces two main challenges: the first challenge is that one has to solve the measurement-to-illuminator association ambiguity in addition to the conventional association ambiguity between the measurements and targets, which introduces a significantly complex three-dimensional (3-D) data association problem among the target-measurement illuminator, this is because all the illuminators transmit the same carrier frequency signals and signals transmitted by different illuminators but reflected via the same target become indistinguishable; the other challenge is that only the bistatic range and range-rate measurements are available while the angle information is unavailable or of very poor quality. In this paper, the authors propose a new target tracking algorithm directly in three-dimensional (3-D) Cartesian coordinates with the capability of track management using the probability of target existence as a track quality measure. The proposed algorithm is termed sequential processing-joint integrated probabilistic data association (SP-JIPDA), which applies the modified sequential processing technique to resolve the additional association ambiguity between measurements and illuminators. The SP-JIPDA algorithm sequentially operates the JIPDA tracker to update each track for each illuminator with all the measurements in the common measurement set at each time. For reasons of fair comparison, the existing modified joint probabilistic data association (MJPDA) algorithm that addresses the 3-D data association problem via "supertargets" using gate grouping and provides tracks directly in 3-D Cartesian coordinates, is enhanced by incorporating the probability of target existence as an effective track quality measure for track management. Both algorithms deal with nonlinear observations using the extended Kalman filtering. A simulation study is performed to verify the superiority of the proposed SP-JIPDA algorithm over the MJIPDA in this multistatic passive radar system.

The Role of Adherence on the Impact of a School-Based Water, Sanitation, and Hygiene Intervention in Mali

PubMed Central

Garn, Joshua V.; Trinies, Victoria; Toubkiss, Jérémie; Freeman, Matthew C.

2017-01-01

Studies assessing the impacts of school-based water, sanitation, and hygiene (WASH) interventions have revealed inconsistent improvements in pupils' health and educational outcomes. This may be in part due to suboptimal project fidelity or adherence. As part of a matched-control trial of a comprehensive school-based WASH project in Mali, we measured the degree to which schools met four prespecified WASH targets, comprised of 15 criteria, 0–3 years after program implementation. We compared achievement of the targets and criteria between beneficiary and matched control schools, and compared achievement within beneficiary schools at baseline and at follow-up visits. We assessed the “as-treated” associations between WASH target achievement and pupil diarrhea, respiratory symptoms, and absence. Between 44% and 81% of beneficiary schools achieved each target. Although adherence was inconsistent across schools, beneficiary schools, on average, met more WASH targets than matched control schools, and beneficiary schools also met more WASH targets at follow-up than at baseline. Very few of the targets were individually associated with health and absenteeism outcomes. Increasing achievement of multiple WASH targets together was associated with a lower odds of pupils having diarrhea (P trend < 0.01) and having respiratory symptoms (P trend < 0.01), but was not associated with roll-call absence (P trend = 0.14) or pupil-reported absence (P trend = 0.41). These results indicate that a comprehensive WASH intervention and a focus on increasing adherence may help maximize the health effects of school WASH programs, but that WASH alone might not be sufficient to decrease pupils' absenteeism. PMID:28093534

Task difficulty modulates brain activation in the emotional oddball task.

PubMed

Siciliano, Rachel E; Madden, David J; Tallman, Catherine W; Boylan, Maria A; Kirste, Imke; Monge, Zachary A; Packard, Lauren E; Potter, Guy G; Wang, Lihong

2017-06-01

Previous functional magnetic resonance imaging (fMRI) studies have reported that task-irrelevant, emotionally salient events can disrupt target discrimination, particularly when attentional demands are low, while others demonstrate alterations in the distracting effects of emotion in behavior and neural activation in the context of attention-demanding tasks. We used fMRI, in conjunction with an emotional oddball task, at different levels of target discrimination difficulty, to investigate the effects of emotional distractors on the detection of subsequent targets. In addition, we distinguished different behavioral components of target detection representing decisional, nondecisional, and response criterion processes. Results indicated that increasing target discrimination difficulty led to increased time required for both the decisional and nondecisional components of the detection response, as well as to increased target-related neural activation in frontoparietal regions. The emotional distractors were associated with activation in ventral occipital and frontal regions and dorsal frontal regions, but this activation was attenuated with increased difficulty. Emotional distraction did not alter the behavioral measures of target detection, but did lead to increased target-related frontoparietal activation for targets following emotional images as compared to those following neutral images. This latter effect varied with target discrimination difficulty, with an increased influence of the emotional distractors on subsequent target-related frontoparietal activation in the more difficult discrimination condition. This influence of emotional distraction was in addition associated specifically with the decisional component of target detection. These findings indicate that emotion-cognition interactions, in the emotional oddball task, vary depending on the difficulty of the target discrimination and the associated limitations on processing resources. Copyright © 2017 Elsevier B.V. All rights reserved.

MicroRNA-guided prioritization of genome-wide association signals reveals the importance of microRNA-target gene networks for complex traits in cattle.

PubMed

Fang, Lingzhao; Sørensen, Peter; Sahana, Goutam; Panitz, Frank; Su, Guosheng; Zhang, Shengli; Yu, Ying; Li, Bingjie; Ma, Li; Liu, George; Lund, Mogens Sandø; Thomsen, Bo

2018-06-19

MicroRNAs (miRNA) are key modulators of gene expression and so act as putative fine-tuners of complex phenotypes. Here, we hypothesized that causal variants of complex traits are enriched in miRNAs and miRNA-target networks. First, we conducted a genome-wide association study (GWAS) for seven functional and milk production traits using imputed sequence variants (13~15 million) and >10,000 animals from three dairy cattle breeds, i.e., Holstein (HOL), Nordic red cattle (RDC) and Jersey (JER). Second, we analyzed for enrichments of association signals in miRNAs and their miRNA-target networks. Our results demonstrated that genomic regions harboring miRNA genes were significantly (P < 0.05) enriched with GWAS signals for milk production traits and mastitis, and that enrichments within miRNA-target gene networks were significantly higher than in random gene-sets for the majority of traits. Furthermore, most between-trait and across-breed correlations of enrichments with miRNA-target networks were significantly greater than with random gene-sets, suggesting pleiotropic effects of miRNAs. Intriguingly, genes that were differentially expressed in response to mammary gland infections were significantly enriched in the miRNA-target networks associated with mastitis. All these findings were consistent across three breeds. Collectively, our observations demonstrate the importance of miRNAs and their targets for the expression of complex traits.

Disclosure of HIV-positive status to Latino gay men's social networks.

PubMed

Zea, María Cecilia; Reisen, Carol A; Poppen, Paul J; Echeverry, John J; Bianchi, Fernanda T

2004-03-01

This study explored disclosure of serostatus in a sample of 155 HIV-positive Latino gay men from New York City and Washington, DC. We examined rates of disclosure to different members of the social network: mothers, fathers, close friends, and primary sexual partners. There were high rates of disclosure of HIV-positive serostatus to main partners and closest friends and lower rates to fathers and mothers. We examined the role of 3 contextual target-dependent factors (emotional closeness to target, anticipated reactions from target, and target's knowledge of sexual orientation), as well as acculturation and time since diagnosis. Three separate logistic regression models were performed to predict disclosure of HIV-positive status to 3 targets: mothers, fathers, and closest friends. We found that disclosure was not a generalized tendency, but rather different factors were influential depending on the target. Whether the target was aware of participant's sexual orientation was associated with disclosure in all 3 models. Greater emotional closeness also predicted disclosure to mother and father; greater U.S. acculturation was associated with disclosure to father and marginally to mother. A longer time since diagnosis was associated with disclosure to the closest friend. These findings highlight the importance of taking into account roles and relationships, and their effect on disclosure.

Who breaches the four-hour emergency department wait time target? A retrospective analysis of 374,000 emergency department attendances between 2008 and 2013 at a type 1 emergency department in England.

PubMed

Bobrovitz, Niklas; Lasserson, Daniel S; Briggs, Adam D M

2017-11-02

The four-hour target is a key hospital emergency department performance indicator in England and one that drives the physical and organisational design of the ED. Some studies have identified time of presentation as a key factor affecting waiting times. Few studies have investigated other determinants of breaching the four-hour target. Therefore, our objective was to describe patterns of emergency department breaches of the four-hour wait time target and identify patients at highest risk of breaching. This was a retrospective cohort study of a large type 1 Emergency department at an NHS teaching hospital in Oxford, England. We analysed anonymised individual level patient data for 378,873 emergency department attendances, representing all attendances between April 2008 and April 2013. We examined patient characteristics and emergency department presentation circumstances associated with the highest likelihood of breaching the four-hour wait time target. We used 374,459 complete cases for analysis. In total, 8.3% of all patients breached the four-hour wait time target. The main determinants of patients breaching the four-hour wait time target were hour of arrival to the ED, day of the week, patient age, ED referral source, and the types of investigations patients receive (p < 0.01 for all associations). Patients most likely to breach the four-hour target were older, presented at night, presented on Monday, received multiple types of investigation in the emergency department, and were not self-referred (p < 0.01 for all associations). Patients attending from October to February had a higher odds of breaching compared to those attending from March to September (OR 1.63, 95% CI 1.59 to 1.66). There are a number of independent patient and circumstantial factors associated with the probability of breaching the four-hour ED wait time target including patient age, ED referral source, the types of investigations patients receive, as well as the hour, day, and month of arrival to the ED. Efforts to reduce the number of breaches could explore late-evening/overnight staffing, access to diagnostic tests, rapid discharge facilities, and early assessment and input on diagnostic and management strategies from a senior practitioner.

Task-irrelevant spider associations affect categorization performance.

PubMed

Woud, Marcella L; Ellwart, Thomas; Langner, Oliver; Rinck, Mike; Becker, Eni S

2011-09-01

In two studies, the Single Target Implicit Association Test (STIAT) was used to investigate automatic associations toward spiders. In both experiments, we measured the strength of associations between pictures of spiders and either threat-related words or pleasant words. Unlike previous studies, we administered a STIAT version in which stimulus contents was task-irrelevant: The target spider pictures were categorized according to the label picture, irrespective of what they showed. In Study 1, spider-fearful individuals versus non-fearful controls were tested, Study 2 compared spider enthusiasts to non-fearful controls. Results revealed that the novel STIAT version was sensitive to group differences in automatic associations toward spiders. In Study 1, it successfully distinguished between spider-fearful individuals and non-fearful controls. Moreover, STIAT scores predicted automatic fear responses best, whereas controlled avoidance behavior was best predicted by the FAS (German translation of the Fear of Spiders Questionnaire). The results of Study 2 demonstrated that the novel STIAT version was also able to differentiate between spider enthusiasts and non-fearful controls. Copyright © 2010 Elsevier Ltd. All rights reserved.

Reward modulation of contextual cueing: Repeated context overshadows repeated target location.

PubMed

Sharifian, Fariba; Contier, Oliver; Preuschhof, Claudia; Pollmann, Stefan

2017-10-01

Contextual cueing can be enhanced by reward. However, there is a debate if reward is associated with the repeated target-distractor configurations or with the repeated target locations that occur in both repeated and new displays. Based on neuroimaging evidence, we hypothesized that reward becomes associated with the target location only in new displays, but not in repeated displays, where the repeated target location is overshadowed by the more salient repeated target-distractor configuration. To test this hypothesis, we varied the reward value associated with the same target location in repeated and new displays. The results confirmed the overshadowing hypothesis in that search facilitation in repeated target-distractor configurations was modulated by the variable value associated with the target location. This effect was observed mainly in early learning.

Surface functionality affects the biodistribution and microglia-targeting of intra-amniotically delivered dendrimers.

PubMed

Zhang, Fan; Nance, Elizabeth; Zhang, Zhi; Jasty, Venkatasai; Kambhampati, Siva P; Mishra, Manoj K; Burd, Irina; Romero, Roberto; Kannan, Sujatha; Kannan, Rangaramanujam M

2016-09-10

Cerebral Palsy (CP) is a chronic childhood disorder with limited therapeutic options. Maternal intrauterine inflammation/infection is a major risk factor in the pathogenesis of CP. In pre-clinical models, dendrimer-based therapies are viable in postnatal period, attenuating inflammation and improving motor function in vivo. However, treatment to the mother, in the prenatal period, may provide the possibility of preventing/resolving inflammation at early stages. Towards this goal, we used a maternal intrauterine inflammation-induced rabbit model of CP to study fetal-maternal transport and neuroinflammation targeting of intra-amniotically administrated dendrimers with neutral/anionic surface functionality. Our study suggested both hydroxyl-terminated 'neutral' (D-OH) and carboxyl-terminated 'anionic' (D-COOH) Polyamidoamine (PAMAM) dendrimers were absorbed by fetuses and demonstrated bi-directional transport between fetuses and mother. D-OH was more effective in crossing the fetal blood-brain barrier, and targeting activated microglia. The cell-specific targeting was associated with the extent of microglia activation. This study demonstrated intra-amniotically administered hydroxyl PAMAM dendrimers could be an effective drug delivery vehicle for targeting fetal inflammation and preventing subsequent neurologic injury associated with chorioamnionitis. Copyright © 2016 Elsevier B.V. All rights reserved.

Surface functionality affects the biodistribution and microglia-targeting of intra-amniotically delivered dendrimers☆

PubMed Central

Zhang, Fan; Nance, Elizabeth; Zhang, Zhi; Jasty, Venkatasai; Kambhampati, Siva P.; Mishra, Manoj K.; Burd, Irina; Romero, Roberto; Kannan, Sujatha; Kannan, Rangaramanujam M.

2017-01-01

Cerebral Palsy (CP) is a chronic childhood disorder with limited therapeutic options. Maternal intrauterine inflammation/infection is a major risk factor in the pathogenesis of CP. In pre-clinical models, dendrimer-based therapies are viable in postnatal period, attenuating inflammation and improving motor function in vivo. However, treatment to the mother, in the prenatal period, may provide the possibility of preventing/resolving inflammation at early stages. Towards this goal, we used a maternal intrauterine inflammation-induced rabbit model of CP to study fetal-maternal transport and neuroinflammation targeting of intra-amniotically administrated dendrimers with neutral/anionic surface functionality. Our study suggested both hydroxyl-terminated ‘neutral’ (D-OH) and carboxyl-terminated ‘anionic’ (D-COOH) Polyamidoamine (PAMAM) dendrimers were absorbed by fetuses and demonstrated bi-directional transport between fetuses and mother. D-OH was more effective in crossing the fetal blood-brain barrier, and targeting activated microglia. The cell-specific targeting was associated with the extent of microglia activation. This study demonstrated intra-amniotically administered hydroxyl PAMAM dendrimers could be an effective drug delivery vehicle for targeting fetal inflammation and preventing subsequent neurologic injury associated with chorioamnionitis. PMID:27378700

Investigation of Experimental Factors That Underlie BRCA1/2 mRNA Isoform Expression Variation: Recommendations for Utilizing Targeted RNA Sequencing to Evaluate Potential Spliceogenic Variants

PubMed Central

Lattimore, Vanessa L.; Pearson, John F.; Currie, Margaret J.; Spurdle, Amanda B.; Robinson, Bridget A.; Walker, Logan C.

2018-01-01

PCR-based RNA splicing assays are commonly used in diagnostic and research settings to assess the potential effects of variants of uncertain clinical significance in BRCA1 and BRCA2. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium completed a multicentre investigation to evaluate differences in assay design and the integrity of published data, raising a number of methodological questions associated with cell culture conditions and PCR-based protocols. We utilized targeted RNA-seq to re-assess BRCA1 and BRCA2 mRNA isoform expression patterns in lymphoblastoid cell lines (LCLs) previously used in the multicentre ENIGMA study. Capture of the targeted cDNA sequences was carried out using 34 BRCA1 and 28 BRCA2 oligonucleotides from the Illumina Truseq Targeted RNA Expression platform. Our results show that targeted RNA-seq analysis of LCLs overcomes many of the methodology limitations associated with PCR-based assays leading us to make the following observations and recommendations: (1) technical replicates (n > 2) of variant carriers to capture methodology induced variability associated with RNA-seq assays, (2) LCLs can undergo multiple freeze/thaw cycles and can be cultured up to 2 weeks without noticeably influencing isoform expression levels, (3) nonsense-mediated decay inhibitors are essential prior to splicing assays for comprehensive mRNA isoform detection, (4) quantitative assessment of exon:exon junction levels across BRCA1 and BRCA2 can help distinguish between normal and aberrant isoform expression patterns. Experimentally derived recommendations from this study will facilitate the application of targeted RNA-seq platforms for the quantitation of BRCA1 and BRCA2 mRNA aberrations associated with sequence variants of uncertain clinical significance. PMID:29774201

Investigation of Experimental Factors That Underlie BRCA1/2 mRNA Isoform Expression Variation: Recommendations for Utilizing Targeted RNA Sequencing to Evaluate Potential Spliceogenic Variants.

PubMed

Lattimore, Vanessa L; Pearson, John F; Currie, Margaret J; Spurdle, Amanda B; Robinson, Bridget A; Walker, Logan C

2018-01-01

PCR-based RNA splicing assays are commonly used in diagnostic and research settings to assess the potential effects of variants of uncertain clinical significance in BRCA1 and BRCA2 . The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium completed a multicentre investigation to evaluate differences in assay design and the integrity of published data, raising a number of methodological questions associated with cell culture conditions and PCR-based protocols. We utilized targeted RNA-seq to re-assess BRCA1 and BRCA2 mRNA isoform expression patterns in lymphoblastoid cell lines (LCLs) previously used in the multicentre ENIGMA study. Capture of the targeted cDNA sequences was carried out using 34 BRCA1 and 28 BRCA2 oligonucleotides from the Illumina Truseq Targeted RNA Expression platform. Our results show that targeted RNA-seq analysis of LCLs overcomes many of the methodology limitations associated with PCR-based assays leading us to make the following observations and recommendations: (1) technical replicates ( n  > 2) of variant carriers to capture methodology induced variability associated with RNA-seq assays, (2) LCLs can undergo multiple freeze/thaw cycles and can be cultured up to 2 weeks without noticeably influencing isoform expression levels, (3) nonsense-mediated decay inhibitors are essential prior to splicing assays for comprehensive mRNA isoform detection, (4) quantitative assessment of exon:exon junction levels across BRCA1 and BRCA2 can help distinguish between normal and aberrant isoform expression patterns. Experimentally derived recommendations from this study will facilitate the application of targeted RNA-seq platforms for the quantitation of BRCA1 and BRCA2 mRNA aberrations associated with sequence variants of uncertain clinical significance.

RNA interference therapy: a new solution for intracranial atherosclerosis?

PubMed Central

Tang, Tao; Wong, Ka-Sing

2014-01-01

Intracranial atherosclerotic stenosis (ICAS) of a major intracranial artery, especially middle cerebral artery (MCA), is reported to be one leading cause of ischemic stroke throughout the world. Compared with other stroke subtypes, ICAS is associated with a higher risk of recurrent stroke despite aggressive medical therapy. Increased understanding of the pathophysiology of ICAS has highlighted several possible targets for therapeutic interventions. Both luminal stenosis and plaque components of ICAS have been found to be associated with ischemic stroke based a post-mortem study. Recent application of high-resolution magnetic resonance imaging (HRMRI) in evaluating ICAS provides new insight into the vascular biology of plaque morphology and component. High signal on T1-weighted fat-suppressed images (HST1) within MCA plaque of HRMRI, highly suggested of fresh or recent intraplaque hemorrhage, has been found to be associated with ipsilateral brain infarction. Thus, the higher prevalence of intraplaque hemorrhage and neovasculature in symptomatic patients with MCA stenosis may provide a potential target for plaque stabilization. We hypothesize that RNA interference (RNAi) therapy delivered by modified nanoparticles may achieve in vivo biomedical imaging and targeted therapy. With the rapid developments in studies about therapeutic and diagnostic nanomaterials, future studies further exploring the molecular biology of atherosclerosis may provide more drug targets for plaque stabilization. PMID:25333054

Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia.

PubMed

de Jong, Simone; Vidler, Lewis R; Mokrab, Younes; Collier, David A; Breen, Gerome

2016-08-01

Genome-wide association studies (GWAS) have identified thousands of novel genetic associations for complex genetic disorders, leading to the identification of potential pharmacological targets for novel drug development. In schizophrenia, 108 conservatively defined loci that meet genome-wide significance have been identified and hundreds of additional sub-threshold associations harbour information on the genetic aetiology of the disorder. In the present study, we used gene-set analysis based on the known binding targets of chemical compounds to identify the 'drug pathways' most strongly associated with schizophrenia-associated genes, with the aim of identifying potential drug repositioning opportunities and clues for novel treatment paradigms, especially in multi-target drug development. We compiled 9389 gene sets (2496 with unique gene content) and interrogated gene-based p-values from the PGC2-SCZ analysis. Although no single drug exceeded experiment wide significance (corrected p<0.05), highly ranked gene-sets reaching suggestive significance including the dopamine receptor antagonists metoclopramide and trifluoperazine and the tyrosine kinase inhibitor neratinib. This is a proof of principle analysis showing the potential utility of GWAS data of schizophrenia for the direct identification of candidate drugs and molecules that show polypharmacy. © The Author(s) 2016.

What Would You Ideally Do if There Were No Targets? An Ethnographic Study of the Unintended Consequences of Top-Down Governance in Two Clinical Settings

ERIC Educational Resources Information Center

Allard, Jon; Bleakley, Alan

2016-01-01

Top-down policy directives, such as targets and their associated protocols, may be driven politically rather than clinically and can be described as macro-political texts. While targets supposedly provide incentives for healthcare services, they may unintentionally shape practices of accommodation rather than implementation, deflecting…

Constitutional Flavonoids Derived from Epimedium Dose-Dependently Reduce Incidence of Steroid-Associated Osteonecrosis Not via Direct Action by Themselves on Potential Cellular Targets

PubMed Central

Xie, Xin-Hui; He, Yi-Xin; Yao, Xin-Sheng; Li, Zi-Rong; Lee, Kwong-Man; He, Wei; Leung, Kwok-Sui; Qin, Ling

2009-01-01

Intravascular-thrombosis and extravascular-lipid-deposit are the two key pathogenic events considered to interrupt intraosseous blood supply during development of steroid-associated osteonecrosis (ON). However, there are no clinically employed agents capable of simultaneously targeting these two key pathogenic events. The present experimental study demonstrated that constitutional flavonoid glycosides derived from herb Epimedium (EF, composed of seven flavonoid compounds with common stem nuclear) exerted dose-dependent effect on inhibition of both thrombosis and lipid-deposition and accordingly reducing incidence of steroid-associated ON in rabbits, which was not via direct action by themselves rather by their common metabolite on potential cellular targets involved in the two pathogenic pathways. The underlying mechanism could be explained by counteracting endothelium injury and excessive adipogenesis. These findings encourage designing clinical trials to investigate potential of EF in prevention of steroid-associated ON. PMID:19641620

Biological nitric oxide signalling: chemistry and terminology

PubMed Central

Heinrich, Tassiele A; da Silva, Roberto S; Miranda, Katrina M; Switzer, Christopher H; Wink, David A; Fukuto, Jon M

2013-01-01

Biological nitrogen oxide signalling and stress is an area of extreme clinical, pharmacological, toxicological, biochemical and chemical research interest. The utility of nitric oxide and derived species as signalling agents is due to their novel and vast chemical interactions with a variety of biological targets. Herein, the chemistry associated with the interaction of the biologically relevant nitrogen oxide species with fundamental biochemical targets is discussed. Specifically, the chemical interactions of nitrogen oxides with nucleophiles (e.g. thiols), metals (e.g. hemeproteins) and paramagnetic species (e.g. dioxygen and superoxide) are addressed. Importantly, the terms associated with the mechanisms by which NO (and derived species) react with their respective biological targets have been defined by numerous past chemical studies. Thus, in order to assist researchers in referring to chemical processes associated with nitrogen oxide biology, the vernacular associated with these chemical interactions is addressed. PMID:23617570

Pushing typists back on the learning curve: contributions of multiple linguistic units in the acquisition of typing skill.

PubMed

Yamaguchi, Motonori; Logan, Gordon D

2014-11-01

The present study investigated the way people acquire and control skilled performance in the context of typewriting. Typing skill was degraded by changing the location of a key (target key) while retaining the locations of other keys to disable an association between the letter and the key. We conducted 4 experiments: Experiment 1 demonstrated that disabling a letter-key association affected not only the execution of the target keystroke but also the planning of other keystrokes for words involving the target key. In Experiments 2-4, typists practiced with a new target location and then transferred to a condition in which they typed the practiced words with the original key location (Experiment 2) or typed new words with the practiced key location (Experiments 3 and 4). Experiment 2 showed that the newly acquired letter-key association interfered with the execution of the original keystroke but not planning. Experiments 3 and 4 demonstrated that acquisition of the new letter-key association depended on multiple levels of linguistic units. Experiment 4 demonstrated that acquisition of the new association depended on sequences both before and after the target keystroke. We discuss implications of the results for 2 prominent approaches to modeling sequential behavior: hierarchical control and recurrent network models. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Cost-effectiveness of first trimester non-invasive fetal RHD screening for targeted antenatal anti-D prophylaxis in RhD-negative pregnant women: a model-based analysis.

PubMed

Neovius, M; Tiblad, E; Westgren, M; Kublickas, M; Neovius, K; Wikman, A

2016-07-01

To estimate the cost-effectiveness of first trimester non-invasive fetal RHD screening for targeted antenatal versus no routine antenatal anti-D prophylaxis (RAADP) or versus non-targeted RAADP. Model based on a population-based cohort study. The Swedish health service. Intervention subjects in the underlying cohort study were RhD-negative pregnant women receiving first trimester fetal RHD screening followed by targeted anti-D in 2010-2011 (n = 6723). Historical comparators were RhD-negative women who delivered in 2008-2009 when standard care did not include RAADP (n = 7099). Healthcare costs for the three strategies were included for the first and subsequent pregnancies. For the comparison with non-targeted RAADP, the immunisation rate was based on the observed rate for targeted therapy and adjusted downwards by removing the influence of false negatives. Additional cost per RhD immunisation averted. Compared with RAADP, targeted prophylaxis was associated with fewer immunisations (0.19 versus 0.46% per pregnancy) and lower costs (cost-savings of €32 per RhD-negative woman). The savings were from lower costs during pregnancy and delivery, and lower costs of future pregnancies through fewer immunisations. Non-targeted anti-D was estimated to result in 0.06% fewer immunisations and an additional €16 in cost-savings per mother, compared with targeted anti-D. Based on effect data from a population-based cohort study, targeted prophylaxis was associated with lower immunisation risk and costs versus no RAADP. Based on effect data from theoretical calculations, non-targeted RAADP was predicted to result in lower costs and immunisation risk compared with targeted prophylaxis. Fetal RHD screening and targeted prophylaxis resulted in lower immunisation risk and costs compared with no RAADP. © 2015 Royal College of Obstetricians and Gynaecologists.

Using attribute amnesia to test the limits of hyper-binding and associative deficits in working memory.

PubMed

McCormick-Huhn, John M; Chen, Hui; Wyble, Bradley P; Dennis, Nancy A

2018-02-01

Previous work has shown mixed evidence regarding age-related deficits for binding in working memory. The current study used the newly developed attribute amnesia effect (H. Chen & Wyble, 2015a) to test the associative-deficit hypothesis during working memory and to probe whether hyper-binding extends to include binding of de-selected information. In studies of attribute amnesia, participants use target attributes (e.g., identity, color) to demonstrate near ceiling levels of reporting of a second target attribute (e.g., location) across a series of trials (H. Chen & Wyble, 2015a, 2016). Yet, despite having just processed the target-defining attribute, they have difficulty reporting it on a surprise trial. This effect provides several predictions for associative binding in aging. The associative-deficit hypothesis predicts age-related decline on the surprise trial, whereas an extension of hyper-binding predicts age-related increase in performance in older adults. In Experiment 1, when working memory load was low, older adults demonstrated attribute amnesia equal to that found in younger adults. When load increased in Experiment 2, older adults again demonstrated attribute amnesia as well as an age deficit for reporting target attributes. In lieu of spontaneous binding, results suggest that expectancy plays a critical role in older adults' propensity to encode and bind target attributes in working memory. Results further suggest that expectancy alone is not enough for older adults to form bound representations when task demands are high. Taken together results revealed a boundary condition of hyper-binding and further provided conditional support for the associative-deficit hypothesis in working memory. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Impact of time to return of spontaneous circulation on neuroprotective effect of targeted temperature management at 33 or 36 degrees in comatose survivors of out-of hospital cardiac arrest.

PubMed

Kjaergaard, Jesper; Nielsen, Niklas; Winther-Jensen, Matilde; Wanscher, Michael; Pellis, Tommaso; Kuiper, Michael; Hartvig Thomsen, Jakob; Wetterslev, Jørn; Cronberg, Tobias; Bro-Jeppesen, John; Erlinge, David; Friberg, Hans; Søholm, Helle; Gasche, Yvan; Horn, Janneke; Hovdenes, Jan; Stammet, Pascal; Wise, Matthew P; Åneman, Anders; Hassager, Christian

2015-11-01

Time to Return of Spontaneous Circulation (ROSC) has a plausible relation to severity of hypoxic injury before and during resuscitation in Out-of-Hospital Cardiac Arrest (OHCA), and has consistently been associated with adverse outcome. The effect of Targeted Temperature Management (TTM) may not be similar over the full spectrum of time to ROSC. This study investigated the possible beneficial effect of targeting 33°C over 36°C on the prognostic importance of time to ROSC. In predefined sub-study of the TTM-trial (NEJM 2013) we investigated the relationship between time to ROSC, level of TTM and mortality and neurological outcome as assessed by the Cerebral Performance Category (CPC) scale and modified Rankin Scale (mRS) after 180 days. Prolonged time to ROSC was significantly associated with increased mortality with a hazard ratio (HR) of 1.02 per minute (95% CI 1.01-1.02). Level of TTM did not modify the association of time to ROSC and mortality, pinteraction=0.85. Prolonged time to ROSC was associated with reduced odds of surviving with a favorable neurological outcome for CPC (p=0.008 for CPC 1-2) and mRS (p=0.17, mRS 0-3) with no significant interaction with level of TTM. Time to ROSC remains a significant prognostic factor in comatose OHCA patients with regards to risk of death and risk of adverse neurological outcome. For any time to ROSC, targeting 33°C in TTM was not associated with benefit with regards to reducing mortality or risk of adverse neurological outcome compared to targeting 36°C. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Associations of general parenting and parent-child relationship with pediatric obesity: a meta-analysis.

PubMed

Pinquart, Martin

2014-05-01

The objective of the meta-analysis is to integrate available results on associations of general parenting (not specific to feeding and activity promotion) and parent-child relations with child weight status, eating, and physical activity. Searching in electronic databases and cross-referencing identified 156 empirical studies. Random-effects meta-analysis was computed. A positive parent-child relationship and higher levels of parental responsiveness were associated with lower weight, healthier eating, and more physical activity of the child. Parental demandingness, overprotection, psychological control, inconsistency, and parenting styles showed associations with some of the assessed outcome variables. Most effect sizes were small and varied by study characteristics. The small effects do not support making general parenting styles, parental demandingness, responsiveness, and the quality of the parent-child relationship a main target of preventing and treating obesity. Reducing parental inconsistency may be a better target if available results are replicated in future studies.

Impact of US and Canadian precursor regulation on methamphetamine purity in the United States.

PubMed

Cunningham, James K; Liu, Lon-Mu; Callaghan, Russell

2009-03-01

Reducing drug purity is a major, but largely unstudied, goal of drug suppression. This study examines whether US methamphetamine purity was impacted by the suppression policy of US and Canadian precursor chemical regulation. Autoregressive integrated moving average (ARIMA)-intervention time-series analysis. Continental United States and Hawaii (1985-May 2005). Interventions US federal regulations targeting precursors, ephedrine and pseudoephedrine, in forms used by large-scale producers were implemented in November 1989, August 1995 and October 1997. US regulations targeting precursors in forms used by small-scale producers (e.g. over-the-counter medications) were implemented in October 1996 and October 2001. Canada implemented federal precursor regulations in January 2003 and July 2003 and an essential chemical (e.g. acetone) regulation in January 2004. Monthly median methamphetamine purity series. US regulations targeting large-scale producers were associated with purity declines of 16-67 points; those targeting small-scale producers had little or no impact. Canada's precursor regulations were associated with purity increases of 13-15 points, while its essential chemical regulation was associated with a 13-point decrease. Hawaii's purity was consistently high, and appeared to vary little with the 1990s/2000s regulations. US precursor regulations targeting large-scale producers were associated with substantial decreases in continental US methamphetamine purity, while regulations targeting over-the-counter medications had little or no impact. Canada's essential chemical regulation was also associated with a decrease in continental US purity. However, Canada's precursor regulations were associated with purity increases: these regulations may have impacted primarily producers of lower-quality methamphetamine, leaving higher-purity methamphetamine on the market by default. Hawaii's well-known preference for 'ice' (high-purity methamphetamine) may have helped to constrain purity there to a high, attenuated range, possibly limiting its sensitivity to precursor regulation.

Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells.

PubMed

Kitchen, Mark O; Yacqub-Usman, Kiren; Emes, Richard D; Richardson, Alan; Clayton, Richard N; Farrell, William E

2015-10-01

Transgenic mice overexpressing the high mobility group A (HMGA) genes, Hmga1 or Hmga2 develop pituitary tumours and their overexpression is also a frequent finding in human pituitary adenomas. In some cases, increased expression of HMGA2 but not that of HMGA1 is consequent to genetic perturbations. However, recent studies show that down-regulation of microRNA (miRNA), that contemporaneously target the HMGA1 and HMGA2 transcripts, are associated with their overexpression. In a cohort of primary pituitary adenoma we determine the impact of epigenetic modifications on the expression of HMGA-targeting miRNA. For these miRNAs, chromatin immunoprecipitations showed that transcript down-regulation is correlated with histone tail modifications associated with condensed silenced genes. The functional impact of epigenetic modification on miRNA expression was determined in the rodent pituitary cell line, GH3. In these cells, histone tail, miRNA-associated, modifications were similar to those apparent in human adenoma and likely account for their repression. Indeed, challenge of GH3 cells with the epidrugs, zebularine and TSA, led to enrichment of the histone modification, H3K9Ac, associated with active genes, and depletion of the modification, H3K27me3, associated with silent genes and re-expression of HMGA-targeting miRNA. Moreover, epidrugs challenges were also associated with a concomitant decrease in hmga1 transcript and protein levels and concurrent increase in bmp-4 expression. These findings show that the inverse relationship between HMGA expression and targeting miRNA is reversible through epidrug interventions. In addition to showing a mechanistic link between epigenetic modifications and miRNA expression these findings underscore their potential as therapeutic targets in this and other diseases.

A novel approach for predicting microRNA-disease associations by unbalanced bi-random walk on heterogeneous network.

PubMed

Luo, Jiawei; Xiao, Qiu

2017-02-01

MicroRNAs (miRNAs) play a critical role by regulating their targets in post-transcriptional level. Identification of potential miRNA-disease associations will aid in deciphering the pathogenesis of human polygenic diseases. Several computational models have been developed to uncover novel miRNA-disease associations based on the predicted target genes. However, due to the insufficient number of experimentally validated miRNA-target interactions as well as the relatively high false-positive and false-negative rates of predicted target genes, it is still challenging for these prediction models to obtain remarkable performances. The purpose of this study is to prioritize miRNA candidates for diseases. We first construct a heterogeneous network, which consists of a disease similarity network, a miRNA functional similarity network and a known miRNA-disease association network. Then, an unbalanced bi-random walk-based algorithm on the heterogeneous network (BRWH) is adopted to discover potential associations by exploiting bipartite subgraphs. Based on 5-fold cross validation, the proposed network-based method achieves AUC values ranging from 0.782 to 0.907 for the 22 human diseases and an average AUC of almost 0.846. The experiments indicated that BRWH can achieve better performances compared with several popular methods. In addition, case studies of some common diseases further demonstrated the superior performance of our proposed method on prioritizing disease-related miRNA candidates. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of Multifactorial Treatment Targets and Relative Importance of Hemoglobin A1c, Blood Pressure, and Low-Density Lipoprotein-Cholesterol on Cardiovascular Diseases in Chinese Primary Care Patients With Type 2 Diabetes Mellitus: A Population-Based Retrospective Cohort Study.

PubMed

Wan, Eric Yuk Fai; Fung, Colman Siu Cheung; Yu, Esther Yee Tak; Chin, Weng Yee; Fong, Daniel Yee Tak; Chan, Anca Ka Chun; Lam, Cindy Lo Kuen

2017-08-17

The relative effect of hemoglobin A1c, blood pressure, and low-density lipoprotein-cholesterol (LDL-C) ("ABC" factors) on the prevention of cardiovascular diseases (CVD) among patients with type 2 diabetes mellitus is poorly understood. This study aimed to evaluate the association of key clinical parameters on CVD risk using a multifactorial optimal control approach in Chinese primary care patients with type 2 diabetes mellitus. A population-based retrospective cohort study was conducted on 144 271 Chinese type 2 diabetes mellitus primary care patients, aged 18 to 79 and without prior clinical diagnosis of CVD in 2008-2011. Cox regressions were conducted to examine the association between the combinations of ABC targets (hemoglobin A1c <7%, blood pressure <130/90 mm Hg, and LDL-C <2.6 mmol/L) and risks of CVD (overall), coronary heart disease, stroke, and heart failure. Achieving more ABC targets incrementally reduced the incidence of total CVD and individual disease including coronary heart disease, stroke, and heart failure, irrespective of other patient characteristics. Compared with suboptimal control in all ABC levels, achieving any 1, 2, and all 3 ABC targets reduced the relative risk of CVD by 13% to 42%, 31% to 52%, and 55%, respectively. Among those achieving only 1 ABC target, LDL-C reduction was associated with the greatest CVD risk reduction (42%), followed by blood pressure reduction (18%), and hemoglobin A1c reduction (13%). To achieve the greatest risk reduction for the incidence of CVD, the ultimate goal of treatment should be to achieve target control of hemoglobin A1c, blood pressure, and LDL-C. If it is not possible to achieve all 3 targets, efforts should be prioritized on treating the LDL-C to minimize CVD risk. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

State Policies Targeting Junk Food in Schools: Racial/Ethnic Differences in the Effect of Policy Change on Soda Consumption

PubMed Central

Stevens, June; Evenson, Kelly R.; Ward, Dianne S.; Poole, Charles; Maciejewski, Matthew L.; Murray, David M.; Brownson, Ross C.

2011-01-01

Objectives. We estimated the association between state policy changes and adolescent soda consumption and body mass index (BMI) percentile, overall and by race/ethnicity. Methods. We obtained data on whether states required or recommended that schools prohibit junk food in vending machines, snack bars, concession stands, and parties from the 2000 and 2006 School Health Policies and Programs Study. We used linear mixed models to estimate the association between 2000–2006 policy changes and 2007 soda consumption and BMI percentile, as reported by 90 730 students in 33 states and the District of Columbia in the Youth Risk Behavior Survey, and to test for racial/ethnic differences in the associations. Results. Policy changes targeting concession stands were associated with 0.09 fewer servings of soda per day among students (95% confidence interval [CI] = −0.17, −0.01); the association was more pronounced among non-Hispanic Blacks (0.19 fewer servings per day). Policy changes targeting parties were associated with 0.07 fewer servings per day (95% CI = −0.13, 0.00). Policy changes were not associated with BMI percentile in any group. Conclusions. State policies targeting junk food in schools may reduce racial/ethnic disparities in adolescent soda consumption, but their impact appears to be too weak to reduce adolescent BMI percentile. PMID:21778484

HSPA5 is an essential host factor for Ebola virus infection.

PubMed

Reid, St Patrick; Shurtleff, Amy C; Costantino, Julie A; Tritsch, Sarah R; Retterer, Cary; Spurgers, Kevin B; Bavari, Sina

2014-09-01

Development of novel strategies targeting the highly virulent ebolaviruses is urgently required. A proteomic study identified the ER chaperone HSPA5 as an ebolavirus-associated host protein. Here, we show using the HSPA5 inhibitor (-)- epigallocatechin gallate (EGCG) that the chaperone is essential for virus infection, thereby demonstrating a functional significance for the association. Furthermore, in vitro and in vivo gene targeting impaired viral replication and protected animals in a lethal infection model. These findings demonstrate that HSPA5 is vital for replication and can serve as a viable target for the design of host-based countermeasures. Published by Elsevier B.V.

Examination of the Specificity of Tumor Cell Derived Exosomes with Tumor Cells In Vitro

PubMed Central

Smyth, Tyson J.; Redzic, Jasmina S.; Graner, Michael W.; Anchordoquy, Thomas J.

2016-01-01

Small endogenous vesicles called exosomes are beginning to be explored as drug delivery vehicles. The in vivo targets of exosomes are poorly understood; however, they are believed to be important in cell-to-cell communication and may play a prominent role in cancer metastasis. We aimed to elucidate whether cancer derived exosomes can be used as drug delivery vehicles that innately target tumors over normal tissue. Our in vitro results suggest that while there is some specificity towards cancer cells over “immortalized” cells, it is unclear if the difference is sufficient to achieve precise in vivo targeting. Additionally, we found that exosomes associate with their cellular targets to a significantly greater extent (> 10-fold) than liposomes of a similar size. Studies on the association of liposomes mimicking the unique lipid content of exosomes revealed that the lipid composition contributes significantly to cellular adherence/internalization. Cleavage of exosome surface proteins yielded exosomes exhibiting reduced association with their cellular targets, demonstrating the importance of proteins in binding/internalization. Furthermore, although acidic conditions are known to augment the metastatic potential of tumors, we found that cells cultured at low pH released exosomes with significantly less potential for cellular association than cells cultured at physiological pH. PMID:25102470

Racial/Ethnic Differences in Knowledge of Personal and Target Levels of Cardiovascular Health Indicators.

PubMed

Ma, Mindy; Ma, Alyson

2015-10-01

This study aimed to examine ethnic differences in knowledge of personal and target levels of cardiovascular health indicators between non-Hispanic whites and African Americans. A secondary objective was to evaluate the associations between knowledge of cardiovascular health indicators and health promotion behaviors. Participants (66.7% female) consisted of 265 whites and 428 African Americans, ages 18 and older recruited from primary care clinics and churches. Respondents completed a brief survey on blood pressure (BP), total cholesterol, blood glucose, body mass index (BMI), diet, and physical activity. Whites were more likely than African Americans to report knowing their personal and target levels of cardiovascular health indicators. Knowledge of personal BP and/or BMI was positively associated with actual physical activity, and awareness of personal blood glucose was positively associated with healthy dietary practices for participants in both groups. Among whites, awareness of personal BP and knowledge of target levels for BP, total cholesterol, and BMI were also associated with healthy diet. Results suggest there are racial/ethnic disparities in knowledge of personal and ideal levels of cardiovascular health indicators, and that this knowledge is related to health promotion behaviors. Targeted educational efforts are warranted to enhance knowledge of personal risk indicators among African Americans.

Cohort Study of the Success of Controlled Weight Loss Programs for Obese Dogs.

PubMed

German, A J; Titcomb, J M; Holden, S L; Queau, Y; Morris, P J; Biourge, V

2015-01-01

Most weight loss studies in obese dogs assess rate and percentage of weight loss in the first 2-3 months, rather than the likelihood of successfully reaching target weight. To determine outcome of controlled weight loss programs for obese dogs, and to determine the factors associated with successful completion. 143 obese dogs undergoing a controlled weight loss program. This was a cohort study of obese dogs attending a referral weight management clinic. Dogs were studied during their period of weight loss, and cases classified according to outcome as "completed" (reached target weight), "euthanized" (was euthanized before reaching target weight), or "stopped prematurely" (program stopped early for other reasons). Factors associated with successful completion were assessed using simple and multiple logistic regression. 87/143 dogs (61%) completed their weight loss program, 11 [8%] died or were euthanized, and the remaining 45 [32%] stopped prematurely. Reasons for dogs stopping prematurely included inability to contact owner, refusal to comply with weight management advice, or development of another illness. Successful weight loss was positively associated with a faster rate (P < .001), a longer duration (P < .001), and feeding a dried weight management diet (P = .010), but negatively associated with starting body fat (P < .001), and use of dirlotapide (P = .0046). Just over half of all obese dogs on a controlled weight loss program reach their target weight. Future studies should better clarify reasons for success in individual cases, and also the role of factors such as activity and behavioral modification. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

[The optimal blood glucose target in critically ill patient: comparison of two intensive insulin therapy protocols].

PubMed

Raurell Torredà, Marta; del Llano Serrano, César; Almirall Solsona, Dolors; Catalan Ibars, Rosa María; Nicolás Arfelis, José María

2014-03-04

Recent studies in critically ill patients receiving insulin intravenous therapy (IIT) have shown an increased incidence of severe hypoglycemia, while intermittent subcutaneous insulin «sliding scales» (conventional insulin therapy [CIT]) is associated with hyperglycemia. The objective of this study is to assess whether glycemic control range IIT can affect glucose levels and their variability and to compare it with CIT. Prospective comparative cohort study in intensive care unit, with 2 study periods: Period 1, IIT with glycemic target range 110-140 mg/dL, and Period 2, IIT of 140-180 mg/dL. In both periods CIT glycemic target was 110-180 mg/dL. We assessed severe hypoglycemia (< 50 mg/dL), moderate hypoglycemia (51-79 mg/dL), hyperglycemia (> 216 mg/L) and the variability of blood glucose. We studied 221 patients with 12.825 blood glucose determinations. Twenty-six and 17% of patients required IIT for glycemic control in Period 1 and 2, respectively. Hypoglycemia was associated with a discontinuous nutritional intake, glycemic target 110-140 mg/dL and low body mass index (BMI) (P = .002). Hyperglycemia was exclusively associated with a history of diabetes mellitus (OR 2.6 [95% CI 1.6 to 4.5]). Glycemic variability was associated with a discontinuous nutritional intake, low BMI, CIT insulinization, diabetes mellitus, elderly and high APACHE II (P < .001). The use of IIT is useful to reduce the variability of blood glucose. Although the 140-180 mg/dL range would be more secure as to presenting greater variability and hyperglycemia, the 110-140 mg/dL range is most suitable. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Implicit Associations with Popularity in Early Adolescence: An Approach-Avoidance Analysis

ERIC Educational Resources Information Center

Lansu, Tessa A. M.; Cillessen, Antonius H. N.; Karremans, Johan C.

2012-01-01

This study examined 241 early adolescents' implicit and explicit associations with popularity. The peer status and gender of both the targets and the perceivers were considered. Explicit associations with popularity were assessed with sociometric methods. Implicit associations with popularity were assessed with an approach-avoidance task (AAT).…

Adeno-associated virus–targeted disruption of the CFTR gene in cloned ferrets

PubMed Central

Sun, Xingshen; Yan, Ziying; Yi, Yaling; Li, Ziyi; Lei, Diana; Rogers, Christopher S.; Chen, Juan; Zhang, Yulong; Welsh, Michael J.; Leno, Gregory H.; Engelhardt, John F.

2008-01-01

Somatic cell gene targeting combined with nuclear transfer cloning presents tremendous potential for the creation of new, large-animal models of human diseases. Mouse disease models often fail to reproduce human phenotypes, underscoring the need for the generation and study of alternative disease models. Mice deficient for CFTR have been poor models for cystic fibrosis (CF), lacking many aspects of human CF lung disease. In this study, we describe the production of a CFTR gene–deficient model in the domestic ferret using recombinant adeno-associated virus–mediated gene targeting in fibroblasts, followed by nuclear transfer cloning. As part of this approach, we developed a somatic cell rejuvenation protocol using serial nuclear transfer to produce live CFTR-deficient clones from senescent gene-targeted fibroblasts. We transferred 472 reconstructed embryos into 11 recipient jills and obtained 8 healthy male ferret clones heterozygous for a disruption in exon 10 of the CFTR gene. To our knowledge, this study represents the first description of genetically engineered ferrets and describes an approach that may be of substantial utility in modeling not only CF, but also other genetic diseases. PMID:18324338

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

PubMed Central

Chasman, Daniel I.; Jackson, Anne U.; Schmidt, Ellen M.; Johnson, Toby; Thorleifsson, Gudmar; Luan, Jian'an; Donnelly, Lousie A.; Kanoni, Stavroula; Petersen, Ann-Kristin; Pihur, Vasyl; Strawbridge, Rona J.; Shungin, Dmitry; Hughes, Maria F.; Meirelles, Osorio; Kaakinen, Marika; Bouatia-Naji, Nabila; Kristiansson, Kati; Shah, Sonia; Kleber, Marcus E.; Guo, Xiuqing; Lyytikäinen, Leo-Pekka; Fava, Cristiano; Eriksson, Niclas; Nolte, Ilja M.; Magnusson, Patrik K.; Salfati, Elias L.; Rallidis, Loukianos S.; Theusch, Elizabeth; Smith, Andrew J.P.; Folkersen, Lasse; Witkowska, Kate; Pers, Tune H.; Joehanes, Roby; Kim, Stuart K.; Lataniotis, Lazaros; Jansen, Rick; Johnson, Andrew D.; Warren, Helen; Kim, Young Jin; Zhao, Wei; Wu, Ying; Tayo, Bamidele O.; Bochud, Murielle; Absher, Devin; Adair, Linda S.; Amin, Najaf; Arking, Dan E.; Axelsson, Tomas; Baldassarre, Damiano; Balkau, Beverley; Bandinelli, Stefania; Barnes, Michael R.; Barroso, Inês; Bevan, Stephen; Bis, Joshua C.; Bjornsdottir, Gyda; Boehnke, Michael; Boerwinkle, Eric; Bonnycastle, Lori L.; Boomsma, Dorret I.; Bornstein, Stefan R.; Brown, Morris J.; Burnier, Michel; Cabrera, Claudia P.; Chambers, John C.; Chang, I-Shou; Cheng, Ching-Yu; Chines, Peter S.; Chung, Ren-Hua; Collins, Francis S.; Connell, John M.; Döring, Angela; Dallongeville, Jean; Danesh, John; de Faire, Ulf; Delgado, Graciela; Dominiczak, Anna F.; Doney, Alex S.F.; Drenos, Fotios; Edkins, Sarah; Eicher, John D.; Elosua, Roberto; Enroth, Stefan; Erdmann, Jeanette; Eriksson, Per; Esko, Tonu; Evangelou, Evangelos; Evans, Alun; Fall, Tove; Farrall, Martin; Felix, Janine F.; Ferrières, Jean; Ferrucci, Luigi; Fornage, Myriam; Forrester, Terrence; Franceschini, Nora; Duran, Oscar H. Franco; Franco-Cereceda, Anders; Fraser, Ross M.; Ganesh, Santhi K.; Gao, He; Gertow, Karl; Gianfagna, Francesco; Gigante, Bruna; Giulianini, Franco; Goel, Anuj; Goodall, Alison H.; Goodarzi, Mark O.; Gorski, Mathias; Gräßler, Jürgen; Groves, Christopher; Gudnason, Vilmundur; Gyllensten, Ulf; Hallmans, Göran; Hartikainen, Anna-Liisa; Hassinen, Maija; Havulinna, Aki S.; Hayward, Caroline; Hercberg, Serge; Herzig, Karl-Heinz; Hicks, Andrew A.; Hingorani, Aroon D.; Hirschhorn, Joel N.; Hofman, Albert; Holmen, Jostein; Holmen, Oddgeir Lingaas; Hottenga, Jouke-Jan; Howard, Phil; Hsiung, Chao A.; Hunt, Steven C.; Ikram, M. Arfan; Illig, Thomas; Iribarren, Carlos; Jensen, Richard A.; Kähönen, Mika; Kang, Hyun; Kathiresan, Sekar; Keating, Brendan J.; Khaw, Kay-Tee; Kim, Yun Kyoung; Kim, Eric; Kivimaki, Mika; Klopp, Norman; Kolovou, Genovefa; Komulainen, Pirjo; Kooner, Jaspal S.; Kosova, Gulum; Krauss, Ronald M.; Kuh, Diana; Kutalik, Zoltan; Kuusisto, Johanna; Kvaløy, Kirsti; Lakka, Timo A; Lee, Nanette R.; Lee, I-Te; Lee, Wen-Jane; Levy, Daniel; Li, Xiaohui; Liang, Kae-Woei; Lin, Honghuang; Lin, Li; Lindström, Jaana; Lobbens, Stéphane; Männistö, Satu; Müller, Gabriele; Müller-Nurasyid, Martina; Mach, François; Markus, Hugh S.; Marouli, Eirini; McCarthy, Mark I.; McKenzie, Colin A.; Meneton, Pierre; Menni, Cristina; Metspalu, Andres; Mijatovic, Vladan; Moilanen, Leena; Montasser, May E.; Morris, Andrew D.; Morrison, Alanna C.; Mulas, Antonella; Nagaraja, Ramaiah; Narisu, Narisu; Nikus, Kjell; O'Donnell, Christopher J.; O'Reilly, Paul F.; Ong, Ken K.; Paccaud, Fred; Palmer, Cameron D.; Parsa, Afshin; Pedersen, Nancy L.; Penninx, Brenda W.; Perola, Markus; Peters, Annette; Poulter, Neil; Pramstaller, Peter P.; Psaty, Bruce M.; Quertermous, Thomas; Rao, Dabeeru C.; Rasheed, Asif; Rayner, N William N.W.R.; Renström, Frida; Rettig, Rainer; Rice, Kenneth M.; Roberts, Robert; Rose, Lynda M.; Rossouw, Jacques; Samani, Nilesh J.; Sanna, Serena; Saramies, Jouko; Schunkert, Heribert; Sebert, Sylvain; Sheu, Wayne H.-H.; Shin, Young-Ah; Sim, Xueling; Smit, Johannes H.; Smith, Albert V.; Sosa, Maria X.; Spector, Tim D.; Stančáková, Alena; Stanton, Alice; Stirrups, Kathleen E.; Stringham, Heather M.; Sundstrom, Johan; Swift, Amy J.; Syvänen, Ann-Christine; Tai, E-Shyong; Tanaka, Toshiko; Tarasov, Kirill V.; Teumer, Alexander; Thorsteinsdottir, Unnur; Tobin, Martin D.; Tremoli, Elena; Uitterlinden, Andre G.; Uusitupa, Matti; Vaez, Ahmad; Vaidya, Dhananjay; van Duijn, Cornelia M.; van Iperen, Erik P.A.; Vasan, Ramachandran S.; Verwoert, Germaine C.; Virtamo, Jarmo; Vitart, Veronique; Voight, Benjamin F.; Vollenweider, Peter; Wagner, Aline; Wain, Louise V.; Wareham, Nicholas J.; Watkins, Hugh; Weder, Alan B.; Westra, Harm-Jan; Wilks, Rainford; Wilsgaard, Tom; Wilson, James F.; Wong, Tien Y.; Yang, Tsun-Po; Yao, Jie; Yengo, Loic; Zhang, Weihua; Zhao, Jing Hua; Zhu, Xiaofeng; Bovet, Pascal; Cooper, Richard S.; Mohlke, Karen L.; Saleheen, Danish; Lee, Jong-Young; Elliott, Paul; Gierman, Hinco J.; Willer, Cristen J.; Franke, Lude; Hovingh, G Kees; Taylor, Kent D.; Dedoussis, George; Sever, Peter; Wong, Andrew; Lind, Lars; Assimes, Themistocles L.; Njølstad, Inger; Schwarz, Peter EH.; Langenberg, Claudia; Snieder, Harold; Caulfield, Mark J.; Melander, Olle; Laakso, Markku; Saltevo, Juha; Rauramaa, Rainer; Tuomilehto, Jaakko; Ingelsson, Erik; Lehtimäki, Terho; Hveem, Kristian; Palmas, Walter; März, Winfried; Kumari, Meena; Salomaa, Veikko; Chen, Yii-Der I.; Rotter, Jerome I.; Froguel, Philippe; Jarvelin, Marjo-Riitta; Lakatta, Edward G.; Kuulasmaa, Kari; Franks, Paul W.; Hamsten, Anders; Wichmann, H.-Erich; Palmer, Colin N.A.; Stefansson, Kari; Ridker, Paul M; Loos, Ruth J.F.; Chakravarti, Aravinda; Deloukas, Panos; Morris, Andrew P.; Newton-Cheh, Christopher; Munroe, Patricia B.

2016-01-01

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation. PMID:27618452

Assessment of Prospectively Assigned Likert Scores for Targeted Magnetic Resonance Imaging-Transrectal Ultrasound Fusion Biopsies in Patients with Suspected Prostate Cancer.

PubMed

Costa, Daniel N; Lotan, Yair; Rofsky, Neil M; Roehrborn, Claus; Liu, Alexander; Hornberger, Brad; Xi, Yin; Francis, Franto; Pedrosa, Ivan

2016-01-01

We assess the performance of prospectively assigned magnetic resonance imaging based Likert scale scores for the detection of clinically significant prostate cancer, and analyze the pre-biopsy imaging variables associated with increased cancer detection using targeted magnetic resonance imaging-transrectal ultrasound fusion biopsy. In this retrospective review of prospectively generated data including men with abnormal multiparametric prostate magnetic resonance imaging (at least 1 Likert score 3 or greater lesion) who underwent subsequent targeted magnetic resonance imaging-transrectal ultrasound fusion biopsy, we determined the association between different imaging variables (Likert score, lesion size, lesion location, prostate volume, radiologist experience) and targeted biopsy positivity rate. We also compared the detection of clinically significant cancer according to Likert scale scores. Tumors with high volume (50% or more of any core) Gleason score 3+4 or any tumor with greater Gleason score were considered clinically significant. Each lesion served as the elementary unit for analysis. We used logistic regression for univariate and multivariate (stepwise selection) analysis to assess for an association between targeted biopsy positivity rate and each tested variable. The relationship between Likert scale and Gleason score was evaluated using the Spearman correlation coefficient. A total of 161 men with 244 lesions met the study eligibility criteria. Targeted biopsies diagnosed cancer in 41% (66 of 161) of the men and 41% (99 of 244) of the lesions. The Likert score was the strongest predictor of targeted biopsy positivity (OR 3.7, p <0.0001). Other imaging findings associated with a higher targeted biopsy positivity rate included smaller prostate volume (OR 0.7, p <0.01), larger lesion size (OR 2.2, p <0.001) and anterior location (OR 2.0, p=0.01). On multiple logistic regression analysis Likert score, lesion size and prostate volume were significant predictors of targeted biopsy positivity. Higher Likert scores were also associated with increased detection of clinically significant tumors (p <0.0001). The Likert scale score used to convey the degree of suspicion on multiparametric magnetic resonance imaging is the strongest predictor of targeted biopsy positivity and of the presence of clinically significant tumor. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Association between Knowledge-Attitude-Practices and Control of Blood Glucose, Blood Pressure, and Blood Lipids in Patients with Type 2 Diabetes in Shanghai, China: A Cross-Sectional Study.

PubMed

Yang, Hua; Gao, Jian; Ren, Limin; Li, Shuyu; Chen, Zhangyan; Huang, Junfang; Zhu, Shanzhu; Pan, Zhigang

2017-01-01

Knowledge-attitude-practices (KAP) significantly impact the outcome of self-management in patients with diabetes, yet the association between KAP and the combined control of the levels of blood glucose, blood pressure, and blood lipids in these patients remains uncertain. This community-based cross-sectional study was conducted from December 2014 to December 2016 on 3977 patients with type 2 diabetes in Shanghai. KAP were evaluated using the modified Chinese version of the Diabetes, Hypertension and Hyperlipidemia (DHL) Knowledge Instrument, Diabetes Empowerment Scale-Short Form (DES-SF), and Summary of Diabetes Self-Care Activities (SDSCA). Clinical and biochemical measurements were performed at each sampling site. The association between KAP scores and achieving the combined target goal was assessed by multiple logistic regression. Patients having a higher score of knowledge were more likely to achieve the combined target goal. Furthermore, a turning point of knowledge score was found that the possibility of achieving the combined target goal presented a sharp increase when the knowledge score was more than 70. However, the scores of attitude and practices had no significant relations with achieving the combined target goal. Health intervention strategies, especially increasing integrated diabetes knowledge, should be targeted to patients with type 2 diabetes in communities.

Effects of Achieving Target Measures in Rheumatoid Arthritis on Functional Status, Quality of Life, and Resource Utilization: Analysis of Clinical Practice Data.

PubMed

Alemao, Evo; Joo, Seongjung; Kawabata, Hugh; Al, Maiwenn J; Allison, Paul D; Rutten-van Mölken, Maureen P M H; Frits, Michelle L; Iannaccone, Christine K; Shadick, Nancy A; Weinblatt, Michael E

2016-03-01

To evaluate associations between achieving guideline-recommended targets of disease activity, defined by the Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) <2.6, the Simplified Disease Activity Index (SDAI) ≤3.3, or the Clinical Disease Activity Index (CDAI) ≤2.8, and other health outcomes in a longitudinal observational study. Other defined thresholds included low disease activity (LDA), moderate (MDA), or severe disease activity (SDA). To control for intraclass correlation and estimate effects of independent variables on outcomes of the modified Health Assessment Questionnaire (M-HAQ), the EuroQol 5-domain (EQ-5D; a quality-of-life measure), hospitalization, and durable medical equipment (DME) use, we employed mixed models for continuous outcomes and generalized estimating equations for binary outcomes. Among 1,297 subjects, achievement (versus nonachievement) of recommended disease targets was associated with enhanced physical functioning and lower health resource utilization. After controlling for baseline covariates, achievement of disease targets (versus LDA) was associated with significantly enhanced physical functioning based on SDAI ≤3.3 (ΔM-HAQ -0.047; P = 0.0100) and CDAI ≤2.8 (-0.073; P = 0.0003) but not DAS28-CRP <2.6 (-0.022; P = 0.1735). Target attainment was associated with significantly improved EQ-5D (0.022-0.096; P < 0.0030 versus LDA, MDA, or SDA). Patients achieving guideline-recommended disease targets were 36-45% less likely to be hospitalized (P < 0.0500) and 23-45% less likely to utilize DME (P < 0.0100). Attaining recommended target disease-activity measures was associated with enhanced physical functioning and health-related quality of life. Some health outcomes were similar in subjects attaining guideline targets versus LDA. Achieving LDA is a worthy clinical objective in some patients. © 2016 The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Where do health benefits of flavonoids come from? Insights from flavonoid targets and their evolutionary history.

PubMed

Lu, Ming-Feng; Xiao, Zheng-Tao; Zhang, Hong-Yu

2013-05-17

Flavonoid intake is negatively correlated with the incidence of some chronic diseases including cardiovascular diseases, type II diabetes, neurodegenerative diseases, and cancers. Thus, the molecular mechanisms underlying this correlation are of great interest. Although ample attention has been given to the free radical-scavenging potential of flavonoids, the poor bioavailability of exogenous flavonoids suggests that the direct antioxidant activity is unlikely responsible for their favorable effects. This study comprehensively analyzed flavonoid targets. The results show that the main functions of these targets are associated with cancers and cardiovascular and metabolic diseases. Moreover, evolutionary analysis of these targets showed that ~1000 of the targets have homologues in human gut bacterial metagenomes. Clusters of orthologous groups of proteins (COG) analysis indicated that most of these bacterial targets are associated with bacterial metabolism. Given that the metabolism of gut microbiota is coupled with the metabolism of the host, this finding implies that flavonoids exert their benefits by regulating gut microbes. Therefore, the health benefits of flavonoids are well explained by their targets rather than their direct antioxidant potential. Copyright © 2013 Elsevier Inc. All rights reserved.

CRISPR-Cas9 Structures and Mechanisms.

PubMed

Jiang, Fuguo; Doudna, Jennifer A

2017-05-22

Many bacterial clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) systems employ the dual RNA-guided DNA endonuclease Cas9 to defend against invading phages and conjugative plasmids by introducing site-specific double-stranded breaks in target DNA. Target recognition strictly requires the presence of a short protospacer adjacent motif (PAM) flanking the target site, and subsequent R-loop formation and strand scission are driven by complementary base pairing between the guide RNA and target DNA, Cas9-DNA interactions, and associated conformational changes. The use of CRISPR-Cas9 as an RNA-programmable DNA targeting and editing platform is simplified by a synthetic single-guide RNA (sgRNA) mimicking the natural dual trans-activating CRISPR RNA (tracrRNA)-CRISPR RNA (crRNA) structure. This review aims to provide an in-depth mechanistic and structural understanding of Cas9-mediated RNA-guided DNA targeting and cleavage. Molecular insights from biochemical and structural studies provide a framework for rational engineering aimed at altering catalytic function, guide RNA specificity, and PAM requirements and reducing off-target activity for the development of Cas9-based therapies against genetic diseases.

Open Targets: a platform for therapeutic target identification and validation

PubMed Central

Koscielny, Gautier; An, Peter; Carvalho-Silva, Denise; Cham, Jennifer A.; Fumis, Luca; Gasparyan, Rippa; Hasan, Samiul; Karamanis, Nikiforos; Maguire, Michael; Papa, Eliseo; Pierleoni, Andrea; Pignatelli, Miguel; Platt, Theo; Rowland, Francis; Wankar, Priyanka; Bento, A. Patrícia; Burdett, Tony; Fabregat, Antonio; Forbes, Simon; Gaulton, Anna; Gonzalez, Cristina Yenyxe; Hermjakob, Henning; Hersey, Anne; Jupe, Steven; Kafkas, Şenay; Keays, Maria; Leroy, Catherine; Lopez, Francisco-Javier; Magarinos, Maria Paula; Malone, James; McEntyre, Johanna; Munoz-Pomer Fuentes, Alfonso; O'Donovan, Claire; Papatheodorou, Irene; Parkinson, Helen; Palka, Barbara; Paschall, Justin; Petryszak, Robert; Pratanwanich, Naruemon; Sarntivijal, Sirarat; Saunders, Gary; Sidiropoulos, Konstantinos; Smith, Thomas; Sondka, Zbyslaw; Stegle, Oliver; Tang, Y. Amy; Turner, Edward; Vaughan, Brendan; Vrousgou, Olga; Watkins, Xavier; Martin, Maria-Jesus; Sanseau, Philippe; Vamathevan, Jessica; Birney, Ewan; Barrett, Jeffrey; Dunham, Ian

2017-01-01

We have designed and developed a data integration and visualization platform that provides evidence about the association of known and potential drug targets with diseases. The platform is designed to support identification and prioritization of biological targets for follow-up. Each drug target is linked to a disease using integrated genome-wide data from a broad range of data sources. The platform provides either a target-centric workflow to identify diseases that may be associated with a specific target, or a disease-centric workflow to identify targets that may be associated with a specific disease. Users can easily transition between these target- and disease-centric workflows. The Open Targets Validation Platform is accessible at https://www.targetvalidation.org. PMID:27899665

Effects of the time dimension and presentation on incidental memory.

PubMed

Toyota, Hiroshi

2009-08-01

Undergraduates were presented targets on two occasions, and each time they were asked to choose one of two alternatives (past or future) associated with the targets in the orienting task, followed by an unexpected free recall. For the pleasant targets, the spaced presentation led to a better recall than the massed presentation for both past and future time. However, for unpleasant targets, the spacing effect was found in recall of targets associated with the past but the effect was not observed in recall of targets associated with the future. These results were interpreted as indicating that the quantity and the quality of the episodes associated with the targets were processed differently as a function of emotional attribute and time dimension.

Notochord-derived Shh concentrates in close association with the apically positioned basal body in neural target cells and forms a dynamic gradient during neural patterning.

PubMed

Chamberlain, Chester E; Jeong, Juhee; Guo, Chaoshe; Allen, Benjamin L; McMahon, Andrew P

2008-03-01

Sonic hedgehog (Shh) ligand secreted by the notochord induces distinct ventral cell identities in the adjacent neural tube by a concentration-dependent mechanism. To study this process, we genetically engineered mice that produce bioactive, fluorescently labeled Shh from the endogenous locus. We show that Shh ligand concentrates in close association with the apically positioned basal body of neural target cells, forming a dynamic, punctate gradient in the ventral neural tube. Both ligand lipidation and target field response influence the gradient profile, but not the ability of Shh to concentrate around the basal body. Further, subcellular analysis suggests that Shh from the notochord might traffic into the neural target field by means of an apical-to-basal-oriented microtubule scaffold. This study, in which we directly observe, measure, localize and modify notochord-derived Shh ligand in the context of neural patterning, provides several new insights into mechanisms of Shh morphogen action.

Facilitated Protein Association via Engineered Target Search Pathways Visualized by Paramagnetic NMR Spectroscopy.

PubMed

An, So Young; Kim, Eun-Hee; Suh, Jeong-Yong

2018-06-05

Proteins assemble to form functional complexes via the progressive evolution of nonspecific complexes formed by transient encounters. This target search process generally involves multiple routes that lead the initial encounters to the final complex. In this study, we have employed NMR paramagnetic relaxation enhancement to visualize the encounter complexes between histidine-containing phosphocarrier protein and the N-terminal domain of enzyme I and demonstrate that protein association can be significantly enhanced by engineering on-pathways. Specifically, mutations in surface charges away from the binding interface can elicit new on-pathway encounter complexes, increasing their binding affinity by an order of magnitude. The structure of these encounter complexes indicates that such on-pathways extend the built-in target search process of the native protein complex. Furthermore, blocking on-pathways by countering mutations reverts their binding affinity. Our study thus illustrates that protein interactions can be engineered by rewiring the target search process. Copyright © 2018 Elsevier Ltd. All rights reserved.

Improved methods of AAV-mediated gene targeting for human cell lines using ribosome-skipping 2A peptide

PubMed Central

Karnan, Sivasundaram; Ota, Akinobu; Konishi, Yuko; Wahiduzzaman, Md; Hosokawa, Yoshitaka; Konishi, Hiroyuki

2016-01-01

The adeno-associated virus (AAV)-based targeting vector has been one of the tools commonly used for genome modification in human cell lines. It allows for relatively efficient gene targeting associated with 1–4-log higher ratios of homologous-to-random integration of targeting vectors (H/R ratios) than plasmid-based targeting vectors, without actively introducing DNA double-strand breaks. In this study, we sought to improve the efficiency of AAV-mediated gene targeting by introducing a 2A-based promoter-trap system into targeting constructs. We generated three distinct AAV-based targeting vectors carrying 2A for promoter trapping, each targeting a GFP-based reporter module incorporated into the genome, PIGA exon 6 or PIGA intron 5. The absolute gene targeting efficiencies and H/R ratios attained using these vectors were assessed in multiple human cell lines and compared with those attained using targeting vectors carrying internal ribosome entry site (IRES) for promoter trapping. We found that the use of 2A for promoter trapping increased absolute gene targeting efficiencies by 3.4–28-fold and H/R ratios by 2–5-fold compared to values obtained with IRES. In CRISPR-Cas9-assisted gene targeting using plasmid-based targeting vectors, the use of 2A did not enhance the H/R ratios but did upregulate the absolute gene targeting efficiencies compared to the use of IRES. PMID:26657635

Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality

PubMed Central

Raffler, Johannes; Friedrich, Nele; Arnold, Matthias; Kacprowski, Tim; Rueedi, Rico; Altmaier, Elisabeth; Bergmann, Sven; Budde, Kathrin; Gieger, Christian; Homuth, Georg; Pietzner, Maik; Römisch-Margl, Werner; Strauch, Konstantin; Völzke, Henry; Waldenberger, Melanie; Wallaschofski, Henri; Nauck, Matthias; Völker, Uwe; Kastenmüller, Gabi; Suhre, Karsten

2015-01-01

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 mechanisms involved in the etiology of diseases. PMID:26352407

Influenza A Virus Hemagglutinin and Neuraminidase Mutually Accelerate Their Apical Targeting through Clustering of Lipid Rafts

PubMed Central

Ohkura, Takashi; Momose, Fumitaka; Ichikawa, Reiko; Takeuchi, Kaoru

2014-01-01

ABSTRACT In polarized epithelial cells, influenza A virus hemagglutinin (HA) and neuraminidase (NA) are intrinsically associated with lipid rafts and target the apical plasma membrane for viral assembly and budding. Previous studies have indicated that the transmembrane domain (TMD) and cytoplasmic tail (CT) of HA and NA are required for association with lipid rafts, but the raft dependencies of their apical targeting are controversial. Here, we show that coexpression of HA with NA accelerated their apical targeting through accumulation in lipid rafts. HA was targeted to the apical plasma membrane even when expressed alone, but the kinetics was much slower than that of HA in infected cells. Coexpression experiments revealed that apical targeting of HA and NA was accelerated by their coexpression. The apical targeting of HA was also accelerated by coexpression with M1 but not M2. The mutations in the outer leaflet of the TMD and the deletion of the CT in HA and NA that reduced their association with lipid rafts abolished the acceleration of their apical transport, indicating that the lipid raft association is essential for efficient apical trafficking of HA and NA. An in situ proximity ligation assay (PLA) revealed that HA and NA were accumulated and clustered in the cytoplasmic compartments only when both were associated with lipid rafts. Analysis with mutant viruses containing nonraft HA/NA confirmed these findings. We further analyzed lipid raft markers by in situ PLA and suggest a possible mechanism of the accelerated apical transport of HA and NA via clustering of lipid rafts. IMPORTANCE Lipid rafts serve as sites for viral entry, particle assembly, and budding, leading to efficient viral replication. The influenza A virus utilizes lipid rafts for apical plasma membrane targeting and particle budding. The hemagglutinin (HA) and neuraminidase (NA) of influenza virus, key players for particle assembly, contain determinants for apical sorting and lipid raft association. However, it remains to be elucidated how lipid rafts contribute to the apical trafficking and budding. We investigated the relation of lipid raft association of HA and NA to the efficiency of apical trafficking. We show that coexpression of HA and NA induces their accumulation in lipid rafts and accelerates their apical targeting, and we suggest that the accelerated apical transport likely occurs by clustering of lipid rafts at the TGN. This finding provides the first evidence that two different raft-associated viral proteins induce lipid raft clustering, thereby accelerating apical trafficking of the viral proteins. PMID:24965459

An event-related brain potential study of schizotypal personality and associative semantic processing

PubMed Central

Kiang, Michael; Prugh, Jocelyn; Kutas, Marta

2009-01-01

To examine whether schizotypal personality is associated with the degree to which concepts activate each other in semantic memory, event-related brain potentials (ERPs) were recorded during a delayed lexical decision task from healthy volunteers rated for schizotypy. Each target word was directly, indirectly, or not at all related to a prime word preceding it at a 300- or 750-ms stimulus-onset asynchrony (SOA). Overall, N400 amplitudes were largest for unrelated targets, smallest for directly related targets, and intermediate for indirectly related targets. Higher total Schizotypal Personality Questionnaire (SPQ) scores correlated with smaller N400 indirect priming effects (i.e., smaller N400 amplitude differences between unrelated and indirectly related targets) at both SOAs. In addition, schizotypal subscale scores were differentially associated with N400 effects. Higher SPQ Cognitive-Perceptual scores correlated with smaller N400 direct priming effects (smaller N400 amplitude differences between unrelated and directly related targets) at both SOAs, and with smaller N400 indirect priming effects at the shorter SOA. These correlations are consistent with the hypothesis that decreased use of meaningful context to activate related concepts in general, and/or to inhibit unrelated concepts, may play some role in the development of unusual beliefs. PMID:19818815

Achieved versus intended pulse oximeter saturation in infants born less than 28 weeks' gestation: the AVIOx study.

PubMed

Hagadorn, James I; Furey, Anne M; Nghiem, Tuyet-Hang; Schmid, Christopher H; Phelps, Dale L; Pillers, De-Ann M; Cole, Cynthia H

2006-10-01

The objective of this study was to document pulse oximeter saturation levels achieved in the first 4 weeks of life in infants who were born at < 28 weeks' gestation, compared with the levels that were targeted by local policy, and examine factors that are associated with compliance with the target range. Infants who were < 28 weeks' gestation and < or = 96 hours of age were enrolled in a prospective, multicenter cohort study. Oximetry data were collected with masked signal-extraction oximeters for a 72-hour period in each of the first 4 weeks of life. Data were compared with the pulse oximeter saturation target range prescribed by local institutional policy. Factors that were associated with intended range compliance were identified with hierarchical modeling. Fourteen centers from 3 countries enrolled 84 infants with mean +/- SD birth weight of 863 +/- 208 g and gestational age of 26 +/- 1.4 weeks. Oxygen saturation policy limits ranged between 83% and 92% for lower limits and 92% and 98% for upper limits. For infants who received respiratory support, median pulse oximeter saturation level achieved was 95%. Center-specific medial levels were within the intended range at 12 centers. Centers maintained infants within their intended range 16% to 64% of the time but were above range 20% to 73% of the time. In hierarchical modeling, wider target ranges, higher target range upper limits, presence of a policy of setting oximeter alarms close to the target range limits, and lower gestational age were associated with improved target range compliance. Success with maintaining the intended pulse oximeter saturation range varied substantially among centers, among patients within centers, and for individual patients over time. Most noncompliance was above the intended range. Methods for improving compliance and the effect of improved compliance on neonatal outcomes require additional research.

Genome Wide Association Study of Sepsis in Extremely Premature Infants

PubMed Central

Srinivasan, Lakshmi; Page, Grier; Kirpalani, Haresh; Murray, Jeffrey C.; Das, Abhik; Higgins, Rosemary D.; Carlo, Waldemar A.; Bell, Edward F.; Goldberg, Ronald N.; Schibler, Kurt; Sood, Beena G.; Stevenson, David K.; Stoll, Barbara J.; Van Meurs, Krisa P.; Johnson, Karen J.; Levy, Joshua; McDonald, Scott A.; Zaterka-Baxter, Kristin M.; Kennedy, Kathleen A.; Sánchez, Pablo J.; Duara, Shahnaz; Walsh, Michele C.; Shankaran, Seetha; Wynn, James L.; Cotten, C. Michael

2017-01-01

Objective To identify genetic variants associated with sepsis (early and late-onset) using a genome wide association (GWA) analysis in a cohort of extremely premature infants. Study Design Previously generated GWA data from the Neonatal Research Network’s anonymized genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole genome amplified DNA was genotyped for 1.2 million single nucleotide polymorphisms (SNPs); 91% of SNPs were successfully genotyped. We imputed 7.2 million additional SNPs. P values and false discovery rates were calculated from multivariate logistic regression analysis adjusting for gender, gestational age and ancestry. Target statistical value was p<10−5. Secondary analyses assessed associations of SNPs with pathogen type. Pathway analyses were also run on primary and secondary end points. Results Data from 757 extremely premature infants were included: 351 infants with sepsis and 406 infants without sepsis. No SNPs reached genome-wide significance levels (5×10−8); two SNPs in proximity to FOXC2 and FOXL1 genes achieved target levels of significance. In secondary analyses, SNPs for ELMO1, IRAK2 (Gram positive sepsis), RALA, IMMP2L (Gram negative sepsis) and PIEZO2 (fungal sepsis) met target significance levels. Pathways associated with sepsis and Gram negative sepsis included gap junctions, fibroblast growth factor receptors, regulators of cell division and Interleukin-1 associated receptor kinase 2 (p values<0.001 and FDR<20%). Conclusions No SNPs met genome-wide significance in this cohort of ELBW infants; however, areas of potential association and pathways meriting further study were identified. PMID:28283553

Social anhedonia, but not positive schizotypy, is associated with poor affective control.

PubMed

Martin, Elizabeth A; Cicero, David C; Kerns, John G

2012-07-01

Emotion researchers have distinguished between automatic versus controlled processing of affective information. One previous study with a small sample size found that extreme levels of social anhedonia (SocAnh) in college students, which predicts future schizophrenia-spectrum disorders, is associated with problems in controlled affective processing on a primed evaluation task. The current study examined whether in a larger college student sample SocAnh but not elevated perceptual aberration/magical ideation (PerMag) was associated with poor controlled affective processing. On the primed evaluation task, primes and targets could be either affectively congruent or incongruent and participants judged the valence of targets. Previous research on this task has found that participants appear to use controlled processing in an attempt to counteract the influence of the prime in evaluating the target. In this study, compared to the PerMag (n = 48) and control groups (n = 338), people with extreme levels of social anhedonia (n = 62) exhibited increased affective interference as they were slower for incongruent than for congruent trials. In contrast, there were no differences between the PerMag and control groups. Overall, these results suggest that SocAnh, but not PerMag, is associated with poor controlled affective processing. PsycINFO Database Record (c) 2012 APA, all rights reserved.

Mortality prediction in patients with severe septic shock: a pilot study using a target metabolomics approach.

PubMed

Ferrario, Manuela; Cambiaghi, Alice; Brunelli, Laura; Giordano, Silvia; Caironi, Pietro; Guatteri, Luca; Raimondi, Ferdinando; Gattinoni, Luciano; Latini, Roberto; Masson, Serge; Ristagno, Giuseppe; Pastorelli, Roberta

2016-02-05

Septic shock remains a major problem in Intensive Care Unit, with high lethality and high-risk second lines treatments. In this preliminary retrospective investigation we examined plasma metabolome and clinical features in a subset of 20 patients with severe septic shock (SOFA score >8), enrolled in the multicenter Albumin Italian Outcome Sepsis study (ALBIOS, NCT00707122). Our purpose was to evaluate the changes of circulating metabolites in relation to mortality as a pilot study to be extended in a larger cohort. Patients were analyzed according to their 28-days and 90-days mortality. Metabolites were measured using a targeted mass spectrometry-based quantitative metabolomic approach that included acylcarnitines, aminoacids, biogenic amines, glycerophospholipids, sphingolipids, and sugars. Data-mining techniques were applied to evaluate the association of metabolites with mortality. Low unsaturated long-chain phosphatidylcholines and lysophosphatidylcholines species were associated with long-term survival (90-days) together with circulating kynurenine. Moreover, a decrease of these glycerophospholipids was associated to the event at 28-days and 90-days in combination with clinical variables such as cardiovascular SOFA score (28-day mortality model) or renal replacement therapy (90-day mortality model). Early changes in the plasma levels of both lipid species and kynurenine associated with mortality have potential implications for early intervention and discovering new target therapy.

Mortality prediction in patients with severe septic shock: a pilot study using a target metabolomics approach

PubMed Central

Ferrario, Manuela; Cambiaghi, Alice; Brunelli, Laura; Giordano, Silvia; Caironi, Pietro; Guatteri, Luca; Raimondi, Ferdinando; Gattinoni, Luciano; Latini, Roberto; Masson, Serge; Ristagno, Giuseppe; Pastorelli, Roberta

2016-01-01

Septic shock remains a major problem in Intensive Care Unit, with high lethality and high-risk second lines treatments. In this preliminary retrospective investigation we examined plasma metabolome and clinical features in a subset of 20 patients with severe septic shock (SOFA score >8), enrolled in the multicenter Albumin Italian Outcome Sepsis study (ALBIOS, NCT00707122). Our purpose was to evaluate the changes of circulating metabolites in relation to mortality as a pilot study to be extended in a larger cohort. Patients were analyzed according to their 28-days and 90-days mortality. Metabolites were measured using a targeted mass spectrometry-based quantitative metabolomic approach that included acylcarnitines, aminoacids, biogenic amines, glycerophospholipids, sphingolipids, and sugars. Data-mining techniques were applied to evaluate the association of metabolites with mortality. Low unsaturated long-chain phosphatidylcholines and lysophosphatidylcholines species were associated with long-term survival (90-days) together with circulating kynurenine. Moreover, a decrease of these glycerophospholipids was associated to the event at 28-days and 90-days in combination with clinical variables such as cardiovascular SOFA score (28-day mortality model) or renal replacement therapy (90-day mortality model). Early changes in the plasma levels of both lipid species and kynurenine associated with mortality have potential implications for early intervention and discovering new target therapy. PMID:26847922

Personality trait inferences of Turkish immigrant and neutral targets: an experimental study.

PubMed

Sandal, Gro M; Bye, Hege H; Pallesen, Ståle

2012-12-01

The study investigated whether personality traits attributed to immigrant targets differ from personality inferences made for a neutral target, and whether trait attributions differ for assimilated and integrated immigrant targets. Participants (n = 340) were randomized to one of three conditions in which they read the same story about a person, but where the person was described as either: (a) an assimilated Turkish immigrant; (b) an integrated Turkish immigrant; or (c) neutral (no nationality or religious practice indicated). Subsequently, they rated the personality of the described person on the NEO-Five Factor Inventory (observer rating version) and completed the Balanced Inventory of Desirable Responding (Impression Management scale) with reference to themselves. Both immigrant targets were rated as significantly higher on extraversion and lower on neuroticism than the neutral target. The integrated target was rated as more open than the neutral target, and as higher than the assimilated target on neuroticism when controlling for impression management. © 2012 The Authors. Scandinavian Journal of Psychology © 2012 The Scandinavian Psychological Associations.

Synergistic target combination prediction from curated signaling networks: Machine learning meets systems biology and pharmacology.

PubMed

Chua, Huey Eng; Bhowmick, Sourav S; Tucker-Kellogg, Lisa

2017-10-01

Given a signaling network, the target combination prediction problem aims to predict efficacious and safe target combinations for combination therapy. State-of-the-art in silico methods use Monte Carlo simulated annealing (mcsa) to modify a candidate solution stochastically, and use the Metropolis criterion to accept or reject the proposed modifications. However, such stochastic modifications ignore the impact of the choice of targets and their activities on the combination's therapeutic effect and off-target effects, which directly affect the solution quality. In this paper, we present mascot, a method that addresses this limitation by leveraging two additional heuristic criteria to minimize off-target effects and achieve synergy for candidate modification. Specifically, off-target effects measure the unintended response of a signaling network to the target combination and is often associated with toxicity. Synergy occurs when a pair of targets exerts effects that are greater than the sum of their individual effects, and is generally a beneficial strategy for maximizing effect while minimizing toxicity. mascot leverages on a machine learning-based target prioritization method which prioritizes potential targets in a given disease-associated network to select more effective targets (better therapeutic effect and/or lower off-target effects); and on Loewe additivity theory from pharmacology which assesses the non-additive effects in a combination drug treatment to select synergistic target activities. Our experimental study on two disease-related signaling networks demonstrates the superiority of mascot in comparison to existing approaches. Copyright © 2017 Elsevier Inc. All rights reserved.

The impact of health information technology on cancer care across the continuum: a systematic review and meta-analysis.

PubMed

Tarver, Will L; Menachemi, Nir

2016-03-01

Health information technology (HIT) has the potential to play a significant role in the management of cancer. The purpose of this review is to identify and examine empirical studies that investigate the impact of HIT in cancer care on different levels of the care continuum. Electronic searches were performed in four academic databases. The authors used a three-step search process to identify 122 studies that met specific inclusion criteria. Next, a coding sheet was used to extract information from each included article to use in an analysis. Logistic regression was used to determine study-specific characteristics that were associated with positive findings. Overall, 72.4% of published analyses reported a beneficial effect of HIT. Multivariate analysis found that the impact of HIT differs across the cancer continuum with studies targeting diagnosis and treatment being, respectively, 77 (P = .001) and 39 (P = .039) percentage points less likely to report a beneficial effect when compared to those targeting prevention. In addition, studies targeting HIT to patients were 31 percentage points less likely to find a beneficial effect than those targeting providers (P = .030). Lastly, studies assessing behavior change as an outcome were 41 percentage points less likely to find a beneficial effect (P = .006), while studies targeting decision making were 27 percentage points more likely to find a beneficial effect (P = .034). Based on current evidence, HIT interventions seem to be more successful when targeting physicians, care in the prevention phase of the cancer continuum, and/or decision making. An agenda for future research is discussed. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Tracking moving radar targets with parallel, velocity-tuned filters

DOEpatents

Bickel, Douglas L.; Harmony, David W.; Bielek, Timothy P.; Hollowell, Jeff A.; Murray, Margaret S.; Martinez, Ana

2013-04-30

Radar data associated with radar illumination of a movable target is processed to monitor motion of the target. A plurality of filter operations are performed in parallel on the radar data so that each filter operation produces target image information. The filter operations are defined to have respectively corresponding velocity ranges that differ from one another. The target image information produced by one of the filter operations represents the target more accurately than the target image information produced by the remainder of the filter operations when a current velocity of the target is within the velocity range associated with the one filter operation. In response to the current velocity of the target being within the velocity range associated with the one filter operation, motion of the target is tracked based on the target image information produced by the one filter operation.

Accurate where it counts: Empathic accuracy on conflict and no-conflict days.

PubMed

Lazarus, Gal; Bar-Kalifa, Eran; Rafaeli, Eshkol

2018-03-01

When we are accurate regarding our partners' negative moods, are we seen as more responsive (and do we see them as such) as a function of the presence/absence of conflict? In 2 daily diary studies, empathic accuracy (EA) was assessed by comparing targets' daily negative moods with perceivers' inferences of these moods. We hypothesized that conflict will be associated with reductions in perceived partner responsiveness (PPR) for both parties; that on no-conflict days, EA will be positively associated with both parties' PPR; that on conflict days, this positive association will be stronger for targets but will become negative for perceivers; and that regardless of conflict, overestimation (vs. underestimation) of negative moods will be tied with higher PPR for targets but with lower PPR for perceivers. Thirty-six (Sample 1) and 77 (Sample 2) committed couples completed daily diaries (for 21 or 35 days, respectively). We utilized multilevel polynomial regression with response surface analyses, a sophisticated approach for studying multisource data of this sort (Edwards & Parry, 1993). Results partially supported our hypotheses: conflict was tied to reduced PPR; on no-conflict days, EA was not consistently predictive of target or perceiver PPR; on conflict days, EA predicted increased target PPR but decreased perceiver PPR; finally, overestimation predicted increased target PPR on no-conflict days and decreased perceiver PPR regardless of conflict. These results highlight the double-edged effects of EA on conflict days, and the importance of investigating dyadic EA in a context-sensitive approach. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

A census of P. longum's phytochemicals and their network pharmacological evaluation for identifying novel drug-like molecules against various diseases, with a special focus on neurological disorders.

PubMed

Choudhary, Neha; Singh, Vikram

2018-01-01

Piper longum (P. longum, also called as long pepper) is one of the common culinary herbs that has been extensively used as a crucial constituent in various indigenous medicines, specifically in traditional Indian medicinal system known as Ayurveda. For exploring the comprehensive effect of its constituents in humans at proteomic and metabolic levels, we have reviewed all of its known phytochemicals and enquired about their regulatory potential against various protein targets by developing high-confidence tripartite networks consisting of phytochemical-protein target-disease association. We have also (i) studied immunomodulatory potency of this herb; (ii) developed subnetwork of human PPI regulated by its phytochemicals and could successfully associate its specific modules playing important role in diseases, and (iii) reported several novel drug targets. P10636 (microtubule-associated protein tau, that is involved in diseases like dementia etc.) was found to be the commonly screened target by about seventy percent of these phytochemicals. We report 20 drug-like phytochemicals in this herb, out of which 7 are found to be the potential regulators of 5 FDA approved drug targets. Multi-targeting capacity of 3 phytochemicals involved in neuroactive ligand receptor interaction pathway was further explored via molecular docking experiments. To investigate the molecular mechanism of P. longum's action against neurological disorders, we have developed a computational framework that can be easily extended to explore its healing potential against other diseases and can also be applied to scrutinize other indigenous herbs for drug-design studies.

Random walks on mutual microRNA-target gene interaction network improve the prediction of disease-associated microRNAs.

PubMed

Le, Duc-Hau; Verbeke, Lieven; Son, Le Hoang; Chu, Dinh-Toi; Pham, Van-Huy

2017-11-14

MicroRNAs (miRNAs) have been shown to play an important role in pathological initiation, progression and maintenance. Because identification in the laboratory of disease-related miRNAs is not straightforward, numerous network-based methods have been developed to predict novel miRNAs in silico. Homogeneous networks (in which every node is a miRNA) based on the targets shared between miRNAs have been widely used to predict their role in disease phenotypes. Although such homogeneous networks can predict potential disease-associated miRNAs, they do not consider the roles of the target genes of the miRNAs. Here, we introduce a novel method based on a heterogeneous network that not only considers miRNAs but also the corresponding target genes in the network model. Instead of constructing homogeneous miRNA networks, we built heterogeneous miRNA networks consisting of both miRNAs and their target genes, using databases of known miRNA-target gene interactions. In addition, as recent studies demonstrated reciprocal regulatory relations between miRNAs and their target genes, we considered these heterogeneous miRNA networks to be undirected, assuming mutual miRNA-target interactions. Next, we introduced a novel method (RWRMTN) operating on these mutual heterogeneous miRNA networks to rank candidate disease-related miRNAs using a random walk with restart (RWR) based algorithm. Using both known disease-associated miRNAs and their target genes as seed nodes, the method can identify additional miRNAs involved in the disease phenotype. Experiments indicated that RWRMTN outperformed two existing state-of-the-art methods: RWRMDA, a network-based method that also uses a RWR on homogeneous (rather than heterogeneous) miRNA networks, and RLSMDA, a machine learning-based method. Interestingly, we could relate this performance gain to the emergence of "disease modules" in the heterogeneous miRNA networks used as input for the algorithm. Moreover, we could demonstrate that RWRMTN is stable, performing well when using both experimentally validated and predicted miRNA-target gene interaction data for network construction. Finally, using RWRMTN, we identified 76 novel miRNAs associated with 23 disease phenotypes which were present in a recent database of known disease-miRNA associations. Summarizing, using random walks on mutual miRNA-target networks improves the prediction of novel disease-associated miRNAs because of the existence of "disease modules" in these networks.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, Yi, E-mail: yihooyi@gmail.com; Ericsson, Ida, E-mail: ida.ericsson@ntnu.no; Doseth, Berit, E-mail: berit.doseth@ntnu.no

Activation-induced cytidine deaminase (AID) is the mutator enzyme in adaptive immunity. AID initiates the antibody diversification processes in activated B cells by deaminating cytosine to uracil in immunoglobulin genes. To some extent other genes are also targeted, which may lead to genome instability and B cell malignancy. Thus, it is crucial to understand its targeting and regulation mechanisms. AID is regulated at several levels including subcellular compartmentalization. However, the complex nuclear distribution and trafficking of AID has not been studied in detail previously. In this work, we examined the subnuclear localization of AID and its interaction partner CTNNBL1 and foundmore » that they associate with spliceosome-associated structures including Cajal bodies and nuclear speckles. Moreover, protein kinase A (PKA), which activates AID by phosphorylation at Ser38, is present together with AID in nuclear speckles. Importantly, we demonstrate that AID physically associates with the major spliceosome subunits (small nuclear ribonucleoproteins, snRNPs), as well as other essential splicing components, in addition to the transcription machinery. Based on our findings and the literature, we suggest a transcription-coupled splicing-associated model for AID targeting and activation. - Highlights: • AID and its interaction partner CTNNBL1 localize to Cajal bodies and nuclear speckles. • AID associates with its activating kinase PKA in nuclear speckles. • AID is linked to the splicing machinery in switching B-cells. • Our findings suggest a transcription-coupled splicing associated mechanism for AID targeting and activation.« less

Older Adults Show Deficits in Retrieving and Decoding Associative Mediators Generated at Study

ERIC Educational Resources Information Center

Hertzog, Christopher; Fulton, Erika K.; Mandviwala, Lulua; Dunlosky, John

2013-01-01

We instructed the use of mediators to encode paired-associate items, and then measured both cued recall of targets and mediators. Older adults (n = 49) and younger adults (n = 57) studied a mixed list of concrete and abstract noun pairs under instructions to either generate a sentence or an image to form a new association between normatively…

Neural substrates of empathic accuracy in people with schizophrenia.

PubMed

Harvey, Philippe-Olivier; Zaki, Jamil; Lee, Junghee; Ochsner, Kevin; Green, Michael F

2013-05-01

Empathic deficits in schizophrenia may lead to social dysfunction, but previous studies of schizophrenia have not modeled empathy through paradigms that (1) present participants with naturalistic social stimuli and (2) link brain activity to "accuracy" about inferring other's emotional states. This study addressed this gap by investigating the neural correlates of empathic accuracy (EA) in schizophrenia. Fifteen schizophrenia patients and 15 controls were scanned while continuously rating the affective state of another person shown in a series of videos (ie, targets). These ratings were compared with targets' own self-rated affect, and EA was defined as the correlation between participants' ratings and targets' self-ratings. Targets' self-reported emotional expressivity also was measured. We searched for brain regions whose activity tracked parametrically with (1) perceivers' EA and (2) targets' expressivity. Patients showed reduced EA compared with controls. The left precuneus, left middle frontal gyrus, and bilateral thalamus were significantly more correlated with EA in controls compared with patients. High expressivity in targets was associated with better EA in controls but not in patients. High expressivity was associated with increased brain activity in a large set of regions in controls (eg, fusiform gyrus, medial prefrontal cortex) but not in patients. These results use a naturalistic performance measure to confirm that schizophrenic patients demonstrate impaired ability to understand others' internal states. They provide novel evidence about a potential mechanism for this impairment: schizophrenic patients failed to capitalize on targets' emotional expressivity and also demonstrate reduced neural sensitivity to targets' affective cues.

Nurse opinions and pulse oximeter saturation target limits for preterm infants.

PubMed

Nghiem, Tuyet-Hang; Hagadorn, James I; Terrin, Norma; Syke, Sally; MacKinnon, Brenda; Cole, Cynthia H

2008-05-01

The objectives of this study were to compare pulse oximeter saturation limits targeted by nurses for extremely preterm infants during routine care with nurse opinions regarding appropriate pulse oximeter saturation limits and with policy-specified pulse oximeter saturation limits and to identify factors that influence pulse oximeter saturation limits targeted by nurses. We surveyed nurses in US NICUs with neonatal-perinatal fellowships in 2004. Data collected included pulse oximeter saturation limits targeted by nurses and by NICU policy when present, nurses' opinions about appropriate pulse oximeter saturation limits, and NICU and nurse characteristics. Factors associated with pulse oximeter saturation limits targeted by nurses were identified with hierarchical linear modeling. Among those eligible, 2805 (45%) nurses in 59 (60%) NICUs responded. Forty (68%) of 59 NICUs had a policy that specified a pulse oximeter saturation target range for extremely preterm infants. Among 1957 nurses at NICUs with policies, 540 (28%) accurately identified the upper and lower limits of their NICU's policy and also targeted these values in practice. NICU-specific SDs for individual nurse target limits were less at NICUs with versus without a policy for both upper and lower limits. Hierarchical linear modeling identified presence of pulse oximeter saturation policy, NICU-specific nurse group opinion, and individual nurse opinion as factors significantly associated with individual pulse oximeter saturation target limits. For each percentage point increase in individual opinion upper limit, the individual target upper limit increased by 0.41 percentage point at NICUs with a policy compared with 0.6 percentage point at NICUs with no policy. Presence of policy-specified pulse oximeter saturation limits, nurse group opinion, and individual nurse opinion were independently associated with individual nurse pulse oximeter saturation target limits during routine care of extremely preterm infants. The presence of a policy reduced the influence of individual nurse opinion on targeted pulse oximeter saturation limits and reduced variation among nurse target limits within NICUs.

Photon-Fluence-Weighted let for Radiation Fields Subjected to Epidemiological Studies.

PubMed

Sasaki, Michiya

2017-08-01

In order to estimate the uncertainty of the radiation risk associated with the photon energy in epidemiological studies, photon-fluence-weighted LET values were quantified for photon radiation fields with the target organs and irradiation conditions taken into consideration. The photon fluences giving a unit absorbed dose to the target organ were estimated by using photon energy spectra together with the dose conversion coefficients given in ICRP Publication 116 for the target organs of the colon, bone marrow, stomach, lung, skin and breast with three irradiation geometries. As a result, it was demonstrated that the weighted LET values did not show a clear difference among the photon radiation fields subjected to epidemiological studies, regardless of the target organ and the irradiation geometry.

Evaluation of Parkinson Disease Risk Variants as Expression-QTLs

PubMed Central

Latourelle, Jeanne C.; Dumitriu, Alexandra; Hadzi, Tiffany C.; Beach, Thomas G.; Myers, Richard H.

2012-01-01

The recent Parkinson Disease GWAS Consortium meta-analysis and replication study reports association at several previously confirmed risk loci SNCA, MAPT, GAK/DGKQ, and HLA and identified a novel risk locus at RIT2. To further explore functional consequences of these associations, we investigated modification of gene expression in prefrontal cortex brain samples of pathologically confirmed PD cases (N = 26) and controls (N = 24) by 67 associated SNPs in these 5 loci. Association between the eSNPs and expression was evaluated using a 2-degrees of freedom test of both association and difference in association between cases and controls, adjusted for relevant covariates. SNPs at each of the 5 loci were tested for cis-acting effects on all probes within 250 kb of each locus. Trans-effects of the SNPs on the 39,122 probes passing all QC on the microarray were also examined. From the analysis of cis-acting SNP effects, several SNPs in the MAPT region show significant association to multiple nearby probes, including two strongly correlated probes targeting the gene LOC644246 and the duplicated genes LRRC37A and LRRC37A2, and a third uncorrelated probe targeting the gene DCAKD. Significant cis-associations were also observed between SNPs and two probes targeting genes in the HLA region on chromosome 6. Expanding the association study to examine trans effects revealed an additional 23 SNP-probe associations reaching statistical significance (p<2.8×10−8) including SNPs from the SNCA, MAPT and RIT2 regions. These findings provide additional context for the interpretation of PD associated SNPs identified in recent GWAS as well as potential insight into the mechanisms underlying the observed SNP associations. PMID:23071545

Recombinant adeno-associated virus targets passenger gene expression to cones in primate retina

NASA Astrophysics Data System (ADS)

Mancuso, Katherine; Hendrickson, Anita E.; Connor, Thomas B., Jr.; Mauck, Matthew C.; Kinsella, James J.; Hauswirth, William W.; Neitz, Jay; Neitz, Maureen

2007-05-01

Recombinant adeno-associated virus (rAAV) is a promising vector for gene therapy of photoreceptor-based diseases. Previous studies have demonstrated that rAAV serotypes 2 and 5 can transduce both rod and cone photoreceptors in rodents and dogs, and it can target rods, but not cones in primates. Here we report that using a human cone-specific enhancer and promoter to regulate expression of a green fluorescent protein (GFP) reporter gene in an rAAV-5 vector successfully targeted expression of the reporter gene to primate cones, and the time course of GFP expression was able to be monitored in a living animal using the RetCam II digital imaging system.

Autism, Attention, and Alpha Oscillations: An Electrophysiological Study of Attentional Capture.

PubMed

Keehn, Brandon; Westerfield, Marissa; Müller, Ralph-Axel; Townsend, Jeanne

2017-09-01

Autism spectrum disorder (ASD) is associated with deficits in adaptively orienting attention to behaviorally-relevant information. Neural oscillatory activity plays a key role in brain function and provides a high-resolution temporal marker of attention dynamics. Alpha band (8-12 Hz) activity is associated with both selecting task-relevant stimuli and filtering task-irrelevant information. The present study used electroencephalography (EEG) to examine alpha-band oscillatory activity associated with attentional capture in nineteen children with ASD and twenty-one age- and IQ-matched typically developing (TD) children. Participants completed a rapid serial visual presentation paradigm designed to investigate responses to behaviorally-relevant targets and contingent attention capture by task-irrelevant distractors, which either did or did not share a behaviorally-relevant feature. Participants also completed six minutes of eyes-open resting EEG. In contrast to their TD peers, children with ASD did not evidence posterior alpha desynchronization to behaviorally-relevant targets. Additionally, reduced target-related desynchronization and poorer target detection were associated with increased ASD symptomatology. TD children also showed behavioral and electrophysiological evidence of contingent attention capture, whereas children with ASD showed no behavioral facilitation or alpha desynchronization to distractors that shared a task-relevant feature. Lastly, children with ASD had significantly decreased resting alpha power, and for all participants increased resting alpha levels were associated with greater task-related alpha desynchronization. These results suggest that in ASD under-responsivity and impairments in orienting to salient events within their environment are reflected by atypical EEG oscillatory neurodynamics, which may signify atypical arousal levels and/or an excitatory/inhibitory imbalance.

Radar cross section studies/compact range research

NASA Technical Reports Server (NTRS)

Burnside, W. D.; Dominek, A. K.; Gupta, I. J.; Newman, E. H.; Pathak, P. H.; Peters, L., Jr.

1989-01-01

Achievements in advancing the state-of-the-art in the measurement, control, and analysis of electromagnetic scattering from general aerodynamic targets are summarized. The major topics associated with this study include: (1) electromagnetic scattering analysis; (2) indoor scattering measurement systems; (3) RCS control; (4) waveform processing techniques; (5) material scattering and design studies; (6) design and evaluation of standard targets; and (7) antenna studies. Progress in each of these areas is reported and related publications are listed.

Understanding the polypharmacological anticancer effects of Xiao Chai Hu Tang via a computational pharmacological model

PubMed Central

ZHENG, CHUN-SONG; WU, YIN-SHENG; BAO, HONG-JUAN; XU, XIAO-JIE; CHEN, XING-QIANG; YE, HONG-ZHI; WU, GUANG-WEN; XU, HUI-FENG; LI, XI-HAI; CHEN, JIA-SHOU; LIU, XIAN-XIANG

2014-01-01

Xiao Chai Hu Tang (XCHT), a traditional herbal formula, is widely administered as a cancer treatment. However, the underlying molecular mechanisms of its anticancer effects are not fully understood. In the present study, a computational pharmacological model that combined chemical space mapping, molecular docking and network analysis was employed to predict which chemical compounds in XCHT are potential inhibitors of cancer-associated targets, and to establish a compound-target (C-T) network and compound-compound (C-C) association network. The identified compounds from XCHT demonstrated diversity in chemical space. Furthermore, they occupied regions of chemical space that were the same, or close to, those occupied by drug or drug-like compounds that are associated with cancer, according to the Therapeutic Targets Database. The analysis of the molecular docking and the C-T network demonstrated that the potential inhibitors possessed the properties of promiscuous drugs and combination therapies. The C-C network was classified into four clusters and the different clusters contained various multi-compound combinations that acted on different targets. The study indicated that XCHT has a polypharmacological role in treating cancer and the potential inhibitory components of XCHT require further investigation as potential therapeutic strategies for cancer patients. PMID:24926384

An electrophysiological investigation of reinforcement effects in attention deficit/hyperactivity disorder: Dissociating cue sensitivity from down-stream effects on target engagement and performance.

PubMed

Chronaki, Georgia; Soltesz, Fruzsina; Benikos, Nicholas; Sonuga-Barke, Edmund J S

2017-12-01

Neural hypo-sensitivity to cues predicting positive reinforcement has been observed in ADHD using the Monetary Incentive Delay (MID) task. Here we report the first study using an electrophysiological analogue of this task to distinguish between (i) cue related anticipation of reinforcement and downstream effects on (ii) target engagement and (iii) performance in a clinical sample of adolescents with ADHD and controls. Thirty-one controls and 32 adolescents with ADHD aged 10-16 years performed the electrophysiological (e)-MID task - in which preparatory cues signal whether a response to an upcoming target will be reinforced or not - under three conditions; positive reinforcement, negative reinforcement (response cost) and no consequence (neutral). We extracted values for both cue-related potentials known to be, both, associated with response preparation and modulated by reinforcement (Cue P3 and Cue CNV) and target-related potentials (target P3) and compared these between ADHD and controls. ADHD and controls did not differ on cue-related components on neutral trials. Against expectation, adolescents with ADHD displayed Cue P3 and Cue CNV reinforcement-related enhancement (versus neutral trials) compared to controls. ADHD individuals displayed smaller target P3 amplitudes and slower and more variable performance - but effects were not modulated by reinforcement contingencies. When age, IQ and conduct problems were controlled effects were marginally significant but the pattern of results did not change. ADHD was associated with hypersensitivity to positive (and marginally negative) reinforcement reflected on components often thought to be associated with response preparation - however these did not translate into improved attention to targets. In the case of ADHD, upregulated CNV may be a specific marker of hyper-arousal rather than an enhancement of anticipatory attention to upcoming targets. Future studies should examine the effects of age, IQ and conduct problems on reinforcement sensitivity in ADHD. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Association of quantitative magnetic resonance imaging parameters with histological findings from MRI/ultrasound fusion prostate biopsy.

PubMed

Dianat, Seyed Saeid; Carter, H Ballentine; Schaeffer, Edward M; Hamper, Ulrik M; Epstein, Jonathan I; Macura, Katarzyna J

2015-10-01

Purpose of this pilot study was to correlate quantitative parameters derived from the multiparametric magnetic resonance imaging (MP-MRI) of the prostate with results from MRI guided transrectal ultrasound (MRI/TRUS) fusion prostate biopsy in men with suspected prostate cancer. Thirty-nine consecutive patients who had 3.0T MP-MRI and subsequent MRI/TRUS fusion prostate biopsy were included and 73 MRI-identified targets were sampled by 177 cores. The pre-biopsy MP-MRI consisted of T2-weighted, diffusion weighted (DWI), and dynamic contrast enhanced (DCE) images. The association of quantitative MRI measurements with biopsy histopathology findings was assessed by Mann-Whitney U- test and Kruskal-Wallis test. Of 73 targets, biopsy showed benign prostate tissue in 46 (63%), cancer in 23 (31.5%), and atypia/high grade prostatic intraepithelial neoplasia in four (5.5%) targets. The median volume of cancer-positive targets was 1.3 cm3. The cancer-positive targets were located in the peripheral zone (56.5%), transition zone (39.1%), and seminal vesicle (4.3%). Nine of 23 (39.1%) cancer-positive targets were higher grade cancer (Gleason grade > 6). Higher grade targets and cancer-positive targets compared to benign lesions exhibited lower mean apparent diffusion coefficient (ADC) value (952.7 < 1167.9 < 1278.9), and lower minimal extracellular volume fraction (ECF) (0.13 < 0.185 < 0.213), respectively. The difference in parameters was more pronounced between higher grade cancer and benign lesions. Our findings from a pilot study indicate that quantitative MRI parameters can predict malignant histology on MRI/TRUS fusion prostate biopsy, which is a valuable technique to ensure adequate sampling of MRI-visible suspicious lesions under TRUS guidance and may impact patient management. The DWI-based quantitative measurement exhibits a stronger association with biopsy findings than the other MRI parameters.

Correlates of low physical activity levels in aging men and women: the DR's EXTRA Study (ISRCTN45977199).

PubMed

Hakola, L; Hassinen, M; Komulainen, P; Lakka, T A; Savonen, K; Rauramaa, R

2015-04-01

Recognizing correlates of low physical activity (PA) can help in targeting PA interventions for individuals who would benefit most from increasing their PA. We studied the associations of demographic, social, health, and lifestyle factors with low PA by sex in a population sample of 1,303 Finnish individuals aged 57-78 years. We defined low PA as no moderate or vigorous leisure-time PA reported in an interview. Altogether, 39% of men and 48% of women reported low PA. Satisfactory or poor perceived health and high BMI were independently associated with low PA in both sexes. In men, factors such as age, being divorced or separated, still working, having a weak social network, poor diet, and a health professional's suggestion to increase PA were associated with low PA. In women, cardiovascular disease and depressive symptoms were associated with low PA. These results can be applied in targeting PA interventions.

Literature evidence in open targets - a target validation platform.

PubMed

Kafkas, Şenay; Dunham, Ian; McEntyre, Johanna

2017-06-06

We present the Europe PMC literature component of Open Targets - a target validation platform that integrates various evidence to aid drug target identification and validation. The component identifies target-disease associations in documents and ranks the documents based on their confidence from the Europe PMC literature database, by using rules utilising expert-provided heuristic information. The confidence score of a given document represents how valuable the document is in the scope of target validation for a given target-disease association by taking into account the credibility of the association based on the properties of the text. The component serves the platform regularly with the up-to-date data since December, 2015. Currently, there are a total number of 1168365 distinct target-disease associations text mined from >26 million PubMed abstracts and >1.2 million Open Access full text articles. Our comparative analyses on the current available evidence data in the platform revealed that 850179 of these associations are exclusively identified by literature mining. This component helps the platform's users by providing the most relevant literature hits for a given target and disease. The text mining evidence along with the other types of evidence can be explored visually through https://www.targetvalidation.org and all the evidence data is available for download in json format from https://www.targetvalidation.org/downloads/data .

Targeted resequencing of candidate genes reveals novel variants associated with severe Behçet's uveitis.

PubMed

Kim, Sang Jin; Lee, Seungbok; Park, Changho; Seo, Jeong-Sun; Kim, Jong-Il; Yu, Hyeong Gon

2013-10-18

Behçet's disease (BD) is a chronic systemic inflammatory disorder characterized by four major manifestations: recurrent uveitis, oral and genital ulcers and skin lesions. To identify some pathogenic variants associated with severe Behçet's uveitis, we used targeted and massively parallel sequencing methods to explore the genetic diversity of target regions. A solution-based target enrichment kit was designed to capture whole-exonic regions of 132 candidate genes. Using a multiplexing strategy, 32 samples from patients with a severe type of Behçet's uveitis were sequenced with a Genome Analyzer IIx. We compared the frequency of each variant with that of 59 normal Korean controls, and selected five rare and eight common single-nucleotide variants as the candidates for a replication study. The selected variants were genotyped in 61 cases and 320 controls and, as a result, two rare and seven common variants showed significant associations with severe Behçet's uveitis (P<0.05). Some of these, including rs199955684 in KIR3DL3, rs1801133 in MTHFR, rs1051790 in MICA and rs1051456 in KIR2DL4, were predicted to be damaging by either the PolyPhen-2 or SIFT prediction program. Variants on FCGR3A (rs396991) and ICAM1 (rs5498) have been previously reported as susceptibility loci of this disease, and those on IFNAR1, MTFHR and MICA also replicated the previous reports at the gene level. The KIR3DL3 and KIR2DL4 genes are novel susceptibility genes that have not been reported in association with BD. In conclusion, this study showed that target enrichment and next-generation sequencing technologies can provide valuable information on the genetic predisposition for Behçet's uveitis.

Molecular Targets for Antiepileptic Drug Development

PubMed Central

Meldrum, Brian S.; Rogawski, Michael A.

2007-01-01

Summary This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the α subunits of voltage-gated Na+ channels and also T-type voltage-gated Ca2+ channels) or influence GABA-mediated inhibition. Recently, α2–δ voltage-gated Ca2+ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na+ channels and GABAA receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca2+ channel subunits and auxiliary proteins, A- or M-type voltage-gated K+ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABAB and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current Ih; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na+ channels underlying persistent Na+ currents or GABAA receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies. PMID:17199015

Genetics of osteoporosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Urano, Tomohiko; Inoue, Satoshi, E-mail: INOUE-GER@h.u-tokyo.ac.jp; Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655

Highlights: • Single-nucleotide polymorphisms (SNPs) associated with osteoporosis were identified. • SNPs mapped close to or within VDR and ESR1 are associated with bone mineral density. • WNT signaling pathway plays a pivotal role in regulating bone mineral density. • Genetic studies will be useful for identification of new therapeutic targets. - Abstract: Osteoporosis is a skeletal disease characterized by low bone mineral density (BMD) and microarchitectural deterioration of bone tissue, which increases susceptibility to fractures. BMD is a complex quantitative trait with normal distribution and seems to be genetically controlled (in 50–90% of the cases), according to studies onmore » twins and families. Over the last 20 years, candidate gene approach and genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) that are associated with low BMD, osteoporosis, and osteoporotic fractures. These SNPs have been mapped close to or within genes including those encoding nuclear receptors and WNT-β-catenin signaling proteins. Understanding the genetics of osteoporosis will help identify novel candidates for diagnostic and therapeutic targets.« less

Role of attentional tags in working memory-driven attentional capture.

PubMed

Kuo, Chun-Yu; Chao, Hsuan-Fu

2014-08-01

Recent studies have demonstrated that the contents of working memory capture attention when performing a visual search task. However, it remains an intriguing and unresolved question whether all kinds of items stored in working memory capture attention. The present study investigated this issue by manipulating the attentional tags (target or distractor) associated with information maintained in working memory. The results showed that working memory-driven attentional capture is a flexible process, and that attentional tags associated with items stored in working memory do modulate attentional capture. When items were tagged as a target, they automatically captured attention; however, when items were tagged as a distractor, attentional capture was reduced.

Landscape of Innovation for Cardiovascular Pharmaceuticals: From Basic Science to New Molecular Entities.

PubMed

Beierlein, Jennifer M; McNamee, Laura M; Walsh, Michael J; Kaitin, Kenneth I; DiMasi, Joseph A; Ledley, Fred D

2017-07-01

This study examines the complete timelines of translational science for new cardiovascular therapeutics from the initiation of basic research leading to identification of new drug targets through clinical development and US Food and Drug Administration (FDA) approval of new molecular entities (NMEs) based on this research. This work extends previous studies by examining the association between the growth of research on drug targets and approval of NMEs associated with these targets. Drawing on research on innovation in other technology sectors, where technological maturity is an important determinant in the success or failure of new product development, an analytical model was used to characterize the growth of research related to the known targets for all 168 approved cardiovascular therapeutics. Categorizing and mapping the technological maturity of cardiovascular therapeutics reveal that (1) there has been a distinct transition from phenotypic to targeted methods for drug discovery, (2) the durations of clinical and regulatory processes were significantly influenced by changes in FDA practice, and (3) the longest phase of the translational process was the time required for technology to advance from initiation of research to a statistically defined established point of technology maturation (mean, 30.8 years). This work reveals a normative association between metrics of research maturation and approval of new cardiovascular therapeutics and suggests strategies for advancing translational science by accelerating basic and applied research and improving the synchrony between the maturation of this research and drug development initiatives. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Targeting Interleukin-13 with Tralokinumab Attenuates Lung Fibrosis and Epithelial Damage in a Humanized SCID Idiopathic Pulmonary Fibrosis Model

PubMed Central

Zhang, Huilan; Oak, Sameer R.; Coelho, Ana Lucia; Herath, Athula; Flaherty, Kevin R.; Lee, Joyce; Bell, Matt; Knight, Darryl A.; Martinez, Fernando J.; Sleeman, Matthew A.; Herzog, Erica L.; Hogaboam, Cory M.

2014-01-01

The aberrant fibrotic and repair responses in the lung are major hallmarks of idiopathic pulmonary fibrosis (IPF). Numerous antifibrotic strategies have been used in the clinic with limited success, raising the possibility that an effective therapeutic strategy in this disease must inhibit fibrosis and promote appropriate lung repair mechanisms. IL-13 represents an attractive target in IPF, but its disease association and mechanism of action remains unknown. In the present study, an overexpression of IL-13 and IL-13 pathway markers was associated with IPF, particularly a rapidly progressive form of this disease. Targeting IL-13 in a humanized experimental model of pulmonary fibrosis using tralokinumab (CAT354) was found to therapeutically block aberrant lung remodeling in this model. However, targeting IL-13 was also found to promote lung repair and to restore epithelial integrity. Thus, targeting IL-13 inhibits fibrotic processes and enhances repair processes in the lung. PMID:24325475

Isohormonal therapy of endocrine autoimmunity.

PubMed

Schloot, N; Eisenbarth, G S

1995-06-01

For most autoimmune disorders, the site (if any) of chronic immunization required for perpetuation of autoimmunity is unknown. However, one possible site is the target organ itself. If this were the case, feedback regulation of target cell activity might influence autoimmunity. Here, Nanette Schloot and George Eisenbarth review several recent studies suggesting that therapies that inhibit hormonal secretion of target endocrine organs, and/or modulate immunity by therapy with the isohormone, are associated with disease suppression.

Cross-modal versus within-modal recall: differences in behavioral and brain responses.

PubMed

Butler, Andrew J; James, Karin H

2011-10-31

Although human experience is multisensory in nature, previous research has focused predominantly on memory for unisensory as opposed to multisensory information. In this work, we sought to investigate behavioral and neural differences between the cued recall of cross-modal audiovisual associations versus within-modal visual or auditory associations. Participants were presented with cue-target associations comprised of pairs of nonsense objects, pairs of nonsense sounds, objects paired with sounds, and sounds paired with objects. Subsequently, they were required to recall the modality of the target given the cue while behavioral accuracy, reaction time, and blood oxygenation level dependent (BOLD) activation were measured. Successful within-modal recall was associated with modality-specific reactivation in primary perceptual regions, and was more accurate than cross-modal retrieval. When auditory targets were correctly or incorrectly recalled using a cross-modal visual cue, there was re-activation in auditory association cortex, and recall of information from cross-modal associations activated the hippocampus to a greater degree than within-modal associations. Findings support theories that propose an overlap between regions active during perception and memory, and show that behavioral and neural differences exist between within- and cross-modal associations. Overall the current study highlights the importance of the role of multisensory information in memory. Copyright © 2011 Elsevier B.V. All rights reserved.

Childhood maternal care is associated with DNA methylation of the genes for brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) in peripheral blood cells in adult men and women.

PubMed

Unternaehrer, Eva; Meyer, Andrea Hans; Burkhardt, Susan C A; Dempster, Emma; Staehli, Simon; Theill, Nathan; Lieb, Roselind; Meinlschmidt, Gunther

2015-01-01

In adults, reporting low and high maternal care in childhood, we compared DNA methylation in two stress-associated genes (two target sequences in the oxytocin receptor gene, OXTR; one in the brain-derived neurotrophic factor gene, BDNF) in peripheral whole blood, in a cross-sectional study (University of Basel, Switzerland) during 2007-2008. We recruited 89 participants scoring < 27 (n = 47, 36 women) or > 33 (n = 42, 35 women) on the maternal care subscale of the Parental Bonding Instrument (PBI) at a previous assessment of a larger group (N = 709, range PBI maternal care = 0-36, age range = 19-66 years; median 24 years). 85 participants gave blood for DNA methylation analyses (Sequenom(R) EpiTYPER, San Diego, CA) and cell count (Sysmex PocH-100i™, Kobe, Japan). Mixed model statistical analysis showed greater DNA methylation in the low versus high maternal care group, in the BDNF target sequence [Likelihood-Ratio (1) = 4.47; p = 0.035] and in one OXTR target sequence Likelihood-Ratio (1) = 4.33; p = 0.037], but not the second OXTR target sequence [Likelihood-Ratio (1) < 0.001; p = 0.995). Mediation analyses indicated that differential blood cell count did not explain associations between low maternal care and BDNF (estimate = -0.005, 95% CI = -0.025 to 0.015; p = 0.626) or OXTR DNA methylation (estimate = -0.015, 95% CI = -0.038 to 0.008; p = 0.192). Hence, low maternal care in childhood was associated with greater DNA methylation in an OXTR and a BDNF target sequence in blood cells in adulthood. Although the study has limitations (cross-sectional, a wide age range, only three target sequences in two genes studied, small effects, uncertain relevance of changes in blood cells to gene methylation in brain), the findings may indicate components of the epiphenotype from early life stress.

Association between control to target blood pressures and healthy lifestyle factors among Japanese hypertensive patients: longitudinal data analysis from Fukushima Research of Hypertension (FRESH).

PubMed

Yokokawa, Hirohide; Goto, Aya; Sanada, Hironobu; Watanabe, Tsuyoshi; Felder, Robin A; Jose, Pedro A; Yasumura, Seiji

2014-01-01

To determine success rates in controlling target blood pressures longitudinally by measuring several factors, including lifestyle characteristics associated with uncontrolled blood pressures for target treatment goals. This prospective observational cohort study (September 2008-September 2010) collected information on blood pressure control status and healthy lifestyle factors listed in Breslow's seven health practices through medical records and self-administered questionnaires from 884 of the 1264 Japanese hypertensive patients initially registered in the FRESH study. Multivariate analysis adjusted for associated factors was performed to estimate the association between lifestyle change and "uncontrolled blood pressures" at the final follow-up survey. Median age and proportion of men were 73 years and 39.1%, respectively. All survey failure rates were 37.6% among non-elderly patients (<65 years of age) without diabetes mellitus or chronic kidney disease, and 35.0% among patients with these diseases or myocardial infarction. Maintaining a healthy lifestyle was a protective factor against uncontrolled blood pressures in multivariate analysis. Obesity and smoking status were associated with uncontrolled blood pressures, and exercise frequency was borderline significance. The number of participants with healthy responses for these factors remained relatively low during follow up. Our study revealed low rates of controlled blood pressures, especially in non-elderly patients without diabetes mellitus or chronic kidney disease, and patients with these diseases or myocardial infarction. Our data indicate the need to maintain a healthy lifestyle, in particular, ideal body weight and adequate exercise frequency, for better hypertension management according to treatment guidelines. Copyright © 2013 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

How Actuated Particles Effectively Capture Biomolecular Targets

PubMed Central

2017-01-01

Because of their high surface-to-volume ratio and adaptable surface functionalization, particles are widely used in bioanalytical methods to capture molecular targets. In this article, a comprehensive study is reported of the effectiveness of protein capture by actuated magnetic particles. Association rate constants are quantified in experiments as well as in Brownian dynamics simulations for different particle actuation configurations. The data reveal how the association rate depends on the particle velocity, particle density, and particle assembly characteristics. Interestingly, single particles appear to exhibit target depletion zones near their surface, caused by the high density of capture molecules. The depletion effects are even more limiting in cases with high particle densities. The depletion effects are overcome and protein capture rates are enhanced by applying dynamic particle actuation, resulting in an increase in the association rate constants by up to 2 orders of magnitude. PMID:28192952

Effects of Text, Audio and Learner Control on Text-Sound Association and Cognitive Load of EFL Learners

ERIC Educational Resources Information Center

Enciso Bernal, Ana Maria

2014-01-01

This study investigated the effects of concurrent audio and equivalent onscreen text on the ability of learners of English as a foreign language (EFL) to form associations between textual and aural forms of target vocabulary words. The study also looked at the effects of learner control over an audio sequence on the association of textual and…

Learned Interval Time Facilitates Associate Memory Retrieval

ERIC Educational Resources Information Center

van de Ven, Vincent; Kochs, Sarah; Smulders, Fren; De Weerd, Peter

2017-01-01

The extent to which time is represented in memory remains underinvestigated. We designed a time paired associate task (TPAT) in which participants implicitly learned cue-time-target associations between cue-target pairs and specific cue-target intervals. During subsequent memory testing, participants showed increased accuracy of identifying…

Targeting Tumor-Associated Macrophages as a Potential Strategy to Enhance the Response to Immune Checkpoint Inhibitors.

PubMed

Cassetta, Luca; Kitamura, Takanori

2018-01-01

Inhibition of immune checkpoint pathways in CD8 + T cell is a promising therapeutic strategy for the treatment of solid tumors that has shown significant anti-tumor effects and is now approved by the FDA to treat patients with melanoma and lung cancer. However the response to this therapy is limited to a certain fraction of patients and tumor types, for reasons still unknown. To ensure success of this treatment, CD8 + T cells, the main target of the checkpoint inhibitors, should exert full cytotoxicity against tumor cells. However recent studies show that tumor-associated macrophages (TAM) can impede this process by different mechanisms. In this mini-review we will summarize recent studies showing the effect of TAM targeting on immune checkpoint inhibitors efficacy. We will also discuss on the limitations of the current strategies as well on the future scientific challenges for the progress of the tumor immunology field.

A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis.

PubMed

Agrawal, Praveen; Fontanals-Cirera, Barbara; Sokolova, Elena; Jacob, Samson; Vaiana, Christopher A; Argibay, Diana; Davalos, Veronica; McDermott, Meagan; Nayak, Shruti; Darvishian, Farbod; Castillo, Mireia; Ueberheide, Beatrix; Osman, Iman; Fenyö, David; Mahal, Lara K; Hernando, Eva

2017-06-12

Association of aberrant glycosylation with melanoma progression is based mainly on analyses of cell lines. Here we present a systems-based study of glycomic changes and corresponding enzymes associated with melanoma metastasis in patient samples. Upregulation of core fucosylation (FUT8) and downregulation of α-1,2 fucosylation (FUT1, FUT2) were identified as features of metastatic melanoma. Using both in vitro and in vivo studies, we demonstrate FUT8 is a driver of melanoma metastasis which, when silenced, suppresses invasion and tumor dissemination. Glycoprotein targets of FUT8 were enriched in cell migration proteins including the adhesion molecule L1CAM. Core fucosylation impacted L1CAM cleavage and the ability of L1CAM to support melanoma invasion. FUT8 and its targets represent therapeutic targets in melanoma metastasis. Copyright © 2017 Elsevier Inc. All rights reserved.

Quantification of non-coding RNA target localization diversity and its application in cancers.

PubMed

Cheng, Lixin; Leung, Kwong-Sak

2018-04-01

Subcellular localization is pivotal for RNAs and proteins to implement biological functions. The localization diversity of protein interactions has been studied as a crucial feature of proteins, considering that the protein-protein interactions take place in various subcellular locations. Nevertheless, the localization diversity of non-coding RNA (ncRNA) target proteins has not been systematically studied, especially its characteristics in cancers. In this study, we provide a new algorithm, non-coding RNA target localization coefficient (ncTALENT), to quantify the target localization diversity of ncRNAs based on the ncRNA-protein interaction and protein subcellular localization data. ncTALENT can be used to calculate the target localization coefficient of ncRNAs and measure how diversely their targets are distributed among the subcellular locations in various scenarios. We focus our study on long non-coding RNAs (lncRNAs), and our observations reveal that the target localization diversity is a primary characteristic of lncRNAs in different biotypes. Moreover, we found that lncRNAs in multiple cancers, differentially expressed cancer lncRNAs, and lncRNAs with multiple cancer target proteins are prone to have high target localization diversity. Furthermore, the analysis of gastric cancer helps us to obtain a better understanding that the target localization diversity of lncRNAs is an important feature closely related to clinical prognosis. Overall, we systematically studied the target localization diversity of the lncRNAs and uncovered its association with cancer.

Gene-based rare allele analysis identified a risk gene of Alzheimer's disease.

PubMed

Kim, Jong Hun; Song, Pamela; Lim, Hyunsun; Lee, Jae-Hyung; Lee, Jun Hong; Park, Sun Ah

2014-01-01

Alzheimer's disease (AD) has a strong propensity to run in families. However, the known risk genes excluding APOE are not clinically useful. In various complex diseases, gene studies have targeted rare alleles for unsolved heritability. Our study aims to elucidate previously unknown risk genes for AD by targeting rare alleles. We used data from five publicly available genetic studies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the database of Genotypes and Phenotypes (dbGaP). A total of 4,171 cases and 9,358 controls were included. The genotype information of rare alleles was imputed using 1,000 genomes. We performed gene-based analysis of rare alleles (minor allele frequency≤3%). The genome-wide significance level was defined as meta P<1.8×10(-6) (0.05/number of genes in human genome = 0.05/28,517). ZNF628, which is located at chromosome 19q13.42, showed a genome-wide significant association with AD. The association of ZNF628 with AD was not dependent on APOE ε4. APOE and TREM2 were also significantly associated with AD, although not at genome-wide significance levels. Other genes identified by targeting common alleles could not be replicated in our gene-based rare allele analysis. We identified that rare variants in ZNF628 are associated with AD. The protein encoded by ZNF628 is known as a transcription factor. Furthermore, the associations of APOE and TREM2 with AD were highly significant, even in gene-based rare allele analysis, which implies that further deep sequencing of these genes is required in AD heritability studies.

Host genetic determinants of HIV pathogenesis: an immunologic perspective.

PubMed

Hunt, Peter W; Carrington, Mary

2008-05-01

The purpose of this review is to highlight recent advances in our understanding of host genetic determinants of HIV pathogenesis and to provide a theoretical framework for interpreting these studies in the context of our evolving understanding of HIV immunopathogenesis. The first genome-wide association analysis of host determinants of HIV pathogenesis and other recent studies evaluating the interaction between killer cell immunoglobulin-like receptors and human leukocyte antigen alleles have implicated both adaptive and innate immune responses in the control of HIV replication. Furthermore, genetic variation associated with the expression of CCR5 and its ligand have been strongly associated with both decreased susceptibility to HIV infection and delayed clinical progression, independent of their effects on viral replication, suggesting a potential role for CCR5 inhibitors as immune-based therapies in HIV disease. Host factors associated with the control of HIV replication may help identify important targets for vaccine design, while those associated with delayed clinical progression provide targets for future immune-based therapies against HIV infection.

Ecological correlates of the non-indigenous parasitoid assemblage associated with a Hawaiian endemic moth.

PubMed

Kaufman, Leyla V; Wright, Mark G

2011-08-01

Understanding what ecological factors might predispose indigenous habitats to invasion by invasive species is an important aspect of conservation and invasive species management, particularly when biological control is considered for suppression of the invasive species. This study seeks to identify ecological factors that might play a role in determining the structure of the parasitoid assemblage associated with caterpillars of the endemic Hawaiian moth Udea stellata (Crambidae). Parasitoids were reared from field-collected U. stellata larvae at 18 locations. Fourteen environmental variables were measured at each site. Two multivariate analyses, principal component analysis (PCA) and partial redundancy analysis (RDA), were used to analyze the parasitoid assemblage across a range of habitats varying in environmental characteristics. The PCA analysis showed that the occurrence of some species were highly correlated, and associated with less disturbed sites, whereas other species were associated with sites of medium and high levels of disturbance. The RDA analysis showed that only three of the measured environmental variables (U. stellata density, elevation, and level of habitat disturbance) significantly explained variability in the parasitoid assemblage among sites. There was greater parasitoid species richness associated with U. stellata larvae at higher elevation sites with a lower degree of habitat disturbance by exotic vegetation. The purposely introduced parasitoid species were associated with the non-target moth at sites located at higher elevations with low levels of disturbance. Multivariate analysis has the potential to provide valuable insights into the identification of important environmental factors that mediate parasitoid assemblage structure and level of parasitism on a particular target or non-target species, and therefore facilitate identification of suitable target habitats or susceptible non-target habitats.

Clathrin-mediated Endocytosis and Subsequent Endo-Lysosomal Trafficking of Adeno-associated Virus/Phage*

PubMed Central

Stoneham, Charlotte A.; Hollinshead, Michael; Hajitou, Amin

2012-01-01

Adeno-associated virus/phage (AAVP) is a gene delivery vector constructed as a hybrid between adeno-associated virus and filamentous phage. Tumor targeting following systemic administration has previously been demonstrated in several in vivo cancer models, with tumor specificity achieved through display of an αv integrin-targeting ligand on the capsid. However, high titers of AAVP are required for transduction of large numbers of mammalian cells. This study is the first to investigate the mechanisms involved in entry and intracellular trafficking of AAVP. Using a combination of flow cytometry, confocal, and electron microscopy techniques, together with pharmacological agents, RNAi and dominant negative mutants, we have demonstrated that targeted AAVP endocytosis is both dynamin and clathrin-dependent. Following entry, the majority of AAVP particles are sequestered by the endosomal-lysosomal degradative pathway. Finally, we have demonstrated that disruption of this pathway leads to improved transgene expression by AAVP, thus demonstrating that escape from the late endosomes/lysosomes is a critical step for improving gene delivery by AAVP. These findings have important implications for the rational design of improved AAVP and RGD-targeted vectors. PMID:22915587

Putative kappa opioid heteromers as targets for developing analgesics free of adverse effects.

PubMed

Le Naour, Morgan; Lunzer, Mary M; Powers, Michael D; Kalyuzhny, Alexander E; Benneyworth, Michael A; Thomas, Mark J; Portoghese, Philip S

2014-08-14

It is now generally recognized that upon activation by an agonist, β-arrestin associates with G protein-coupled receptors and acts as a scaffold in creating a diverse signaling network that could lead to adverse effects. As an approach to reducing side effects associated with κ opioid agonists, a series of β-naltrexamides 3-10 was synthesized in an effort to selectively target putative κ opioid heteromers without recruiting β-arrestin upon activation. The most potent derivative 3 (INTA) strongly activated KOR-DOR and KOR-MOR heteromers in HEK293 cells. In vivo studies revealed 3 to produce potent antinociception, which, when taken together with antagonism data, was consistent with the activation of both heteromers. 3 was devoid of tolerance, dependence, and showed no aversive effect in the conditioned place preference assay. As immunofluorescence studies indicated no recruitment of β-arrestin2 to membranes in coexpressed KOR-DOR cells, this study suggests that targeting of specific putative heteromers has the potential to identify leads for analgesics devoid of adverse effects.

Comparison of cancer-associated genetic abnormalities in columnar-lined esophagus tissues with and without goblet cells.

PubMed

Bandla, Santhoshi; Peters, Jeffrey H; Ruff, David; Chen, Shiaw-Min; Li, Chieh-Yuan; Song, Kunchang; Thoms, Kimberly; Litle, Virginia R; Watson, Thomas; Chapurin, Nikita; Lada, Michal; Pennathur, Arjun; Luketich, James D; Peterson, Derick; Dulak, Austin; Lin, Lin; Bass, Adam; Beer, David G; Godfrey, Tony E; Zhou, Zhongren

2014-07-01

To determine and compare the frequency of cancer-associated genetic abnormalities in esophageal metaplasia biopsies with and without goblet cells. Barrett's esophagus is associated with increased risk of esophageal adenocarcinoma (EAC), but the appropriate histologic definition of Barrett's esophagus is debated. Intestinal metaplasia (IM) is defined by the presence of goblet cells whereas nongoblet cell metaplasia (NGM) lacks goblet cells. Both have been implicated in EAC risk but this is controversial. Although IM is known to harbor genetic changes associated with EAC, little is known about NGM. We hypothesized that if NGM and IM infer similar EAC risk, then they would harbor similar genetic aberrations in genes associated with EAC. Ninety frozen NGM, IM, and normal tissues from 45 subjects were studied. DNA copy number abnormalities were identified using microarrays and fluorescence in situ hybridization. Targeted sequencing of all exons from 20 EAC-associated genes was performed on metaplasia biopsies using Ion AmpliSeq DNA sequencing. Frequent copy number abnormalities targeting cancer-associated genes were found in IM whereas no such changes were observed in NGM. In 1 subject, fluorescence in situ hybridization confirmed loss of CDKN2A and amplification of chromosome 8 in IM but not in a nearby NGM biopsy. Targeted sequencing revealed 11 nonsynonymous mutations in 16 IM samples and 2 mutations in 19 NGM samples. This study reports the largest and most comprehensive comparison of DNA aberrations in IM and NGM genomes. Our results show that IM has a much higher frequency of cancer-associated mutations than NGM.

The Effects of Receptive and Productive Learning of Word Pairs on Vocabulary Knowledge

ERIC Educational Resources Information Center

Webb, Stuart

2009-01-01

English as a foreign language students in Japan learned target words in word pairs receptively and productively. Five aspects of vocabulary knowledge--orthography, association, syntax, grammatical functions, and meaning and form--were each measured by receptive and productive tests. The study uses an innovative methodology in that each target word…

Therapeutic target discovery using Boolean network attractors: improvements of kali

PubMed Central

Guziolowski, Carito

2018-01-01

In a previous article, an algorithm for identifying therapeutic targets in Boolean networks modelling pathological mechanisms was introduced. In the present article, the improvements made on this algorithm, named kali, are described. These improvements are (i) the possibility to work on asynchronous Boolean networks, (ii) a finer assessment of therapeutic targets and (iii) the possibility to use multivalued logic. kali assumes that the attractors of a dynamical system, such as a Boolean network, are associated with the phenotypes of the modelled biological system. Given a logic-based model of pathological mechanisms, kali searches for therapeutic targets able to reduce the reachability of the attractors associated with pathological phenotypes, thus reducing their likeliness. kali is illustrated on an example network and used on a biological case study. The case study is a published logic-based model of bladder tumorigenesis from which kali returns consistent results. However, like any computational tool, kali can predict but cannot replace human expertise: it is a supporting tool for coping with the complexity of biological systems in the field of drug discovery. PMID:29515890

Loop-Mediated Isothermal Amplification Targeting Actin DNA of Trichomonas vaginalis.

PubMed

Goo, Youn-Kyoung; Shin, Won-Sik; Yang, Hye-Won; Joo, So-Young; Song, Su-Min; Ryu, Jae-Sook; Kong, Hyun-Hee; Lee, Won-Ki; Chung, Dong-Il; Hong, Yeonchul

2016-06-01

Trichomoniasis caused by Trichomonas vaginalis is a common sexually transmitted disease. Its association with several health problems, including preterm birth, pelvic inflammatory disease, cervical cancer, and transmission of human immunodeficiency virus, emphasizes the importance of improved access to early and accurate detection of T. vaginalis. In this study, a rapid and efficient loop-mediated isothermal amplification-based method for the detection of T. vaginalis was developed and validated, using vaginal swab specimens from subjects suspected to have trichomoniasis. The LAMP assay targeting the actin gene was highly sensitive with detection limits of 1 trichomonad and 1 pg of T. vaginalis DNA per reaction, and specifically amplified the target gene only from T. vaginalis. Validation of this assay showed that it had the highest sensitivity and better agreement with PCR (used as the gold standard) compared to microscopy and multiplex PCR. This study showed that the LAMP assay, targeting the actin gene, could be used to diagnose early infections of T. vaginalis. Thus, we have provided an alternative molecular diagnostic tool and a point-of-care test that may help to prevent trichomoniasis transmission and associated complications.

Can exercise change the stereotypes associated with individuals with cancer?

PubMed

Clément-Guillotin, C; Falzon, C; d'Arripe-Longueville, F

2015-08-01

The purpose of this study was to examine whether exercising can positively influence the stereotypes associated with individuals with cancer and, more specifically, have an effect on the impression formation related to warmth and competence. A total of 193 French college students (Mage  = 21.08, SD = 1.44 years; 88 females and 105 males) were randomly assigned to one of the conditions of a 2 (participant sex) × 2 (target health status: cancer vs no information) × 3 (target exercise status: exerciser vs non-exerciser vs no information) experimental design. Results indicated that exercising target with cancer was perceived as the most competent compared with targets with cancer and those without information about cancer. These results suggest that exercising could be an effective way to undermine cancer stereotypes and reduce discrimination against people with cancer. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Roles of the nuclear lamina in stable nuclear association and assembly of a herpesviral transactivator complex on viral immediate-early genes.

PubMed

Silva, Lindsey; Oh, Hyung Suk; Chang, Lynne; Yan, Zhipeng; Triezenberg, Steven J; Knipe, David M

2012-01-01

Little is known about the mechanisms of gene targeting within the nucleus and its effect on gene expression, but most studies have concluded that genes located near the nuclear periphery are silenced by heterochromatin. In contrast, we found that early herpes simplex virus (HSV) genome complexes localize near the nuclear lamina and that this localization is associated with reduced heterochromatin on the viral genome and increased viral immediate-early (IE) gene transcription. In this study, we examined the mechanism of this effect and found that input virion transactivator protein, virion protein 16 (VP16), targets sites adjacent to the nuclear lamina and is required for targeting of the HSV genome to the nuclear lamina, exclusion of heterochromatin from viral replication compartments, and reduction of heterochromatin on the viral genome. Because cells infected with the VP16 mutant virus in1814 showed a phenotype similar to that of lamin A/C(-/-) cells infected with wild-type virus, we hypothesized that the nuclear lamina is required for VP16 activator complex formation. In lamin A/C(-/-) mouse embryo fibroblasts, VP16 and Oct-1 showed reduced association with the viral IE gene promoters, the levels of VP16 and HCF-1 stably associated with the nucleus were lower than in wild-type cells, and the association of VP16 with HCF-1 was also greatly reduced. These results show that the nuclear lamina is required for stable nuclear localization and formation of the VP16 activator complex and provide evidence for the nuclear lamina being the site of assembly of the VP16 activator complex. The targeting of chromosomes in the cell nucleus is thought to be important in the regulation of expression of genes on the chromosomes. The major documented effect of intranuclear targeting has been silencing of chromosomes at sites near the nuclear periphery. In this study, we show that targeting of the herpes simplex virus DNA genome to the nuclear periphery promotes formation of transcriptional activator complexes on the viral genome, demonstrating that the nuclear periphery also has sites for activation of transcription. These results highlight the importance of the nuclear lamina, the structure that lines the inner nuclear membrane, in both transcriptional activation and repression. Future studies defining the molecular structures of these two types of nuclear sites should define new levels of gene regulation.

Adverse drug reaction prediction using scores produced by large-scale drug-protein target docking on high-performance computing machines.

PubMed

LaBute, Montiago X; Zhang, Xiaohua; Lenderman, Jason; Bennion, Brian J; Wong, Sergio E; Lightstone, Felice C

2014-01-01

Late-stage or post-market identification of adverse drug reactions (ADRs) is a significant public health issue and a source of major economic liability for drug development. Thus, reliable in silico screening of drug candidates for possible ADRs would be advantageous. In this work, we introduce a computational approach that predicts ADRs by combining the results of molecular docking and leverages known ADR information from DrugBank and SIDER. We employed a recently parallelized version of AutoDock Vina (VinaLC) to dock 906 small molecule drugs to a virtual panel of 409 DrugBank protein targets. L1-regularized logistic regression models were trained on the resulting docking scores of a 560 compound subset from the initial 906 compounds to predict 85 side effects, grouped into 10 ADR phenotype groups. Only 21% (87 out of 409) of the drug-protein binding features involve known targets of the drug subset, providing a significant probe of off-target effects. As a control, associations of this drug subset with the 555 annotated targets of these compounds, as reported in DrugBank, were used as features to train a separate group of models. The Vina off-target models and the DrugBank on-target models yielded comparable median area-under-the-receiver-operating-characteristic-curves (AUCs) during 10-fold cross-validation (0.60-0.69 and 0.61-0.74, respectively). Evidence was found in the PubMed literature to support several putative ADR-protein associations identified by our analysis. Among them, several associations between neoplasm-related ADRs and known tumor suppressor and tumor invasiveness marker proteins were found. A dual role for interstitial collagenase in both neoplasms and aneurysm formation was also identified. These associations all involve off-target proteins and could not have been found using available drug/on-target interaction data. This study illustrates a path forward to comprehensive ADR virtual screening that can potentially scale with increasing number of CPUs to tens of thousands of protein targets and millions of potential drug candidates.

Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: a propensity score-derived analysis of a population-based, multicentre prospective cohort.

PubMed

López-Cortés, L E; Almirante, B; Cuenca-Estrella, M; Garnacho-Montero, J; Padilla, B; Puig-Asensio, M; Ruiz-Camps, I; Rodríguez-Baño, J

2016-08-01

We compared the clinical efficacy of fluconazole and echinocandins in the treatment of candidemia in real practice. The CANDIPOP study is a prospective, population-based cohort study on candidemia carried out between May 2010 and April 2011 in 29 Spanish hospitals. Using strict inclusion criteria, we separately compared the impact of empirical and targeted therapy with fluconazole or echinocandins on 30-day mortality. Cox regression, including a propensity score (PS) for receiving echinocandins, stratified analysis on the PS quartiles and PS-based matched analyses, were performed. The empirical and targeted therapy cohorts comprised 316 and 421 cases, respectively; 30-day mortality was 18.7% with fluconazole and 33.9% with echinocandins (p 0.02) in the empirical therapy group and 19.8% with fluconazole and 27.7% with echinocandins (p 0.06) in the targeted therapy group. Multivariate Cox regression analysis including PS showed that empirical therapy with fluconazole was associated with better prognosis (adjusted hazard ratio 0.38; 95% confidence interval 0.17-0.81; p 0.01); no differences were found within each PS quartile or in cases matched according to PS. Targeted therapy with fluconazole did not show a significant association with mortality in the Cox regression analysis (adjusted hazard ratio 0.77; 95% confidence interval 0.41-1.46; p 0.63), in the PS quartiles or in PS-matched cases. The results were similar among patients with severe sepsis and septic shock. Empirical or targeted treatment with fluconazole was not associated with increased 30-day mortality compared to echinocandins among adults with candidemia. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Prevalence of new candidate pathogens Prevotella baroniae, Prevotella multisaccharivorax and as-yet-uncultivated Bacteroidetes clone X083 in primary endodontic infections.

PubMed

Rôças, Isabela N; Siqueira, José F

2009-10-01

Culture-independent studies have revealed a broad spectrum of oral bacterial taxa that may be associated with disease. This study investigated the prevalence of three new candidate oral pathogens: Prevotella baroniae, Prevotella multisaccharivorax, and as-yet-uncultivated Bacteroidetes oral clone X083 in primary endodontic infections using a devised culture-independent approach. Genomic DNA was isolated from samples taken from 52 teeth with different forms of apical periodontitis and used as template in a taxon-specific 16S rRNA gene-based nested polymerase chain reaction assay to determine the prevalence of the 3 target taxa. Bacteroidetes clone X083, P. baroniae, and P. multisaccharivorax were respectively detected in 81%, 43%, and 38% of the root canals of teeth associated with chronic apical periodontitis, in 60%, 40% and 40% of the canals of teeth with acute apical periodontitis, and in 14%, 24%, and 5% of the pus aspirates from acute apical abscesses. No targeted taxon was positively associated with abscesses or clinical symptoms. Overall, Bacteroidetes clone X083, P. baroniae, and P. multisaccharivorax were found in 50%, 35%, and 25% of the samples taken from primary endodontic infections, respectively. Findings confirmed that the two newly named species and the uncultivated phylotype targeted in this study are associated with different forms of apical periodontitis, and a pathogenetic or at least an ecologic role is suspected.

Comprehensive gene- and pathway-based analysis of depressive symptoms in older adults.

PubMed

Nho, Kwangsik; Ramanan, Vijay K; Horgusluoglu, Emrin; Kim, Sungeun; Inlow, Mark H; Risacher, Shannon L; McDonald, Brenna C; Farlow, Martin R; Foroud, Tatiana M; Gao, Sujuan; Callahan, Christopher M; Hendrie, Hugh C; Niculescu, Alexander B; Saykin, Andrew J

2015-01-01

Depressive symptoms are common in older adults and are particularly prevalent in those with or at elevated risk for dementia. Although the heritability of depression is estimated to be substantial, single nucleotide polymorphism-based genome-wide association studies of depressive symptoms have had limited success. In this study, we performed genome-wide gene- and pathway-based analyses of depressive symptom burden. Study participants included non-Hispanic Caucasian subjects (n = 6,884) from three independent cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Health and Retirement Study (HRS), and the Indiana Memory and Aging Study (IMAS). Gene-based meta-analysis identified genome-wide significant associations (ANGPT4 and FAM110A, q-value = 0.026; GRM7-AS3 and LRFN5, q-value = 0.042). Pathway analysis revealed enrichment of association in 105 pathways, including multiple pathways related to ERK/MAPK signaling, GSK3 signaling in bipolar disorder, cell development, and immune activation and inflammation. GRM7, ANGPT4, and LRFN5 have been previously implicated in psychiatric disorders, including the GRM7 region displaying association with major depressive disorder. The ERK/MAPK signaling pathway is a known target of antidepressant drugs and has important roles in neuronal plasticity, and GSK3 signaling has been previously implicated in Alzheimer's disease and as a promising therapeutic target for depression. Our results warrant further investigation in independent and larger cohorts and add to the growing understanding of the genetics and pathobiology of depressive symptoms in aging and neurodegenerative disorders. In particular, the genes and pathways demonstrating association with depressive symptoms may be potential therapeutic targets for these symptoms in older adults.

Targeted Nanoparticles for Image-guided Treatment of Triple Negative Breast Cancer: Clinical Significance and Technological Advances

PubMed Central

Miller-Kleinhenz, Jasmine M.; Bozeman, Erica N.

2015-01-01

Effective treatment of triple negative breast cancer (TNBC) with its aggressive tumor biology, highly heterogeneous tumor cells, and poor prognosis requires an integrated therapeutic approach that addresses critical issues in cancer therapy. Multifunctional nanoparticles with the abilities of targeted drug delivery and non-invasive imaging for monitoring drug delivery and responses to therapy, such as theranostic nanoparticles, hold great promise towards the development of novel therapeutic approaches for the treatment of TNBC using a single therapeutic platform. The biological and pathological characteristics of TNBC provide insight into several potential molecular targets for current and future nanoparticle based therapeutics. Extensive tumor stroma, highly proliferative cells, and a high rate of drug-resistance are all barriers that must be appropriately addressed in order for these nanotherapeutic platforms to be effective. Utilization of the enhanced permeability and retention (EPR) effect coupled with active targeting of cell surface receptors expressed by TNBC cells, and tumor associated endothelial cells, stromal fibroblasts and macrophages is likely to overcome such barriers to facilitate more effective drug delivery. An in depth summary of current studies investigating targeted nanoparticles in preclinical TNBC mouse and human xenograft models is presented. This review aims to outline the current status of nanotherapeutic options for TNBC patients, identification of promising molecular targets, challenges associated with the development of targeted nanotherapeutics, the research done by our group as well as others and future perspectives on the nanomedicine field and ways to translate current preclinical studies into the clinic. PMID:25966677

Creativity and cognitive control: Behavioral and ERP evidence that divergent thinking, but not real-life creative achievement, relates to better cognitive control.

PubMed

Zabelina, Darya L; Ganis, Giorgio

2018-02-13

Two studies used event-related potentials (ERPs) to examine whether and how divergent thinking and creative achievement are linked to attentional flexibility and cognitive control as indexed by response times and by the amplitude of the anterior N2 ERP component. Both experiments used an oddball paradigm in which participants viewed hierarchical letter stimuli and identified target letters in frequent and rare target trials. The successful identification of targets required attentional flexibility when switching levels of attention (from the frequent global to the rare local attentional level, or vice-versa). Divergent thinkers showed smaller switching times on rare target trials, indicating higher levels of attentional flexibility. Furthermore, divergent thinkers engaged cognitive control processes more strongly at the moment of the attentional switch (and before the response), as indicated by a larger N2 difference between frequent and rare targets. In contrast, creative achievement was associated neither with the switching times on rare target trials, nor with a larger N2 difference between frequent and rare targets. All results held when controlling for general intelligence. Results from these studies provide evidence that divergent thinking is associated with higher attentional flexibility and that such attentional flexibility relies on cognitive control processes required when disengaging from one level of attention (e.g., global), and shifting to the other level of attention (e.g., local). Copyright © 2018 Elsevier Ltd. All rights reserved.

Reduction in mRNA and protein expression of a nicotinic acetylcholine receptor α8 subunit is associated with resistance to imidacloprid in the brown planthopper, Nilaparvata lugens.

PubMed

Zhang, Yixi; Wang, Xin; Yang, Baojun; Hu, Yuanyuan; Huang, Lixin; Bass, Chris; Liu, Zewen

2015-11-01

Target-site resistance is commonly caused by qualitative changes in insecticide target-receptors and few studies have implicated quantitative changes in insecticide targets in resistance. Here we show that resistance to imidacloprid in a selected strain of Nilaparvata lugens is associated with a reduction in expression levels of the nicotinic acetylcholine receptor (nAChR) subunit Nlα8. Synergism bioassays of the selected strain suggested resistance was conferred, in part, by a target-site mechanism. Sequencing of N. lugens nAChR subunit genes identified no mutations associated with resistance, however, a decrease in mRNA and protein levels of Nlα8 was observed during selection. RNA interference knockdown of Nlα8 decreased the sensitivity of N. lugens to imidacloprid, demonstrating that a decrease in Nlα8 expression is sufficient to confer resistance in vivo. Radioligand binding assays revealed that the affinity of the high-affinity imidacloprid-binding site of native nAChRs was reduced by selection, and reducing the amount of Nlα8 cRNA injected into Xenopus oocytes significantly decreased imidacloprid potency on recombinant receptors. Taken together, these results provide strong evidence that a decrease in Nlα8 levels confers resistance to imidacloprid in N. lugens, and thus provides a rare example of target-site resistance associated with a quantitative rather than qualitative change. In insects, target-site mutations often cause high resistance to insecticides, such as neonicotinoids acting on nicotinic acetylcholine receptors (nAChRs). Here we found that a quantitative change in target-protein level, decrease in mRNA and protein levels of Nlα8, contributed importantly to imidacloprid resistance in Nilaparvata lugens. This finding provides a new target-site mechanism of insecticide resistance. © 2015 International Society for Neurochemistry.

Demographic and individual correlates of achieving 10,000 steps/day: use of pedometers in a population-based study.

PubMed

McCormack, Gavin; Giles-Corti, Billie; Milligan, Rex

2006-04-01

The 10,000 steps per day message has become popular, yet few studies have examined correlates associated with achieving this behaviour target. This paper examines demographic and individual factors associated with adults achieving 10,000 steps/day. Participants in a state-wide, cross-sectional physical activity survey were invited to take part in a pedometer study (n=603, 45% response rate). A pedometer was worn for one week and daily steps recorded in a diary. Participants providing four or more days of pedometer data (n=428) were dichotomised based on achievement of > or =10,000 steps/day. Men performed significantly more daily steps than women on average (10,079+/-3,848 and 9,169+/-3,800, p=0.01). In males, those less likely to achieve > or =10,000 steps/day were > or =60 years of age (OR=0.21) and overweight (i.e. body mass index > or =25kgm2) (OR=0.40), while men who regularly walked in the workplace (OR=1.44), who did vigorous activity at work (OR= 3.75), or who were employed in a blue-collar occupation (OR=4.45) were more likely to report reaching this target. In women, being overweight (OR=0.55) was negatively associated with achieving > or =10,000 steps/day, while participating in > or =150 minutes of leisure-time physical activity/week (OR=2.26) was positively associated with reaching this target. Workplace physical activity and working in blue-collar occupations contributes to the achievement of 10,000 steps/day in males. People who achieve current national physical activity guidelines also achieve 10,000 steps/day. Older adults and those overweight are less likely to achieve this behaviour target.

Targeted genome editing in a quail cell line using a customized CRISPR/Cas9 system.

PubMed

Ahn, Jinsoo; Lee, Joonbum; Park, Ju Yeon; Oh, Keon Bong; Hwang, Seongsoo; Lee, Chang-Won; Lee, Kichoon

2017-05-01

Soon after RNA-guided Cas9 (CRISPR-associated protein 9) endonuclease opened a new era of targeted genome editing, the CRISPR/Cas9 platform began to be extensively used to modify genes in various types of cells and organisms. However, successful CRISPR/Cas9-mediated insertion/deletion (indel) mutation remains to be demonstrated in avian cell lines. The objective of this study was to design a poultry-specific CRISPR/Cas9 system to efficiently introduce targeted deletion mutation in chromosomes of the quail muscle clone 7 (QM7) cell line using a customized quail CRISPR vector. In this study, two avian-specific promoters, quail 7SK (q7SK) promoter and CBh promoter, the hybrid form of cytomegalovirus and chicken β-actin promoters, were cloned into a CRISPR vector for the expression of guide RNA and Cas9 protein, respectively. Then, guide RNA, which was designed to target 20-base pair (bp) nucleotides in the quail melanophilin (MLPH) locus, was ligated to the modified CRISPR vector and transfected to QM7 cells. Our results showed multiple indel mutations in the quail MLPH locus in nearly half of the alleles being tested, suggesting the high efficiency of the system for targeted gene modification. The new CRISPR vector developed from this study has the potential application to generate knockout avian cell lines and knockout poultry. © 2016 Poultry Science Association Inc.

Associative memory model with spontaneous neural activity

NASA Astrophysics Data System (ADS)

Kurikawa, Tomoki; Kaneko, Kunihiko

2012-05-01

We propose a novel associative memory model wherein the neural activity without an input (i.e., spontaneous activity) is modified by an input to generate a target response that is memorized for recall upon the same input. Suitable design of synaptic connections enables the model to memorize input/output (I/O) mappings equaling 70% of the total number of neurons, where the evoked activity distinguishes a target pattern from others. Spontaneous neural activity without an input shows chaotic dynamics but keeps some similarity with evoked activities, as reported in recent experimental studies.

Implicit associative learning in synesthetes and nonsynesthetes

PubMed Central

Bankieris, Kaitlyn R.; Aslin, Richard N.

2016-01-01

Although cross-modal neural connections and genetic underpinnings are prominent in most current theories regarding the development of synesthesia, the potential role of associative learning in the formation of synesthetic associations has recently been revitalized. In this study, we investigated implicit associative learning in synesthetes and nonsynesthetes by recording reaction times to a target whose color was probabilistically correlated with its shape. A continuous measure of target detection at multiple time points during learning revealed that synesthetes and nonsynesthetes learn associations differently. Specifically, our results demonstrate a ‘fast facilitation’ learning effect for nonsynesthetes and ‘fast interference, slow facilitation’ learning effect for synesthetes. Additionally, synesthetes exhibited superior long-term memory for learned associations in a surprise-delayed retest. After this retest, participants implicitly learned new (shuffled) shape-color associations. We found that synesthetes experienced greater interference while learning these new shape-color associations. These results detail ways in which implicit associative learning and memory differ between synesthetes and nonsynesthetes. PMID:27612860

Proteomic study of acute respiratory distress syndrome: current knowledge and implications for drug development

PubMed Central

Levitt, Joseph E.; Rogers, Angela J.

2017-01-01

The acute respiratory distress syndrome (ARDS) is a common cause of acute respiratory failure, and is associated with substantial mortality and morbidity. Dozens of clinical trials targeting ARDS have failed, with no drug specifically targeting lung injury in widespread clinical use. Thus, the need for drug development in ARDS is great. Targeted proteomic studies in ARDS have identified many key pathways in the disease, including inflammation, epithelial injury, endothelial injury or activation, and disordered coagulation and repair. Recent studies reveal the potential for proteomic changes to identify novel subphenotypes of ARDS patients who may be most likely to respond to therapy and could thus be targeted for enrollment in clinical trials. Nontargeted studies of proteomics in ARDS are just beginning and have the potential to identify novel drug targets and key pathways in the disease. Proteomics will play an important role in phenotyping of patients and developing novel therapies for ARDS in the future. PMID:27031735

Hippocampal-targeted Theta-burst Stimulation Enhances Associative Memory Formation.

PubMed

Tambini, Arielle; Nee, Derek Evan; D'Esposito, Mark

2018-06-19

The hippocampus plays a critical role in episodic memory, among other cognitive functions. However, few tools exist to causally manipulate hippocampal function in healthy human participants. Recent work has targeted hippocampal-cortical networks by performing TMS to a region interconnected with the hippocampus, posterior inferior parietal cortex (pIPC). Such hippocampal-targeted TMS enhances associative memory and influences hippocampal functional connectivity. However, it is currently unknown which stages of mnemonic processing (encoding or retrieval) are affected by hippocampal-targeted TMS. Here, we examined whether hippocampal-targeted TMS influences the initial encoding of associations (vs. items) into memory. To selectively influence encoding and not retrieval, we performed continuous theta-burst TMS before participants encoded object-location associations and assessed memory after the direct effect of stimulation dissipated. Relative to control TMS and baseline memory, pIPC TMS enhanced associative memory success and confidence. Item memory was unaffected, demonstrating a selective influence on associative versus item memory. The strength of hippocampal-pIPC functional connectivity predicted TMS-related memory benefits, which was mediated by parahippocampal and retrosplenial cortices. Our findings indicate that hippocampal-targeted TMS can specifically modulate the encoding of new associations into memory without directly influencing retrieval processes and suggest that the ability to influence associative memory may be related to the fidelity of hippocampal TMS targeting. Our results support the notion that pIPC TMS may serve as a potential tool for manipulating hippocampal function in healthy participants. Nonetheless, future work combining hippocampal-targeted continuous theta-burst TMS with neuroimaging is needed to better understand the neural basis of TMS-induced memory changes.

Genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

PubMed Central

Scott, Robert A.; Freitag, Daniel F.; Li, Li; Chu, Audrey Y.; Surendran, Praveen; Young, Robin; Grarup, Niels; Stancáková, Alena; Chen, Yuning; V.Varga, Tibor; Yaghootkar, Hanieh; Luan, Jian'an; Zhao, Jing Hua; Willems, Sara M.; Wessel, Jennifer; Wang, Shuai; Maruthur, Nisa; Michailidou, Kyriaki; Pirie, Ailith; van der Lee, Sven J.; Gillson, Christopher; Olama, Ali Amin Al; Amouyel, Philippe; Arriola, Larraitz; Arveiler, Dominique; Aviles-Olmos, Iciar; Balkau, Beverley; Barricarte, Aurelio; Barroso, Inês; Garcia, Sara Benlloch; Bis, Joshua C.; Blankenberg, Stefan; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Borecki, Ingrid B.; Bork-Jensen, Jette; Bowden, Sarah; Caldas, Carlos; Caslake, Muriel; Cupples, L. Adrienne; Cruchaga, Carlos; Czajkowski, Jacek; den Hoed, Marcel; Dunn, Janet A.; Earl, Helena M.; Ehret, Georg B.; Ferrannini, Ele; Ferrieres, Jean; Foltynie, Thomas; Ford, Ian; Forouhi, Nita G.; Gianfagna, Francesco; Gonzalez, Carlos; Grioni, Sara; Hiller, Louise; Jansson, Jan-Håkan; Jørgensen, Marit E.; Jukema, J. Wouter; Kaaks, Rudolf; Kee, Frank; Kerrison, Nicola D.; Key, Timothy J.; Kontto, Jukka; Kote-Jarai, Zsofia; Kraja, Aldi T.; Kuulasmaa, Kari; Kuusisto, Johanna; Linneberg, Allan; Liu, Chunyu; Marenne, Gaëlle; Mohlke, Karen L.; Morris, Andrew P.; Muir, Kenneth; Müller-Nurasyid, Martina; Munroe, Patricia B.; Navarro, Carmen; Nielsen, Sune F.; Nilsson, Peter M.; Nordestgaard, Børge G.; Packard, Chris J.; Palli, Domenico; Panico, Salvatore; Peloso, Gina M.; Perola, Markus; Peters, Annette; Poole, Christopher J.; Quirós, J. Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Salomaa, Veikko; Sánchez, María-José; Sattar, Naveed; Sharp, Stephen J.; Sims, Rebecca; Slimani, Nadia; Smith, Jennifer A.; Thompson, Deborah J.; Trompet, Stella; Tumino, Rosario; van der A, Daphne L.; van der Schouw, Yvonne T.; Virtamo, Jarmo; Walker, Mark; Walter, Klaudia; Abraham, Jean E.; Amundadottir, Laufey T.; Aponte, Jennifer L.; Butterworth, Adam S.; Dupuis, Josée; Easton, Douglas F.; Eeles, Rosalind A.; Erdmann, Jeanette; Franks, Paul W.; Frayling, Timothy M.; Hansen, Torben; Howson, Joanna M. M.; Jørgensen, Torben; Kooner, Jaspal; Laakso, Markku; Langenberg, Claudia; McCarthy, Mark I.; Pankow, James S.; Pedersen, Oluf; Riboli, Elio; Rotter, Jerome I.; Saleheen, Danish; Samani, Nilesh J.; Schunkert, Heribert; Vollenweider, Peter; O'Rahilly, Stephen; Deloukas, Panos; Danesh, John; Goodarzi, Mark O.; Kathiresan, Sekar; Meigs, James B.; Ehm, Margaret G.; Wareham, Nicholas J.; Waterworth, Dawn M.

2016-01-01

Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to inform development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in 6 genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing, and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr;rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and lower T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomised controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process. PMID:27252175

Yes-associated protein 1 and transcriptional coactivator with PDZ-binding motif activate the mammalian target of rapamycin complex 1 pathway by regulating amino acid transporters in hepatocellular carcinoma.

PubMed

Park, Yun-Yong; Sohn, Bo Hwa; Johnson, Randy L; Kang, Myoung-Hee; Kim, Sang Bae; Shim, Jae-Jun; Mangala, Lingegowda S; Kim, Ji Hoon; Yoo, Jeong Eun; Rodriguez-Aguayo, Cristian; Pradeep, Sunila; Hwang, Jun Eul; Jang, Hee-Jin; Lee, Hyun-Sung; Rupaimoole, Rajesha; Lopez-Berestein, Gabriel; Jeong, Woojin; Park, Inn Sun; Park, Young Nyun; Sood, Anil K; Mills, Gordon B; Lee, Ju-Seog

2016-01-01

Metabolic activation is a common feature of many cancer cells and is frequently associated with the clinical outcomes of various cancers, including hepatocellular carcinoma. Thus, aberrantly activated metabolic pathways in cancer cells are attractive targets for cancer therapy. Yes-associated protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ) are oncogenic downstream effectors of the Hippo tumor suppressor pathway, which is frequently inactivated in many cancers. Our study revealed that YAP1/TAZ regulates amino acid metabolism by up-regulating expression of the amino acid transporters solute carrier family 38 member 1 (SLC38A1) and solute carrier family 7 member 5 (SLC7A5). Subsequently, increased uptake of amino acids by the transporters (SLC38A1 and SLC7A5) activates mammalian target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, and stimulates cell proliferation. We also show that high expression of SLC38A1 and SLC7A5 is significantly associated with shorter survival in hepatocellular carcinoma patients. Furthermore, inhibition of the transporters and mTORC1 significantly blocks YAP1/TAZ-mediated tumorigenesis in the liver. These findings elucidate regulatory networks connecting the Hippo pathway to mTORC1 through amino acid metabolism and the mechanism's potential clinical implications for treating hepatocellular carcinoma. YAP1 and TAZ regulate cancer metabolism and mTORC1 through regulation of amino acid transportation, and two amino acid transporters, SLC38A1 and SLC7A5, might be important therapeutic targets. © 2015 by the American Association for the Study of Liver Diseases.

Linking rare and common disease: mapping clinical disease-phenotypes to ontologies in therapeutic target validation.

PubMed

Sarntivijai, Sirarat; Vasant, Drashtti; Jupp, Simon; Saunders, Gary; Bento, A Patrícia; Gonzalez, Daniel; Betts, Joanna; Hasan, Samiul; Koscielny, Gautier; Dunham, Ian; Parkinson, Helen; Malone, James

2016-01-01

The Centre for Therapeutic Target Validation (CTTV - https://www.targetvalidation.org/) was established to generate therapeutic target evidence from genome-scale experiments and analyses. CTTV aims to support the validity of therapeutic targets by integrating existing and newly-generated data. Data integration has been achieved in some resources by mapping metadata such as disease and phenotypes to the Experimental Factor Ontology (EFO). Additionally, the relationship between ontology descriptions of rare and common diseases and their phenotypes can offer insights into shared biological mechanisms and potential drug targets. Ontologies are not ideal for representing the sometimes associated type relationship required. This work addresses two challenges; annotation of diverse big data, and representation of complex, sometimes associated relationships between concepts. Semantic mapping uses a combination of custom scripting, our annotation tool 'Zooma', and expert curation. Disease-phenotype associations were generated using literature mining on Europe PubMed Central abstracts, which were manually verified by experts for validity. Representation of the disease-phenotype association was achieved by the Ontology of Biomedical AssociatioN (OBAN), a generic association representation model. OBAN represents associations between a subject and object i.e., disease and its associated phenotypes and the source of evidence for that association. The indirect disease-to-disease associations are exposed through shared phenotypes. This was applied to the use case of linking rare to common diseases at the CTTV. EFO yields an average of over 80% of mapping coverage in all data sources. A 42% precision is obtained from the manual verification of the text-mined disease-phenotype associations. This results in 1452 and 2810 disease-phenotype pairs for IBD and autoimmune disease and contributes towards 11,338 rare diseases associations (merged with existing published work [Am J Hum Genet 97:111-24, 2015]). An OBAN result file is downloadable at http://sourceforge.net/p/efo/code/HEAD/tree/trunk/src/efoassociations/. Twenty common diseases are linked to 85 rare diseases by shared phenotypes. A generalizable OBAN model for association representation is presented in this study. Here we present solutions to large-scale annotation-ontology mapping in the CTTV knowledge base, a process for disease-phenotype mining, and propose a generic association model, 'OBAN', as a means to integrate disease using shared phenotypes. EFO is released monthly and available for download at http://www.ebi.ac.uk/efo/.

Development of Y-shaped peptide for constructing nanoparticle systems targeting tumor-associated macrophages in vitro and in vivo

NASA Astrophysics Data System (ADS)

Yan, Lu; Gao, Yunxiang; Pierce, Ryan; Dai, Liming; Kim, Julian; Zhang, Mei

2014-04-01

Tumor-associated macrophage (TAM) is increasingly being viewed as a target of great interest in tumor microenvironment due to its important role in the progression and metastasis of cancers. It has been shown that TAM indeed overexpresses unique surface marker legumain. In this study, we designed and synthesized a Y-shaped legumain-targeting peptide (Y-Leg) with functional groups allowing for further conjugation with imaging and therapeutic moieties (vide infra). The in vitro cell experiments using FITC-conjugated Y-Leg revealed its specific and selective interaction with M2-polarized macrophages (i.e., TAMs) with preference to M1 macrophages, and that the interaction was not interfered with by conjugating FITC to its functional group. Further, we constructed a nanotube system by grafting Y-Leg onto oxidized carbon nanotubes (OCNTs) loaded with paramagnetic Fe3O4 nanoparticles. The intravenous injection of the resultant Y-Leg-OCNT/Fe3O4 nanotubes to 4T1 mammary tumor-bearing mouse led to the magnetic resonance imaging (MRI) of TAM-infiltrated tumor microenvironment, revealing the targeting specificity of Y-Leg-conjugated nanotubes in vivo. The Y shape of peptide and its functional groups containing amines and imidazole can protonate at different pHs, contributing to the in vitro and in vivo targeting specificity. This study represents the first development of novel peptide and peptide-grafted nanotube system targeting M2-polarized TAMs in vivo. The methodology developed in this study is applicable to the construction of various multifunctional nanoparticle systems for selectively targeting, imaging and manipulating of TAMs for the diagnosis and treatment of cancers and inflammatory diseases identified with macrophage-infiltrated disease tissue.

Reward-associated stimuli capture the eyes in spite of strategic attentional set.

PubMed

Hickey, Clayton; van Zoest, Wieske

2013-11-01

Theories of reinforcement learning have proposed that the association of reward to visual stimuli may cause these objects to become fundamentally salient and thus attention-drawing. A number of recent studies have investigated the oculomotor correlates of this reward-priming effect, but there is some ambiguity in this literature regarding the involvement of top-down attentional set. Existing paradigms tend to create a situation where participants are actively looking for a reward-associated stimulus before subsequently showing that this selective bias sustains when it no longer has strategic purpose. This perseveration of attentional set is potentially different in nature than the direct impact of reward proposed by theory. Here we investigate the effect of reward on saccadic selection in a paradigm where strategic attentional set is decoupled from the effect of reward. We find that during search for a uniquely oriented target, the receipt of reward following selection of a target characterized by an irrelevant unique color causes subsequent stimuli characterized by this color to be preferentially selected. Importantly, this occurs regardless of whether the color characterizes the target or distractor. Other analyses demonstrate that only features associated with correct selection of the target prime the target representation, and that the magnitude of this effect can be predicted by variability in saccadic indices of feedback processing. These results add to a growing literature demonstrating that reward guides visual selection, often in spite of our strategic efforts otherwise. Copyright © 2013 Elsevier B.V. All rights reserved.

A comparative study of disease genes and drug targets in the human protein interactome

PubMed Central

2015-01-01

Background Disease genes cause or contribute genetically to the development of the most complex diseases. Drugs are the major approaches to treat the complex disease through interacting with their targets. Thus, drug targets are critical for treatment efficacy. However, the interrelationship between the disease genes and drug targets is not clear. Results In this study, we comprehensively compared the network properties of disease genes and drug targets for five major disease categories (cancer, cardiovascular disease, immune system disease, metabolic disease, and nervous system disease). We first collected disease genes from genome-wide association studies (GWAS) for five disease categories and collected their corresponding drugs based on drugs' Anatomical Therapeutic Chemical (ATC) classification. Then, we obtained the drug targets for these five different disease categories. We found that, though the intersections between disease genes and drug targets were small, disease genes were significantly enriched in targets compared to their enrichment in human protein-coding genes. We further compared network properties of the proteins encoded by disease genes and drug targets in human protein-protein interaction networks (interactome). The results showed that the drug targets tended to have higher degree, higher betweenness, and lower clustering coefficient in cancer Furthermore, we observed a clear fraction increase of disease proteins or drug targets in the near neighborhood compared with the randomized genes. Conclusions The study presents the first comprehensive comparison of the disease genes and drug targets in the context of interactome. The results provide some foundational network characteristics for further designing computational strategies to predict novel drug targets and drug repurposing. PMID:25861037

A comparative study of disease genes and drug targets in the human protein interactome.

PubMed

Sun, Jingchun; Zhu, Kevin; Zheng, W; Xu, Hua

2015-01-01

Disease genes cause or contribute genetically to the development of the most complex diseases. Drugs are the major approaches to treat the complex disease through interacting with their targets. Thus, drug targets are critical for treatment efficacy. However, the interrelationship between the disease genes and drug targets is not clear. In this study, we comprehensively compared the network properties of disease genes and drug targets for five major disease categories (cancer, cardiovascular disease, immune system disease, metabolic disease, and nervous system disease). We first collected disease genes from genome-wide association studies (GWAS) for five disease categories and collected their corresponding drugs based on drugs' Anatomical Therapeutic Chemical (ATC) classification. Then, we obtained the drug targets for these five different disease categories. We found that, though the intersections between disease genes and drug targets were small, disease genes were significantly enriched in targets compared to their enrichment in human protein-coding genes. We further compared network properties of the proteins encoded by disease genes and drug targets in human protein-protein interaction networks (interactome). The results showed that the drug targets tended to have higher degree, higher betweenness, and lower clustering coefficient in cancer Furthermore, we observed a clear fraction increase of disease proteins or drug targets in the near neighborhood compared with the randomized genes. The study presents the first comprehensive comparison of the disease genes and drug targets in the context of interactome. The results provide some foundational network characteristics for further designing computational strategies to predict novel drug targets and drug repurposing.

Ancestry estimation and control of population stratification for sequence-based association studies.

PubMed

Wang, Chaolong; Zhan, Xiaowei; Bragg-Gresham, Jennifer; Kang, Hyun Min; Stambolian, Dwight; Chew, Emily Y; Branham, Kari E; Heckenlively, John; Fulton, Robert; Wilson, Richard K; Mardis, Elaine R; Lin, Xihong; Swaroop, Anand; Zöllner, Sebastian; Abecasis, Gonçalo R

2014-04-01

Estimating individual ancestry is important in genetic association studies where population structure leads to false positive signals, although assigning ancestry remains challenging with targeted sequence data. We propose a new method for the accurate estimation of individual genetic ancestry, based on direct analysis of off-target sequence reads, and implement our method in the publicly available LASER software. We validate the method using simulated and empirical data and show that the method can accurately infer worldwide continental ancestry when used with sequencing data sets with whole-genome shotgun coverage as low as 0.001×. For estimates of fine-scale ancestry within Europe, the method performs well with coverage of 0.1×. On an even finer scale, the method improves discrimination between exome-sequenced study participants originating from different provinces within Finland. Finally, we show that our method can be used to improve case-control matching in genetic association studies and to reduce the risk of spurious findings due to population structure.

RESISTANCE TO EXTINCTION AND RELAPSE IN COMBINED STIMULUS CONTEXTS

PubMed Central

Podlesnik, Christopher A; Bai, John Y. H; Elliffe, Douglas

2012-01-01

Reinforcing an alternative response in the same context as a target response reduces the rate of occurrence but increases the persistence of that target response. Applied researchers who use such techniques to decrease the rate of a target problem behavior risk inadvertently increasing the persistence of the same problem behavior. Behavioral momentum theory asserts that the increased persistence is a function of the alternative reinforcement enhancing the Pavlovian relation between the target stimulus context and reinforcement. A method showing promise for reducing the persistence-enhancing effects of alternative reinforcement is to train the alternative response in a separate stimulus context before combining with the target stimulus in extinction. The present study replicated previous findings using pigeons by showing that combining an “alternative” richer VI schedule (96 reinforcers/hr) with a “target” leaner VI schedule (24 reinforcers/hr) reduced resistance to extinction of target responding compared with concurrent training of the alternative and target responses (totaling 120 reinforcers/hr). We also found less relapse with a reinstatement procedure following extinction with separate-context training, supporting previous findings that training conditions similarly influence both resistance to extinction and relapse. Finally, combining the alternative stimulus context was less disruptive to target responding previously trained in the concurrent schedule, relative to combining with the target response trained alone. Overall, the present findings suggest the technique of combining stimulus contexts associated with alternative responses with those associated with target responses disrupts target responding. Furthermore, the effectiveness of this disruption is a function of training context of reinforcement for target responding, consistent with assertions of behavioral momentum theory. PMID:23008521

Knowledge of hypoglycemia and its associated factors among type 2 diabetes mellitus patients in a Tertiary Care Hospital in South India.

PubMed

Shriraam, Vanishree; Mahadevan, Shriraam; Anitharani, M; Jagadeesh, Nalini Sirala; Kurup, Sreelekha Bhaskara; Vidya, T A; Seshadri, Krishna G

2015-01-01

Hypoglycemia being the rate limiting complication in the attainment of strict glycemic control in diabetes management, in this study, we intended to study the knowledge of its symptoms, target blood levels during treatment and ways of prevention among type 2 diabetes patients attending Outpatient Department (OPD) of a medical college hospital. Every fifth patient attending the OPD during the 4 months between March and June 2013 was interviewed using a questionnaire. The study included 366 type 2 diabetic patients, of which 76.5% were females. The target fasting and postprandial blood glucose levels while on treatment was known to 135 (36.9%) and 126 (34.4%) patients, respectively. The common symptoms of hypoglycemia known to the study subjects were dizziness (81.4%), weakness (73.8%), and drowsiness (72.1%). Overall, 242 (66.1%) diabetic patients had good knowledge on hypoglycemia (knowledge of at least three symptoms of hypoglycemia together with at least one precipitating factor and at least one remedial measure). Higher age, illiteracy, low socioeconomic status were associated with poor knowledge whereas treatment with insulin along with oral hypoglycemic agents was associated with good knowledge on hypoglycemia. Sex and duration of disease were not associated with knowledge on hypoglycemia. Although the knowledge on symptoms of hypoglycemia, precipitating factors, remedial measures are high in this study, the target blood levels, complications were known to just a third of them. There is a knowledge gap on important aspects of hypoglycemia among type 2 diabetic patients.

Combined genome-wide linkage and targeted association analysis of head circumference in autism spectrum disorder families.

PubMed

Woodbury-Smith, M; Bilder, D A; Morgan, J; Jerominski, L; Darlington, T; Dyer, T; Paterson, A D; Coon, H

2017-01-01

It has long been recognized that there is an association between enlarged head circumference (HC) and autism spectrum disorder (ASD), but the genetics of HC in ASD is not well understood. In order to investigate the genetic underpinning of HC in ASD, we undertook a genome-wide linkage study of HC followed by linkage signal targeted association among a sample of 67 extended pedigrees with ASD. HC measurements on members of 67 multiplex ASD extended pedigrees were used as a quantitative trait in a genome-wide linkage analysis. The Illumina 6K SNP linkage panel was used, and analyses were carried out using the SOLAR implemented variance components model. Loci identified in this way formed the target for subsequent association analysis using the Illumina OmniExpress chip and imputed genotypes. A modification of the qTDT was used as implemented in SOLAR. We identified a linkage signal spanning 6p21.31 to 6p22.2 (maximum LOD = 3.4). Although targeted association did not find evidence of association with any SNP overall, in one family with the strongest evidence of linkage, there was evidence for association (rs17586672, p  = 1.72E-07). Although this region does not overlap with ASD linkage signals in these same samples, it has been associated with other psychiatric risk, including ADHD, developmental dyslexia, schizophrenia, specific language impairment, and juvenile bipolar disorder. The genome-wide significant linkage signal represents the first reported observation of a potential quantitative trait locus for HC in ASD and may be relevant in the context of complex multivariate risk likely leading to ASD.

Fusion-based multi-target tracking and localization for intelligent surveillance systems

NASA Astrophysics Data System (ADS)

Rababaah, Haroun; Shirkhodaie, Amir

2008-04-01

In this paper, we have presented two approaches addressing visual target tracking and localization in complex urban environment. The two techniques presented in this paper are: fusion-based multi-target visual tracking, and multi-target localization via camera calibration. For multi-target tracking, the data fusion concepts of hypothesis generation/evaluation/selection, target-to-target registration, and association are employed. An association matrix is implemented using RGB histograms for associated tracking of multi-targets of interests. Motion segmentation of targets of interest (TOI) from the background was achieved by a Gaussian Mixture Model. Foreground segmentation, on other hand, was achieved by the Connected Components Analysis (CCA) technique. The tracking of individual targets was estimated by fusing two sources of information, the centroid with the spatial gating, and the RGB histogram association matrix. The localization problem is addressed through an effective camera calibration technique using edge modeling for grid mapping (EMGM). A two-stage image pixel to world coordinates mapping technique is introduced that performs coarse and fine location estimation of moving TOIs. In coarse estimation, an approximate neighborhood of the target position is estimated based on nearest 4-neighbor method, and in fine estimation, we use Euclidean interpolation to localize the position within the estimated four neighbors. Both techniques were tested and shown reliable results for tracking and localization of Targets of interests in complex urban environment.

A targeted genotyping approach enhances identification of variants in taste receptor and appetite/reward genes of potential functional importance for obesity-related porcine traits.

PubMed

Cirera, S; Clop, A; Jacobsen, M J; Guerin, M; Lesnik, P; Jørgensen, C B; Fredholm, M; Karlskov-Mortensen, P

2018-04-01

Taste receptors (TASRs) and appetite and reward (AR) mechanisms influence eating behaviour, which in turn affects food intake and risk of obesity. In a previous study, we used next generation sequencing to identify potentially functional mutations in TASR and AR genes and found indications for genetic associations between identified variants and growth and fat deposition in a subgroup of animals (n = 38) from the UNIK resource pig population. This population was created for studying obesity and obesity-related diseases. In the present study we validated results from our previous study by investigating genetic associations between 24 selected single nucleotide variants in TASR and AR gene variants and 35 phenotypes describing obesity and metabolism in the entire UNIK population (n = 564). Fifteen variants showed significant association with specific obesity-related phenotypes after Bonferroni correction. Six of the 15 genes, namely SIM1, FOS, TAS2R4, TAS2R9, MCHR2 and LEPR, showed good correlation between known biological function and associated phenotype. We verified a genetic association between potentially functional variants in TASR/AR genes and growth/obesity and conclude that the combination of identification of potentially functional variants by next generation sequencing followed by targeted genotyping and association studies is a powerful and cost-effective approach for increasing the power of genetic association studies. © 2018 Stichting International Foundation for Animal Genetics.

A census of P. longum’s phytochemicals and their network pharmacological evaluation for identifying novel drug-like molecules against various diseases, with a special focus on neurological disorders

PubMed Central

Choudhary, Neha

2018-01-01

Piper longum (P. longum, also called as long pepper) is one of the common culinary herbs that has been extensively used as a crucial constituent in various indigenous medicines, specifically in traditional Indian medicinal system known as Ayurveda. For exploring the comprehensive effect of its constituents in humans at proteomic and metabolic levels, we have reviewed all of its known phytochemicals and enquired about their regulatory potential against various protein targets by developing high-confidence tripartite networks consisting of phytochemical—protein target—disease association. We have also (i) studied immunomodulatory potency of this herb; (ii) developed subnetwork of human PPI regulated by its phytochemicals and could successfully associate its specific modules playing important role in diseases, and (iii) reported several novel drug targets. P10636 (microtubule-associated protein tau, that is involved in diseases like dementia etc.) was found to be the commonly screened target by about seventy percent of these phytochemicals. We report 20 drug-like phytochemicals in this herb, out of which 7 are found to be the potential regulators of 5 FDA approved drug targets. Multi-targeting capacity of 3 phytochemicals involved in neuroactive ligand receptor interaction pathway was further explored via molecular docking experiments. To investigate the molecular mechanism of P. longum’s action against neurological disorders, we have developed a computational framework that can be easily extended to explore its healing potential against other diseases and can also be applied to scrutinize other indigenous herbs for drug-design studies. PMID:29320554

The Association between Persistent Disruptive Childhood Behaviour and the Psychopathic Personality Constellation in Adolescence: A Twin Study

ERIC Educational Resources Information Center

Forsman, Mats; Larsson, Henrik; Andershed, Henrik; Lichtenstein, Paul

2007-01-01

This study tested if persistent externalizing behaviour and symptoms of Attention Deficit Hyperactivity Disorder (ADHD) in childhood are associated with personality and behavioural aspects of the psychopathic personality constellation in adolescence. The target sample consisted of all 1,480 twin pairs born in Sweden between 1985 and 1986.…

Targeted polypeptide degradation

DOEpatents

Church, George M [Brookline, MA; Janse, Daniel M [Brookline, MA

2008-05-13

This invention pertains to compositions, methods, cells and organisms useful for selectively localizing polypeptides to the proteasome for degradation. Therapeutic methods and pharmaceutical compositions for treating disorders associated with the expression and/or activity of a polypeptide by targeting these polypeptides for degradation, as well as methods for targeting therapeutic polypeptides for degradation and/or activating therapeutic polypeptides by degradation are provided. The invention provides methods for identifying compounds that mediate proteasome localization and/or polypeptide degradation. The invention also provides research tools for the study of protein function.

Targeted Embolization of Aneurysms Associated With Brain Arteriovenous Malformations at High Risk for Surgical Resection: A Case-Control Study.

PubMed

Alexander, Matthew D; Hippe, Daniel S; Cooke, Daniel L; Hallam, Danial K; Hetts, Steven W; Kim, Helen; Lawton, Michael T; Sekhar, Laligam N; Kim, Louis J; Ghodke, Basavaraj V

2018-03-01

High-risk components of brain arteriovenous malformations (BAVMs) can be targeted to reduce the risk of lesion rupture. To evaluate targeted embolization of aneurysms against other means of treatment with a case-control analysis; we previously investigated this approach associated with BAVMs. Retrospective analysis of patients with BAVMs was performed, identifying patients treated with intention to occlude only an aneurysm associated with a BAVM. For each targeted aneurysm embolization (TAE) patient identified, 4 control patients were randomly selected, controlling for rupture status, age, and Spetzler-Martin plus Lawton-Young supplemental score. Analysis was performed to compare rates of adverse events (hemorrhage, new seizure, and death) between the 2 groups. Thirty-two patients met inclusion criteria, and 128 control patients were identified, out of 1103 patients treated during the study period. Thirty-four adverse events occurred (15 ruptures, 15 new seizures, and 11 deaths) during the follow-up period (mean 1157 d for the TAE cohort and 1036 d for the non-TAE cohort). Statistically lower associations were noted for the TAE group for any adverse event (hazard ratio 0.28, P = .037) and the composite outcome of hemorrhage or new seizure (hazard ratio 0.20, P = .029). For BAVMs at high risk for surgical resection, TAE can be performed safely and effectively. Patients treated with TAE had better outcomes than matched patients undergoing other combinations of treatment. TAE can be considered for BAVMs with high operative risk prior to radiosurgery or when no other treatment options are available. Copyright © 2017 by the Congress of Neurological Surgeons

TARGETING THE MUC1-C ONCOPROTEIN DOWNREGULATES HER2 ACTIVATION AND ABROGATES TRASTUZUMAB RESISTANCE IN BREAST CANCER CELLS

PubMed Central

Raina, Deepak; Uchida, Yasumitsu; Kharbanda, Akriti; Rajabi, Hasan; Panchamoorthy, Govind; Jin, Caining; Kharbanda, Surender; Scaltriti, Maurizio; Baselga, Jose; Kufe, Donald

2014-01-01

Patients with HER2 positive breast cancer often exhibit intrinsic or acquired resistance to trastuzumab treatment. The transmembrane MUC1-C oncoprotein is aberrantly overexpressed in breast cancer cells and associates with HER2. The present studies demonstrate that silencing MUC1-C in HER2-overexpressing SKBR3 and BT474 breast cancer cells results in downregulation of constitutive HER2 activation. Moreover, treatment with the MUC1-C inhibitor, GO-203, was associated with disruption of MUC1-C/HER2 complexes and decreases in tyrosine phosphorylated HER2 (p-HER2) levels. In studies of trastuzumab-resistant SKBR3R and BT474R cells, we found that the association between MUC1-C and HER2 is markedly increased (~20-fold) as compared to that in sensitive cells. Additionally, silencing MUC1-C in the trastuzumab-resistant cells or treatment with GO-203 decreased p-HER2 and AKT activation. Moreover, targeting MUC1-C was associated with downregulation of phospho-p27 and cyclin E, which confer trastuzumab resistance. Consistent with these results, targeting MUC1-C inhibited the growth and clonogenic survival of both trastuzumab-resistant cells. Our results further demonstrate that silencing MUC1-C reverses resistance to trastuzumab and that the combination of GO-203 and trastuzumab is highly synergistic. These findings indicate that MUC1-C contributes to constitutive activation of the HER2 pathway and that targeting MUC1-C represents a potential approach to abrogate trastuzumab resistance. PMID:23912457

Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas

PubMed Central

Westermann, Frank; Muth, Daniel; Benner, Axel; Bauer, Tobias; Henrich, Kai-Oliver; Oberthuer, André; Brors, Benedikt; Beissbarth, Tim; Vandesompele, Jo; Pattyn, Filip; Hero, Barbara; König, Rainer; Fischer, Matthias; Schwab, Manfred

2008-01-01

Background Amplified MYCN oncogene resulting in deregulated MYCN transcriptional activity is observed in 20% of neuroblastomas and identifies a highly aggressive subtype. In MYCN single-copy neuroblastomas, elevated MYCN mRNA and protein levels are paradoxically associated with a more favorable clinical phenotype, including disseminated tumors that subsequently regress spontaneously (stage 4s-non-amplified). In this study, we asked whether distinct transcriptional MYCN or c-MYC activities are associated with specific neuroblastoma phenotypes. Results We defined a core set of direct MYCN/c-MYC target genes by applying gene expression profiling and chromatin immunoprecipitation (ChIP, ChIP-chip) in neuroblastoma cells that allow conditional regulation of MYCN and c-MYC. Their transcript levels were analyzed in 251 primary neuroblastomas. Compared to localized-non-amplified neuroblastomas, MYCN/c-MYC target gene expression gradually increases from stage 4s-non-amplified through stage 4-non-amplified to MYCN amplified tumors. This was associated with MYCN activation in stage 4s-non-amplified and predominantly c-MYC activation in stage 4-non-amplified tumors. A defined set of MYCN/c-MYC target genes was induced in stage 4-non-amplified but not in stage 4s-non-amplified neuroblastomas. In line with this, high expression of a subset of MYCN/c-MYC target genes identifies a patient subtype with poor overall survival independent of the established risk markers amplified MYCN, disease stage, and age at diagnosis. Conclusions High MYCN/c-MYC target gene expression is a hallmark of malignant neuroblastoma progression, which is predominantly driven by c-MYC in stage 4-non-amplified tumors. In contrast, moderate MYCN function gain in stage 4s-non-amplified tumors induces only a restricted set of target genes that is still compatible with spontaneous regression. PMID:18851746

Variation in Genes Related to Cochlear Biology Is Strongly Associated with Adult-Onset Deafness in Border Collies

PubMed Central

Ruhe, Alison L.; Erdman, Carolyn A.; Robertson, Kathryn R.; Webb, Aubrey A.; Williams, D. Colette; Chang, Melanie L.; Hytönen, Marjo K.; Lohi, Hannes; Hamilton, Steven P.; Neff, Mark W.

2012-01-01

Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3–5 years) than typically expected for aging dogs (8–10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS) to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p-value = 1.09×10−13). To further localize disease-associated variants, targeted next-generation sequencing (NGS) of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total) and controls (n = 101 total) and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-κB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS–guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders. PMID:23028339

Inhibitory Effect of Individual or Combinations of Broadly Neutralizing Antibodies and Antiviral Reagents against Cell-Free and Cell-to-Cell HIV-1 Transmission

PubMed Central

Kolodkin-Gal, Dror; Eslamizar, Leila; Owuor, Joshua O.; Mazzola, Emanuele; Gonzalez, Ana M.; Korioth-Schmitz, Birgit; Gelman, Rebecca S.; Montefiori, David C.; Haynes, Barton F.; Schmitz, Joern E.

2015-01-01

ABSTRACT To date, most therapeutic and vaccine candidates for human immunodeficiency virus type 1 (HIV-1) are evaluated preclinically for efficacy against cell-free viral challenges. However, cell-associated HIV-1 is suggested to be a major contributor to sexual transmission by mucosal routes. To determine if neutralizing antibodies or inhibitors block cell-free and cell-associated virus transmission of diverse HIV-1 strains with different efficiencies, we tested 12 different antibodies and five inhibitors against four green fluorescent protein (GFP)-labeled HIV-1 envelope (Env) variants from transmitted/founder (T/F) or chronic infection isolates. We evaluated antibody/inhibitor-mediated virus neutralization using either TZM-bl target cells, in which infectivity was determined by virus-driven luciferase expression, or A3R5 lymphoblastoid target cells, in which infectivity was evaluated by GFP expression. In both the TZM-bl and A3R5 assays, cell-free virus or infected CD4+ lymphocytes were used as targets for neutralization. We further hypothesized that the combined use of specific neutralizing antibodies targeting HIV-1 Env would more effectively prevent cell-associated virus transmission than the use of individual antibodies. The tested antibody combinations included two gp120-directed antibodies, VRC01 and PG9, or VRC01 with the gp41-directed antibody 10E8. Our results demonstrated that cell-associated virus was less sensitive to neutralizing antibodies and inhibitors, particularly using the A3R5 neutralization assay, and the potencies of these neutralizing agents differed among Env variants. A combination of different neutralizing antibodies that target specific sites on gp120 led to a significant reduction in cell-associated virus transmission. These assays will help identify ideal combinations of broadly neutralizing antibodies to use for passive preventive antibody administration and further characterize targets for the most effective neutralizing antibodies/inhibitors. IMPORTANCE Prevention of the transmission of human immunodeficiency virus type 1 (HIV-1) remains a prominent goal of HIV research. The relative contribution of HIV-1 within an infected cell versus cell-free HIV-1 to virus transmission remains debated. It has been suggested that cell-associated virus is more efficient at transmitting HIV-1 and more difficult to neutralize than cell-free virus. Several broadly neutralizing antibodies and retroviral inhibitors are currently being studied as potential therapies against HIV-1 transmission. The present study demonstrates a decrease in neutralizing antibody and inhibitor efficiencies against cell-associated compared to cell-free HIV-1 transmission among different strains of HIV-1. We also observed a significant reduction in virus transmission using a combination of two different neutralizing antibodies that target specific sites on the outermost region of HIV-1, the virus envelope. Therefore, our findings support the use of antibody combinations against both cell-free and cell-associated virus in future candidate therapy regimens. PMID:25995259

Vascular Targeting of a Gold Nanoparticle to Breast Cancer Metastasis.

PubMed

Peiris, Pubudu M; Deb, Partha; Doolittle, Elizabeth; Doron, Gilad; Goldberg, Amy; Govender, Priya; Shah, Shruti; Rao, Swetha; Carbone, Sarah; Cotey, Thomas; Sylvestre, Meilyn; Singh, Sohaj; Schiemann, William P; Lee, Zhenghong; Karathanasis, Efstathios

2015-08-01

The vast majority of breast cancer deaths are due to metastatic disease. Although deep tissue targeting of nanoparticles is suitable for some primary tumors, vascular targeting may be a more attractive strategy for micrometastasis. This study combined a vascular targeting strategy with the enhanced targeting capabilities of a nanoparticle to evaluate the ability of a gold nanoparticle (AuNP) to specifically target the early spread of metastatic disease. As a ligand for the vascular targeting strategy, we utilized a peptide targeting alpha(v) beta(3) integrin, which is functionally linked to the development of micrometastases at a distal site. By employing a straightforward radiolabeling method to incorporate Technetium-99m into the AuNPs, we used the high sensitivity of radionuclide imaging to monitor the longitudinal accumulation of the nanoparticles in metastatic sites. Animal and histological studies showed that vascular targeting of the nanoparticle facilitated highly accurate targeting of micrometastasis in the 4T1 mouse model of breast cancer metastasis using radionuclide imaging and a low dose of the nanoparticle. Because of the efficient targeting scheme, 14% of the injected AuNP deposited at metastatic sites in the lungs within 60 min after injection, indicating that the vascular bed of metastasis is a viable target site for nanoparticles. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach

PubMed Central

Ruderfer, Douglas M; Charney, Alexander W; Readhead, Ben; Kidd, Brian A; Kähler, Anna K; Kenny, Paul J; Keiser, Michael J; Moran, Jennifer L; Hultman, Christina M; Scott, Stuart A; Sullivan, Patrick F; Purcell, Shaun M; Dudley, Joel T; Sklar, Pamela

2016-01-01

Summary Background Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia. Methods We defined schizophrenia risk loci as genomic regions reaching genome-wide significance in the latest Psychiatric Genomics Consortium schizophrenia genome-wide association study (GWAS) of 36 989 cases and 113 075 controls and loss of function variants observed only once among 5079 individuals in an exome-sequencing study of 2536 schizophrenia cases and 2543 controls (Swedish Schizophrenia Study). Using two large and orthogonally created databases, we collated drug targets into 167 gene sets targeted by pharmacologically similar drugs and examined enrichment of schizophrenia risk loci in these sets. We further linked the exome-sequenced data with a national drug registry (the Swedish Prescribed Drug Register) to assess the contribution of rare variants to treatment response, using clozapine prescription as a proxy for treatment resistance. Findings We combined results from testing rare and common variation and, after correction for multiple testing, two gene sets were associated with schizophrenia risk: agents against amoebiasis and other protozoal diseases (106 genes, p=0·00046, pcorrected =0·024) and antipsychotics (347 genes, p=0·00078, pcorrected=0·046). Further analysis pointed to antipsychotics as having independent enrichment after removing genes that overlapped these two target sets. We noted significant enrichment both in known targets of antipsychotics (70 genes, p=0·0078) and novel predicted targets (277 genes, p=0·019). Patients with treatment-resistant schizophrenia had an excess of rare disruptive variants in gene targets of antipsychotics (347 genes, p=0·0067) and in genes with evidence for a role in antipsychotic efficacy (91 genes, p=0·0029). Interpretation Our results support genetic overlap between schizophrenia pathogenesis and antipsychotic mechanism of action. This finding is consistent with treatment efficacy being polygenic and suggests that single-target therapeutics might be insufficient. We provide evidence of a role for rare functional variants in antipsychotic treatment response, pointing to a subset of patients where their genetic information could inform treatment. Finally, we present a novel framework for identifying treatments from genetic data and improving our understanding of therapeutic mechanism. PMID:26915512

Social Cognition as Reinforcement Learning: Feedback Modulates Emotion Inference.

PubMed

Zaki, Jamil; Kallman, Seth; Wimmer, G Elliott; Ochsner, Kevin; Shohamy, Daphna

2016-09-01

Neuroscientific studies of social cognition typically employ paradigms in which perceivers draw single-shot inferences about the internal states of strangers. Real-world social inference features much different parameters: People often encounter and learn about particular social targets (e.g., friends) over time and receive feedback about whether their inferences are correct or incorrect. Here, we examined this process and, more broadly, the intersection between social cognition and reinforcement learning. Perceivers were scanned using fMRI while repeatedly encountering three social targets who produced conflicting visual and verbal emotional cues. Perceivers guessed how targets felt and received feedback about whether they had guessed correctly. Visual cues reliably predicted one target's emotion, verbal cues predicted a second target's emotion, and neither reliably predicted the third target's emotion. Perceivers successfully used this information to update their judgments over time. Furthermore, trial-by-trial learning signals-estimated using two reinforcement learning models-tracked activity in ventral striatum and ventromedial pFC, structures associated with reinforcement learning, and regions associated with updating social impressions, including TPJ. These data suggest that learning about others' emotions, like other forms of feedback learning, relies on domain-general reinforcement mechanisms as well as domain-specific social information processing.

Mouse models expressing human carcinoembryonic antigen (CEA) as a transgene: Evaluation of CEA-based cancer vaccines

PubMed Central

Hance, Kenneth W.; Zeytin, Hasan E.; Greiner, John W.

2010-01-01

In recent years, investigators have carried out several studies designed to evaluate whether human tumor-associated antigens might be exploited as targets for active specific immunotherapy, specifically human cancer vaccines. Not too long ago such an approach would have been met with considerable skepticism because the immune system was believed to be a rigid discriminator between self and non-self which, in turn, protected the host from a variety of pathogens. That viewpoint has been challenged in recent years by a series of studies indicating that antigenic determinants of self have not induced absolute host immune tolerance. Moreover, under specific conditions that evoke danger signals, peptides from self-antigen can be processed by the antigen-presenting cellular machinery, loaded onto the major histocompatibility antigen groove to serve as targets for immune intervention. Those findings provide the rationale to investigate a wide range of tumor-associated antigens, including differentiation antigens, oncogenes, and tumor suppressor genes as possible immune-based targets. One of those tumor-associated antigens is the carcinoembryonic antigen (CEA). Described almost 40 years ago, CEA is a Mr 180–200,000 oncofetal antigen that is one of the more widely studied human tumor-associated antigens. This review will provide: (i) a brief overview of the CEA gene family, (ii) a summary of early preclinical findings on overcoming immune tolerance to CEA, and (iii) the rationale to develop mouse models which spontaneously develop gastrointestinal tumors and express the CEA transgene. Those models have been used extensively in the study of overcoming host immune tolerance to CEA, a self, tumor-associated antigen, and the experimental findings have served as the rationale for the design of early clinical trials to evaluate CEA-based cancer vaccines. PMID:15888344

The Effect of Symbology Location and Format on Attentional Deployment within a Cockpit Display of Traffic Information

NASA Technical Reports Server (NTRS)

Johnson, Walter W.; Liao, Min-Ju; Tse, Stephen

2003-01-01

The present experiment employed target detection tasks to investigate attentional deployment during visual search for target aircraft symbols on a cockpit display of traffic information (CDTI). Targets were defined by either a geometric property (aircraft on a collision course with Ownship) or a textual property (aircraft with associated altitude tags indicating an even altitude level). Effects of target location and target brightness (highlighting) were examined. Target location was systematically related to target detection time, and this interacted with the target's defining property (collision geometry or associated text). Highlighting (which was not linked to whether an aircraft symbol was the target) did not influence target detection time.

Targeted DNA sequencing of non-small cell lung cancer identifies mutations associated with brain metastases.

PubMed

Wilson, George D; Johnson, Matthew D; Ahmed, Samreen; Cardenas, Paola Yumpo; Grills, Inga S; Thibodeau, Bryan J

2018-05-25

This study explores the hypothesis that dominant molecular oncogenes in non-small cell lung cancer (NSCLC) are associated with metastatic spread to the brain. NSCLC patient groups with no evidence of metastasis, with metastatic disease to a non-CNS site, who developed brain metastasis after diagnosis, and patients with simultaneous diagnosis of NSCLC and metastatic brain lesions were studied using targeted sequencing. In patients with brain metastasis versus those without, only 2 variants (one each in BCL6 and NOTHC2) were identified that occurred in ≥ 4 NSCLC of patients with brain metastases but ≤ 1 of the NSCLC samples without brain metastases. At the gene level, 20 genes were found to have unique variants in more than 33% of the patients with brain metastases. When analyzed at the patient level, these 20 genes formed the basis of a predictive test to discriminate those with brain metastasis. Further analysis showed that PI3K/AKT signaling is altered in both the primary and metastases of NSCLC patients with brain lesions. While no single variant was associated with brain metastasis, this study describes a potential gene panel for the identification of patients at risk and implicates PI3K/AKT signaling as a therapeutic target.

Targeted DNA sequencing of non-small cell lung cancer identifies mutations associated with brain metastases

PubMed Central

Wilson, George D.; Johnson, Matthew D.; Ahmed, Samreen; Cardenas, Paola Yumpo; Grills, Inga S.; Thibodeau, Bryan J.

2018-01-01

Introduction This study explores the hypothesis that dominant molecular oncogenes in non-small cell lung cancer (NSCLC) are associated with metastatic spread to the brain. Methods NSCLC patient groups with no evidence of metastasis, with metastatic disease to a non-CNS site, who developed brain metastasis after diagnosis, and patients with simultaneous diagnosis of NSCLC and metastatic brain lesions were studied using targeted sequencing. Results In patients with brain metastasis versus those without, only 2 variants (one each in BCL6 and NOTHC2) were identified that occurred in ≥ 4 NSCLC of patients with brain metastases but ≤ 1 of the NSCLC samples without brain metastases. At the gene level, 20 genes were found to have unique variants in more than 33% of the patients with brain metastases. When analyzed at the patient level, these 20 genes formed the basis of a predictive test to discriminate those with brain metastasis. Further analysis showed that PI3K/AKT signaling is altered in both the primary and metastases of NSCLC patients with brain lesions. Conclusion While no single variant was associated with brain metastasis, this study describes a potential gene panel for the identification of patients at risk and implicates PI3K/AKT signaling as a therapeutic target. PMID:29899834

CRISPR-Cas9 Targeting of PCSK9 in Human Hepatocytes In Vivo-Brief Report.

PubMed

Wang, Xiao; Raghavan, Avanthi; Chen, Tao; Qiao, Lyon; Zhang, Yongxian; Ding, Qiurong; Musunuru, Kiran

2016-05-01

Although early proof-of-concept studies of somatic in vivo genome editing of the mouse ortholog of proprotein convertase subtilisin/kexin type 9 (Pcsk9) in mice have established its therapeutic potential for the prevention of cardiovascular disease, the unique nature of genome-editing technology-permanent alteration of genomic DNA sequences-mandates that it be tested in vivo against human genes in normal human cells with human genomes to give reliable preclinical insights into the efficacy (on-target mutagenesis) and safety (lack of off-target mutagenesis) of genome-editing therapy before it can be used in patients. We used a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) 9 genome-editing system to target the human PCSK9 gene in chimeric liver-humanized mice bearing human hepatocytes. We demonstrated high on-target mutagenesis (approaching 50%), greatly reduced blood levels of human PCSK9 protein, and minimal off-target mutagenesis. This work yields important information on the efficacy and safety of CRISPR-Cas9 therapy targeting the human PCSK9 gene in human hepatocytes in vivo, and it establishes humanized mice as a useful platform for the preclinical assessment of applications of somatic in vivo genome editing. © 2016 American Heart Association, Inc.

The Association Between Cognitive Performance and Speech-in-Noise Perception for Adult Listeners: A Systematic Literature Review and Meta-Analysis

PubMed Central

Allen, Harriet A.; Henshaw, Helen; Heinrich, Antje

2017-01-01

Published studies assessing the association between cognitive performance and speech-in-noise (SiN) perception examine different aspects of each, test different listeners, and often report quite variable associations. By examining the published evidence base using a systematic approach, we aim to identify robust patterns across studies and highlight any remaining gaps in knowledge. We limit our assessment to adult unaided listeners with audiometric profiles ranging from normal hearing to moderate hearing loss. A total of 253 articles were independently assessed by two researchers, with 25 meeting the criteria for inclusion. Included articles assessed cognitive measures of attention, memory, executive function, IQ, and processing speed. SiN measures varied by target (phonemes or syllables, words, and sentences) and masker type (unmodulated noise, modulated noise, >2-talker babble, and ≤2-talker babble. The overall association between cognitive performance and SiN perception was r = .31. For component cognitive domains, the association with (pooled) SiN perception was as follows: processing speed (r = .39), inhibitory control (r = .34), working memory (r = .28), episodic memory (r = .26), and crystallized IQ (r = .18). Similar associations were shown for the different speech target and masker types. This review suggests a general association of r≈.3 between cognitive performance and speech perception, although some variability in association appeared to exist depending on cognitive domain and SiN target or masker assessed. Where assessed, degree of unaided hearing loss did not play a major moderating role. We identify a number of cognitive performance and SiN perception combinations that have not been tested and whose future investigation would enable further fine-grained analyses of these relationships. PMID:29237334

The Association Between Cognitive Performance and Speech-in-Noise Perception for Adult Listeners: A Systematic Literature Review and Meta-Analysis.

PubMed

Dryden, Adam; Allen, Harriet A; Henshaw, Helen; Heinrich, Antje

2017-01-01

Published studies assessing the association between cognitive performance and speech-in-noise (SiN) perception examine different aspects of each, test different listeners, and often report quite variable associations. By examining the published evidence base using a systematic approach, we aim to identify robust patterns across studies and highlight any remaining gaps in knowledge. We limit our assessment to adult unaided listeners with audiometric profiles ranging from normal hearing to moderate hearing loss. A total of 253 articles were independently assessed by two researchers, with 25 meeting the criteria for inclusion. Included articles assessed cognitive measures of attention, memory, executive function, IQ, and processing speed. SiN measures varied by target (phonemes or syllables, words, and sentences) and masker type (unmodulated noise, modulated noise, >2-talker babble, and ≤2-talker babble. The overall association between cognitive performance and SiN perception was r = .31. For component cognitive domains, the association with (pooled) SiN perception was as follows: processing speed ( r = .39), inhibitory control ( r = .34), working memory ( r = .28), episodic memory ( r = .26), and crystallized IQ ( r = .18). Similar associations were shown for the different speech target and masker types. This review suggests a general association of r≈.3 between cognitive performance and speech perception, although some variability in association appeared to exist depending on cognitive domain and SiN target or masker assessed. Where assessed, degree of unaided hearing loss did not play a major moderating role. We identify a number of cognitive performance and SiN perception combinations that have not been tested and whose future investigation would enable further fine-grained analyses of these relationships.

A Qualitative Study of Tribal Colleges and Universities that Have Transitioned: From Two-Year Associate Degree Granting Institutions to Targeted Four-Year Bachelor Degree Granting Institutions

ERIC Educational Resources Information Center

Chandler, Lynette

2010-01-01

The purpose of this qualitative case study was to analyze how tribal colleges and Universities have transitioned from two-year associate degree granting institutions to offering four-year bachelor degree granting institutions. This case study includes three tribal colleges: Sitting Bull College, Salish Kootenai College and Turtle Mountain…

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome.

PubMed

Burkhart, Keith K; Abernethy, Darrell; Jackson, David

2015-06-01

Drug features that are associated with Stevens-Johnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disproportionality among the molecular targets, metabolizing enzymes, and transporters for drugs associated with SJS. The FAERS in-house version was also analyzed for an internal comparison of the drugs most highly associated with SJS. Cyclooxygenases 1 and 2, carbonic anhydrase 2, and sodium channel 2 alpha were identified as disproportionately associated with SJS. Cytochrome P450 (CYPs) 3A4 and 2C9 are disproportionately represented as metabolizing enzymes of the drugs associated with SJS adverse event reports. Multidrug resistance protein 1 (MRP-1), organic anion transporter 1 (OAT1), and PEPT2 were also identified and are highly associated with the transport of these drugs. A detailed review of the molecular targets identifies important roles for these targets in immune response. The association with CYP metabolizing enzymes suggests that reactive metabolites and oxidative stress may have a contributory role. Drug transporters may enhance intracellular tissue concentrations and also have vital physiologic roles that impact keratinocyte proliferation and survival. Data mining FAERS may be used to hypothesize mechanisms for adverse drug events by identifying molecular targets that are highly associated with drug-induced adverse events. The information gained may contribute to systems biology disease models.

In Silico Identification of Proteins Associated with Drug-induced Liver Injury Based on the Prediction of Drug-target Interactions.

PubMed

Ivanov, Sergey; Semin, Maxim; Lagunin, Alexey; Filimonov, Dmitry; Poroikov, Vladimir

2017-07-01

Drug-induced liver injury (DILI) is the leading cause of acute liver failure as well as one of the major reasons for drug withdrawal from clinical trials and the market. Elucidation of molecular interactions associated with DILI may help to detect potentially hazardous pharmacological agents at the early stages of drug development. The purpose of our study is to investigate which interactions with specific human protein targets may cause DILI. Prediction of interactions with 1534 human proteins was performed for the dataset with information about 699 drugs, which were divided into three categories of DILI: severe (178 drugs), moderate (310 drugs) and without DILI (211 drugs). Based on the comparison of drug-target interactions predicted for different drugs' categories and interpretation of those results using clustering, Gene Ontology, pathway and gene expression analysis, we identified 61 protein targets associated with DILI. Most of the revealed proteins were linked with hepatocytes' death caused by disruption of vital cellular processes, as well as the emergence of inflammation in the liver. It was found that interaction of a drug with the identified targets is the essential molecular mechanism of the severe DILI for the most of the considered pharmaceuticals. Thus, pharmaceutical agents interacting with many of the identified targets may be considered as candidates for filtering out at the early stages of drug research. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Conserved Amphipathic Helices Mediate Lipid Droplet Targeting of Perilipins 1–3*

PubMed Central

Rowe, Emily R.; Mimmack, Michael L.; Barbosa, Antonio D.; Haider, Afreen; Isaac, Iona; Ouberai, Myriam M.; Thiam, Abdou Rachid; Patel, Satish; Saudek, Vladimir; Siniossoglou, Symeon; Savage, David B.

2016-01-01

Perilipins (PLINs) play a key role in energy storage by orchestrating the activity of lipases on the surface of lipid droplets. Failure of this activity results in severe metabolic disease in humans. Unlike all other lipid droplet-associated proteins, PLINs localize almost exclusively to the phospholipid monolayer surrounding the droplet. To understand how they sense and associate with the unique topology of the droplet surface, we studied the localization of human PLINs in Saccharomyces cerevisiae, demonstrating that the targeting mechanism is highly conserved and that 11-mer repeat regions are sufficient for droplet targeting. Mutations designed to disrupt folding of this region into amphipathic helices (AHs) significantly decreased lipid droplet targeting in vivo and in vitro. Finally, we demonstrated a substantial increase in the helicity of this region in the presence of detergent micelles, which was prevented by an AH-disrupting missense mutation. We conclude that highly conserved 11-mer repeat regions of PLINs target lipid droplets by folding into AHs on the droplet surface, thus enabling PLINs to regulate the interface between the hydrophobic lipid core and its surrounding hydrophilic environment. PMID:26742848

A nucleolar targeting signal in PML-I addresses PML to nucleolar caps in stressed or senescent cells.

PubMed

Condemine, Wilfried; Takahashi, Yuki; Le Bras, Morgane; de Thé, Hugues

2007-09-15

The promyelocytic leukemia (PML) tumour suppressor is the organiser of PML nuclear bodies, which are domains the precise functions of which are still disputed. We show that upon several types of stress, endogenous PML proteins form nucleolar caps and eventually engulf nucleolar components. Only two specific PML splice variants (PML-I and PML-IV) are efficiently targeted to the nucleolus and the abundant PML-I isoform is required for the targeting of endogenous PML proteins to this organelle. We identified a nucleolar targeting domain within the evolutionarily conserved C-terminus of PML-I. This domain contains a predicted exonuclease III fold essential for the targeting of the PML-I C-terminus to nucleolar fibrillar centres. Furthermore, spontaneous or oncogene retrieval-induced senescence is associated with the formation of very large PML nuclear bodies that initially contain nucleolar components. Later, poly-ubiquitin conjugates are found on the outer shell or within most of these senescence-associated PML bodies. Thus, unexpectedly, the scarcely studied PML-I isoform links PML bodies, nucleolus, senescence and proteolysis.

Foregrounding Effects during Reading, Revisited

ERIC Educational Resources Information Center

Cook, Anne E.; Gueraud, Sabine; Was, Christopher A.; O'Brien, Edward J.

2007-01-01

Previous researchers have argued that objects associated with a protagonist may be foregrounded, or held active, in memory. This study expanded on previous work by using an inconsistency paradigm to investigate the effects of protagonist association on object accessibility. Readers experienced more processing difficulty when a target sentence…

Possible association between phantom vibration syndrome and occupational burnout.

PubMed

Chen, Chao-Pen; Wu, Chi-Cheng; Chang, Li-Ren; Lin, Yu-Hsuan

2014-01-01

Phantom vibration syndrome (PVS) and phantom ringing syndrome (PRS) occur in many cell phone users. Previous studies have indicated an association between PVS/PRS and job stress. The aim of this study was to determine if PVS/PRS were also associated with occupational burnout. This was a cross-sectional study of 384 employees of a high-tech company in northern Taiwan. They all completed a phantom vibration and ringing questionnaire, the Hospital Anxiety and Depression Scale, and the Chinese version of the Occupational Burnout Inventory. Significantly more women and people with at least a college education were in the population with PRS and PVS, respectively. Anxiety and depression had no associations with PVS/PRS. Higher scores for personal fatigue, job fatigue, and service target fatigue had an independent impact on the presence of PVS, but only a higher score for service target fatigue had an independent impact on the presence of PRS. The independent association between work-related burnout and PVS/PRS suggests that PVS/PRS may be a harbinger of mental stress or a component of the clinical burnout syndrome, and may even be a more convenient and accurate predictor of occupational burnout.

Possible association between phantom vibration syndrome and occupational burnout

PubMed Central

Chen, Chao-Pen; Wu, Chi-Cheng; Chang, Li-Ren; Lin, Yu-Hsuan

2014-01-01

Background Phantom vibration syndrome (PVS) and phantom ringing syndrome (PRS) occur in many cell phone users. Previous studies have indicated an association between PVS/PRS and job stress. The aim of this study was to determine if PVS/PRS were also associated with occupational burnout. Methods This was a cross-sectional study of 384 employees of a high-tech company in northern Taiwan. They all completed a phantom vibration and ringing questionnaire, the Hospital Anxiety and Depression Scale, and the Chinese version of the Occupational Burnout Inventory. Results Significantly more women and people with at least a college education were in the population with PRS and PVS, respectively. Anxiety and depression had no associations with PVS/PRS. Higher scores for personal fatigue, job fatigue, and service target fatigue had an independent impact on the presence of PVS, but only a higher score for service target fatigue had an independent impact on the presence of PRS. Conclusion The independent association between work-related burnout and PVS/PRS suggests that PVS/PRS may be a harbinger of mental stress or a component of the clinical burnout syndrome, and may even be a more convenient and accurate predictor of occupational burnout. PMID:25750984

Predicting Drug-Target Interactions With Multi-Information Fusion.

PubMed

Peng, Lihong; Liao, Bo; Zhu, Wen; Li, Zejun; Li, Keqin

2017-03-01

Identifying potential associations between drugs and targets is a critical prerequisite for modern drug discovery and repurposing. However, predicting these associations is difficult because of the limitations of existing computational methods. Most models only consider chemical structures and protein sequences, and other models are oversimplified. Moreover, datasets used for analysis contain only true-positive interactions, and experimentally validated negative samples are unavailable. To overcome these limitations, we developed a semi-supervised based learning framework called NormMulInf through collaborative filtering theory by using labeled and unlabeled interaction information. The proposed method initially determines similarity measures, such as similarities among samples and local correlations among the labels of the samples, by integrating biological information. The similarity information is then integrated into a robust principal component analysis model, which is solved using augmented Lagrange multipliers. Experimental results on four classes of drug-target interaction networks suggest that the proposed approach can accurately classify and predict drug-target interactions. Part of the predicted interactions are reported in public databases. The proposed method can also predict possible targets for new drugs and can be used to determine whether atropine may interact with alpha1B- and beta1- adrenergic receptors. Furthermore, the developed technique identifies potential drugs for new targets and can be used to assess whether olanzapine and propiomazine may target 5HT2B. Finally, the proposed method can potentially address limitations on studies of multitarget drugs and multidrug targets.

Dengue virus NS2 and NS4: Minor proteins, mammoth roles.

PubMed

Gopala Reddy, Sindhoora Bhargavi; Chin, Wei-Xin; Shivananju, Nanjunda Swamy

2018-04-17

Despite the ever-increasing global incidence of dengue fever, there are no specific chemotherapy regimens for its treatment. Structural studies on dengue virus (DENV) proteins have revealed potential drug targets. Major DENV proteins such as the envelope protein and non-structural (NS) proteins 3 and 5 have been extensively investigated in antiviral studies, but with limited success in vitro. However, the minor NS proteins NS2 and NS4 have remained relatively underreported. Emerging evidence indicating their indispensable roles in virus propagation and host immunomodulation should encourage us to target these proteins for drug discovery. This review covers current knowledge on DENV NS2 and NS4 proteins from structural and functional perspectives and assesses their potential as targets for antiviral design. Antiviral targets in NS2A include surface-exposed transmembrane regions involved in pathogenesis, while those in NS2B include protease-binding sites in a conserved hydrophilic domain. Ideal drug targets in NS4A include helix α4 and the PEPEKQR sequence, which are essential for NS4A-2K cleavage and NS4A-NS4B association, respectively. In NS4B, the cytoplasmic loop connecting helices α5 and α7 is an attractive target for antiviral design owing to its role in dimerization and NS4B-NS3 interaction. Findings implicating NS2A, NS2B, and NS4A in membrane-modulation and viroporin-like activities indicate an opportunity to target these proteins by disrupting their association with membrane lipids. Despite the lack of 3D structural data, recent topological findings and progress in structure-prediction methods should be sufficient impetus for targeting NS2 and NS4 for drug design. Copyright © 2018 Elsevier Inc. All rights reserved.

Identification and Molecular Characterization of the Chloroplast Targeting Domain of Turnip yellow mosaic virus Replication Proteins

PubMed Central

Moriceau, Lucille; Jomat, Lucile; Bressanelli, Stéphane; Alcaide-Loridan, Catherine; Jupin, Isabelle

2017-01-01

Turnip yellow mosaic virus (TYMV) is a positive-strand RNA virus infecting plants. The TYMV 140K replication protein is a key organizer of viral replication complex (VRC) assembly, being responsible for recruitment of the viral polymerase and for targeting the VRCs to the chloroplast envelope where viral replication takes place. However, the structural requirements determining the subcellular localization and membrane association of this essential viral protein have not yet been defined. In this study, we investigated determinants for the in vivo chloroplast targeting of the TYMV 140K replication protein. Subcellular localization studies of deletion mutants identified a 41-residue internal sequence as the chloroplast targeting domain (CTD) of TYMV 140K; this sequence is sufficient to target GFP to the chloroplast envelope. The CTD appears to be located in the C-terminal extension of the methyltransferase domain—a region shared by 140K and its mature cleavage product 98K, which behaves as an integral membrane protein during infection. We predicted the CTD to fold into two amphipathic α-helices—a folding that was confirmed in vitro by circular dichroism spectroscopy analyses of a synthetic peptide. The importance for subcellular localization of the integrity of these amphipathic helices, and the function of 140K/98K, was demonstrated by performing amino acid substitutions that affected chloroplast targeting, membrane association and viral replication. These results establish a short internal α-helical peptide as an unusual signal for targeting proteins to the chloroplast envelope membrane, and provide new insights into membrane targeting of viral replication proteins—a universal feature of positive-strand RNA viruses. PMID:29312393

Targeted nanoparticles for image-guided treatment of triple-negative breast cancer: clinical significance and technological advances.

PubMed

Miller-Kleinhenz, Jasmine M; Bozeman, Erica N; Yang, Lily

2015-01-01

Effective treatment of triple-negative breast cancer (TNBC) with its aggressive tumor biology, highly heterogeneous tumor cells, and poor prognosis requires an integrated therapeutic approach that addresses critical issues in cancer therapy. Multifunctional nanoparticles with the abilities of targeted drug delivery and noninvasive imaging for monitoring drug delivery and responses to therapy, such as theranostic nanoparticles, hold great promise toward the development of novel therapeutic approaches for the treatment of TNBC using a single therapeutic platform. The biological and pathological characteristics of TNBC provide insight into several potential molecular targets for current and future nanoparticle-based therapeutics. Extensive tumor stroma, highly proliferative cells, and a high rate of drug resistance are all barriers that must be appropriately addressed in order for these nanotherapeutic platforms to be effective. Utilization of the enhanced permeability and retention effect coupled with active targeting of cell surface receptors expressed by TNBC cells, and tumor-associated endothelial cells, stromal fibroblasts, and macrophages is likely to overcome such barriers to facilitate more effective drug delivery. An in-depth summary of current studies investigating targeted nanoparticles in preclinical TNBC mouse and human xenograft models is presented. This review aims to outline the current status of nanotherapeutic options for TNBC patients, identification of promising molecular targets, challenges associated with the development of targeted nanotherapeutics, the research done by our group as well as by others, and future perspectives on the nanomedicine field and ways to translate current preclinical studies into the clinic. © 2015 Wiley Periodicals, Inc.

Relationship between temperature variability and brain injury on magnetic resonance imaging in cooled newborn infants after perinatal asphyxia.

PubMed

Brotschi, B; Gunny, R; Rethmann, C; Held, U; Latal, B; Hagmann, C

2017-09-01

The objective of the study was whether temperature management during therapeutic hypothermia correlates with the severity of brain injury assessed on magnetic resonance imaging in term infants with hypoxic-ischemic encephalopathy. Prospectively collected register data from the National Asphyxia and Cooling Register of Switzerland were analyzed. Fifty-five newborn infants were cooled for 72 h with a target temperature range of 33 to 34 °C. Individual temperature variability (odds ratio (OR) 40.17 (95% confidence interval (CI) 1.37 to 1037.67)) and percentage of temperatures within the target range (OR 0.95 (95% CI 0.90 to 0.98)) were associated with the severity of brain injury seen on magnetic resonance imaging (MRI). Neither the percentage of measured temperatures above (OR 1.08 (95% CI 0.96 to 1.21)) nor below (OR 0.99 (95% CI 0.92 to 1.07) the target range was associated with the severity of brain injury seen on MRI. In a national perinatal asphyxia cohort, temperature variability and percentage of temperatures within the target temperature range were associated with the severity of brain injury.

Small molecule targeting of the actin associating protein tropomyosin Tpm3.1 increases neuroblastoma cell response to Rac inhibition of multicellular invasion.

PubMed

Mitchell, Camilla B; Stehn, Justine R; O'Neill, Geraldine M

2018-05-12

The migration and invasion of cells through tissues in the body is facilitated by a dynamic actin cytoskeleton. The actin-associating protein, tropomyosin Tpm3.1 has emerged to play important roles in cell migration and invasion. To date, investigations have focused on single cell migration and invasion where Tpm3.1 expression is inversely associated with Rac GTPase-mediated cell invasion. While single cell and collective cell invasion have many features in common, collective invasion is additionally impacted by cell-cell adhesion, and the role of Tpm3.1 in collective invasion has not been established. In the present study we have modelled multicellular invasion using neuroblastoma spheroids embedded in 3D collagen and analysed the function of Tpm3.1 using recently established compounds that target the Tpm3.1 C-terminus. The major findings from our study reveal that combined Rac inhibition and Tpm3.1 targeting result in greater inhibition of multicellular invasion than either treatment alone. Together, the data suggest that Tpm3.1 disruption sensitizes neuroblastoma cells to Rac inhibition of multicellular invasion. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Irrelevant reward and selection histories have different influences on task-relevant attentional selection.

PubMed

MacLean, Mary H; Giesbrecht, Barry

2015-07-01

Task-relevant and physically salient features influence visual selective attention. In the present study, we investigated the influence of task-irrelevant and physically nonsalient reward-associated features on visual selective attention. Two hypotheses were tested: One predicts that the effects of target-defining task-relevant and task-irrelevant features interact to modulate visual selection; the other predicts that visual selection is determined by the independent combination of relevant and irrelevant feature effects. These alternatives were tested using a visual search task that contained multiple targets, placing a high demand on the need for selectivity, and that was data-limited and required unspeeded responses, emphasizing early perceptual selection processes. One week prior to the visual search task, participants completed a training task in which they learned to associate particular colors with a specific reward value. In the search task, the reward-associated colors were presented surrounding targets and distractors, but were neither physically salient nor task-relevant. In two experiments, the irrelevant reward-associated features influenced performance, but only when they were presented in a task-relevant location. The costs induced by the irrelevant reward-associated features were greater when they oriented attention to a target than to a distractor. In a third experiment, we examined the effects of selection history in the absence of reward history and found that the interaction between task relevance and selection history differed, relative to when the features had previously been associated with reward. The results indicate that under conditions that demand highly efficient perceptual selection, physically nonsalient task-irrelevant and task-relevant factors interact to influence visual selective attention.

Study of the temperature dependent immuno-reaction kinetics for the bio-functionalized magnetic nanoparticle assay of bio-markers of colorectal cancer

NASA Astrophysics Data System (ADS)

Yang, S. Y.; Chang, J. F.; Chen, T. C.; Yang, C. C.; Ho, C. S.

2014-01-01

By conjugating antibodies on magnetic nanoparticles, target antigens can be quantitatively detected by measuring the magnetic signals of the magnetic nanoparticles due to their association with target antigens. This method of detection is called magnetically labeled immunoassay. The assay characteristics of magnetically labeled immunoassay have been reported widely. However, the immuno-reaction kinetics of magnetically labeled immunoassay has not been studied. In this work, the reaction rates between magnetic nanoparticles and target antigens are measured at various temperatures. It is found that the temperature dependent reaction rate obeys Arrhenius's equation, which shows the collision frequency and activation energy for the immuno-reaction between antibody-functionalized magnetic nanoparticles and target antigens. The carcinoembryonic antigen, which is a regular blood bio-marker for in-vitro diagnosis of colorectal cancer, is used as a target antigen for the example.

Onset factors in cerebral palsy: A systematic review.

PubMed

van Lieshout, Pascal; Candundo, Hamilton; Martino, Rosemary; Shin, Sabina; Barakat-Haddad, Caroline

2017-07-01

Studies have noted several factors associated with the occurrence of Cerebral Palsy (CP), yet considerable uncertainty remains about modifiable factors related to disease onset. A systematic review was performed to identify existing systematic reviews and primary studies pertaining to targeted factors associated with the onset of CP. The following databases were searched: MEDLINE, MEDLINE In Process, EMBASE, PsycINFO, Scopus, Web of Science, Cochrane Database of Systematic Reviews, CINHAL, ProQuest Dissertations & Theses, Huge Navigator, AARP Ageline. Variations of MeSH and keyword search terms were used. Critical appraisal was conducted on selected articles. Data extraction targeted reported factors, risk estimates, and 95% confidence intervals (CI). Findings identified two systematic reviews and three meta- analyses, as well as 83 studies of case control, cohort, and cross-sectional methodological designs. Selected studies indicated that lower gestational age was associated with the onset of CP. Medical diagnoses for the mother, in particular chorioamnionitis, was found to be positively associated with onset of CP. Preeclampsia was reported to be either inconclusive or positively associated with CP onset. Low birth weight predominantly indicated a positive association with the onset of CP, while male gender showed mixed findings. The combination of male gender with pre-term or low birth weight was also found to be positively associated with CP. Evidence was identified in the literature pertaining to specific factors relating to the onset of CP, in particular showing positive associations with lower gestational age and low birth weight. Copyright © 2016. Published by Elsevier B.V.

Effectiveness of treat-to-target strategy for LDL-cholesterol control in type 2 diabetes: post-hoc analysis of data from the MIND.IT study.

PubMed

Ardigò, Diego; Vaccaro, Olga; Cavalot, Franco; Rivellese, Albarosa Angela; Franzini, Laura; Miccoli, Roberto; Patti, Lidia; Boemi, Massimo; Trovati, Mariella; Zavaroni, Ivana

2014-04-01

The paper presents a post-hoc analysis of the intensity of dyslipidaemia care operated in the first 2 years of Multiple-Intervention-in-type-2-Diabetes.ITaly (MIND.IT) study. MIND.IT is a multicentric, randomized, two-parallel arm trial involving 1461 type 2 diabetic patients at high cardiovascular (CV) risk. The study compares the usual care (UC) of CV prevention with a multifactorial intensive care (IC) approach aiming at achieving target values for the main CV risk factors according to a step-wise treat-to-target approach. Proportion of patients on target for low-density lipoprotein cholesterol (LDL-C) was about 10% at baseline and increased significantly more with IC than UC (43 vs. 27%; p < 0.001). However, the majority (57%) of patients, in this intended intensively treated cohort, failed to achieve the proposed target. Average LDL-C decreased from 144 ± 35 to 108 ± 31 mg/dl with IC and from 142 ± 28 to 118 ± 32 with UC (p-for-interaction <0.0001). IC was associated with a significantly greater increase in statin prescription and lower withdrawal from treatment than UC (43 vs. 11% and 28 vs. 61%, respectively; both p < 0.001). However, the new treatments were characterized in both groups by the use of low starting doses (≤ 10 mg of atorvastatin, equivalent dose in more than 90% of patients) without increase in case of missed target. The application of a multifactorial treat-to-target intervention is associated with a significant improvement in LDL-C beyond usual practice. However, the change in LDL-C appears to be more related to an increased number of treated patients and a decreased treatment withdrawal than to a true treat-to-target approach.

Identification of MicroRNAs and their Targets Associated with Embryo Abortion during Chrysanthemum Cross Breeding via High-Throughput Sequencing.

PubMed

Zhang, Fengjiao; Dong, Wen; Huang, Lulu; Song, Aiping; Wang, Haibin; Fang, Weimin; Chen, Fadi; Teng, Nianjun

2015-01-01

MicroRNAs (miRNAs) are important regulators in plant development. They post-transcriptionally regulate gene expression during various biological and metabolic processes by binding to the 3'-untranslated region of target mRNAs to facilitate mRNA degradation or inhibit translation. Chrysanthemum (Chrysanthemum morifolium) is one of the most important ornamental flowers with increasing demand each year. However, embryo abortion is the main reason for chrysanthemum cross breeding failure. To date, there have been no experiments examining the expression of miRNAs associated with chrysanthemum embryo development. Therefore, we sequenced three small RNA libraries to identify miRNAs and their functions. Our results will provide molecular insights into chrysanthemum embryo abortion. Three small RNA libraries were built from normal chrysanthemum ovules at 12 days after pollination (DAP), and normal and abnormal chrysanthemum ovules at 18 DAP. We validated 228 miRNAs with significant changes in expression frequency during embryonic development. Comparative profiling revealed that 69 miRNAs exhibited significant differential expression between normal and abnormal embryos at 18 DAP. In addition, a total of 1037 miRNA target genes were predicted, and their annotations were defined by transcriptome data. Target genes associated with metabolic pathways were most highly represented according to the annotation. Moreover, 52 predicted target genes were identified to be associated with embryonic development, including 31 transcription factors and 21 additional genes. Gene ontology (GO) annotation also revealed that high-ranking miRNA target genes related to cellular processes and metabolic processes were involved in transcription regulation and the embryo developmental process. The present study generated three miRNA libraries and gained information on miRNAs and their targets in the chrysanthemum embryo. These results enrich the growing database of new miRNAs and lay the foundation for the further understanding of miRNA biological function in the regulation of chrysanthemum embryo abortion.

The role of parental warmth and hostility on adolescents' prosocial behavior toward multiple targets.

PubMed

Padilla-Walker, Laura M; Nielson, Matthew G; Day, Randal D

2016-04-01

The current study examined the influence that parental warmth/support and verbal hostility had on adolescents' prosocial behavior toward multiple targets (stranger, friend, family) using multiple reporters (self, parent, observations). Data were taken from Times 2 and 3 of a longitudinal project and included 500 adolescents and their parents (M age of child at Time 2 = 12.34). Structural equation models suggested that mother warmth was associated with prosocial behavior toward family, while father warmth was associated with prosocial behavior toward friends. Findings also suggested that adolescents' prosocial behavior was more consistently influenced by father hostility than it was by father warmth. Finally, observational reports of father hostility were associated with adolescent prosocial behavior more consistently than self- or child-reported parenting. The discussion focuses on the importance of considering target of prosocial behavior, the differences between mothers and fathers, and the role of self-reports compared to observations. (c) 2016 APA, all rights reserved).

Cue-independent memory impairment by reactivation-coupled interference in human declarative memory.

PubMed

Zhu, Zijian; Wang, Yingying; Cao, Zhijun; Chen, Biqing; Cai, Huaqian; Wu, Yanhong; Rao, Yi

2016-10-01

Memory is a dynamic process. While memory becomes increasingly resistant to interference after consolidation, a brief reactivation renders it unstable again. Previous studies have shown that interference, when applied upon reactivation, impairs the consolidated memory, presumably by disrupting the reconsolidation of the memory. However, attempts have failed in disrupting human declarative memory, raising a question about whether declarative memory becomes unstable upon reactivation. Here, we used a double-cue/one-target paradigm, which associated the same target with two different cues in initial memory formation. Only one cue/target association was later reactivated and treated with behavioral interference. Our results showed, for the first time, that reactivation-coupled interference caused cue-independent memory impairment that generalized to other cues associated with the memory. Critically, such memory impairment appeared immediately after interference, before the reconsolidation process was completed, suggesting that common manipulations of reactivation-coupled interference procedures might disrupt other processes in addition to the reconsolidation process in human declarative memory. Copyright © 2016. Published by Elsevier B.V.

Preclinical evaluation of radiation and systemic, RGD-targeted, adeno-associated virus phage-TNF gene therapy in a mouse model of spontaneously metastatic melanoma.

PubMed

Quinn, T J; Healy, N; Sara, A; Maggi, E; Claros, C S; Kabarriti, R; Scandiuzzi, L; Liu, L; Gorecka, J; Adem, A; Basu, I; Yuan, Z; Guha, C

2017-01-01

The incidence of melanoma in the United States continues to rise, with metastatic lesions notoriously recalcitrant to therapy. There are limited effective treatment options available and a great need for more effective therapies that can be rapidly integrated in the clinic. In this study, we demonstrate that the combination of RGD-targeted adeno-associated virus phage (RGD-AAVP-TNF) with hypofractionated radiation therapy results in synergistic inhibition of primary syngeneic B16 melanoma in a C57 mouse model. Furthermore, this combination appeared to modify the tumor microenvironment, resulting in decreased Tregs in the draining LN and increased tumor-associated macrophages within the primary tumor. Finally, there appeared to be a reduction in metastatic potential and a prolongation of overall survival in the combined treatment group. These results indicate the use of targeted TNF gene therapy vector with radiation treatment could be a valuable treatment option for patients with metastatic melanoma.

Inflammation in acute and chronic pancreatitis.

PubMed

Habtezion, Aida

2015-09-01

This report reviews recent animal model and human studies associated with inflammatory responses in acute and chronic pancreatitis. Animal model and limited human acute and chronic pancreatitis studies unravel the dynamic nature of the inflammatory processes and the ability of the immune cells to sense danger and environmental signals. In acute pancreatitis, such molecules include pathogen-associated molecular pattern recognition receptors such as toll-like receptors, and the more recently appreciated damage-associated molecular pattern molecules or 'alarmin' high mobility group box 1 and IL-33. In chronic pancreatitis, a recent understanding of a critical role for macrophage-pancreatic stellate cell interaction offers a potential targetable pathway that can alter fibrogenesis. Microbiome research in pancreatitis is a new field gaining interest but will require further investigation. Immune cell contribution to the pathogenesis of acute and chronic pancreatitis is gaining more appreciation and further understanding in immune signaling presents potential therapeutic targets that can alter disease progression.

Choice of saccade endpoint under risk

PubMed Central

Ackermann, John F.; Landy, Michael S.

2013-01-01

Eye movements function to bring detailed information onto the high-resolution region of the retina. Previous research has shown that human observers select fixation points that maximize information acquisition and minimize target location uncertainty. In this study, we ask whether human observers choose the saccade endpoint that maximizes gain when there are explicit rewards associated with correctly detecting the target. Observers performed an 8-alternative forced-choice detection task for a contrast-defined target in noise. After a single saccade, observers indicated the target location. Each potential target location had an associated reward that was known to the observer. In some conditions, the reward at one location was higher than at the other locations. We compared human saccade endpoints to those of an ideal observer that maximizes expected gain given the respective human observer's visibility map, i.e., d′ for target detection as a function of retinal location. Varying the location of the highest reward had a significant effect on human observers' distribution of saccade endpoints. Both human and ideal observers show a high density of saccades made toward the highest rewarded and actual target locations. But humans' overall spatial distributions of saccade endpoints differed significantly from the ideal observer as they made a greater number of saccade to locations far from the highest rewarded and actual target locations. Suboptimal choice of saccade endpoint, possibly in combination with suboptimal integration of information across saccades, had a significant effect on human observers' ability to correctly detect the target and maximize gain. PMID:24023277

Clinical performance targets and quality of life in hemodialysis patients.

PubMed

Mazairac, Albert H A; de Wit, G Ardine; Grooteman, Muriel P C; Penne, E Lars; van der Weerd, Neelke C; den Hoedt, Claire H; Lévesque, Renée; van den Dorpel, Marinus A; Nubé, Menso J; Ter Wee, Piet M; Blankestijn, Peter J; Bots, Michiel L

2012-01-01

Patients value health-related quality of life (HRQOL) over survival. It was our aim to study the relation between attainment of widely accepted performance targets and HRQOL in hemodialysis patients. This study included baseline data from 715 hemodialysis patients from 29 dialysis centers. Six clinical performance targets, as recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI), were evaluated: single-pool Kt/V (≥1.2), hemoglobin (11-13 g/dl), vascular access (fistula), phosphorus (2.3-4.5 mg/dl), parathyroid hormone (150-300 pg/ml), and blood pressure (predialysis <140/90 and postdialysis <130/ 80 mm Hg). After correction for case-mix and multiple comparisons, no association was found between the 6 KDOQI clinical performance targets and the 14 HRQOL domains, or between the number of performance targets reached and HRQOL. Attainment with widely accepted clinical performance targets was not related to the HRQOL of hemodialysis patients. Hence, in clinical guidelines, HRQOL should be adopted as an explicit treatment goal for these individuals. Copyright © 2011 S. Karger AG, Basel.

FOXP2 Targets Show Evidence of Positive Selection in European Populations

PubMed Central

Ayub, Qasim; Yngvadottir, Bryndis; Chen, Yuan; Xue, Yali; Hu, Min; Vernes, Sonja C.; Fisher, Simon E.; Tyler-Smith, Chris

2013-01-01

Forkhead box P2 (FOXP2) is a highly conserved transcription factor that has been implicated in human speech and language disorders and plays important roles in the plasticity of the developing brain. The pattern of nucleotide polymorphisms in FOXP2 in modern populations suggests that it has been the target of positive (Darwinian) selection during recent human evolution. In our study, we searched for evidence of selection that might have followed FOXP2 adaptations in modern humans. We examined whether or not putative FOXP2 targets identified by chromatin-immunoprecipitation genomic screening show evidence of positive selection. We developed an algorithm that, for any given gene list, systematically generates matched lists of control genes from the Ensembl database, collates summary statistics for three frequency-spectrum-based neutrality tests from the low-coverage resequencing data of the 1000 Genomes Project, and determines whether these statistics are significantly different between the given gene targets and the set of controls. Overall, there was strong evidence of selection of FOXP2 targets in Europeans, but not in the Han Chinese, Japanese, or Yoruba populations. Significant outliers included several genes linked to cellular movement, reproduction, development, and immune cell trafficking, and 13 of these constituted a significant network associated with cardiac arteriopathy. Strong signals of selection were observed for CNTNAP2 and RBFOX1, key neurally expressed genes that have been consistently identified as direct FOXP2 targets in multiple studies and that have themselves been associated with neurodevelopmental disorders involving language dysfunction. PMID:23602712

Host and viral RNA-binding proteins involved in membrane targeting, replication and intercellular movement of plant RNA virus genomes

PubMed Central

Hyodo, Kiwamu; Kaido, Masanori; Okuno, Tetsuro

2014-01-01

Many plant viruses have positive-strand RNA [(+)RNA] as their genome. Therefore, it is not surprising that RNA-binding proteins (RBPs) play important roles during (+)RNA virus infection in host plants. Increasing evidence demonstrates that viral and host RBPs play critical roles in multiple steps of the viral life cycle, including translation and replication of viral genomic RNAs, and their intra- and intercellular movement. Although studies focusing on the RNA-binding activities of viral and host proteins, and their associations with membrane targeting, and intercellular movement of viral genomes have been limited to a few viruses, these studies have provided important insights into the molecular mechanisms underlying the replication and movement of viral genomic RNAs. In this review, we briefly overview the currently defined roles of viral and host RBPs whose RNA-binding activity have been confirmed experimentally in association with their membrane targeting, and intercellular movement of plant RNA virus genomes. PMID:25071804

MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma.

PubMed

Gautam, Shailendra K; Kumar, Sushil; Cannon, Andrew; Hall, Bradley; Bhatia, Rakesh; Nasser, Mohd Wasim; Mahapatra, Sidharth; Batra, Surinder K; Jain, Maneesh

2017-07-01

Pancreatic cancer (PC) is characterized by mucin overexpression. MUC4 is the most differentially overexpressed membrane-bound mucin that plays a functional role in disease progression and therapy resistance. Area covered: We describe the clinicopathological significance of MUC4, summarize mechanisms contributing to its deregulated expression, review preclinical studies aimed at inhibiting MUC4, and discuss how MUC4 overexpression provides opportunities for developing targeted therapies. Finally, we discuss the challenges for developing MUC4-based therapeutics, and identify areas where efforts should be directed to effectively exploit MUC4 as a therapeutic target for PC. Expert opinion: Studies demonstrating that abrogation of MUC4 expression reduces proliferation and metastasis of PC cells and enhances sensitivity to therapeutic agents affirm its utility as a therapeutic target. Emerging evidence also supports the suitability of MUC4 as a potential immunotherapy target. However, these studies have been limited to in vitro, ex vivo or in vivo approaches using xenograft tumors in immunodeficient murine models. For translational relevance, MUC4-targeted therapies should be evaluated in murine models with intact immune system and accurate tumor microenvironment. Additionally, future studies evaluating MUC4 as a target for immunotherapy must entail characterization of immune response in PC patients and investigate its association with immunosuppression and survival.

Open reading frames associated with cancer in the dark matter of the human genome.

PubMed

Delgado, Ana Paula; Brandao, Pamela; Chapado, Maria Julia; Hamid, Sheilin; Narayanan, Ramaswamy

2014-01-01

The uncharacterized proteins (open reading frames, ORFs) in the human genome offer an opportunity to discover novel targets for cancer. A systematic analysis of the dark matter of the human proteome for druggability and biomarker discovery is crucial to mining the genome. Numerous data mining tools are available to mine these ORFs to develop a comprehensive knowledge base for future target discovery and validation. Using the Genetic Association Database, the ORFs of the human dark matter proteome were screened for evidence of association with neoplasms. The Phenome-Genome Integrator tool was used to establish phenotypic association with disease traits including cancer. Batch analysis of the tools for protein expression analysis, gene ontology and motifs and domains was used to characterize the ORFs. Sixty-two ORFs were identified for neoplasm association. The expression Quantitative Trait Loci (eQTL) analysis identified thirteen ORFs related to cancer traits. Protein expression, motifs and domain analysis and genome-wide association studies verified the relevance of these OncoORFs in diverse tumors. The OncoORFs are also associated with a wide variety of human diseases and disorders. Our results link the OncoORFs to diverse diseases and disorders. This suggests a complex landscape of the uncharacterized proteome in human diseases. These results open the dark matter of the proteome to novel cancer target research. Copyright© 2014, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

Turning the pump handle: Evolving methods for integrating the evidence on gene-disease association

USDA-ARS?s Scientific Manuscript database

Recent findings from genome-wide association studies have demonstrated their considerable potential for identifying genetic determinants of common diseases of public health significance such as cancer, heart disease, and diabetes, but they have also highlighted the continued importance of targeted g...

Discoidin Domain Receptors: Novel Targets in Breast Cancer Bone Metastasis

DTIC Science & Technology

2017-02-01

BrCa cases with different molecular subtypes, and found a significant inverse association between cytoplasmic DDR1 localization and progesterone...DDR1 antibody, and completed the study of DDR1 expression and association with disease progression with one TMA. We found a significant inverse

Does Discourse Congruence Influence Spoken Language Comprehension before Lexical Association? Evidence from Event-Related Potentials

ERIC Educational Resources Information Center

Boudewyn, Megan A.; Gordon, Peter C.; Long, Debra; Polse, Lara; Swaab, Tamara Y.

2012-01-01

The goal of this study was to examine how lexical association and discourse congruence affect the time course of processing incoming words in spoken discourse. In an event-related potential (ERP) norming study, we presented prime-target pairs in the absence of a sentence context to obtain a baseline measure of lexical priming. We observed a…

Resource implications of a national health target: The New Zealand experience of a Shorter Stays in Emergency Departments target.

PubMed

Jones, Peter; Sopina, Elizaveta; Ashton, Toni

2014-12-01

The Shorter Stays in Emergency Departments health target was introduced in New Zealand in 2009. District Health Boards (DHBs) are expected to meet the target with no additional funding or incentives. The costs of implementing such targets have not previously been studied. A survey of clinical/service managers in ED throughout New Zealand determined the type and cost of resources used for the target. Responses to the target were classified according to their impact in ED, the hospital and the community. Quantifiable resource changes were assigned a financial value and grouped into categories: structure (facilities/beds), staff and processes. Simple statistics were used to describe the data, and the correlation between expenditure and target performance was determined. There was 100% response to the survey. Most DHBs reported some expenditure specifically on the target, with estimated total expenditure of over NZ$52 m. The majority of expenditure occurred in ED (60.8%) and hospital (38.7%) with little spent in the community. New staff accounted for 76.5% of expenditure. Per capita expenditure in the ED was associated with improved target performance (r = 0.48, P = 0.03), whereas expenditure in the hospital was not (r = 0.08, P = 0.75). The fact that estimated expenditure on the target was over $50 million without additional funding suggests that DHBs were able to make savings through improved efficiencies and/or that funds were reallocated from other services. The majority of expenditure occurred in the ED. Most of the funds were spent on staff, and this was associated with improved target performance. © 2014 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.

Cancer heterogeneity: origins and implications for genetic association studies

PubMed Central

Urbach, Davnah; Lupien, Mathieu; Karagas, Margaret R.; Moore, Jason H.

2012-01-01

Genetic association studies have become standard approaches to characterize the genetic and epigenetic variability associated with cancer development, including predispositions and mutations. However, the bewildering genetic and phenotypic heterogeneity inherent in cancer both magnifies the conceptual and methodological problems associated with these approaches and renders the translation of available genetic information into a knowledge that is both biologically sound and clinically relevant difficult. Here, we elaborate on the underlying causes of this complexity, illustrate why it represents a challenge for genetic association studies, and briefly discuss how it can be reconciled with the ultimate goal of identifying targetable disease pathways and successfully treating individual patients. PMID:22858414

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Cell surface receptors and associated signaling pathways).

PubMed

Aguilar-Company, J; Fernández-Ruiz, M; García-Campelo, R; Garrido-Castro, A C; Ruiz-Camps, I

2018-06-01

The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biologic therapies. To review, from an infectious diseases perspective, the safety profile of therapies targeting cell surface receptors and associated signaling pathways among cancer patients and to suggest preventive recommendations. Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. Vascular endothelial growth factor (VEGF)-targeted agents (bevacizumab and aflibercept) are associated with a meaningful increase in the risk of infection, likely due to drug-induced neutropaenia, although no clear benefit is expected from the universal use of anti-infective prophylaxis. VEGF tyrosine kinase inhibitors (i.e. sorafenib or sunitinib) do not seem to significantly affect host's susceptibility to infection, and universal anti-infective prophylaxis is not recommended either. Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) induce neutropaenia and secondary skin and soft tissue infection in cases of severe papulopustular rash. Systemic antibiotics (doxycycline or minocycline) should be administered to prevent the latter complication, whereas no recommendation can be established on the benefit from antiviral, antifungal or anti-Pneumocystis prophylaxis. A lower risk of infection is reported for anti-ErbB2/HER2 monoclonal antibodies (trastuzumab and pertuzumab) and ErbB receptor tyrosine kinase inhibitors (including dual-EGFR/ErbB2 inhibitors such as lapatinib or neratinib) compared to conventional chemotherapy, presumably as a result of the decreased occurrence of drug-induced neutropaenia. With the exception of VEGF-targeted agents, the overall risk of infection associated with the reviewed therapies seems to be low. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

HER2 Amplification and HER2 Mutation Are Distinct Molecular Targets in Lung Cancers.

PubMed

Li, Bob T; Ross, Dara S; Aisner, Dara L; Chaft, Jamie E; Hsu, Meier; Kako, Severine L; Kris, Mark G; Varella-Garcia, Marileila; Arcila, Maria E

2016-03-01

Human epidermal growth factor receptor 2 gene (HER2 [also known as ERBB2]) alterations have been identified as oncogenic drivers and potential therapeutic targets in lung cancers. The molecular associations of HER2 gene amplification, mutation, and HER2 protein overexpression in lung cancers have not been distinctly defined. To explore these associations, Memorial Sloan Kettering Cancer Center and the University of Colorado combined their data on HER2 alterations in lung cancers. Tumor specimens from 175 patients with lung adenocarcinomas and no prior targeted therapy were evaluated for the presence of HER2 amplification and mutation and HER2 protein overexpression. Amplification was assessed by fluorescence in situ hybridization (FISH) and defined as an HER2-to-chromosome enumeration probe 17 ratio of at least 2.0. Mutation was assessed by fragment analysis, mass spectrometry genotyping, and Sanger sequencing. Overexpression was assessed by immunohistochemical (IHC) staining. The frequencies of HER2 amplification and mutation and HER2 overexpression were calculated and their overlap examined. HER2 amplification was detected by FISH in 5 of 175 cases (3%). HER2 mutation was detected in 4 of 148 specimens (3%), including three identical 12-base pair insertions (p.A775_G776insYVMA) and a 9-base pair insertion, all in exon 20. None of the HER2-mutant cases was amplified. HER2 overexpression (2+ or 3+) on IHC staining was not detected in the 25 specimens available for testing, and negative IHC staining correlated with the negative results according to FISH. HER2 mutations are not associated with HER2 amplification, thus suggesting a distinct entity and therapeutic target. HER2-positive lung cancer may not be an adequate term, and patient cohorts for the study of HER2-targeted agents should be defined by the specific HER2 alteration present. Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiong, Xinkui; Sun, Daoyi; Chai, Hao

The dysregulation of micro (mi)RNAs is associated with cancer development. The miRNA miR-145 is downregulated in intrahepatic cholangiocarcinoma (ICC); however, its precise role in tumor progression has not yet been elucidated. Novel (nua) kinase family (NUAK)1 functions as an oncogene in various cancers and is a putative target of miR-145 regulation. In this study, we investigated the regulation of NUAK1 by miR-145 in ICC. We found that miR-145 level was significantly decreased in ICC tissue and cell lines, which corresponded with an increase in NUAK1 expression. NUAK1 was found to be a direct target of miR-145 regulation. The overexpression ofmore » miR-145 in ICC cell lines inhibited proliferation, growth, and invasion by suppressing NUAK1 expression, which was associated with a decrease in Akt signaling and matrix metalloproteinase protein expression. Similar results were observed by inhibiting NUAK1 expression. These results demonstrate that miR-145 can prevent ICC progression by targeting NUAK1 and its downstream effectors, and can therefore be useful for clinical diagnosis and targeted therapy of ICC. - Highlights: • MiR-145 suppresses ICC proliferation and invasion abilities. • We demonstrated that miR-145 directly targets NUAK1 in ICC. • MiR-145 expression in ICC was associated with Akt signaling and MMPs expression.« less

Risk of developing tuberculosis disease among persons diagnosed with latent tuberculosis infection in the Netherlands.

PubMed

Erkens, Connie G M; Slump, Erika; Verhagen, Maurits; Schimmel, Henrieke; Cobelens, Frank; van den Hof, Susan

2016-11-01

Diagnosis and preventive treatment of latent tuberculosis infection (LTBI) among high-risk groups is recommended to achieve tuberculosis (TB) elimination in low-incidence countries.We studied TB incidence rates among those notified with LTBI in the Netherlands from 2005 to 2013 and analysed associated risk factors. We stratified analyses by target group for screening, and by initiation and completion of preventive treatment.The incidence for those completing, stopping and not receiving preventive treatment was 187, 436 and 355 per 100 000 person-years for contacts of TB patients, respectively, and 63, 96 and 110 per 100 000 person-years for other target groups. The rate ratio for TB development among contacts compared to other target groups was 3.1 (95% CI 2.0-4.9). In both groups, incidence was highest in the first year after diagnosis. Independent factors associated with progression to TB among contacts were age <5 years and stopping preventive treatment within 28 days compared to those not receiving preventive treatment. Among other target groups, being foreign born was the only risk factor associated with the risk of developing TB.We conclude that the epidemiological impact of preventive treatment is highest in contacts of TB patients and limited in other target groups for LTBI management in the Netherlands. Copyright ©ERS 2016.

Transcription factor HIF1A: downstream targets, associated pathways, polymorphic hypoxia response element (HRE) sites, and initiative for standardization of reporting in scientific literature.

PubMed

Slemc, Lucija; Kunej, Tanja

2016-11-01

Hypoxia-inducible factor-1α (HIF-1α) has crucial role in adapting cells to hypoxia through expression regulation of many genes. Identification of HIF-1α target genes (HIF-1α-TGs) is important for understanding the adapting mechanism. The aim of the present study was to collect known HIF-1α-TGs and identify their associated pathways. Targets and associated genomics data were retrieved using PubMed, WoS ( http://apps.webofknowledge.com/ ), HGNC ( http://www.genenames.org/ ), NCBI ( http://www.ncbi.nlm.nih.gov/ ), Ensemblv.84 ( http://www.ensembl.org/index.html ), DAVID Bioinformatics Resources ( https://david.ncifcrf.gov /), and Disease Ontology database ( http://disease-ontology.org/ ). From 51 papers, we collected 98 HIF-1α TGs found to be associated with 20 pathways, including metabolism of carbohydrates and pathways in cancer. Reanalysis of genomic coordinates of published HREs (hypoxia response elements) revealed six polymorphisms within HRE sites (HRE-SNPs): ABCG2, ACE, CA9, and CP. Due to large heterogeneity of results presentation in scientific literature, we also propose a first step towards reporting standardization of HIF-1α-target interactions consisting of ten relevant data types. Suggested minimal checklist for reporting will enable faster development of a complete catalog of HIF-1α-TGs, data sharing, bioinformatics analyses, and setting novel more targeted hypotheses. The proposed format for data standardization is not yet complete but presents a baseline for further optimization of the protocol with additional details, for example, regarding the experimental validation.

Nucleic acid-based vaccines targeting respiratory syncytial virus: Delivering the goods.

PubMed

Smith, Trevor R F; Schultheis, Katherine; Broderick, Kate E

2017-11-02

Respiratory syncytial virus (RSV) is a massive medical burden on a global scale. Infants, children and the elderly represent the vulnerable populations. Currently there is no approved vaccine to protect against the disease. Vaccine development has been hindered by several factors including vaccine enhanced disease (VED) associated with formalin-inactivated RSV vaccines, inability of target populations to raise protective immune responses after vaccination or natural viral infection, and a lack of consensus concerning the most appropriate virus-associated target antigen. However, with recent advances in the molecular understanding of the virus, and design of highly characterized vaccines with enhanced immunogenicity there is new belief a RSV vaccine is possible. One promising approach is nucleic acid-based vaccinology. Both DNA and mRNA RSV vaccines are showing promising results in clinically relevant animal models, supporting their transition into humans. Here we will discuss this strategy to target RSV, and the ongoing studies to advance the nucleic acid vaccine platform as a viable option to protect vulnerable populations from this important disease.

Reallocating attention during multiple object tracking.

PubMed

Ericson, Justin M; Christensen, James C

2012-07-01

Wolfe, Place, and Horowitz (Psychonomic Bulletin & Review 14:344-349, 2007) found that participants were relatively unaffected by selecting and deselecting targets while performing a multiple object tracking task, such that maintaining tracking was possible for longer durations than the few seconds typically studied. Though this result was generally consistent with other findings on tracking duration (Franconeri, Jonathon, & Scimeca Psychological Science 21:920-925, 2010), it was inconsistent with research involving cuing paradigms, specifically precues (Pylyshyn & Annan Spatial Vision 19:485-504, 2006). In the present research, we broke down the addition and removal of targets into separate conditions and incorporated a simple performance model to evaluate the costs associated with the selection and deselection of moving targets. Across three experiments, we demonstrated evidence against a cost being associated with any shift in attention, but rather that varying the type of cue used for target deselection produces no additional cost to performance and that hysteresis effects are not induced by a reduction in tracking load.

More than Just Openness: Developing and Validating a Measure of Targeted Parent-Child Communication about Alcohol

PubMed Central

Miller-Day, Michelle; Kam, Jennifer A.

2010-01-01

Research addressing parent-child communication on the topic of alcohol use relies heavily on assessing frequency of discussions and general assessments of openness in parent-child communication, ignoring the complexity of this communication phenomenon. This study adds to the literature by articulating a conceptualization and developing a measurement of parent-child communication—targeted parent-child communication about alcohol—and comparing the efficacy of targeted parent-child communication about alcohol in predicting positive expectancies of alcohol use and recent alcohol use. The predictive power of general openness in parent-child communication and frequency of communication about alcohol also were assessed. Students in 5th and 6th grade (N = 1407) from 29 public schools completed surveys. Targeted parent-child communication about alcohol was negatively associated with both outcomes. Frequency and general openness were only negatively associated with positive expectancies regarding alcohol. Implications of these findings for the etiology and prevention of substance use are discussed. PMID:20512711

More than just openness: developing and validating a measure of targeted parent-child communication about alcohol.

PubMed

Miller-Day, Michelle; Kam, Jennifer A

2010-06-01

Research addressing parent-child communication on the topic of alcohol use relies heavily on assessing frequency of discussions and general assessments of openness in parent-child communication, ignoring the complexity of this communication phenomenon. This study adds to the literature by articulating a conceptualization and developing a measurement of parent-child communication-targeted parent-child communication about alcohol-and comparing the efficacy of targeted parent-child communication about alcohol in predicting positive expectancies of alcohol use and recent alcohol use. The predictive power of general openness in parent-child communication and frequency of communication about alcohol also were assessed. Students in fifth and sixth grade (N = 1,407) from 29 public schools completed surveys. Targeted parent-child communication about alcohol was negatively associated with both outcomes. Frequency and general openness were only negatively associated with positive expectancies regarding alcohol. Implications of these findings for the etiology and prevention of substance use are discussed.

Facilitated diffusion in chromatin lattices: mechanistic diversity and regulatory potential.

PubMed

Kampmann, Martin

2005-08-01

The interaction between a protein and a specific DNA site is the molecular basis for vital processes in all organisms. Location of the DNA target site by the protein commonly involves facilitated diffusion. Mechanisms of facilitated diffusion vary among proteins; they include one- and two-dimensional sliding along DNA, direct transfer between uncorrelated sites, as well as combinations of these mechanisms. Facilitated diffusion has almost exclusively been studied in vitro. This review discusses facilitated diffusion in the context of the living cell and proposes a theoretical model for facilitated diffusion in chromatin lattices. Chromatin structure differentially affects proteins in different modes of diffusion. The interplay of facilitated diffusion and chromatin structure can determine the rate of protein association with the target site, the frequency of association-dissociation events at the target site, and, under particular conditions, the occupancy of the target site. Facilitated diffusion is required in vivo for efficient DNA repair and bacteriophage restriction and has potential roles in fine-tuning gene regulatory networks and kinetically compartmentalizing the eukaryotic nucleus.

Factors associated with reaching or not reaching target HbA1c after initiation of basal or premixed insulin in patients with type 2 diabetes.

PubMed

Scheen, A J; Schmitt, H; Jiang, H H; Ivanyi, T

2017-02-01

To evaluate factors associated with reaching or not reaching target glycated haemoglobin (HbA 1c ) levels by analysing the respective contributions of fasting hyperglycaemia (FHG), also referred to as basal hyperglycaemia, vs postprandial hyperglycaemia (PHG) before and after initiation of a basal or premixed insulin regimen in patients with type 2 diabetes. This post-hoc analysis of insulin-naïve patients in the DURABLE study randomised to receive either insulin glargine or insulin lispro mix 25 evaluated the percentages of patients achieving a target HbA 1c of <7.0% (<53mmol/mol) per baseline HbA 1c quartiles, and the effect of each insulin regimen on the relative contributions of PHG and FHG to overall hyperglycaemia. Patients had comparable demographic characteristics and similar HbA 1c and FHG values at baseline in each HbA 1c quartile regardless of whether they reached the target HbA 1c . The higher the HbA 1c quartile, the greater was the decrease in HbA 1c , but also the smaller the percentage of patients achieving the target HbA 1c . HbA 1c and FHG decreased more in patients reaching the target, resulting in significantly lower values at endpoint in all baseline HbA 1c quartiles with either insulin treatment. Patients not achieving the target HbA 1c had slightly higher insulin doses, but lower total hypoglycaemia rates. Smaller decreases in FHG were associated with not reaching the target HbA 1c , suggesting a need to increase basal or premixed insulin doses to achieve targeted fasting plasma glucose and improve patient response before introducing more intensive prandial insulin regimens. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Development, optimization and characterization of glycyrrhetinic acid-chitosan nanoparticles of atorvastatin for liver targeting.

PubMed

Rohilla, Raman; Garg, Tarun; Bariwal, Jitender; Goyal, Amit K; Rath, Goutam

2016-09-01

Glycyrrhetinic acid-modified chitosan (mGA-suc-CTS) is used as liver-targeted carrier for drug delivery. In this study, nanoparticles were prepared by ionic gelation process, and glycyrrhetinic acid act as the targeting ligand. The structure of the product was confirmed by IR and NMR techniques. The main aim of this study was to deliver atorvastatin directly to the liver by using same conjugate and reduce the associated side-effects, i.e. hepatotoxicity at high dose. Characterization of the developed formulation was performed by differential scanning calorimetry, particle size measurements and cellular uptake studies. Release profile, pharmacokinetics studies and organ distribution studies showed that developed formulation shows a relative higher liver uptake. The optimized formulation showed increased plasma concentration than the CTS nanoparticles as well as plain drug and the accumulation in the liver was nearly 2.59 times more than that of obtained with the CTS nanoparticles. Pharmaceutical and pharmacological indicators suggested that the proposed strategy can be successfully utilized for liver targeting of therapeutics.

Irrelevant learned reward associations disrupt voluntary spatial attention.

PubMed

MacLean, Mary H; Diaz, Gisella K; Giesbrecht, Barry

2016-10-01

Attention can be guided involuntarily by physical salience and by non-salient, previously learned reward associations that are currently task-irrelevant. Attention can be guided voluntarily by current goals and expectations. The current study examined, in two experiments, whether irrelevant reward associations could disrupt current, goal-driven, voluntary attention. In a letter-search task, attention was directed voluntarily (i.e., cued) on half the trials by a cue stimulus indicating the hemifield in which the target letter would appear with 100 % accuracy. On the other half of the trials, a cue stimulus was presented, but it did not provide information about the target hemifield (i.e., uncued). On both cued and uncued trials, attention could be involuntarily captured by the presence of a task-irrelevant, and physically non-salient, color, either within the cued or the uncued hemifield. Importantly, one week prior to the letter search task, the irrelevant color had served as a target feature that was predictive of reward in a separate training task. Target identification accuracy was better on cued compared to uncued trials. However, this effect was reduced when the irrelevant, and physically non-salient, reward-associated feature was present in the uncued hemifield. This effect was not observed in a second, control experiment in which the irrelevant color was not predictive of reward during training. Our results indicate that involuntary, value-driven capture can disrupt the voluntary control of spatial attention.

Partial sleep deprivation does not alter processes involved in semantic word priming: event-related potential evidence.

PubMed

Tavakoli, Paniz; Muller-Gass, Alexandra; Campbell, Kenneth

2015-03-01

Sleep deprivation has generally been observed to have a detrimental effect on tasks that require sustained attention for successful performance. It might however be possible to counter these effects by altering cognitive strategies. A recent semantic word priming study indicated that subjects used an effortful predictive-expectancy search of semantic memory following normal sleep, but changed to an automatic, effortless strategy following total sleep deprivation. Partial sleep deprivation occurs much more frequently than total sleep deprivation. The present study therefore employed a similar priming task following either 4h of sleep or following normal sleep. The purpose of the study was to determine whether partial sleep deprivation would also lead to a shift in cognitive strategy to compensate for an inability to sustain attention and effortful processing necessary for using the predicative expectancy strategy. Sixteen subjects were presented with word pairs, a prime and a target that were either strongly semantically associated (cat...dog), weakly associated (cow...barn) or not associated (apple...road). The subject's task was to determine if the target word was semantically associated to the prime. A strong priming effect was observed in both conditions. RTs were slower, accuracy lower, and N400 larger to unassociated targets, independent of the amount of sleep. The overall N400 did not differ as a function of sleep. The scalp distribution of the N400 was also similar following both normal sleep and sleep loss. There was thus little evidence of a difference in the processing of the target stimulus as a function of the amount sleep. Similarly, ERPs in the period between the onset of the prime and the subsequent target also did not differ between the normal sleep and sleep loss conditions. In contrast to total sleep deprivation, subjects therefore appeared to use a common predictive expectancy strategy in both conditions. This strategy does however require an effortful sustaining of attention, and may not have been entirely successful when sleep was restricted. A slight but significant decrease in accuracy was noted. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Association Study between Cervical Lesions and Single or Multiple Vaccine-Target and Non-Vaccine Target Human Papillomavirus (HPV) Types in Women from Northeastern Brazil

PubMed Central

Chagas, Bárbara Simas; Comar, Manola; Gurgel, Ana Pavla Almeida Diniz; Paiva, Sérgio; Seraceni, Silva; de Freitas, Antonio Carlos; Crovella, Sergio

2015-01-01

We performed an association between high-grade squamous intraepithelial lesions (HSIL), low-grade squamous intraepithelial lesions (LSIL) and single or multiple vaccine-target as well as non-vaccine target Human papillomavirus (HPV) types. Using bead-based HPV genotyping, 594 gynecological samples were genotyped. An association between squamous intraepithelial lesion (SIL) and presence of HPV16, 18, 31, 58 and 56 types were calculated. The risk was estimated by using odds ratio (OR) and 95% of confidence intervals (CI). A total of 370 (62.3%) women were HPV positive. Among these, 157 (42.7%) presented a single HPV infection, and 212 (57.3%) were infected by more than one HPV type. HPV31 was the most prevalent genotype, regardless single and multiple HPV infections. Single infection with HPV31 was associated with LSIL (OR=2.32; 95%CI: 1.01 to 5.32; p=0.04); HPV31 was also associated with LSIL (OR=3.28; 95%CI: 1.74 to 6.19; p= 0.0002) and HSIL (OR=3.82; 95%CI: 2.10 to 6.97; p<0.001) in multiple HPV infections. Risk to harbor cervical lesions was observed in multiple HPV infections with regard to the HPV56 (OR=5.39; 95%CI: 2.44 to 11.90; p<0.001for LSIL; OR=5.37; 95%CI: 2.71 to 10.69; p<0.001) and HPV58 (OR=3.29; 95%CI: 1.34 to 8.09; p=0.0091 for LSIL; OR=3.55; 95%CI: 1.56 to 8.11; p=0.0026) genotypes. In addition, women coinfected with HPV16/31/56 types had 6 and 5-fold increased risk of HSIL (OR=6.46; 95%CI: 1.89 to 22.09; p=0.002) and LSIL (OR=5.22; 95%CI: 1.10 to 24.70; p=0.03), respectively. Multiple HPV infections without HPV16/18 has 2-fold increased risk of HSIL (OR=2.57; 95%CI: 1.41 to 4.70; p=0.002) and LSIL OR=2.03; 95%CI: 1.08 to 3.79; p=0.02). The results of this study suggest that single and multiple vaccine target as well as non-vaccine target HPV types are associated with LSIL and HSIL. These finding should be taken into consideration in the design of HPV vaccination strategies. PMID:26176537

Bulimic symptoms and interpersonal functioning among college students.

PubMed

Kwan, Mun Yee; Minnich, Allison M; Douglas, Valerie; Gordon, Kathryn H; Castro, Yessenia

2017-11-01

Integrating interpersonal theory and the stress generation hypothesis, two studies investigated the association between bulimic symptoms and interpersonal distress and the mechanism underlying this association. In Study 1, 36 pairs of female roommates completed self-report questionnaires in a laboratory while Study 2 recruited 539 undergraduate men and women to participate in a longitudinal online study by completing self-report measures at two time points. Multilevel modeling revealed that targets' bulimic symptoms predicted roommates' intention to continue living with them in Study 1. Greater bulimic symptoms predicted lower intention. In Study 2, bulimic symptoms had a direct and an indirect effect on interpersonal distress, with reassurance-seeking as a mediator in the indirect effect. Findings replicated previous studies showing that bulimic symptoms generate further distress and, in our studies, interpersonal distress specifically. Moreover, reassurance-seeking was a newly identified mechanism underlying this association. These findings provide support for the usefulness of interpersonal theory and the stress generation hypothesis as a framework for understanding bulimic symptomatology. Clinicians may find it useful to target reassurance-seeking behaviors during the treatment of bulimic symptoms in order to improve treatment outcomes. Copyright © 2017 Elsevier B.V. All rights reserved.

Influence of quasi-specific sites on kinetics of target DNA search by a sequence-specific DNA-binding protein.

PubMed

Kemme, Catherine A; Esadze, Alexandre; Iwahara, Junji

2015-11-10

Functions of transcription factors require formation of specific complexes at particular sites in cis-regulatory elements of genes. However, chromosomal DNA contains numerous sites that are similar to the target sequences recognized by transcription factors. The influence of such "quasi-specific" sites on functions of the transcription factors is not well understood at present by experimental means. In this work, using fluorescence methods, we have investigated the influence of quasi-specific DNA sites on the efficiency of target location by the zinc finger DNA-binding domain of the inducible transcription factor Egr-1, which recognizes a 9 bp sequence. By stopped-flow assays, we measured the kinetics of Egr-1's association with a target site on 143 bp DNA in the presence of various competitor DNAs, including nonspecific and quasi-specific sites. The presence of quasi-specific sites on competitor DNA significantly decelerated the target association by the Egr-1 protein. The impact of the quasi-specific sites depended strongly on their affinity, their concentration, and the degree of their binding to the protein. To quantitatively describe the kinetic impact of the quasi-specific sites, we derived an analytical form of the apparent kinetic rate constant for the target association and used it for fitting to the experimental data. Our kinetic data with calf thymus DNA as a competitor suggested that there are millions of high-affinity quasi-specific sites for Egr-1 among the 3 billion bp of genomic DNA. This study quantitatively demonstrates that naturally abundant quasi-specific sites on DNA can considerably impede the target search processes of sequence-specific DNA-binding proteins.

Influence of Quasi-Specific Sites on Kinetics of Target DNA Search by a Sequence-Specific DNA-Binding Protein

PubMed Central

2015-01-01

Functions of transcription factors require formation of specific complexes at particular sites in cis-regulatory elements of genes. However, chromosomal DNA contains numerous sites that are similar to the target sequences recognized by transcription factors. The influence of such “quasi-specific” sites on functions of the transcription factors is not well understood at present by experimental means. In this work, using fluorescence methods, we have investigated the influence of quasi-specific DNA sites on the efficiency of target location by the zinc finger DNA-binding domain of the inducible transcription factor Egr-1, which recognizes a 9 bp sequence. By stopped-flow assays, we measured the kinetics of Egr-1’s association with a target site on 143 bp DNA in the presence of various competitor DNAs, including nonspecific and quasi-specific sites. The presence of quasi-specific sites on competitor DNA significantly decelerated the target association by the Egr-1 protein. The impact of the quasi-specific sites depended strongly on their affinity, their concentration, and the degree of their binding to the protein. To quantitatively describe the kinetic impact of the quasi-specific sites, we derived an analytical form of the apparent kinetic rate constant for the target association and used it for fitting to the experimental data. Our kinetic data with calf thymus DNA as a competitor suggested that there are millions of high-affinity quasi-specific sites for Egr-1 among the 3 billion bp of genomic DNA. This study quantitatively demonstrates that naturally abundant quasi-specific sites on DNA can considerably impede the target search processes of sequence-specific DNA-binding proteins. PMID:26502071

ARNetMiT R Package: association rules based gene co-expression networks of miRNA targets.

PubMed

Özgür Cingiz, M; Biricik, G; Diri, B

2017-03-31

miRNAs are key regulators that bind to target genes to suppress their gene expression level. The relations between miRNA-target genes enable users to derive co-expressed genes that may be involved in similar biological processes and functions in cells. We hypothesize that target genes of miRNAs are co-expressed, when they are regulated by multiple miRNAs. With the usage of these co-expressed genes, we can theoretically construct co-expression networks (GCNs) related to 152 diseases. In this study, we introduce ARNetMiT that utilize a hash based association rule algorithm in a novel way to infer the GCNs on miRNA-target genes data. We also present R package of ARNetMiT, which infers and visualizes GCNs of diseases that are selected by users. Our approach assumes miRNAs as transactions and target genes as their items. Support and confidence values are used to prune association rules on miRNA-target genes data to construct support based GCNs (sGCNs) along with support and confidence based GCNs (scGCNs). We use overlap analysis and the topological features for the performance analysis of GCNs. We also infer GCNs with popular GNI algorithms for comparison with the GCNs of ARNetMiT. Overlap analysis results show that ARNetMiT outperforms the compared GNI algorithms. We see that using high confidence values in scGCNs increase the ratio of the overlapped gene-gene interactions between the compared methods. According to the evaluation of the topological features of ARNetMiT based GCNs, the degrees of nodes have power-law distribution. The hub genes discovered by ARNetMiT based GCNs are consistent with the literature.

Cognitive processing load during listening is reduced more by decreasing voice similarity than by increasing spatial separation between target and masker speech.

PubMed

Zekveld, Adriana A; Rudner, Mary; Kramer, Sophia E; Lyzenga, Johannes; Rönnberg, Jerker

2014-01-01

We investigated changes in speech recognition and cognitive processing load due to the masking release attributable to decreasing similarity between target and masker speech. This was achieved by using masker voices with either the same (female) gender as the target speech or different gender (male) and/or by spatially separating the target and masker speech using HRTFs. We assessed the relation between the signal-to-noise ratio required for 50% sentence intelligibility, the pupil response and cognitive abilities. We hypothesized that the pupil response, a measure of cognitive processing load, would be larger for co-located maskers and for same-gender compared to different-gender maskers. We further expected that better cognitive abilities would be associated with better speech perception and larger pupil responses as the allocation of larger capacity may result in more intense mental processing. In line with previous studies, the performance benefit from different-gender compared to same-gender maskers was larger for co-located masker signals. The performance benefit of spatially-separated maskers was larger for same-gender maskers. The pupil response was larger for same-gender than for different-gender maskers, but was not reduced by spatial separation. We observed associations between better perception performance and better working memory, better information updating, and better executive abilities when applying no corrections for multiple comparisons. The pupil response was not associated with cognitive abilities. Thus, although both gender and location differences between target and masker facilitate speech perception, only gender differences lower cognitive processing load. Presenting a more dissimilar masker may facilitate target-masker separation at a later (cognitive) processing stage than increasing the spatial separation between the target and masker. The pupil response provides information about speech perception that complements intelligibility data.

Cognitive processing load during listening is reduced more by decreasing voice similarity than by increasing spatial separation between target and masker speech

PubMed Central

Zekveld, Adriana A.; Rudner, Mary; Kramer, Sophia E.; Lyzenga, Johannes; Rönnberg, Jerker

2014-01-01

We investigated changes in speech recognition and cognitive processing load due to the masking release attributable to decreasing similarity between target and masker speech. This was achieved by using masker voices with either the same (female) gender as the target speech or different gender (male) and/or by spatially separating the target and masker speech using HRTFs. We assessed the relation between the signal-to-noise ratio required for 50% sentence intelligibility, the pupil response and cognitive abilities. We hypothesized that the pupil response, a measure of cognitive processing load, would be larger for co-located maskers and for same-gender compared to different-gender maskers. We further expected that better cognitive abilities would be associated with better speech perception and larger pupil responses as the allocation of larger capacity may result in more intense mental processing. In line with previous studies, the performance benefit from different-gender compared to same-gender maskers was larger for co-located masker signals. The performance benefit of spatially-separated maskers was larger for same-gender maskers. The pupil response was larger for same-gender than for different-gender maskers, but was not reduced by spatial separation. We observed associations between better perception performance and better working memory, better information updating, and better executive abilities when applying no corrections for multiple comparisons. The pupil response was not associated with cognitive abilities. Thus, although both gender and location differences between target and masker facilitate speech perception, only gender differences lower cognitive processing load. Presenting a more dissimilar masker may facilitate target-masker separation at a later (cognitive) processing stage than increasing the spatial separation between the target and masker. The pupil response provides information about speech perception that complements intelligibility data. PMID:24808818

Adjuvant Vascular Endothelial Growth Factor-targeted Therapy in Renal Cell Carcinoma: A Systematic Review and Pooled Analysis.

PubMed

Sun, Maxine; Marconi, Lorenzo; Eisen, Tim; Escudier, Bernard; Giles, Rachel H; Haas, Naomi B; Harshman, Lauren C; Quinn, David I; Larkin, James; Pal, Sumanta K; Powles, Thomas; Ryan, Christopher W; Sternberg, Cora N; Uzzo, Robert; Choueiri, Toni K; Bex, Axel

2018-05-18

Contradictory data exist with regard to adjuvant vascular endothelial growth factor receptor (VEGFR)-targeted therapy in surgically managed patients for localized renal cell carcinoma (RCC). To systematically evaluate the current evidence regarding the therapeutic benefit (disease-free survival [DFS] and overall survival [OS]) and grade 3-4 adverse events (AEs) for adjuvant VEGFR-targeted therapy for resected localized RCC. A critical review of PubMed/Medline, Embase, and the Cochrane Library in January 2018 according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement was performed. We identified reports and reviewed them according to the Consolidated Standards of Reporting Trials and Standards for the Reporting of Diagnostic Accuracy Studies criteria. Of eight full-text articles that were eligible for inclusion, five studies (two of five were updated analyses) were retained in the final synthesis. Study characteristics were abstracted and the number needed to treat (NNT) per trial was estimated. The three randomized controlled phase III trials included the following comparisons: sunitinib versus placebo or sorafenib versus placebo (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma [ASSURE] study, n=1943), sunitinib versus placebo (S-TRAC, n=615), and pazopanib versus placebo (Pazopanib As Adjuvant Therapy in Localized/Locally Advanced RCC After Nephrectomy study, n=1135). The NNT ranged from 10 (S-TRAC) to 137 (ASSURE study). The pooled analysis showed that VEGFR-targeted therapy was not statistically significantly associated with improved DFS (hazard ratio [HR random ]: 0.92, 95% confidence interval [CI]: 0.82-1.03, p=0.16) or OS (HR random : 0.98, 95% CI: 0.84-1.15, p=0.84) compared with the control group. The adjuvant therapy group experienced significantly higher odds of grade 3-4 AEs (OR random : 5.89, 95% CI: 4.85-7.15, p<0.001). In exploratory analyses focusing on patients who started on the full-dose regimen, DFS was improved in patients who received adjuvant therapy (HR random : 0.83, 95% CI: 0.73-0.95, p=0.005). This pooled analysis of reported randomized trials did not reveal a statistically significant effect between adjuvant VEGFR-targeted therapy and improved DFS or OS in patients with intermediate/high-risk local or regional fully resected RCC. Improvement in DFS may be more likely with the use of full-dose regimens, pending further results. However, adjuvant treatment was associated with high-grade AEs. Vascular endothelial growth factor receptor-targeted therapy after nephrectomy for localized kidney cancer is not associated with consistent improvements in delaying cancer recurrence or prolonging life and comes at the expense of potentially significant side effects. Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Illusions of integration are subjectively impenetrable: Phenomenological experience of Lag 1 percepts during dual-target RSVP.

PubMed

Simione, Luca; Akyürek, Elkan G; Vastola, Valentina; Raffone, Antonino; Bowman, Howard

2017-05-01

We investigated the relationship between different kinds of target reports in a rapid serial visual presentation task, and their associated perceptual experience. Participants reported the identity of two targets embedded in a stream of stimuli and their associated subjective visibility. In our task, target stimuli could be combined together to form more complex ones, thus allowing participants to report temporally integrated percepts. We found that integrated percepts were associated with high subjective visibility scores, whereas reports in which the order of targets was reversed led to a poorer perceptual experience. We also found a reciprocal relationship between the chance of the second target not being reported correctly and the perceptual experience associated with the first one. Principally, our results indicate that integrated percepts are experienced as a unique, clear perceptual event, whereas order reversals are experienced as confused, similar to cases in which an entirely wrong response was given. Copyright © 2017 Elsevier Inc. All rights reserved.

A principal components analysis of dynamic spatial memory biases.

PubMed

Motes, Michael A; Hubbard, Timothy L; Courtney, Jon R; Rypma, Bart

2008-09-01

Research has shown that spatial memory for moving targets is often biased in the direction of implied momentum and implied gravity, suggesting that representations of the subjective experiences of these physical principles contribute to such biases. The present study examined the association between these spatial memory biases. Observers viewed targets that moved horizontally from left to right before disappearing or viewed briefly shown stationary targets. After a target disappeared, observers indicated the vanishing position of the target. Principal components analysis revealed that biases along the horizontal axis of motion loaded on separate components from biases along the vertical axis orthogonal to motion. The findings support the hypothesis that implied momentum and implied gravity biases have unique influences on spatial memory. (c) 2008 APA, all rights reserved.

Inhibition of atherosclerosis-promoting microRNAs via targeted polyelectrolyte complex micelles

PubMed Central

Kuo, Cheng-Hsiang; Leon, Lorraine; Chung, Eun Ji; Huang, Ru-Ting; Sontag, Timothy J.; Reardon, Catherine A.; Getz, Godfrey S.; Tirrell, Matthew; Fang, Yun

2015-01-01

Polyelectrolyte complex micelles have great potential as gene delivery vehicles because of their ability to encapsulate charged nucleic acids forming a core by neutralizing their charge, while simultaneously protecting the nucleic acids from non-specific interactions and enzymatic degradation. Furthermore, to enhance specificity and transfection efficiency, polyelectrolyte complex micelles can be modified to include targeting capabilities. Here, we describe the design of targeted polyelectrolyte complex micelles containing inhibitors against dys-regulated microRNAs (miRNAs) that promote atherosclerosis, a leading cause of human mortality and morbidity. Inhibition of dys-regulated miRNAs in diseased cells associated with atherosclerosis has resulted in therapeutic efficacy in animal models and has been proposed to treat human diseases. However, the non-specific targeting of microRNA inhibitors via systemic delivery has remained an issue that may cause unwanted side effects. For this reason, we incorporated two different peptide sequences to our miRNA inhibitor containing polyelectrolyte complex micelles. One of the peptides (Arginine-Glutamic Acid-Lysine-Alanine or REKA) was used in another micellar system that demonstrated lesion-specific targeting in a mouse model of atherosclerosis. The other peptide (Valine-Histidine-Proline-Lysine-Glutamine-Histidine-Arginine or VHPKQHR) was identified via phage display and targets vascular endothelial cells through the vascular cell adhesion molecule-1 (VCAM-1). In this study we have tested the in vitro efficacy and efficiency of lesion- and cell-specific delivery of microRNA inhibitors to the cells associated with atherosclerotic lesions via peptide-targeted polyelectrolyte complex micelles. Our results show that REKA-containing micelles (fibrin-targeting) and VHPKQHR-containing micelles (VCAM-1 targeting) can be used to carry and deliver microRNA inhibitors into macrophages and human endothelial cells, respectively. Additionally, the functionality of miRNA inhibitors in cells was demonstrated by analyzing miRNA expression as well as the expression or the biological function of its downstream target protein. Our study provides the first demonstration of targeting dys-regulated miRNAs in atherosclerosis using targeted polyelectrolyte complex micelles and holds promising potential for translational applications. PMID:25685357

Multifunctional nanoparticle-EpCAM aptamer bioconjugates: a paradigm for targeted drug delivery and imaging in cancer therapy.

PubMed

Das, Manasi; Duan, Wei; Sahoo, Sanjeeb K

2015-02-01

The promising proposition of multifunctional nanoparticles for cancer diagnostics and therapeutics has inspired the development of theranostic approach for improved cancer therapy. Moreover, active targeting of drug carrier to specific target site is crucial for providing efficient delivery of therapeutics and imaging agents. In this regard, the present study investigates the theranostic capabilities of nutlin-3a loaded poly (lactide-co-glycolide) nanoparticles, functionalized with a targeting ligand (EpCAM aptamer) and an imaging agent (quantum dots) for cancer therapy and bioimaging. A wide spectrum of in vitro analysis (cellular uptake study, cytotoxicity assay, cell cycle and apoptosis analysis, apoptosis associated proteins study) revealed superior therapeutic potentiality of targeted NPs over other formulations in EpCAM expressing cells. Moreover, our nanotheranostic system served as a superlative bio-imaging modality both in 2D monolayer culture and tumor spheroid model. Our result suggests that, these aptamer-guided multifunctional NPs may act as indispensable nanotheranostic approach toward cancer therapy. This study investigated the theranostic capabilities of nutlin-3a loaded poly (lactide-co-glycolide) nanoparticles functionalized with a targeting ligand (EpCAM aptamer) and an imaging agent (quantum dots) for cancer therapy and bioimaging. It was concluded that the studied multifunctional targeted nanoparticle may become a viable and efficient approach in cancer therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

Differentially expressed microRNAs in the corpus cavernosum from a murine model with type 2 diabetes mellitus-associated erectile dysfunction.

PubMed

Pan, Feng; You, Jinwei; Liu, Yuan; Qiu, Xuefeng; Yu, Wen; Ma, Jiehua; Pan, Lianjun; Zhang, Aixia; Zhang, Qipeng

2016-12-01

To better understand the molecular aetiology of type 2 diabetes mellitus-associated erectile dysfunction (T2DMED) and to provide candidates for further study of its diagnosis and treatment, this study was designed to investigate differentially expressed microRNAs (miRNAs) in the corpus cavernosum (CC) of mice with T2DMED using GeneChip array techniques (Affymetrix miRNA 4.0 Array) and to predict target genes and signalling pathways regulated by these miRNAs based on bioinformatic analysis using TargetScan, the DAIAN web platform and DAVID. In the initial screening, 21 miRNAs appeared distinctly expressed in the T2DMED group (fold change ≥3, p ≤ 0.01). Among them, the differential expression of miR-18a, miR-206, miR-122, and miR-133 were confirmed by qRT-PCR (p < 0.05 and FDR <5 %). According to bioinformatic analysis, the four miRNAs were speculated to play potential roles in the mechanisms of T2DMED via regulating 28 different genes and several pathways, including apoptosis, fibrosis, eNOS/cGMP/PKG, and vascular smooth muscle contraction processes, which mainly focused on influencing the functions of the endothelium and smooth muscle in the CC. IGF-1, as one of the target genes, was verified to decrease in the CCs of T2DMED animals via ELISA and was confirmed as the target of miR-18a or miR-206 via luciferase assay. Finally, these four miRNAs deserve further confirmation as biomarkers of T2DMED in larger studies. Additionally, miR-18a and/or miR-206 may provide new preventive/therapeutic targets for ED management by targeting IGF-1.

Shared target antigens on cancer cells and tissue stem cells: go or no-go for CAR T cells?

PubMed

Hombach, Andreas A; Abken, Hinrich

2017-02-01

Adoptive therapy with chimeric antigen receptor (CAR) T cells redirected towards CD19 produces remissions of B cell malignancies, however, it also eradicates healthy B cells sharing the target antigen. Such 'on-target off-tumor' toxicity raises serious safety concerns when the target antigen is also expressed by tissue stem cells, with the risk of lasting tissue destruction. Areas covered: We discuss CAR T cell targeting of activation antigens versus lineage associated antigens on the basis of recent experimental and animal data and the literature in the field. Expert commentary: Targeting an activation associated antigen which is transiently expressed by stem cells seems to be safe, like CAR T cells targeting CD30 spare CD30 + hematopoietic stem and progenitor cells while eliminating CD30 + lymphoma cells, whereas targeting lineage associated antigens which increase in expression during cell maturation, like folate receptor-β and CD123, is of risk to destruct tissue stem cells.

Utilizing high-throughput bioassays associated with US EPA ToxCast Program to assess biological activity of environmental contaminants: A case study of chemical mixtures

EPA Science Inventory

Effects-based monitoring and surveillance is increasingly being utilized in conjunction with chemical monitoring to determine potential biological activity associated with environmental contaminants. Supervised approaches targeting specific chemical activity or molecular pathways...

Are secondary metabolites dispensable for virulence?

USDA-ARS?s Scientific Manuscript database

The production of toxins by conidial fungal pathogens and their association with virulence has been assumed to occur in vivo and is widely accepted as dogma, but this association has yet to be definitively proven by either genetic or chemical means. Several studies from our labs have used targeted g...

Learning the Association between a Context and a Target Location in Infancy

ERIC Educational Resources Information Center

Bertels, Julie; San Anton, Estibaliz; Gebuis, Titia; Destrebecqz, Arnaud

2017-01-01

Extracting the statistical regularities present in the environment is a central learning mechanism in infancy. For instance, infants are able to learn the associations between simultaneously or successively presented visual objects (Fiser & Aslin, 2002; Kirkham, Slemmer & Johnson, 2002). The present study extends these results by…

Dietary Pterostilbene is a novel MTA1-targeted chemopreventive and therapeutic agent in prostate cancer

USDA-ARS?s Scientific Manuscript database

Dietary nutrients with ability to reverse adverse epigenetic events have great potential for cancer chemoprevention. Overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) is associated with aggressive human prostate cancer. The purpose of this study was to determine MTA1-d...

Target-controlled total intravenous anesthesia associated with femoral nerve block for arthroscopic knee meniscectomy.

PubMed

Nora, Fernando Squeff

2009-01-01

The increased popularity of minimally invasive surgical techniques reduced recovery time of procedures that were usually associated with prolonged hospitalization. This study reports the technique of total intravenous anesthesia with propofol and remifentanil associated with femoral nerve block using the inguinal perivascular approach. Ninety patients undergoing knee arthroscopy for meniscectomy were included in this study. Target-controlled infusion (TCI) of propofol (target = 4 microg.mL(-1)) and remifentanil (target = 3 ng.mL(-1)) was used for induction of anesthesia. The concentrations of propofol and remifentanil were changed according to the bispectral index (BIS) and mean arterial pressure (MAP). Volume-controlled mechanical ventilation with a laryngeal mask was used. The concentrations of propofol and remifentanil at the effector site, corresponding to the predictive concentrations, were obtained using the pharmacokinetic models of the drugs inserted in the TCI pumps. Time for hospital discharge encompassed the period between the moment the patient arrived at the recovery room and hospital discharge. Maximal and minimal mean concentrations at the effector site (ng.mL(-1)) of remifentanil were 3.5 and 2.4, respectively. Maximal and minimal mean concentrations of propofol at the effector site (microg.mL(-1)) were 3.1 and 2.6, respectively. The mean flow of infusion of propofol and remifentanil was 8.54 mg.kg(-1).h(-1) and 0.12 microg.kg(-1).min(-1), respectively. Mean hospital discharge time was 180 min. All patients were maintained within established parameters.

Intermittent Preventive Treatment for Malaria in Pregnancy: Optimization of Target Concentrations of Dihydroartemisinin-Piperaquine.

PubMed

Savic, Rada M; Jagannathan, Prasanna; Kajubi, Richard; Huang, Liusheng; Zhang, Nan; Were, Moses; Kakuru, Abel; Muhindo, Mary K; Mwebaza, Norah; Wallender, Erika; Clark, Tamara D; Opira, Bishop; Kamya, Moses; Havlir, Diane V; Rosenthal, Philip J; Dorsey, Grant; Aweeka, Francesca T

2018-03-14

Dihydroartemsinin-piperaquine is highly efficacious as intermittent preventive therapy for malaria during pregnancy (IPTp). Determining associations between piperaquine exposure, malaria risk, and adverse birth outcomes informs optimal dosing strategies. HIV-uninfected pregnant women were enrolled in a placebo-controlled trial of IPTp at 12-20 weeks gestation and randomized to: sulfadoxine-pyrimethamine every 8 weeks (n=106), dihydroartemsinin-piperaquine every 8 weeks (n=94), or dihydroartemsinin-piperaquine every 4 weeks (n=100) during pregnancy. Pharmacokinetic sampling for piperaquine was performed every 4 weeks, and an intensive pharmacokinetic sub-study was performed in 30 women at 28 weeks gestation. Concentration-effect relationships were assessed between exposure to piperaquine; the prevalence of P. falciparum infection during pregnancy; outcomes at delivery including placental malaria, low birthweight, and preterm birth; and risks for toxicity. Simulations of new dosing scenarios were performed. Model-defined piperaquine target venous plasma concentrations of 13.9 ng/ml provided 99% protection from P. falciparum infection during pregnancy. Each 10 day increase in time>target piperaquine concentrations was associated with reduced odds of placental parasitemia (0∙67, P<0.0001), preterm birth (0.74, P<0.01), and low birthweight (0.74, P<0.05), though increases in piperaquine concentrations were associated with QTc prolongation (5 msec increase per 100 ng/ml). Modeling suggests that daily or weekly administration of lower dosages of piperaquine, compared to standard dosing, will maintain piperaquine trough levels above target concentrations with reduced piperaquine peak levels, potentially limiting toxicity. The protective efficacy of IPTp with dihydroartemsinin-piperaquine was strongly associated with higher drug exposure. Studies of the efficacy and safety of alternative dihydroartemsinin-piperaquine IPTp dosing strategies are warranted. NCT02163447.

CRISPR-directed mitotic recombination enables genetic mapping without crosses.

PubMed

Sadhu, Meru J; Bloom, Joshua S; Day, Laura; Kruglyak, Leonid

2016-05-27

Linkage and association studies have mapped thousands of genomic regions that contribute to phenotypic variation, but narrowing these regions to the underlying causal genes and variants has proven much more challenging. Resolution of genetic mapping is limited by the recombination rate. We developed a method that uses CRISPR (clustered, regularly interspaced, short palindromic repeats) to build mapping panels with targeted recombination events. We tested the method by generating a panel with recombination events spaced along a yeast chromosome arm, mapping trait variation, and then targeting a high density of recombination events to the region of interest. Using this approach, we fine-mapped manganese sensitivity to a single polymorphism in the transporter Pmr1. Targeting recombination events to regions of interest allows us to rapidly and systematically identify causal variants underlying trait differences. Copyright © 2016, American Association for the Advancement of Science.

Plant immunity triggered by microbial molecular signatures.

PubMed

Zhang, Jie; Zhou, Jian-Min

2010-09-01

Pathogen/microbe-associated molecular patterns (PAMPs/MAMPs) are recognized by host cell surface-localized pattern-recognition receptors (PRRs) to activate plant immunity. PAMP-triggered immunity (PTI) constitutes the first layer of plant immunity that restricts pathogen proliferation. PTI signaling components often are targeted by various Pseudomonas syringae virulence effector proteins, resulting in diminished plant defenses and increased bacterial virulence. Some of the proteins targeted by pathogen effectors have evolved to sense the effector activity by associating with cytoplasmic immune receptors classically known as resistance proteins. This allows plants to activate a second layer of immunity termed effector-triggered immunity (ETI). Recent studies on PTI regulation and P. syringae effector targets have uncovered new components in PTI signaling. Although MAP kinase (MAPK) cascades have been considered crucial for PTI, emerging evidence indicates that a MAPK-independent pathway also plays an important role in PTI signaling.

Examining associations between adolescent binge eating and binge eating in parents and friends.

PubMed

Goldschmidt, Andrea B; Wall, Melanie M; Choo, Tse-Hwei J; Bruening, Meg; Eisenberg, Marla E; Neumark-Sztainer, Dianne

2014-04-01

Binge eating is prevalent among adolescents, but little is known about how parents and friends may influence such behaviors. This study examined associations between adolescent binge eating behaviors, and similar behaviors in their parents and friends. Participants were 2,770 target adolescent boys and girls who had at least one friend and/or parent who also participated. Logistic regression, stratified by gender, examined associations between parents' and friends' self-reported binge eating, and similar behaviors in target adolescents. Girls' binge eating was associated with their male friends' (odds ratio = 2.33; p = 0.03) and fathers' binge eating (odds ratio = 3.38; p = 0.02), but not with their female friends' or mothers' binge eating (p > 0.05). For boys, binge eating was not associated with parents' or friends' behavior. Adolescent girls' binge eating is associated with similar behaviors in their other-sex parents and friends. Results should be replicated, and mechanisms explaining this relation should be further explored. Copyright © 2013 Wiley Periodicals, Inc.

Examining associations between adolescent binge eating and binge eating in parents and friends

PubMed Central

Goldschmidt, Andrea B.; Wall, Melanie M.; Choo, Tse-Hwei J.; Bruening, Meg; Eisenberg, Marla E.; Neumark-Sztainer, Dianne

2014-01-01

Objective Binge eating is prevalent among adolescents, but little is known about how parents and friends may influence such behaviors. This study examined associations between adolescent binge eating behaviors, and similar behaviors in their parents and friends. Method Participants were 2,770 target adolescent boys and girls who had at least one friend and/or parent who also participated. Logistic regression, stratified by gender, examined associations between parents’ and friends’ self-reported binge eating, and similar behaviors in target adolescents. Results Girls’ binge eating was associated with their male friends’ (odds ratio=2.33; p=.03) and fathers’ binge eating (odds ratio=3.38; p=.02), but not with their female friends’ or mothers’ binge eating (p>.05). For boys, binge eating was not associated with parents’ or friends’ behavior. Discussion Adolescent girls’ binge eating is associated with similar behaviors in their other-sex parents and friends. Results should be replicated, and mechanisms explaining this relation should be further explored. PMID:24105696

Target Fishing for Chemical Compounds using Target-Ligand Activity data and Ranking based Methods

PubMed Central

Wale, Nikil; Karypis, George

2009-01-01

In recent years the development of computational techniques that identify all the likely targets for a given chemical compound, also termed as the problem of Target Fishing, has been an active area of research. Identification of likely targets of a chemical compound helps to understand problems such as toxicity, lack of efficacy in humans, and poor physical properties associated with that compound in the early stages of drug discovery. In this paper we present a set of techniques whose goal is to rank or prioritize targets in the context of a given chemical compound such that most targets that this compound may show activity against appear higher in the ranked list. These methods are based on our extensions to the SVM and Ranking Perceptron algorithms for this problem. Our extensive experimental study shows that the methods developed in this work outperform previous approaches by 2% to 60% under different evaluation criterions. PMID:19764745

USE OF POPULATION STUDIES TO IDENTIFY ASSOCIATIONS BETWEEN ADVERSE HEALTH EFFECTS AND ENVIRONMENTAL EXPOSURES TO ENDOCRINE DISRUPTING HERBICIDES

EPA Science Inventory

Not only animal studies, but also population (ecologic) studies can contribute to the identification of endocrine disrupting chemicals. Population studies are fundamental in identifying public health hazards, and provide hypotheses for more targeted studies. Chlorophenoxy herb...

PTSD and Gene Variants: New Pathways and New Thinking

PubMed Central

Skelton, Kelly; Ressler, Kerry J.; Norrholm, Seth D.; Jovanovic, Tanja; Bradley-Davino, Bekh

2011-01-01

Posttraumatic Stress Disorder (PTSD) is an anxiety disorder which can develop as a result of exposure to a traumatic event and is associated with significant functional impairment. Family and twin studies have found that risk for PTSD is associated with an underlying genetic vulnerability and that more than 30% of the variance associated with PTSD is related to a heritable component. Using a fear conditioning model to conceptualize the neurobiology of PTSD, three primary neuronal systems have been investigated – the hypothalamic-pituitary-adrenal axis, the locus coeruleus-noradrenegic system, and neurocircuitry interconnecting the limbic system and frontal cortex. The majority of the initial investigations into main effects of candidate genes hypothesized to be associated with PTSD risk have been negative, but studies examining the interaction of genetic polymorphisms with specific environments in predicting PTSD have produced several positive results which have increased our understanding of the determinants of risk and resilience in the aftermath of trauma. Promising avenues of inquiry into the role of epigenetic modification have also been proposed to explain the enduring impact of environmental exposures which occur during key, often early, developmental periods on gene expression. Studies of PTSD endophenotypes, which are heritable biomarkers associated with a circumscribed trait within the more complex psychiatric disorder, may be more directly amenable to analysis of the underlying genetics and neural pathways and have provided promising targets for elucidating the neurobiology of PTSD. Knowledge of the genetic underpinnings and neuronal pathways involved in the etiology and maintenance of PTSD will allow for improved targeting of primary prevention amongst vulnerable individuals or populations, as well as timely, targeted treatment interventions. PMID:21356219

Workforce characteristics and interventions associated with high-quality care and support to older people with cancer: a systematic review

PubMed Central

Lucas, Grace; Wiseman, Theresa; Griffiths, Peter

2017-01-01

Objectives To provide an overview of the evidence base on the effectiveness of workforce interventions for improving the outcomes for older people with cancer, as well as analysing key features of the workforce associated with those improvements. Design Systematic review. Methods Relevant databases were searched for primary research, published in English, reporting on older people and cancer and the outcomes of interventions to improve workforce knowledge, attitudes or skills; involving a change in workforce composition and/or skill mix; and/or requiring significant workforce reconfiguration or new roles. Studies were also sought on associations between the composition and characteristics of the cancer care workforce and older people's outcomes. A narrative synthesis was conducted and supported by tabulation of key study data. Results Studies (n=24) included 4555 patients aged 60+ from targeted cancer screening to end of life care. Interventions were diverse and two-thirds of the studies were assessed as low quality. Only two studies directly targeted workforce knowledge and skills and only two studies addressed the nature of workforce features related to improved outcomes. Interventions focused on discrete groups of older people with specific needs offering guidance or psychological support were more effective than those broadly targeting survival outcomes. Advanced Practice Nursing roles, voluntary support roles and the involvement of geriatric teams provided some evidence of effectiveness. Conclusions An array of workforce interventions focus on improving outcomes for older people with cancer but these are diverse and thinly spread across the cancer journey. Higher quality and larger scale research that focuses on workforce features is now needed to guide developments in this field, and review findings indicate that interventions targeted at specific subgroups of older people with complex needs, and that involve input from advanced practice nurses, geriatric teams and trained volunteers appear most promising. PMID:28760795

Mineral Metabolism in European Children Living with a Renal Transplant: A European Society for Paediatric Nephrology/European Renal Association–European Dialysis and Transplant Association Registry Study

PubMed Central

Bonthuis, Marjolein; Busutti, Marco; Jager, Kitty J.; Baiko, Sergey; Bakkaloğlu, Sevcan; Battelino, Nina; Gaydarova, Maria; Gianoglio, Bruno; Parvex, Paloma; Gomes, Clara; Heaf, James G.; Podracka, Ludmila; Kuzmanovska, Dafina; Molchanova, Maria S.; Pankratenko, Tatiana E.; Papachristou, Fotios; Reusz, György; Sanahuja, Maria José; Shroff, Rukshana; Groothoff, Jaap W.; Schaefer, Franz; Verrina, Enrico

2015-01-01

Background and objectives Data on mineral metabolism in pediatric renal transplant recipients largely arise from small single-center studies. In adult patients, abnormal mineral levels are related to a higher risk of graft failure. This study used data from the European Society for Paediatric Nephrology/European Renal Association–European Dialysis and Transplant Association Registry to study the prevalence and potential determinants of mineral abnormalities, as well as the predictive value of a disturbed mineral level on graft survival in a large cohort of European pediatric renal transplant recipients. Design, setting, participants, & measurements This study included 1237 children (0–17 years) from 10 European countries, who had serum calcium, phosphorus, and parathyroid hormone measurements from 2000 onward. Abnormalities of mineral metabolism were defined according to European guidelines on prevention and treatment of renal osteodystrophy in children on chronic renal failure. Results Abnormal serum phosphorus levels were observed in 25% (14% hypophosphatemia and 11% hyperphosphatemia), altered serum calcium in 30% (19% hypocalcemia, 11% hypercalcemia), and hyperparathyroidism in 41% of the patients. A longer time since transplantation was associated with a lower risk of having mineral levels above target range. Serum phosphorus levels were inversely associated with eGFR, and levels above the recommended targets were associated with a higher risk of graft failure independently of eGFR. Conclusions Abnormalities in mineral metabolism are common after pediatric renal transplantation in Europe and are associated with graft dysfunction. PMID:25710805

Daily relations among affect, urge, targeted naltrexone, and alcohol use in young adults

PubMed Central

Bold, Krysten W.; Fucito, Lisa M.; Corbin, William R.; DeMartini, Kelly S.; Leeman, Robert F.; Kranzler, Henry R.; O’Malley, Stephanie S.

2016-01-01

Heavy drinking among young adults is a serious public health problem. Naltrexone, an opioid antagonist, has been shown to reduce drinking in young adults compared to placebo and can be taken on a targeted (i.e., as needed) basis. Understanding risk factors for drinking and naltrexone effects within-person in young adults may help to optimize the use of targeted naltrexone. The current study was a secondary analysis of daily diary data from 127 (n=40 female) young adults (age 18-25) enrolled in a double-blind clinical trial of daily (25 mg) plus targeted (25 mg) naltrexone versus placebo. Hierarchical linear models were used to examine the effects of daily affect, urge, and taking targeted medication on same-day risk of drinking to intoxication (defined as estimated blood-alcohol-concentration, BAC≥.08g%). Results indicated urge significantly mediated within-person positive affect–drinking relations on a daily level. Specifically, positive affect was associated with greater urge to drink, which in turn was associated with greater odds of BAC≥.08g%. Furthermore, days of greater positive affect and urge were associated with taking a targeted dose of medication, which reduced the likelihood of intoxication by nearly 23% in the naltrexone group compared to placebo. Gender and family history of alcohol dependence were examined as moderators of these daily level effects. These results provide further evidence of naltrexone’s ability to reduce alcohol consumption in young adults and identify potential within-person risk processes related to heavy drinking that could inform alcohol-related interventions for this population. PMID:27690505

Diverse patterns of genomic targeting by transcriptional regulators in Drosophila melanogaster.

PubMed

Slattery, Matthew; Ma, Lijia; Spokony, Rebecca F; Arthur, Robert K; Kheradpour, Pouya; Kundaje, Anshul; Nègre, Nicolas; Crofts, Alex; Ptashkin, Ryan; Zieba, Jennifer; Ostapenko, Alexander; Suchy, Sarah; Victorsen, Alec; Jameel, Nader; Grundstad, A Jason; Gao, Wenxuan; Moran, Jennifer R; Rehm, E Jay; Grossman, Robert L; Kellis, Manolis; White, Kevin P

2014-07-01

Annotation of regulatory elements and identification of the transcription-related factors (TRFs) targeting these elements are key steps in understanding how cells interpret their genetic blueprint and their environment during development, and how that process goes awry in the case of disease. One goal of the modENCODE (model organism ENCyclopedia of DNA Elements) Project is to survey a diverse sampling of TRFs, both DNA-binding and non-DNA-binding factors, to provide a framework for the subsequent study of the mechanisms by which transcriptional regulators target the genome. Here we provide an updated map of the Drosophila melanogaster regulatory genome based on the location of 84 TRFs at various stages of development. This regulatory map reveals a variety of genomic targeting patterns, including factors with strong preferences toward proximal promoter binding, factors that target intergenic and intronic DNA, and factors with distinct chromatin state preferences. The data also highlight the stringency of the Polycomb regulatory network, and show association of the Trithorax-like (Trl) protein with hotspots of DNA binding throughout development. Furthermore, the data identify more than 5800 instances in which TRFs target DNA regions with demonstrated enhancer activity. Regions of high TRF co-occupancy are more likely to be associated with open enhancers used across cell types, while lower TRF occupancy regions are associated with complex enhancers that are also regulated at the epigenetic level. Together these data serve as a resource for the research community in the continued effort to dissect transcriptional regulatory mechanisms directing Drosophila development. © 2014 Slattery et al.; Published by Cold Spring Harbor Laboratory Press.

Boundary conditions for the influence of unfamiliar non-target primes in unconscious evaluative priming: The moderating role of attentional task sets.

PubMed

Kiefer, Markus; Sim, Eun-Jim; Wentura, Dirk

2015-09-01

Evaluative priming by masked emotional stimuli that are not consciously perceived has been taken as evidence that affective stimulus evaluation can also occur unconsciously. However, as masked priming effects were small and frequently observed only for familiar primes that there also presented as visible targets in an evaluative decision task, priming was thought to reflect primarily response activation based on acquired S-R associations and not evaluative semantic stimulus analysis. The present study therefore assessed across three experiments boundary conditions for the emergence of masked evaluative priming effects with unfamiliar primes in an evaluative decision task and investigated the role of the frequency of target repetition on priming with pictorial and verbal stimuli. While familiar primes elicited robust priming effects in all conditions, priming effects by unfamiliar primes were reliably obtained for low repetition (pictures) or unrepeated targets (words), but not for targets repeated at a high frequency. This suggests that unfamiliar masked stimuli only elicit evaluative priming effects when the task set associated with the visible target involves evaluative semantic analysis and is not based on S-R triggered responding as for high repetition targets. The present results therefore converge with the growing body of evidence demonstrating attentional control influences on unconscious processing. Copyright © 2015 Elsevier Inc. All rights reserved.

Potential role of DNA methylation as a facilitator of target search processes for transcription factors through interplay with methyl-CpG-binding proteins

PubMed Central

Kemme, Catherine A.; Marquez, Rolando; Luu, Ross H.

2017-01-01

Abstract Eukaryotic genomes contain numerous non-functional high-affinity sequences for transcription factors. These sequences potentially serve as natural decoys that sequester transcription factors. We have previously shown that the presence of sequences similar to the target sequence could substantially impede association of the transcription factor Egr-1 with its targets. In this study, using a stopped-flow fluorescence method, we examined the kinetic impact of DNA methylation of decoys on the search process of the Egr-1 zinc-finger protein. We analyzed its association with an unmethylated target site on fluorescence-labeled DNA in the presence of competitor DNA duplexes, including Egr-1 decoys. DNA methylation of decoys alone did not affect target search kinetics. In the presence of the MeCP2 methyl-CpG-binding domain (MBD), however, DNA methylation of decoys substantially (∼10-30-fold) accelerated the target search process of the Egr-1 zinc-finger protein. This acceleration did not occur when the target was also methylated. These results suggest that when decoys are methylated, MBD proteins can block them and thereby allow Egr-1 to avoid sequestration in non-functional locations. This effect may occur in vivo for DNA methylation outside CpG islands (CGIs) and could facilitate localization of some transcription factors within regulatory CGIs, where DNA methylation is rare. PMID:28486614

Protein tyrosine phosphatases as potential therapeutic targets

PubMed Central

He, Rong-jun; Yu, Zhi-hong; Zhang, Ruo-yu; Zhang, Zhong-yin

2014-01-01

Protein tyrosine phosphorylation is a key regulatory process in virtually all aspects of cellular functions. Dysregulation of protein tyrosine phosphorylation is a major cause of human diseases, such as cancers, diabetes, autoimmune disorders, and neurological diseases. Indeed, protein tyrosine phosphorylation-mediated signaling events offer ample therapeutic targets, and drug discovery efforts to date have brought over two dozen kinase inhibitors to the clinic. Accordingly, protein tyrosine phosphatases (PTPs) are considered next-generation drug targets. For instance, PTP1B is a well-known targets of type 2 diabetes and obesity, and recent studies indicate that it is also a promising target for breast cancer. SHP2 is a bona-fide oncoprotein, mutations of which cause juvenile myelomonocytic leukemia, acute myeloid leukemia, and solid tumors. In addition, LYP is strongly associated with type 1 diabetes and many other autoimmune diseases. This review summarizes recent findings on several highly recognized PTP family drug targets, including PTP1B, Src homology phosphotyrosyl phosphatase 2(SHP2), lymphoid-specific tyrosine phosphatase (LYP), CD45, Fas associated phosphatase-1 (FAP-1), striatal enriched tyrosine phosphatases (STEP), mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1), phosphatases of regenerating liver-1 (PRL), low molecular weight PTPs (LMWPTP), and CDC25. Given that there are over 100 family members, we hope this review will serve as a road map for innovative drug discovery targeting PTPs. PMID:25220640

Intensive Treat-to-Target Statin Therapy in High-Risk Japanese Patients With Hypercholesterolemia and Diabetic Retinopathy: Report of a Randomized Study.

PubMed

Itoh, Hiroshi; Komuro, Issei; Takeuchi, Masahiro; Akasaka, Takashi; Daida, Hiroyuki; Egashira, Yoshiki; Fujita, Hideo; Higaki, Jitsuo; Hirata, Ken-Ichi; Ishibashi, Shun; Isshiki, Takaaki; Ito, Sadayoshi; Kashiwagi, Atsunori; Kato, Satoshi; Kitagawa, Kazuo; Kitakaze, Masafumi; Kitazono, Takanari; Kurabayashi, Masahiko; Miyauchi, Katsumi; Murakami, Tomoaki; Murohara, Toyoaki; Node, Koichi; Ogawa, Susumu; Saito, Yoshihiko; Seino, Yoshihiko; Shigeeda, Takashi; Shindo, Shunya; Sugawara, Masahiro; Sugiyama, Seigo; Terauchi, Yasuo; Tsutsui, Hiroyuki; Ueshima, Kenji; Utsunomiya, Kazunori; Yamagishi, Masakazu; Yamazaki, Tsutomu; Yo, Shoei; Yokote, Koutaro; Yoshida, Kiyoshi; Yoshimura, Michihiro; Yoshimura, Nagahisa; Nakao, Kazuwa; Nagai, Ryozo

2018-06-01

Diabetes is associated with high risk of cardiovascular (CV) events, particularly in patients with dyslipidemia and diabetic complications. We investigated the incidence of CV events with intensive or standard lipid-lowering therapy in patients with hypercholesterolemia, diabetic retinopathy, and no history of coronary artery disease (treat-to-target approach). In this multicenter, prospective, randomized, open-label, blinded end point study, eligible patients were randomly assigned (1:1) to intensive statin therapy targeting LDL cholesterol (LDL-C) <70 mg/dL ( n = 2,518) or standard statin therapy targeting LDL-C 100-120 mg/dL ( n = 2,524). Mean follow-up was 37 ± 13 months. LDL-C at 36 months was 76.5 ± 21.6 mg/dL in the intensive group and 104.1 ± 22.1 mg/dL in the standard group ( P < 0.001). The primary end point events occurred in 129 intensive group patients and 153 standard group patients (hazard ratio [HR] 0.84 [95% CI 0.67-1.07]; P = 0.15). The relationship between the LDL-C difference in the two groups and the event reduction rate was consistent with primary prevention studies in patients with diabetes. Exploratory findings showed significantly fewer cerebral events in the intensive group (HR 0.52 [95% CI 0.31-0.88]; P = 0.01). Safety did not differ significantly between the two groups. We found no significant decrease in CV events or CV-associated deaths with intensive therapy, possibly because our between-group difference of LDL-C was lower than expected (27.7 mg/dL at 36 months of treatment). The potential benefit of achieving LDL-C <70 mg/dL in a treat-to-target strategy in high-risk patients deserves further investigation. © 2018 by the American Diabetes Association.

In silico prediction of novel therapeutic targets using gene-disease association data.

PubMed

Ferrero, Enrico; Dunham, Ian; Sanseau, Philippe

2017-08-29

Target identification and validation is a pressing challenge in the pharmaceutical industry, with many of the programmes that fail for efficacy reasons showing poor association between the drug target and the disease. Computational prediction of successful targets could have a considerable impact on attrition rates in the drug discovery pipeline by significantly reducing the initial search space. Here, we explore whether gene-disease association data from the Open Targets platform is sufficient to predict therapeutic targets that are actively being pursued by pharmaceutical companies or are already on the market. To test our hypothesis, we train four different classifiers (a random forest, a support vector machine, a neural network and a gradient boosting machine) on partially labelled data and evaluate their performance using nested cross-validation and testing on an independent set. We then select the best performing model and use it to make predictions on more than 15,000 genes. Finally, we validate our predictions by mining the scientific literature for proposed therapeutic targets. We observe that the data types with the best predictive power are animal models showing a disease-relevant phenotype, differential expression in diseased tissue and genetic association with the disease under investigation. On a test set, the neural network classifier achieves over 71% accuracy with an AUC of 0.76 when predicting therapeutic targets in a semi-supervised learning setting. We use this model to gain insights into current and failed programmes and to predict 1431 novel targets, of which a highly significant proportion has been independently proposed in the literature. Our in silico approach shows that data linking genes and diseases is sufficient to predict novel therapeutic targets effectively and confirms that this type of evidence is essential for formulating or strengthening hypotheses in the target discovery process. Ultimately, more rapid and automated target prioritisation holds the potential to reduce both the costs and the development times associated with bringing new medicines to patients.

ASDB: a resource for probing protein functions with small molecules.

PubMed

Liu, Zhihong; Ding, Peng; Yan, Xin; Zheng, Minghao; Zhou, Huihao; Xu, Yuehua; Du, Yunfei; Gu, Qiong; Xu, Jun

2016-06-01

: Identifying chemical probes or seeking scaffolds for a specific biological target is important for protein function studies. Therefore, we create the Annotated Scaffold Database (ASDB), a computer-readable and systematic target-annotated scaffold database, to serve such needs. The scaffolds in ASDB were derived from public databases including ChEMBL, DrugBank and TCMSP, with a scaffold-based classification approach. Each scaffold was assigned with an InChIKey as its unique identifier, energy-minimized 3D conformations, and other calculated properties. A scaffold is also associated with drugs, natural products, drug targets and medical indications. The database can be retrieved through text or structure query tools. ASDB collects 333 601 scaffolds, which are associated with 4368 targets. The scaffolds consist of 3032 scaffolds derived from drugs and 5163 scaffolds derived from natural products. For given scaffolds, scaffold-target networks can be generated from the database to demonstrate the relations of scaffolds and targets. ASDB is freely available at http://www.rcdd.org.cn/asdb/with the major web browsers. junxu@biochemomes.com or xujun9@mail.sysu.edu.cn Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Intracellular Membrane Association of the Aplysia cAMP Phosphodiesterase Long and Short Forms via Different Targeting Mechanisms*

PubMed Central

Kim, Kun-Hyung; Jun, Yong-Woo; Park, Yongsoo; Lee, Jin-A; Suh, Byung-Chang; Lim, Chae-Seok; Lee, Yong-Seok; Kaang, Bong-Kiun; Jang, Deok-Jin

2014-01-01

Phosphodiesterases (PDEs) play key roles in cAMP compartmentalization, which is required for intracellular signaling processes, through specific subcellular targeting. Previously, we showed that the long and short forms of Aplysia PDE4 (ApPDE4), which are localized to the membranes of distinct subcellular organelles, play key roles in 5-hydroxytryptamine-induced synaptic facilitation in Aplysia sensory and motor synapses. However, the molecular mechanism of the isoform-specific distinct membrane targeting was not clear. In this study, we further investigated the molecular mechanism of the membrane targeting of the ApPDE4 long and short forms. We found that the membrane targeting of the long form was mediated by hydrophobic interactions, mainly via 16 amino acids at the N-terminal region, whereas the short form was targeted solely to the plasma membrane, mainly by nonspecific electrostatic interactions between their N termini and the negatively charged lipids such as the phosphatidylinositol polyphosphates PI4P and PI(4,5)P2, which are embedded in the inner leaflet of the plasma membrane. Moreover, oligomerization of the long or short form by interaction of their respective upstream conserved region domains, UCR1 and UCR2, enhanced their plasma membrane targeting. These results suggest that the long and short forms of ApPDE4 are distinctly targeted to intracellular membranes through their direct association with the membranes via hydrophobic and electrostatic interactions, respectively. PMID:25077971

Molecular Imaging of Vasa Vasorum Neovascularization via DEspR-targeted Contrast-enhanced Ultrasound Micro-imaging in Transgenic Atherosclerosis Rat Model

PubMed Central

Decano, Julius L.; Moran, Anne Marie; Ruiz-Opazo, Nelson; Herrera, Victoria L. M.

2011-01-01

Purpose Given that carotid vasa vasorum neovascularization is associated with increased risk for stroke and cardiac events, the present in vivo study was designed to investigate molecular imaging of carotid artery vasa vasorum neovascularization via target-specific contrast-enhanced ultrasound (CEU) micro-imaging. Procedures Molecular imaging was performed in male transgenic rats with carotid artery disease and non-transgenic controls using dual endothelin1/VEGFsp receptor (DEspR)-targeted microbubbles (MBD) and the Vevo770 micro-imaging system and CEU imaging software. Results DEspR-targeted CEU-positive imaging exhibited significantly higher contrast intensity signal (CIS)-levels and pre-/post-destruction CIS-differences in seven of 13 transgenic rats, in contrast to significantly lower CIS-levels and differences in control isotype-targeted microbubble (MBC)-CEU imaging (n =8) and in MBD CEU-imaging of five non-transgenic control rats (P<0.0001). Ex vivo immunofluorescence analysis demonstrated binding of MBD to DEspR-positive endothelial cells; and association of DEspR-targeted increased contrast intensity signals with DEspR expression in vasa vasorum neovessel and intimal lesions. In vitro analysis demonstrated dose-dependent binding of MBD to DEspR-positive human endothelial cells with increasing %cells bound and number of MBD per cell, in contrast to MBC or non-labeled microbubbles (P<0.0001). Conclusion In vivo DEspR-targeted molecular imaging detected increased DEspR-expression in carotid artery lesions and in expanded vasa vasorum neovessels in transgenic rats with carotid artery disease. Future studies are needed to determine predictive value for stroke or heart disease in this transgenic atherosclerosis rat model and translational applications. PMID:20972637

The SWEET SPOTS study: a real-world interpretation of the 2012 American Diabetes Association Position Statement regarding individualized A1C targets.

PubMed

Bieszk, Nella; Grabner, Michael; Wei, Wenhui; Bonine, Nicole G; Stephenson, Judith J

2016-01-01

To evaluate awareness of the 2012 American Diabetes Association (ADA) Position Statement among physicians and assess its effects on patient-centered glycated hemoglobin (A1C) goals in the management of type 2 diabetes (T2D). The Summarizing Real-World Individualized TrEatmEnT GoalS and Potential SuppOrT Systems in Type 2 Diabetes (SWEET SPOTS) study used the HealthCore claims database to identify T2D patients, stratified by risk, and their treating physicians to assess primary care physician and endocrinologist awareness of the 2012 ADA Position Statement. Physicians completed online surveys on A1C targets before and after receiving an educational intervention to review the position statement. Of 125 responding physicians (mean age 50.3 years, 12.8% endocrinologists) who were linked to 125 patient profiles (mean age 56.9 years, 42% female, mean A1C 7.2%), 92% were at least somewhat aware of the position statement prior to the intervention and 59% believed that the statement would impact how they set A1C targets. The educational intervention resulted in mostly less stringent goal setting for both lower and higher risk patients, but changes were not significant. The proportion of physician-assigned A1C targets within ADA-recommended ranges increased from 56% to 66% post-intervention ( P <0.0001). Physicians treating T2D are aware of the 2012 ADA Position Statement and believe that it may influence treatment goals. While patient-specific A1C targets were not significantly impacted, physicians indicated that they would make targets more or less stringent for lower and higher risk patients, respectively, across their practice. Further research into optimizing physician education regarding individualized A1C targets is warranted.

Indel-seq: a fast-forward genetics approach for identification of trait-associated putative candidate genomic regions and its application in pigeonpea (Cajanus cajan).

PubMed

Singh, Vikas K; Khan, Aamir W; Saxena, Rachit K; Sinha, Pallavi; Kale, Sandip M; Parupalli, Swathi; Kumar, Vinay; Chitikineni, Annapurna; Vechalapu, Suryanarayana; Sameer Kumar, Chanda Venkata; Sharma, Mamta; Ghanta, Anuradha; Yamini, Kalinati Narasimhan; Muniswamy, Sonnappa; Varshney, Rajeev K

2017-07-01

Identification of candidate genomic regions associated with target traits using conventional mapping methods is challenging and time-consuming. In recent years, a number of single nucleotide polymorphism (SNP)-based mapping approaches have been developed and used for identification of candidate/putative genomic regions. However, in the majority of these studies, insertion-deletion (Indel) were largely ignored. For efficient use of Indels in mapping target traits, we propose Indel-seq approach, which is a combination of whole-genome resequencing (WGRS) and bulked segregant analysis (BSA) and relies on the Indel frequencies in extreme bulks. Deployment of Indel-seq approach for identification of candidate genomic regions associated with fusarium wilt (FW) and sterility mosaic disease (SMD) resistance in pigeonpea has identified 16 Indels affecting 26 putative candidate genes. Of these 26 affected putative candidate genes, 24 genes showed effect in the upstream/downstream of the genic region and two genes showed effect in the genes. Validation of these 16 candidate Indels in other FW- and SMD-resistant and FW- and SMD-susceptible genotypes revealed a significant association of five Indels (three for FW and two for SMD resistance). Comparative analysis of Indel-seq with other genetic mapping approaches highlighted the importance of the approach in identification of significant genomic regions associated with target traits. Therefore, the Indel-seq approach can be used for quick and precise identification of candidate genomic regions for any target traits in any crop species. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

Determinants of sugar‐sweetened beverage consumption in young children: a systematic review

PubMed Central

Mazarello Paes, V.; Hesketh, K.; O'Malley, C.; Moore, H.; Summerbell, C.; Griffin, S.; van Sluijs, E. M. F.; Ong, K. K.

2015-01-01

Summary Sugar‐sweetened beverage (SSB) consumption is associated with adverse health outcomes. Improved understanding of the determinants will inform effective interventions to reduce SSB consumption. A total of 46,876 papers were identified through searching eight electronic databases. Evidence from intervention (n = 13), prospective (n = 6) and cross‐sectional (n = 25) studies on correlates/determinants of SSB consumption was quality assessed and synthesized. Twelve correlates/determinants were associated with higher SSB consumption (child's preference for SSBs, TV viewing/screen time and snack consumption; parents' lower socioeconomic status, lower age, SSB consumption, formula milk feeding, early introduction of solids, using food as rewards, parental‐perceived barriers, attending out‐of‐home care and living near a fast food/convenience store). Five correlates/determinants were associated with lower SSB consumption (parental positive modelling, parents' married/co‐habiting, school nutrition policy, staff skills and supermarket nearby). There was equivocal evidence for child's age and knowledge, parental knowledge, skills, rules/restrictions and home SSB availability. Eight intervention studies targeted multi‐level (child, parents, childcare/preschool setting) determinants; four were effective. Four intervention studies targeted parental determinants; two were effective. One (effective) intervention targeted the preschool environment. There is consistent evidence to support potentially modifiable correlates/determinants of SSB consumption in young children acting at parental (modelling), child (TV viewing) and environmental (school policy) levels. PMID:26252417

Geochemical evidence for a brooks range mineral belt, Alaska

USGS Publications Warehouse

Marsh, S.P.; Cathrall, J.B.

1981-01-01

Geochemical studies in the central Brooks Range, Alaska, delineate a regional, structurally controlled mineral belt in east-west-trending metamorphic rocks and adjacent metasedimentary rocks. The mineral belt extends eastward from the Ambler River quadrangle to the Chandalar and Philip Smith quadrangles, Alaska, from 147?? to 156??W. longitude, a distance of more than 375 km, and spans a width from 67?? to 69??N. latitude, a distance of more than 222 km. Within this belt are several occurrences of copper and molybdenum mineralization associated with meta-igneous, metasedimentary, and metavolcanic rocks; the geochemical study delineates target areas for additional occurrences. A total of 4677 stream-sediment and 2286 panned-concentrate samples were collected in the central Brooks Range, Alaska, from 1975 to 1979. The -80 mesh ( 2.86) nonmagnetic fraction of the panned concentrates from stream sediment were analyzed by semiquantitative spectrographic methods. Two geochemical suites were recognized in this investigation; a base-metal suite of copper-lead-zinc and a molybdenum suite of molybdenum-tin-tungsten. These suites suggest several types of mineralization within the metamorphic belt. Anomalies in molybdenum with associated Cu and W suggest a potential porphyry molybdenum system associated with meta-igneous rocks. This regional study indicates that areas of metaigneous rocks in the central metamorphic belt are target areas for potential mineralized porphyry systems and that areas of metavolcanic rocks are target areas for potential massive sulfide mineralization. ?? 1981.

Suicidal ideation and suicide attempts in children and adolescents with bipolar disorder: a systematic review of prevalence and incidence rates, risk factors, and targeted interventions

PubMed Central

Hauser, Marta; Galling, Britta; Correll, Christoph U

2013-01-01

Objective Pediatric bipolar disorder (PBD) is associated with poor outcomes, including suicidal ideation (SI) and suicide attempt (SA). However, frequencies and risk factors of SI/SA and targeted intervention trials for SI/SA in PBD have not been reviewed systematically. Methods We conducted a systematic PubMed review, searching for articles reporting on prevalences/incidences, correlates and intervention studies targeting SI/SA in PBD. Weighted means were calculated, followed by an exploratory meta-regression of SI and SA correlates. Results Fourteen studies (n = 1,595) with 52.1% males aged 14.4 years reported data on SI/SA prevalence (N = 13, n = 1,508) and/or correlates (N = 10, n = 1,348) in PBD. Weighted mean prevalences were: past SI = 57.4%, past SA = 21.3%, current SI = 50.4%, and current SA = 25.5%; incidences (mean: 42 months follow-up were: SI = 14.6% and SA = 14.7%. Regarding significant correlates, SI (N = 3) was associated with a higher percentage of Caucasian race, narrow (as opposed to broad) PBD phenotype, younger age, and higher quality of life than SA. Significant correlates of SA (N = 10) included female gender, older age, earlier illness onset, more severe/episodic PBD, mixed episodes, comorbid disorders, past self-injurious behavior/SI/SA, physical/sexual abuse, parental depression, family history of suicidality, and poor family functioning. Race, socioeconomic status, living situation, and life events were not clearly associated with SA. In a meta-regression analysis, bipolar I disorder and comorbid attention-deficit hyperactivity disorder were significantly associated with SA. Only one open label study targeting the reduction of SI/SA in PBD was identified. Conclusions SI and SA are highly common but under-investigated in PBD. Exploration of predictors and protective factors is imperative for the establishment of effective preventive and intervention strategies, which are urgently needed. PMID:23829436

Dengue Virus Subverts Host Innate Immunity by Targeting Adaptor Protein MAVS

PubMed Central

He, Zhenjian; Zhu, Xun; Wen, Weitao; Yuan, Jie; Hu, Yiwen; Chen, Jiahui; An, Shu; Dong, Xinhuai; Lin, Cuiji; Yu, Jianchen; Wu, Jueheng; Yang, Yi; Cai, Junchao; Li, Jun

2016-01-01

ABSTRACT Dengue virus (DENV) is the most common mosquito-borne virus infecting humans and is currently a serious global health challenge. To establish infection in its host cells, DENV must subvert the production and/or antiviral effects of interferon (IFN). The aim of this study was to understand the mechanisms by which DENV suppresses IFN production. We determined that DENV NS4A interacts with mitochondrial antiviral signaling protein (MAVS), which was previously found to activate NF-κB and IFN regulatory factor 3 (IRF3), thus inducing type I IFN in the mitochondrion-associated endoplasmic reticulum membranes (MAMs). We further demonstrated that NS4A is associated with the N-terminal CARD-like (CL) domain and the C-terminal transmembrane (TM) domain of MAVS. This association prevented the binding of MAVS to RIG-I, resulting in the repression of RIG-I-induced IRF3 activation and, consequently, the abrogation of IFN production. Collectively, our findings illustrate a new molecular mechanism by which DENV evades the host immune system and suggest new targets for anti-DENV strategies. IMPORTANCE Type I interferon (IFN) constitutes the first line of host defense against invading viruses. To successfully establish infection, dengue virus (DENV) must counteract either the production or the function of IFN. The mechanism by which DENV suppresses IFN production is poorly understood and characterized. In this study, we demonstrate that the DENV NS4A protein plays an important role in suppressing interferon production through binding MAVS and disrupting the RIG-I–MAVS interaction in mitochondrion-associated endoplasmic reticulum membranes (MAMs). Our study reveals that MAVS is a novel host target of NS4A and provides a molecular mechanism for DENV evasion of the host innate immune response. These findings have important implications for understanding the pathogenesis of DENV and may provide new insights into using NS4A as a therapeutic and/or prevention target. PMID:27252539

Molecular targets of alcohol action: translational research for pharmacotherapy development and screening

PubMed Central

Gorini, Giorgio; Bell, Richard L.; Mayfield, R. Dayne

2016-01-01

Summary Alcohol abuse and dependence are multifaceted disorders with neurobiological, psychological, and environmental components. Research on other complex neuropsychiatric diseases suggests that genetically influenced intermediate characteristics affect the risk for heavy alcohol consumption and its consequences. Diverse therapeutic interventions can be developed through identification of reliable biomarkers for this disorder and new pharmacological targets for its treatment. Advances in the fields of genomics and proteomics offer a number of possible targets for the development of new therapeutic approaches. This brain-focused review highlights studies identifying neurobiological systems associated with these targets and possible pharmacotherapies, summarizing evidence from clinically relevant animal and human studies, as well as sketching improvements and challenges facing the fields of proteomics and genomics. Concluding thoughts on using results from these profiling technologies for medication development are also presented. PMID:21199775

Reviewing Hit Discovery Literature for Difficult Targets: Glutathione Transferase Omega-1 as an Example.

PubMed

Xie, Yiyue; Dahlin, Jayme L; Oakley, Aaron J; Casarotto, Marco G; Board, Philip G; Baell, Jonathan B

2018-05-10

Early stage drug discovery reporting on relatively new or difficult targets is often associated with insufficient hit triage. Literature reviews of such targets seldom delve into the detail required to critically analyze the associated screening hits reported. Here we take the enzyme glutathione transferase omega-1 (GSTO1-1) as an example of a relatively difficult target and review the associated literature involving small-molecule inhibitors. As part of this process we deliberately pay closer-than-usual attention to assay interference and hit quality aspects. We believe this Perspective will be a useful guide for future development of GSTO1-1 inhibitors, as well serving as a template for future review formats of new or difficult targets.

Are national targets the right way to improve infection control practice?

PubMed

Millar, M

2009-12-01

The 'right way to improve infection control practice' should be cost-effective and lead to a fair distribution of infection control resources. Cost-effectiveness is a measure of aggregate 'good', and fairness emphasises similar treatment for individuals under similar circumstances. The UK national meticillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) target encourages National Health Service trusts to prioritise strategies aimed at MRSA BSI prevention. Under resource-limited conditions, the MRSA BSI target inevitably encourages deprioritisation of patients at risk of non-target healthcare-associated infection (HCAI), some of which are associated with an equal or larger burden of adverse outcome. Established healthcare improvement strategies, such as the Plan, Do, Study, Act (PDSA) cycle advocated by the Health Foundation, require the setting of aims (or targets). If we are to improve infection control practice then we need to decide on what to measure, how to measure it, and what the improvement (target) should be. In selecting targets for infection prevention, account should be taken of the contribution of HCAI to adverse health outcomes overall. Human risk compensation behaviour and microbial adaptation may both counteract the overall benefit of infection targets isolated from overall outcomes. Risk taking is part of a healthy healthcare system. We must be careful not to isolate HCAI outcomes from overall outcomes or to isolate 'risk takers' from 'risk controllers'. We must try to limit the scope for human risk compensation and we must watch out for microbial adaptation. Targets should be set locally, taking account of fairness and cost-effectiveness. Locally relevant information is key; positive incentives work best.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid or myeloid cells surface antigens [II]: CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4).

PubMed

Drgona, L; Gudiol, C; Lanini, S; Salzberger, B; Ippolito, G; Mikulska, M

2018-03-20

The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. To review, from an Infectious Diseases perspective, the safety profile of agents targeting CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4 and to suggest preventive recommendations. Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. The risk and spectrum of infections in patients receiving CD22-targeted agents (i.e. inotuzumab ozogamicin) are similar to those observed with anti-CD20 antibodies. Anti-Pneumocystis prophylaxis and monitoring for cytomegalovirus (CMV) infection is recommended for patients receiving CD30-targeted agents (brentuximab vedotin). Due to the scarcity of data, the risk posed by CD33-targeted agents (gemtuzumab ozogamicin) cannot be assessed. Patients receiving CD38-targeted agents (i.e. daratumumab) face an increased risk of varicella-zoster virus (VZV) infection. Therapy with CD40-targeted agents (lucatumumab or dacetuzumab) is associated with opportunistic infections similar to those observed in hyper-IgM syndrome, and prevention strategies (including anti-Pneumocystis prophylaxis and pre-emptive therapy for CMV infection) are warranted. SLAMF-7 (CD319)-targeted agents (elotuzumab) induce lymphopenia and increase the risk of infection (particularly due to VZV). The impact of CCR4-targeted agents (mogamulizumab) on infection susceptibility is difficult to distinguish from the effect of underlying diseases and concomitant therapies. However, anti-Pneumocystis and anti-herpesvirus prophylaxis and screening for chronic hepatitis B virus (HBV) infection are recommended. Specific management strategies should be put in place to reduce the risk and/or the severity of infectious complications associated to the reviewed agents. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Revisiting TW Hydrae association in light of Gaia-DR1

NASA Astrophysics Data System (ADS)

Teixeira, R.; Gonoretzky, E. R.; Ducourant, C.; Galli, P. A. B.; Krone-Martins, A. G. O.

2018-04-01

TW Hydrae is a very young and nearby association with about 30 known members which is an excellent target for studies on stellar evolution since several of its members present a particular interest (planetary system, brown dwarfs, etc.). With the new data from TGAS and the Gaia DR1 eventually combined with others astrometric data we intend to improve our kinematic knowledge of this association.

Sleep- and circadian rhythm-associated pathways as therapeutic targets in bipolar disorder.

PubMed

Bellivier, Frank; Geoffroy, Pierre-Alexis; Etain, Bruno; Scott, Jan

2015-06-01

Disruptions in sleep and circadian rhythms are observed in individuals with bipolar disorders (BD), both during acute mood episodes and remission. Such abnormalities may relate to dysfunction of the molecular circadian clock and could offer a target for new drugs. This review focuses on clinical, actigraphic, biochemical and genetic biomarkers of BDs, as well as animal and cellular models, and highlights that sleep and circadian rhythm disturbances are closely linked to the susceptibility to BDs and vulnerability to mood relapses. As lithium is likely to act as a synchronizer and stabilizer of circadian rhythms, we will review pharmacogenetic studies testing circadian gene polymorphisms and prophylactic response to lithium. Interventions such as sleep deprivation, light therapy and psychological therapies may also target sleep and circadian disruptions in BDs efficiently for treatment and prevention of bipolar depression. We suggest that future research should clarify the associations between sleep and circadian rhythm disturbances and alterations of the molecular clock in order to identify critical targets within the circadian pathway. The investigation of such targets using human cellular models or animal models combined with 'omics' approaches are crucial steps for new drug development.

Analysis of homeobox gene action may reveal novel angiogenic pathways in normal placental vasculature and in clinical pregnancy disorders associated with abnormal placental angiogenesis.

PubMed Central

Murthi, Padma; Abumaree, Mohamed; Kalionis, Bill

2014-01-01

Homeobox genes are essential for both the development of the blood and lymphatic vascular systems, as well as for their maintenance in the adult. Homeobox genes comprise an important family of transcription factors, which are characterized by a well conserved DNA binding motif; the homeodomain. The specificity of the homeodomain allows the transcription factor to bind to the promoter regions of batteries of target genes and thereby regulates their expression. Target genes identified for homeodomain proteins have been shown to control fundamental cell processes such as proliferation, differentiation, and apoptosis. We and others have reported that homeobox genes are expressed in the placental vasculature, but our knowledge of their downstream target genes is limited. This review highlights the importance of studying the cellular and molecular mechanisms by which homeobox genes and their downstream targets may regulate important vascular cellular processes such as proliferation, migration, and endothelial tube formation, which are essential for placental vasculogenesis and angiogenesis. A better understanding of the molecular targets of homeobox genes may lead to new therapies for aberrant angiogenesis associated with clinically important pregnancy pathologies, including fetal growth restriction and preeclampsia. PMID:24926269

MicroRNA-302 Cluster Downregulates Enterovirus 71-Induced Innate Immune Response by Targeting KPNA2.

PubMed

Peng, Nanfang; Yang, Xuecheng; Zhu, Chengliang; Zhou, Li; Yu, Haisheng; Li, Mengqi; Lin, Yong; Wang, Xueyu; Li, Qian; She, Yinglong; Wang, Jun; Zhao, Qian; Lu, Mengji; Zhu, Ying; Liu, Shi

2018-05-18

Enterovirus 71 (EV71) induces significantly elevated levels of cytokines and chemokines, leading to local or systemic inflammation and severe complications. As shown in our previous study, microRNA (miR) 302c regulates influenza A virus-induced IFN expression by targeting NF-κB-inducing kinase. However, little is known about the role of the miR-302 cluster in EV71-mediated proinflammatory responses. In this study, we found that the miR-302 cluster controls EV71-induced cytokine expression. Further studies demonstrated that karyopherin α2 (KPNA2) is a direct target of the miR-302 cluster. Interestingly, we also found that EV71 infection upregulates KPNA2 expression by downregulating miR-302 cluster expression. Upon investigating the mechanisms behind this event, we found that KPNA2 intracellularly associates with JNK1/JNK2 and p38, leading to translocation of those transcription factors from the cytosol into the nucleus. In EV71-infected patients, miR-302 cluster expression was downregulated and KPNA2 expression was upregulated compared with controls, and their expression levels were closely correlated. Taken together, our work establishes a link between the miR-302/ KPNA2 axis and EV71-induced cytokine expression and represents a promising target for future antiviral therapy. Copyright © 2018 by The American Association of Immunologists, Inc.

An fMRI investigation into the effect of preceding stimuli during visual oddball tasks.

PubMed

Fajkus, Jiří; Mikl, Michal; Shaw, Daniel Joel; Brázdil, Milan

2015-08-15

This study investigates the modulatory effect of stimulus sequence on neural responses to novel stimuli. A group of 34 healthy volunteers underwent event-related functional magnetic resonance imaging while performing a three-stimulus visual oddball task, involving randomly presented frequent stimuli and two types of infrequent stimuli - targets and distractors. We developed a modified categorization of rare stimuli that incorporated the type of preceding rare stimulus, and analyzed the event-related functional data according to this sequence categorization; specifically, we explored hemodynamic response modulation associated with increasing rare-to-rare stimulus interval. For two consecutive targets, a modulation of brain function was evident throughout posterior midline and lateral temporal cortex, while responses to targets preceded by distractors were modulated in a widely distributed fronto-parietal system. As for distractors that follow targets, brain function was modulated throughout a set of posterior brain structures. For two successive distractors, however, no significant modulation was observed, which is consistent with previous studies and our primary hypothesis. The addition of the aforementioned technique extends the possibilities of conventional oddball task analysis, enabling researchers to explore the effects of the whole range of rare stimuli intervals. This methodology can be applied to study a wide range of associated cognitive mechanisms, such as decision making, expectancy and attention. Copyright © 2015 Elsevier B.V. All rights reserved.

Beyond endometriosis GWAS: from Genomics to Phenomics to the Patient

PubMed Central

Zondervan, Krina T.; Rahmioglu, Nilufer; Morris, Andrew P.; Nyholt, Dale R.; Montgomery, Grant W.; Becker, Christian M.; Missmer, Stacey A.

2017-01-01

Endometriosis is a heritable, complex chronic inflammatory disease, for which much of the causal pathogenic mechanism remain unknown. Genome-wide association studies (GWAS) to date have identified 12 single nucleotide polymorphisms or SNPs at 10 independent genetic loci associated with endometriosis. Most of these were more strongly associated with rAFS stage III/IV, rather than I/II. The loci are almost all located in inter-genic regions that are known to play a role in the regulation of expression of target genes yet to be identified. To identify the target genes and pathways perturbed by the implicated variants, studies are required involving functional genomic annotation of the surrounding chromosomal regions, in terms of transcriptor factor binding, epigenetic modification (e.g. DNA methylation and histone modification) sites, as well as their correlation with RNA transcription. These studies need to be conducted in tissue types relevant to endometriosis – in particular endometrium. In addition, to allow biologically and clinically relevant interpretation of molecular profiling data, they need to be combined and correlated with detailed, systematically collected phenotypic information (surgical and clinical). The WERF Endometriosis Phenome and Biobanking Harmonization project (EPHect) is a global standardisation initiative that has produced consensus data and sample collection protocols for endometriosis research. These now pave the way for collaborative studies integrating phenomic with genomic data, to identify informative subtypes of endometriosis that will enhance understanding of the pathogenic mechanisms of the disease and discovery of novel, targeted treatments. PMID:27513026

Phenome-genome association studies of pancreatic cancer: new targets for therapy and diagnosis.

PubMed

Narayanan, Ramaswamy

2015-01-01

Pancreatic cancer, has a very high mortality rate and requires novel molecular targets for diagnosis and therapy. Genetic association studies over databases offer an attractive starting point for gene discovery. The National Center for Biotechnology Information (NCBI) Phenome Genome Integrator (PheGenI) tool was enriched for pancreatic cancer-associated traits. The genes associated with the trait were characterized using diverse bioinformatics tools for Genome-Wide Association (GWA), transcriptome and proteome profile and protein classes for motif and domain. Two hundred twenty-six genes were identified that had a genetic association with pancreatic cancer in the human genome. This included 25 uncharacterized open reading frames (ORFs). Bioinformatics analysis of these ORFs identified putative druggable proteins and biomarkers including enzymes, transporters and G-protein-coupled receptor signaling proteins. Secreted proteins including a neuroendocrine factor and a chemokine were identified. Five out of these ORFs encompassed non coding RNAs. The ORF protein expression was detected in numerous body fluids, such as ascites, bile, pancreatic juice, milk, plasma, serum and saliva. Transcriptome and proteome analyses showed a correlation of mRNA and protein expression for nine ORFs. Analysis of the Catalogue of Somatic Mutations in Cancer (COSMIC) database revealed a strong correlation across copy number variations and mRNA over-expression for four ORFs. Mining of the International Cancer Gene Consortium (ICGC) database identified somatic mutations in a significant number of pancreatic patients' tumors for most of these ORFs. The pancreatic cancer-associated ORFs were also found to be genetically associated with other neoplasms, including leukemia, malignant melanoma, neuroblastoma and prostate carcinomas, as well as other unrelated diseases and disorders, such as Alzheimer's disease, Crohn's disease, coronary diseases, attention deficit disorder and addiction. Based on Genome-Wide Association Studies (GWAS), copy number variations, somatic mutational status and correlation of gene expression in pancreatic tumors at the mRNA and protein level, expression specificity in normal tissues and detection in body fluids, six ORFs emerged as putative leads for pancreatic cancer. These six targets provide a basis for accelerated drug discovery and diagnostic marker development for pancreatic cancer. Copyright© 2015, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

Screening biomarkers of bladder cancer using combined miRNA and mRNA microarray analysis.

PubMed

Jin, Ning; Jin, Xuefei; Gu, Xinquan; Na, Wanli; Zhang, Muchun; Zhao, Rui

2015-08-01

Biomarkers, such as microRNAs (miRNAs) may be useful for the diagnosis of bladder cancer. In order to understand the molecular mechanisms underlying bladder cancer, differentially expressed miRNAs (DE-miRNAs) and their target genes in bladder cancer were analyzed. In the present study, miRNA and mRNA expression profiles (GSE40355) were obtained from the Gene Expression Omnibus. These consisted of healthy bladder samples (n=8) and urothelial carcinoma samples (low-grade, n=8 and high-grade, n=8). DE-miRNAs and differentially expressed genes (DEGs) were identified using the limma package and the Benjamin and Hochberg method from the multtest package in R. Target genes of DE-miRNAs were screened. Associations between DEGs were investigated using STRING, and an interaction network was constructed using Cytoscape. Functional and pathway enrichment analyses were performed for DEGs from the interaction network. 87 DE-miRNAs and 2058 DEGs were screened from low-grade bladder cancer samples, and 40 DE-miRNAs and 2477 DEGs were screened from high-grade bladder cancer samples. DE-target genes were significantly associated with the regulation of cell apoptosis. Bladder cancer, non-small cell lung cancer and pancreatic cancer biological pathways were found to be enriched. The results of the present study demonstrated that E2F transcription factor 1, which is targeted by miR-106b, and cyclin-dependent kinase inhibitor 2A (CDKN2A) and V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog-2, which are targeted by miR-125b, participate in the bladder cancer pathway. In conclusion, DE-miRNAs in bladder cancer tissue samples and DE-targeted genes, such as miR-106b and CDKN2A, which were identified in the present study, may provide the basis for targeted therapy for breast cancer and enhance understanding of its pathogenesis.

DeepMirTar: a deep-learning approach for predicting human miRNA targets.

PubMed

Wen, Ming; Cong, Peisheng; Zhang, Zhimin; Lu, Hongmei; Li, Tonghua

2018-06-01

MicroRNAs (miRNAs) are small noncoding RNAs that function in RNA silencing and post-transcriptional regulation of gene expression by targeting messenger RNAs (mRNAs). Because the underlying mechanisms associated with miRNA binding to mRNA are not fully understood, a major challenge of miRNA studies involves the identification of miRNA-target sites on mRNA. In silico prediction of miRNA-target sites can expedite costly and time-consuming experimental work by providing the most promising miRNA-target-site candidates. In this study, we reported the design and implementation of DeepMirTar, a deep-learning-based approach for accurately predicting human miRNA targets at the site level. The predicted miRNA-target sites are those having canonical or non-canonical seed, and features, including high-level expert-designed, low-level expert-designed, and raw-data-level, were used to represent the miRNA-target site. Comparison with other state-of-the-art machine-learning methods and existing miRNA-target-prediction tools indicated that DeepMirTar improved overall predictive performance. DeepMirTar is freely available at https://github.com/Bjoux2/DeepMirTar_SdA. lith@tongji.edu.cn, hongmeilu@csu.edu.cn. Supplementary data are available at Bioinformatics online.

Identification of Loci Associated with Drought Resistance Traits in Heterozygous Autotetraploid Alfalfa (Medicago sativa L.) Using Genome-Wide Association Studies with Genotyping by Sequencing.

PubMed

Zhang, Tiejun; Yu, Long-Xi; Zheng, Ping; Li, Yajun; Rivera, Martha; Main, Dorrie; Greene, Stephanie L

2015-01-01

Drought resistance is an important breeding target for enhancing alfalfa productivity in arid and semi-arid regions. Identification of genes involved in drought tolerance will facilitate breeding for improving drought resistance and water use efficiency in alfalfa. Our objective was to use a diversity panel of alfalfa accessions comprised of 198 cultivars and landraces to identify genes involved in drought tolerance. The panel was selected from the USDA-ARS National Plant Germplasm System alfalfa collection and genotyped using genotyping by sequencing. A greenhouse procedure was used for phenotyping two important traits associated with drought tolerance: drought resistance index (DRI) and relative leaf water content (RWC). Marker-trait association identified nineteen and fifteen loci associated with DRI and RWC, respectively. Alignments of target sequences flanking to the resistance loci against the reference genome of M. truncatula revealed multiple chromosomal locations. Markers associated with DRI are located on all chromosomes while markers associated with RWC are located on chromosomes 1, 2, 3, 4, 5, 6 and 7. Co-localizations of significant markers between DRI and RWC were found on chromosomes 3, 5 and 7. Most loci associated with DRI in this work overlap with the reported QTLs associated with biomass under drought in alfalfa. Additional significant markers were targeted to several contigs with unknown chromosomal locations. BLAST search using their flanking sequences revealed homology to several annotated genes with functions in stress tolerance. With further validation, these markers may be used for marker-assisted breeding new alfalfa varieties with drought resistance and enhanced water use efficiency.

Generation and associative encoding in young and old adults: the effect of the strength of association between cues and targets on a cued recall task.

PubMed

Taconnat, Laurence; Froger, Charlotte; Sacher, Mathilde; Isingrini, Michel

2008-01-01

The generation effect (i.e., better recall of the generated items than the read items) was investigated with a between-list design in young and elderly participants. The generation task difficulty was manipulated by varying the strength of association between cues and targets. Overall, strong associates were better recalled than weak associates. However, the results showed different generation effect patterns according to strength of association and age, with a greater generation effect for weak associates in younger adults only. These findings suggest that generating weak associates leads to more elaborated encoding, but that elderly adults cannot use this elaborated encoding as well as younger adults to recall the target words at test.

Head-and-Neck Target Delineation Among Radiation Oncology Residents After a Teaching Intervention: A Prospective, Blinded Pilot Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bekelman, Justin E.; Wolden, Suzanne; Lee, Nancy

Purpose: We conducted this study to determine the feasibility of incorporating a teaching intervention on target delineation into the educational curriculum of a radiation oncology residency program and to assess the short-term effects on resident skills. Methods and Materials: The study schema consisted of a baseline evaluation, the teaching intervention, and a follow-up evaluation. At the baseline evaluation, the participants contoured three clinical tumor volumes (CTVs) (70 Gy, 59.4 Gy, and 54 Gy) on six contrast-enhanced axial computed tomography images of a de-identified patient with Stage T2N2bM0 squamous cell carcinoma of the right base of the tongue. The participants attendedmore » a series of head-and-neck oncology and anatomy seminars. The teaching intervention consisted of a didactic lecture and an interactive hands-on practical session designed to improve the knowledge and skills for target delineation in the head and neck. At the follow-up evaluation, the residents again contoured the CTVs. Results: Of the 14 eligible residents, 11 (79%) actually participated in the study. For all participants, but especially for those who had not had previous experience with head-and-neck target delineation, the teaching intervention was associated with improvement in the delineation of the node-negative neck (CTV 54 Gy contour). Regardless of clinical experience, participants had difficulty determining what should be included in the CTV 59.4 Gy contour to ensure adequate coverage of potential microscopic disease. Conclusion: Incorporating a teaching intervention into the education curriculum of a radiation oncology residency program is feasible and was associated with short-term improvements in target delineation skills. Subsequent interventions will require content refinement, additional validation, longer term follow-up, and multi-institutional collaboration.« less

Rapid target foraging with reach or gaze: The hand looks further ahead than the eye

PubMed Central

2017-01-01

Real-world tasks typically consist of a series of target-directed actions and often require choices about which targets to act on and in what order. Such choice behavior can be assessed from an optimal foraging perspective whereby target selection is shaped by a balance between rewards and costs. Here we evaluated such decision-making in a rapid movement foraging task. On a given trial, participants were presented with 15 targets of varying size and value and were instructed to harvest as much reward as possible by either moving a handle to the targets (hand task) or by briefly fixating them (eye task). The short trial duration enabled participants to harvest about half the targets, ensuring that total reward was due to choice behavior. We developed a probabilistic model to predict target-by-target harvesting choices that considered the rewards and movement-related costs (i.e., target distance and size) associated with the current target as well as future targets. In the hand task, in comparison to the eye task, target choice was more strongly influenced by movement-related costs and took into account a greater number of future targets, consistent with the greater costs associated with arm movement. In both tasks, participants exhibited near-optimal behaviour and in a constrained version of the hand task in which choices could only be based on target positions, participants consistently chose among the shortest movement paths. Our results demonstrate that people can rapidly and effectively integrate values and movement-related costs associated with current and future targets when sequentially harvesting targets. PMID:28683138

Evaluation of a breastfeeding peer support program for fathers of Hispanic participants in a Texas special supplemental nutrition program for women, infants, and children.

PubMed

Lovera, Dalia; Sanderson, Maureen; Bogle, Margaret L; Vela Acosta, Martha S

2010-11-01

A mother's decision to breastfeed and the duration of breastfeeding depends on different factors; among them are the support of her husband or male partner and other social support. There have been different types of support programs for mothers and few have targeted fathers. In 2002, the Texas Special Supplemental Nutrition Program for Women, Infants, and Children introduced an innovative approach for encouraging breastfeeding among mothers and their spouses. The pilot Peer Dad Program targeted fathers to promote and support their spouse in breastfeeding. This cohort study evaluated duration of breastfeeding among Hispanic couples who enrolled in the pilot Peer Dad Program (n=101) and those who did not enroll (n=99). Structured interviews were conducted with Special Supplemental Nutrition Program for Women, Infants, and Children participants and their male partners. Unconditional logistic regression was used to estimate the likelihood of continuing breastfeeding past 6 months associated with participation in the Peer Dad Program and significant predictors. Mothers whose partner participated in the pilot Peer Dad Program were no more likely to continue breastfeeding past 6 months (odds ratio 1.44, 95% confidence interval 0.82 to 2.54) compared with mothers who received peer counseling only. The percentage of women in the intervention group (63.4%) who breastfed for 6 months or longer compared with women in the control group (54.6%) was not significant (P=0.20). Although other studies suggest that father's support lengthens breastfeeding duration, our study, which targeted Hispanic fathers, found no association due to its small sample size. Further research with larger studies is needed to establish this association. Copyright © 2010 American Dietetic Association. Published by Elsevier Inc. All rights reserved.

Factors associated with African Americans' enrollment in a national cancer genetics registry.

PubMed

Skinner, C S; Schildkraut, J M; Calingaert, B; Hoyo, C; Crankshaw, S S; Fish, L; Susswein, L; Jasper, C; Reid, L

2008-01-01

This study explored whether reactions to the Cancer Genetics Network (CGN) or CGN enrollment differed by receipt of a standard informational brochure versus a targeted version addressing factors previously associated with African Americans' health behavior decisions and research participation. The 262 participants, identified through tumor registries or clinic contacts, were mailed brochures and completed phone interviews. When asked whether - based on the brochure - they were or were not 'leaning toward' CGN enrollment, about 75% of both standard and targeted groups reported leaning toward. When given the opportunity at the end of the interview, 68% enrolled in the CGN. Trust was strongly related to enrollment. Less education, less satisfaction with cancer care, and individualistic rather than collective orientation were associated with lower trust. Education was also bivariately associated with enrollment, but mediation analysis indicated that the operational mechanism of education's influence on enrollment was through trust. Copyright 2008 S. Karger AG, Basel.

Hypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease

PubMed Central

Kaplan, Joshua M.; Sharma, Neeraj

2018-01-01

Hypoxia-inducible factor (HIF) plays a crucial role in the response to hypoxia at the cellular, tissue, and organism level. New agents under development to pharmacologically manipulate HIF may provide new and exciting possibilities in the treatment of anemia of chronic kidney disease (CKD) as well as in multiple other disease states involving ischemia–reperfusion injury. This article provides an overview of recent studies describing current standards of care for patients with anemia in CKD and associated clinical issues, and those supporting the clinical potential for targeting HIF stabilization with HIF prolyl-hydroxylase inhibitors (HIF-PHI) in these patients. Additionally, articles reporting the clinical potential for HIF-PHIs in ‘other’ putative therapeutic areas, the tissue and intracellular distribution of HIF- and prolyl-hydroxylase domain (PHD) isoforms, and HIF isoforms targeted by the different PHDs, were identified. There is increasing uncertainty regarding the optimal treatment for anemia of CKD with poorer outcomes associated with treatment to higher hemoglobin targets, and the increasing use of iron and consequent risk of iron imbalance. Attainment and maintenance of more physiologic erythropoietin levels associated with HIF stabilization may improve the management of patients resistant to treatment with erythropoiesis-stimulating agents and improve outcomes at higher hemoglobin targets. PMID:29382128

Targeted proteins for diagnostic imaging: does chemistry make a difference?

PubMed

Fritzberg, A R; Beaumier, P L

1992-03-01

The Oyen et al. study is valuable in that it systematically evaluates several of the factors involved in radiolabeled protein uptake and retention in infectious foci. The role of particular proteins and their receptor specific interactions seems to be inconsequential in agreement with the findings of other. However, the role of the radiolabel was shown to be important and significant differences were delineated from comparisons of the radionuclides and their associated chemistries. The conclusion implicating radionuclide chemistry and associated linkages underscores the need to optimize the attachment and labeling chemical modifications of protein carriers. Evaluation criteria should include serum stability, determination and assessment of the effect of molar substitution ratio, and potential for improving blood clearance without reducing the target-to-non-target ratio. Important areas for future study include characterization of radioactive metabolites and the design and synthesis of new ligands which direct the disposition of metabolites reducing retention in normal organs or accelerating renal excretion. Additionally, intracellular processing of radiolabel, compartmental distribution and strategies for augmenting internalization and retention within the target cell merit detailed exploration. For each radionuclide of interest, 111In, radioiodines, 99mTc and others, improved chemical moieties exist for controlling radiolabel fate. When carrying out mechanistic and evaluative studies, clear-cut conclusions will only be reached when defined and controlled chemistry is used. Having established a "gold standard," simplifications in radiolabeling and other chemical refinements can then be pursued with a quantitative understanding of the trade-offs in targeting agent performance versus other considerations such as cost reduction, simplicity, and convenience.

miRNA and Degradome Sequencing Reveal miRNA and Their Target Genes That May Mediate Shoot Growth in Spur Type Mutant “Yanfu 6”

PubMed Central

Song, Chunhui; Zhang, Dong; Zheng, Liwei; Zhang, Jie; Zhang, Baojuan; Luo, Wenwen; Li, Youmei; Li, Guangfang; Ma, Juanjuan; Han, Mingyu

2017-01-01

The spur-type growth habit in apple trees is characterized by short internodes, increased number of fruiting spurs, and compact growth that promotes flowering and facilitates management practices, such as pruning. The molecular mechanisms responsible for regulating spur-type growth have not been elucidated. In the present study, miRNAs and the expression of their potential target genes were evaluated in shoot tips of “Nagafu 2” (CF) and spur-type bud mutation “Yanfu 6” (YF). A total of 700 mature miRNAs were identified, including 202 known apple miRNAs and 498 potential novel miRNA candidates. A comparison of miRNA expression in CF and YF revealed 135 differentially expressed genes, most of which were downregulated in YF. YF also had lower levels of GA, ZR, IAA, and ABA hormones, relative to CF. Exogenous applications of GA promoted YF shoot growth. Based on the obtained results, a regulatory network involving plant hormones, miRNA, and their potential target genes is proposed for the molecular mechanism regulating the growth of YF. miRNA164, miRNA166, miRNA171, and their potential targets, and associated plant hormones, appear to regulate shoot apical meristem (SAM) growth. miRNA159, miRNA167, miRNA396, and their potential targets, and associated plant hormones appear to regulate cell division and internode length. This study provides a foundation for further studies designed to elucidate the mechanism underlying spur-type apple architecture. PMID:28424721

High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pan, Jian-Bo; Ji, Nan; Pan, Wen

2014-01-01

Drugs may induce adverse drug reactions (ADRs) when they unexpectedly bind to proteins other than their therapeutic targets. Identification of these undesired protein binding partners, called off-targets, can facilitate toxicity assessment in the early stages of drug development. In this study, a computational framework was introduced for the exploration of idiosyncratic mechanisms underlying analgesic-induced severe adverse drug reactions (SADRs). The putative analgesic-target interactions were predicted by performing reverse docking of analgesics or their active metabolites against human/mammal protein structures in a high-throughput manner. Subsequently, bioinformatics analyses were undertaken to identify ADR-associated proteins (ADRAPs) and pathways. Using the pathways and ADRAPsmore » that this analysis identified, the mechanisms of SADRs such as cardiac disorders were explored. For instance, 53 putative ADRAPs and 24 pathways were linked with cardiac disorders, of which 10 ADRAPs were confirmed by previous experiments. Moreover, it was inferred that pathways such as base excision repair, glycolysis/glyconeogenesis, ErbB signaling, calcium signaling, and phosphatidyl inositol signaling likely play pivotal roles in drug-induced cardiac disorders. In conclusion, our framework offers an opportunity to globally understand SADRs at the molecular level, which has been difficult to realize through experiments. It also provides some valuable clues for drug repurposing. - Highlights: • A novel computational framework was developed for mechanistic study of SADRs. • Off-targets of drugs were identified in large scale and in a high-throughput manner. • SADRs like cardiac disorders were systematically explored in molecular networks. • A number of ADR-associated proteins were identified.« less

What can we learn about lipoprotein metabolism and coronary heart disease from studying rare variants?

PubMed

Jeff, Janina M; Peloso, Gina M; Do, Ron

2016-04-01

Rare variant association studies (RVAS) target the class of genetic variation with frequencies less than 1%. Recently, investigators have used exome sequencing in RVAS to identify rare alleles responsible for Mendelian diseases but have experienced greater difficulty discovering such alleles for complex diseases. In this review, we describe what we have learned about lipoprotein metabolism and coronary heart disease through the conduct of RVAS. Rare protein-altering genetic variation can provide important insights that are not as easily attainable from common variant association studies. First, RVAS can facilitate gene discovery by identifying novel rare protein-altering variants in specific genes that are associated with disease. Second, rare variant associations can provide supportive evidence for putative drug targets for novel therapies. Finally, rare variants can uncover new pathways and reveal new biologic mechanisms. The field of human genetics has already made tremendous progress in understanding lipoprotein metabolism and the causes of coronary heart disease in the context of rare variants. As next generation sequencing becomes more cost-effective, RVAS with larger sample sizes will be conducted. This will lead to more novel rare variant discoveries and the translation of genomic data into biological knowledge and clinical insights for cardiovascular disease.

Mouse Models of Human T Lymphotropic Virus Type-1–Associated Adult T-Cell Leukemia/Lymphoma

PubMed Central

Zimmerman, B.; Niewiesk, S.; Lairmore, M. D.

2011-01-01

Human T-lymphotropic virus type-1 (HTLV-1), the first human retrovirus discovered, is the causative agent of adult T-cell leukemia/lymphoma (ATL) and a number of lymphocyte-mediated inflammatory conditions including HTLV-1–associated myelopathy/tropical spastic paraparesis. Development of animal models to study the pathogenesis of HTLV-1–associated diseases has been problematic. Mechanisms of early infection and cell-to-cell transmission can be studied in rabbits and nonhuman primates, but lesion development and reagents are limited in these species. The mouse provides a cost-effective, highly reproducible model in which to study factors related to lymphoma development and the preclinical efficacy of potential therapies against ATL. The ability to manipulate transgenic mice has provided important insight into viral genes responsible for lymphocyte transformation. Expansion of various strains of immunodeficient mice has accelerated the testing of drugs and targeted therapy against ATL. This review compares various mouse models to illustrate recent advances in the understanding of HTLV-1–associated ATL development and how improvements in these models are critical to the future development of targeted therapies against this aggressive T-cell lymphoma. PMID:20442421

Correlates of Leisure Time Physical Inactivity in a Scandinavian Population: A Basis for Interventions.

PubMed

Bonn, Stephanie E; Alfredsson, Lars; Saevarsdottir, Saedis; Schelin, Maria E C

2016-11-01

Effective interventions are needed to increase physical activity in the general population. To target interventions, we need knowledge of insufficiently active groups in society. This study aims to identify demographic and health-related correlates of leisure-time physical inactivity in a general Scandinavian population. Study participants comprised 5734 control subjects, age 18 to 70 years, from 2 ongoing Swedish case-control studies. Participants self-reported their leisure-time physical activity level. The odds of being physically inactive were calculated using logistic regression. A total of 42% of participants were classified as physically inactive during leisure time. A lower prevalence of inactivity was associated with middle age, higher education, having previous experience of sports participation, following a low glycemic index/Mediterranean diet and having a light physical workload. A high prevalence of inactivity was associated with greater age, high body mass index, smoking, never drinking alcohol, having children, having a weak social network or lower levels of emotional support, and a low vegetable intake. Several factors were associated with leisure-time physical inactivity. Directing interventions to target groups defined by specific factors associated with physical inactivity could be an efficient way to increase activity and improve health in the general population.

FOXP2 targets show evidence of positive selection in European populations.

PubMed

Ayub, Qasim; Yngvadottir, Bryndis; Chen, Yuan; Xue, Yali; Hu, Min; Vernes, Sonja C; Fisher, Simon E; Tyler-Smith, Chris

2013-05-02

Forkhead box P2 (FOXP2) is a highly conserved transcription factor that has been implicated in human speech and language disorders and plays important roles in the plasticity of the developing brain. The pattern of nucleotide polymorphisms in FOXP2 in modern populations suggests that it has been the target of positive (Darwinian) selection during recent human evolution. In our study, we searched for evidence of selection that might have followed FOXP2 adaptations in modern humans. We examined whether or not putative FOXP2 targets identified by chromatin-immunoprecipitation genomic screening show evidence of positive selection. We developed an algorithm that, for any given gene list, systematically generates matched lists of control genes from the Ensembl database, collates summary statistics for three frequency-spectrum-based neutrality tests from the low-coverage resequencing data of the 1000 Genomes Project, and determines whether these statistics are significantly different between the given gene targets and the set of controls. Overall, there was strong evidence of selection of FOXP2 targets in Europeans, but not in the Han Chinese, Japanese, or Yoruba populations. Significant outliers included several genes linked to cellular movement, reproduction, development, and immune cell trafficking, and 13 of these constituted a significant network associated with cardiac arteriopathy. Strong signals of selection were observed for CNTNAP2 and RBFOX1, key neurally expressed genes that have been consistently identified as direct FOXP2 targets in multiple studies and that have themselves been associated with neurodevelopmental disorders involving language dysfunction. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Mitochondrial targeting of recombinant RNAs modulates the level of a heteroplasmic mutation in human mitochondrial DNA associated with Kearns Sayre Syndrome

PubMed Central

Comte, Caroline; Tonin, Yann; Heckel-Mager, Anne-Marie; Boucheham, Abdeldjalil; Smirnov, Alexandre; Auré, Karine; Lombès, Anne; Martin, Robert P.; Entelis, Nina; Tarassov, Ivan

2013-01-01

Mitochondrial mutations, an important cause of incurable human neuromuscular diseases, are mostly heteroplasmic: mutated mitochondrial DNA is present in cells simultaneously with wild-type genomes, the pathogenic threshold being generally >70% of mutant mtDNA. We studied whether heteroplasmy level could be decreased by specifically designed oligoribonucleotides, targeted into mitochondria by the pathway delivering RNA molecules in vivo. Using mitochondrially imported RNAs as vectors, we demonstrated that oligoribonucleotides complementary to mutant mtDNA region can specifically reduce the proportion of mtDNA bearing a large deletion associated with the Kearns Sayre Syndrome in cultured transmitochondrial cybrid cells. These findings may be relevant to developing of a new tool for therapy of mtDNA associated diseases. PMID:23087375

Targeting epigenetic regulations in cancer

PubMed Central

Ning, Bo; Li, Wenyuan; Zhao, Wei; Wang, Rongfu

2016-01-01

Epigenetic regulation of gene expression is a dynamic and reversible process with DNA methylation, histone modifications, and chromatin remodeling. Recently, groundbreaking studies have demonstrated the importance of DNA and chromatin regulatory proteins from different aspects, including stem cell, development, and tumor genesis. Abnormal epigenetic regulation is frequently associated with diseases and drugs targeting DNA methylation and histone acetylation have been approved for cancer therapy. Although the network of epigenetic regulation is more complex than people expect, new potential druggable chromatin-associated proteins are being discovered and tested for clinical application. Here we review the key proteins that mediate epigenetic regulations through DNA methylation, the acetylation and methylation of histones, and the reader proteins that bind to modified histones. We also discuss cancer associations and recent progress of pharmacological development of these proteins. PMID:26508480

EGFR, HER2 and VEGF pathways: validated targets for cancer treatment.

PubMed

Press, Michael F; Lenz, Heinz-Josef

2007-01-01

Targeted therapies are rationally designed to interfere with specific molecular events that are important in tumour growth, progression or survival. Several targeted therapies with anti-tumour activity in human cancer cell lines and xenograft models have now been shown to produce objective responses, delay disease progression and, in some cases, improve survival of patients with advanced malignancies. These targeted therapies include cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody; gefitinib and erlotinib, EGFR-specific tyrosine kinase inhibitors; trastuzumab, an anti-human EGFR type 2 (HER2)-related monoclonal antibody; lapatinib, a dual inhibitor of both EGFR- and HER2-associated tyrosine kinases; and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody. On the basis of preclinical and clinical evidence, EGFR, HER2 and VEGF represent validated targets for cancer therapy and remain the subject of intensive investigation. Both EGFR and HER2 are targets found on cancer cells, whereas VEGF is a target that acts in the tumour microenvironment. Clinical studies are focusing on how to best incorporate targeted therapy into current treatment regimens and other studies are exploring whether different strategies for inhibiting these targets will offer greater benefit. It is clear that optimal use of targeted therapy will depend on understanding how these drugs work mechanistically, and recognising that their activities may differ across patient populations, tumour types and disease stages, as well as when and how they are used in cancer treatment. The results achieved with targeted therapies to date are promising, although they illustrate the need for additional preclinical and clinical study.

The role of empathy in experiencing vicarious anxiety.

PubMed

Shu, Jocelyn; Hassell, Samuel; Weber, Jochen; Ochsner, Kevin N; Mobbs, Dean

2017-08-01

With depictions of others facing threats common in the media, the experience of vicarious anxiety may be prevalent in the general population. However, the phenomenon of vicarious anxiety-the experience of anxiety in response to observing others expressing anxiety-and the interpersonal mechanisms underlying it have not been fully investigated in prior research. In 4 studies, we investigate the role of empathy in experiencing vicarious anxiety, using film clips depicting target victims facing threats. In Studies 1 and 2, trait emotional empathy was associated with greater self-reported anxiety when observing target victims, and with perceiving greater anxiety to be experienced by the targets. Study 3 extended these findings by demonstrating that trait empathic concern-the tendency to feel concern and compassion for others-was associated with experiencing vicarious anxiety, whereas trait personal distress-the tendency to experience distress in stressful situations-was not. Study 4 manipulated state empathy to establish a causal relationship between empathy and experience of vicarious anxiety. Participants who took an empathic perspective when observing target victims, as compared to those who took an objective perspective using reappraisal-based strategies, reported experiencing greater anxiety, risk-aversion, and sleep disruption the following night. These results highlight the impact of one's social environment on experiencing anxiety, particularly for those who are highly empathic. In addition, these findings have implications for extending basic models of anxiety to incorporate interpersonal processes, understanding the role of empathy in social learning, and potential applications for therapeutic contexts. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Interarm blood pressure difference and target organ damage in the general population.

PubMed

Johansson, Jouni K; Puukka, Pauli J; Jula, Antti M

2014-02-01

The objective of the study was to investigate interarm differences of blood pressure (BP) and its determinants, and to clarify whether both arms are equally good in assessing BP and target organ damage in the general population. We studied a representative sample of Finnish adult population with 484 study participants, ages 25-74 years. BP was measured twice by an oscillometric monitor simultaneously on both arms. Study participants underwent a clinical examination including measurements of serum lipids, glucose and indicators of target organ damage. BP was 2.3/0.2 mmHg higher on right than on left arm (P < 0.001/P = 0.15 for SBP/DBP differences). SBP and DBP measured on right and left arms correlated equally with left ventricular mass index (LVMI), interventricular septal thickness (IVST), posterior wall thickness (PWT), pulse wave velocity (PWV) and albuminuria. Higher SBP level was an independent determinant of both greater systolic and diastolic interarm BP difference. Exaggerated absolute diastolic interarm BP difference (>5 mmHg) was associated with higher BMI, arm circumference, LVMI, IVST and PWT, whereas exaggerated absolute systolic interarm BP difference (>10 mmHg) was not associated with any clinical variables. There was only a small difference in BP between arms in a healthy general population. Both arms are equally good determinants of target organ damage. BP should be measured at least once on both arms and prefer the arm with higher BP readings in the future BP measurements.

Molecular characterization of oral squamous cell carcinoma using targeted next-generation sequencing.

PubMed

Er, Tze-Kiong; Wang, Yen-Yun; Chen, Chih-Chieh; Herreros-Villanueva, Marta; Liu, Ta-Chih; Yuan, Shyng-Shiou F

2015-10-01

Many genetic factors play an important role in the development of oral squamous cell carcinoma. The aim of this study was to assess the mutational profile in oral squamous cell carcinoma using formalin-fixed, paraffin-embedded tumors from a Taiwanese population by performing targeted sequencing of 26 cancer-associated genes that are frequently mutated in solid tumors. Next-generation sequencing was performed in 50 formalin-fixed, paraffin-embedded tumor specimens obtained from patients with oral squamous cell carcinoma. Genetic alterations in the 26 cancer-associated genes were detected using a deep sequencing (>1000X) approach. TP53, PIK3CA, MET, APC, CDH1, and FBXW7 were most frequently mutated genes. Most remarkably, TP53 mutations and PIK3CA mutations, which accounted for 68% and 18% of tumors, respectively, were more prevalent in a Taiwanese population. Other genes including MET (4%), APC (4%), CDH1 (2%), and FBXW7 (2%) were identified in our population. In summary, our study shows the feasibility of performing targeted sequencing using formalin-fixed, paraffin-embedded samples. Additionally, this study also reports the mutational landscape of oral squamous cell carcinoma in the Taiwanese population. We believe that this study will shed new light on fundamental aspects in understanding the molecular pathogenesis of oral squamous cell carcinoma and may aid in the development of new targeted therapies. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Risk assessment of Bt crops on the non-target plant-associated insects and soil organisms.

PubMed

Yaqoob, Amina; Shahid, Ahmad Ali; Samiullah, Tahir Rehman; Rao, Abdul Qayyum; Khan, Muhammad Azmat Ullah; Tahir, Sana; Mirza, Safdar Ali; Husnain, Tayyab

2016-06-01

Transgenic plants containing Bacillus thuringiensis (Bt) genes are being cultivated worldwide to express toxic insecticidal proteins. However, the commercial utilisation of Bt crops greatly highlights biosafety issues worldwide. Therefore, assessing the risks caused by genetically modified crops prior to their commercial cultivation is a critical issue to be addressed. In agricultural biotechnology, the goal of safety assessment is not just to identify the safety of a genetically modified (GM) plant, rather to demonstrate its impact on the ecosystem. Various experimental studies have been made worldwide during the last 20 years to investigate the risks and fears associated with non-target organisms (NTOs). The NTOs include beneficial insects, natural pest controllers, rhizobacteria, growth promoting microbes, pollinators, soil dwellers, aquatic and terrestrial vertebrates, mammals and humans. To highlight all the possible risks associated with different GM events, information has been gathered from a total of 76 articles, regarding non-target plant and soil inhabiting organisms, and summarised in the form of the current review article. No significant harmful impact has been reported in any case study related to approved GM events, although critical risk assessments are still needed before commercialisation of these crops. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy

PubMed Central

Yu, Mi Kyung; Park, Jinho; Jon, Sangyong

2012-01-01

Nanomaterials offer new opportunities for cancer diagnosis and treatment. Multifunctional nanoparticles harboring various functions including targeting, imaging, therapy, and etc have been intensively studied aiming to overcome limitations associated with conventional cancer diagnosis and therapy. Of various nanoparticles, magnetic iron oxide nanoparticles with superparamagnetic property have shown potential as multifunctional nanoparticles for clinical translation because they have been used asmagnetic resonance imaging (MRI) constrast agents in clinic and their features could be easily tailored by including targeting moieties, fluorescence dyes, or therapeutic agents. This review summarizes targeting strategies for construction of multifunctional nanoparticles including magnetic nanoparticles-based theranostic systems, and the various surface engineering strategies of nanoparticles for in vivo applications. PMID:22272217

Short communication: Validation of 4 candidate causative trait variants in 2 cattle breeds using targeted sequence imputation.

PubMed

Pausch, Hubert; Wurmser, Christine; Reinhardt, Friedrich; Emmerling, Reiner; Fries, Ruedi

2015-06-01

Most association studies for pinpointing trait-associated variants are performed within breed. The availability of sequence data from key ancestors of several cattle breeds now enables immediate assessment of the frequency of trait-associated variants in populations different from the mapping population and their imputation into large validation populations. The objective of this study was to validate the effects of 4 putatively causative variants on milk production traits, male fertility, and stature in German Fleckvieh and Holstein-Friesian animals using targeted sequence imputation. We used whole-genome sequence data of 456 animals to impute 4 missense mutations in DGAT1, GHR, PRLR, and PROP1 into 10,363 Fleckvieh and 8,812 Holstein animals. The accuracy of the imputed genotypes exceeded 95% for all variants. Association testing with imputed variants revealed consistent antagonistic effects of the DGAT1 p.A232K and GHR p.F279Y variants on milk yield and protein and fat contents, respectively, in both breeds. The allele frequency of both polymorphisms has changed considerably in the past 20 yr, indicating that they were targets of recent selection for milk production traits. The PRLR p.S18N variant was associated with yield traits in Fleckvieh but not in Holstein, suggesting that it may be in linkage disequilibrium with a mutation affecting yield traits rather than being causal. The reported effects of the PROP1 p.H173R variant on milk production, male fertility, and stature could not be confirmed. Our results demonstrate that population-wide imputation of candidate causal variants from sequence data is feasible, enabling their rapid validation in large independent populations. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Carotid and aortic stiffness in essential hypertension and their relation with target organ damage: the CATOD study

PubMed Central

Bruno, Rosa Maria; Cartoni, Giulia; Stea, Francesco; Armenia, Sabina; Bianchini, Elisabetta; Buralli, Simona; Giannarelli, Chiara; Taddei, Stefano; Ghiadoni, Lorenzo

2017-01-01

Objective The objective of the study is to investigate in the hypertensive population the possible differential association between increased aortic and/or carotid stiffness and organ damage in multiple districts, such as the kidney, the vessels, and the heart. Methods In 314 essential hypertensive patients, carotid–femoral pulse wave velocity (cfPWV, by applanation tonometry) and carotid stiffness (from ultrasound images analysis), together with left ventricular hypertrophy, carotid intima–media thickness, urinary albumin–creatinin ratio, and glomerular filtration rate were measured. Increased cfPWV and carotid stiffness were defined according to either international reference values or the 90th percentile of a local control group (110 age and sex-matched healthy individuals). Results When considering the 90th percentile of a local control group, increased cfPWV was associated with reduced glomerular filtration rate, either when carotid stiffness was increased [odds ratio (OR) 13.27 (confidence limits (CL) 95% 3.86–45.58)] or not [OR 7.39 (CL95% 2.25–24.28)], whereas increased carotid stiffness was associated with left ventricular hypertrophy, either when cfPWV was increased [OR 2.86 (CL95% 1.15–7.09)] or not [OR 2.81 (CL95% 1.13–6.97)]. No association between increased cfPWV or carotid stiffness and target organ damage was found when cutoffs obtained by international reference values were used. The concomitance of both increased cfPWV and carotid stiffness did not have an additive effect on organ damage. Conclusion Aortic and carotid stiffness are differentially associated with target organ damage in hypertensive patients. Regional arterial stiffness as assessed by cfPWV is associated with renal organ damage and local carotid stiffness with cardiac organ damage. PMID:27841779

Bipolar Disorder Associated microRNA, miR-1908-5p, Regulates the Expression of Genes Functioning in Neuronal Glutamatergic Synapses

PubMed Central

Kim, Yoonhee; Zhang, Yinhua; Pang, Kaifang; Kang, Hyojin; Park, Heejoo; Lee, Yeunkum; Lee, Bokyoung; Lee, Heon-Jeong; Kim, Won-Ki; Geum, Dongho

2016-01-01

Bipolar disorder (BD), characterized by recurrent mood swings between depression and mania, is a highly heritable and devastating mental illness with poorly defined pathophysiology. Recent genome-wide molecular genetic studies have identified several protein-coding genes and microRNAs (miRNAs) significantly associated with BD. Notably, some of the proteins expressed from BD-associated genes function in neuronal synapses, suggesting that abnormalities in synaptic function could be one of the key pathogenic mechanisms of BD. In contrast, however, the role of BD-associated miRNAs in disease pathogenesis remains largely unknown, mainly because of a lack of understanding about their target mRNAs and pathways in neurons. To address this problem, in this study, we focused on a recently identified BD-associated but uncharacterized miRNA, miR-1908-5p. We identified and validated its novel target genes including DLGAP4, GRIN1, STX1A, CLSTN1 and GRM4, which all function in neuronal glutamatergic synapses. Moreover, bioinformatic analyses of human brain expression profiles revealed that the expression levels of miR-1908-5p and its synaptic target genes show an inverse-correlation in many brain regions. In our preliminary experiments, the expression of miR-1908-5p was increased after chronic treatment with valproate but not lithium in control human neural progenitor cells. In contrast, it was decreased by valproate in neural progenitor cells derived from dermal fibroblasts of a BD subject. Together, our results provide new insights into the potential role of miR-1908-5p in the pathogenesis of BD and also propose a hypothesis that neuronal synapses could be a key converging pathway of some BD-associated protein-coding genes and miRNAs. PMID:28035180

Vancomycin AUC/MIC ratio and 30-day mortality in patients with Staphylococcus aureus bacteremia.

PubMed

Holmes, Natasha E; Turnidge, John D; Munckhof, Wendy J; Robinson, J Owen; Korman, Tony M; O'Sullivan, Matthew V N; Anderson, Tara L; Roberts, Sally A; Warren, Sanchia J C; Gao, Wei; Howden, Benjamin P; Johnson, Paul D R

2013-04-01

A ratio of the vancomycin area under the concentration-time curve to the MIC (AUC/MIC) of ≥ 400 has been associated with clinical success when treating Staphylococcus aureus pneumonia, and this target was recommended by recently published vancomycin therapeutic monitoring consensus guidelines for treating all serious S. aureus infections. Here, vancomycin serum trough levels and vancomycin AUC/MIC were evaluated in a "real-world" context by following a cohort of 182 patients with S. aureus bacteremia (SAB) and analyzing these parameters within the critical first 96 h of vancomycin therapy. The median vancomycin trough level at this time point was 19.5 mg/liter. There was a significant difference in vancomycin AUC/MIC when using broth microdilution (BMD) compared with Etest MIC (medians of 436.1 and 271.5, respectively; P < 0.001). Obtaining the recommended vancomycin target AUC/MIC of ≥ 400 using BMD was not associated with lower 30-day all-cause or attributable mortality from SAB (P = 0.132 and P = 0.273, respectively). However, an alternative vancomycin AUC/MIC of >373, derived using classification and regression tree analysis, was associated with reduced mortality (P = 0.043) and remained significant in a multivariable model. This study demonstrated that we obtained vancomycin trough levels in the target therapeutic range early during the course of therapy and that obtaining a higher vancomycin AUC/MIC (in this case, >373) within 96 h was associated with reduced mortality. The MIC test method has a significant impact on vancomycin AUC/MIC estimation. Clinicians should be aware that the current target AUC/MIC of ≥ 400 was derived using the reference BMD method, so adjustments to this target need to be made when calculating AUC/MIC ratio using other MIC testing methods.

Vancomycin AUC/MIC Ratio and 30-Day Mortality in Patients with Staphylococcus aureus Bacteremia

PubMed Central

Turnidge, John D.; Munckhof, Wendy J.; Robinson, J. Owen; Korman, Tony M.; O'Sullivan, Matthew V. N.; Anderson, Tara L.; Roberts, Sally A.; Warren, Sanchia J. C.; Gao, Wei; Howden, Benjamin P.; Johnson, Paul D. R.

2013-01-01

A ratio of the vancomycin area under the concentration-time curve to the MIC (AUC/MIC) of ≥400 has been associated with clinical success when treating Staphylococcus aureus pneumonia, and this target was recommended by recently published vancomycin therapeutic monitoring consensus guidelines for treating all serious S. aureus infections. Here, vancomycin serum trough levels and vancomycin AUC/MIC were evaluated in a “real-world” context by following a cohort of 182 patients with S. aureus bacteremia (SAB) and analyzing these parameters within the critical first 96 h of vancomycin therapy. The median vancomycin trough level at this time point was 19.5 mg/liter. There was a significant difference in vancomycin AUC/MIC when using broth microdilution (BMD) compared with Etest MIC (medians of 436.1 and 271.5, respectively; P < 0.001). Obtaining the recommended vancomycin target AUC/MIC of ≥400 using BMD was not associated with lower 30-day all-cause or attributable mortality from SAB (P = 0.132 and P = 0.273, respectively). However, an alternative vancomycin AUC/MIC of >373, derived using classification and regression tree analysis, was associated with reduced mortality (P = 0.043) and remained significant in a multivariable model. This study demonstrated that we obtained vancomycin trough levels in the target therapeutic range early during the course of therapy and that obtaining a higher vancomycin AUC/MIC (in this case, >373) within 96 h was associated with reduced mortality. The MIC test method has a significant impact on vancomycin AUC/MIC estimation. Clinicians should be aware that the current target AUC/MIC of ≥400 was derived using the reference BMD method, so adjustments to this target need to be made when calculating AUC/MIC ratio using other MIC testing methods. PMID:23335735

Advances in Bone-targeted Drug Delivery Systems for Neoadjuvant Chemotherapy for Osteosarcoma.

PubMed

Li, Cheng-Jun; Liu, Xiao-Zhou; Zhang, Lei; Chen, Long-Bang; Shi, Xin; Wu, Su-Jia; Zhao, Jian-Ning

2016-05-01

Targeted therapy for osteosarcoma includes organ, cell and molecular biological targeting; of these, organ targeting is the most mature. Bone-targeted drug delivery systems are used to concentrate chemotherapeutic drugs in bone tissues, thus potentially resolving the problem of reaching the desired foci and minimizing the toxicity and adverse effects of neoadjuvant chemotherapy. Some progress has been made in bone-targeted drug delivery systems for treatment of osteosarcoma; however, most are still at an experimental stage and there is a long transitional period to clinical application. Therefore, determining how to combine new, polymolecular and multi-pathway targets is an important research aspect of designing new bone-targeted drug delivery systems in future studies. The purpose of this article was to review the status of research on targeted therapy for osteosarcoma and to summarize the progress made thus far in developing bone-targeted drug delivery systems for neoadjuvant chemotherapy for osteosarcoma with the aim of providing new ideas for highly effective therapeutic protocols with low toxicity for patients with osteosarcoma. © 2016 Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.

Stereoacuity of preschool children with and without vision disorders.

PubMed

Ciner, Elise B; Ying, Gui-Shuang; Kulp, Marjean Taylor; Maguire, Maureen G; Quinn, Graham E; Orel-Bixler, Deborah; Cyert, Lynn A; Moore, Bruce; Huang, Jiayan

2014-03-01

To evaluate associations between stereoacuity and presence, type, and severity of vision disorders in Head Start preschool children and determine testability and levels of stereoacuity by age in children without vision disorders. Stereoacuity of children aged 3 to 5 years (n = 2898) participating in the Vision in Preschoolers (VIP) Study was evaluated using the Stereo Smile II test during a comprehensive vision examination. This test uses a two-alternative forced-choice paradigm with four stereoacuity levels (480 to 60 seconds of arc). Children were classified by the presence (n = 871) or absence (n = 2027) of VIP Study-targeted vision disorders (amblyopia, strabismus, significant refractive error, or unexplained reduced visual acuity), including type and severity. Median stereoacuity between groups and among severity levels of vision disorders was compared using Wilcoxon rank sum and Kruskal-Wallis tests. Testability and stereoacuity levels were determined for children without VIP Study-targeted disorders overall and by age. Children with VIP Study-targeted vision disorders had significantly worse median stereoacuity than that of children without vision disorders (120 vs. 60 seconds of arc, p < 0.001). Children with the most severe vision disorders had worse stereoacuity than that of children with milder disorders (median 480 vs. 120 seconds of arc, p < 0.001). Among children without vision disorders, testability was 99.6% overall, increasing with age to 100% for 5-year-olds (p = 0.002). Most of the children without vision disorders (88%) had stereoacuity at the two best disparities (60 or 120 seconds of arc); the percentage increasing with age (82% for 3-, 89% for 4-, and 92% for 5-year-olds; p < 0.001). The presence of any VIP Study-targeted vision disorder was associated with significantly worse stereoacuity in preschool children. Severe vision disorders were more likely associated with poorer stereopsis than milder or no vision disorders. Testability was excellent at all ages. These results support the validity of the Stereo Smile II for assessing random-dot stereoacuity in preschool children.

Temperature variability during targeted temperature management is not associated with neurological outcomes following cardiac arrest.

PubMed

Nayeri, Arash; Bhatia, Nirmanmoh; Holmes, Benjamin; Borges, Nyal; Armstrong, William; Xu, Meng; Farber-Eger, Eric; Wells, Quinn S; McPherson, John A

2017-06-01

Recent studies on comatose survivors of cardiac arrest undergoing targeted temperature management (TTM) have shown similar outcomes at multiple target temperatures. However, details regarding core temperature variability during TTM and its prognostic implications remain largely unknown. We sought to assess the association between core temperature variability and neurological outcomes in patients undergoing TTM following cardiac arrest. We analyzed a prospectively collected cohort of 242 patients treated with TTM following cardiac arrest at a tertiary care hospital between 2007 and 2014. Core temperature variability was defined as the statistical variance (i.e. standard deviation squared) amongst all core temperature recordings during the maintenance phase of TTM. Poor neurological outcome at hospital discharge, defined as a Cerebral Performance Category (CPC) score>2, was the primary outcome. Death prior to hospital discharge was assessed as the secondary outcome. Multivariable logistic regression was used to examine the association between temperature variability and neurological outcome or death at hospital discharge. A poor neurological outcome was observed in 147 (61%) patients and 136 (56%) patients died prior to hospital discharge. In multivariable logistic regression, increased core temperature variability was not associated with increased odds of poor neurological outcomes (OR 0.38, 95% CI 0.11-1.38, p=0.142) or death (OR 0.43, 95% CI 0.12-1.53, p=0.193) at hospital discharge. In this study, individual core temperature variability during TTM was not associated with poor neurological outcomes or death at hospital discharge. Copyright © 2017 Elsevier Inc. All rights reserved.

Characterizing protein domain associations by Small-molecule ligand binding

PubMed Central

Li, Qingliang; Cheng, Tiejun; Wang, Yanli; Bryant, Stephen H.

2012-01-01

Background Protein domains are evolutionarily conserved building blocks for protein structure and function, which are conventionally identified based on protein sequence or structure similarity. Small molecule binding domains are of great importance for the recognition of small molecules in biological systems and drug development. Many small molecules, including drugs, have been increasingly identified to bind to multiple targets, leading to promiscuous interactions with protein domains. Thus, a large scale characterization of the protein domains and their associations with respect to small-molecule binding is of particular interest to system biology research, drug target identification, as well as drug repurposing. Methods We compiled a collection of 13,822 physical interactions of small molecules and protein domains derived from the Protein Data Bank (PDB) structures. Based on the chemical similarity of these small molecules, we characterized pairwise associations of the protein domains and further investigated their global associations from a network point of view. Results We found that protein domains, despite lack of similarity in sequence and structure, were comprehensively associated through binding the same or similar small-molecule ligands. Moreover, we identified modules in the domain network that consisted of closely related protein domains by sharing similar biochemical mechanisms, being involved in relevant biological pathways, or being regulated by the same cognate cofactors. Conclusions A novel protein domain relationship was identified in the context of small-molecule binding, which is complementary to those identified by traditional sequence-based or structure-based approaches. The protein domain network constructed in the present study provides a novel perspective for chemogenomic study and network pharmacology, as well as target identification for drug repurposing. PMID:23745168

The confidence-accuracy relationship in eyewitness identification: effects of lineup instructions, foil similarity, and target-absent base rates.

PubMed

Brewer, Neil; Wells, Gary L

2006-03-01

Discriminating accurate from mistaken eyewitness identifications is a major issue facing criminal justice systems. This study examined whether eyewitness confidence assists such decisions under a variety of conditions using a confidence-accuracy (CA) calibration approach. Participants (N = 1,200) viewed a simulated crime and attempted 2 separate identifications from 8-person target-present or target-absent lineups. Confidence and accuracy were calibrated for choosers (but not nonchoosers) for both targets under all conditions. Lower overconfidence was associated with higher diagnosticity, lower target-absent base rates, and shorter identification latencies. Although researchers agree that courtroom expressions of confidence are uninformative, our findings indicate that confidence assessments obtained immediately after a positive identification can provide a useful guide for investigators about the likely accuracy of an identification.

Development and Validation of Targeted Next-Generation Sequencing Panels for Detection of Germline Variants in Inherited Diseases.

PubMed

Santani, Avni; Murrell, Jill; Funke, Birgit; Yu, Zhenming; Hegde, Madhuri; Mao, Rong; Ferreira-Gonzalez, Andrea; Voelkerding, Karl V; Weck, Karen E

2017-06-01

- The number of targeted next-generation sequencing (NGS) panels for genetic diseases offered by clinical laboratories is rapidly increasing. Before an NGS-based test is implemented in a clinical laboratory, appropriate validation studies are needed to determine the performance characteristics of the test. - To provide examples of assay design and validation of targeted NGS gene panels for the detection of germline variants associated with inherited disorders. - The approaches used by 2 clinical laboratories for the development and validation of targeted NGS gene panels are described. Important design and validation considerations are examined. - Clinical laboratories must validate performance specifications of each test prior to implementation. Test design specifications and validation data are provided, outlining important steps in validation of targeted NGS panels by clinical diagnostic laboratories.

Deuteron irradiation of W and WO 3 for production of high specific activity 186Re: Challenges associated with thick target preparation

DOE PAGES

Balkin, Ethan R.; Gagnon, Katherine; Strong, Kevin T.; ...

2016-06-28

This investigation evaluated target fabrication and beam parameters for scale-up production of high specific activity 186Re using deuteron irradiation of enriched 186W via the 186W(d,2n) 186Re reaction. Thick W and WO 3 targets were prepared, characterized and evaluated in deuteron irradiations. Full-thickness targets, as determined using SRIM, were prepared by uniaxi-ally pressing powdered natural abundance W and WO 3, or 96.86% enriched 186W, into Al target supports. Alternatively, thick targets were prepared by pressing 186W between two layers of graphite powder or by placing pre-sintered (1105°C, 12 hours) natural abundance WO 3 pellets into an Al target support. Assessments ofmore » structural integrity were made on each target pre-pared. Prior to irradiation, material composition analyses were conducted using SEM, XRD, and Raman spectroscopy. With-in a minimum of 24 hours post irradiation, gamma-ray spectroscopy was performed on all targets to assess production yields and radionuclidic byproducts. Problems were encountered with the structural integrity of some pressed W and WO 3 pellets before and during irradiation, and target material characterization results could be correlated with the structural integrity of the pressed target pellets. Under the conditions studied, the findings suggest that all WO 3 targets prepared and studied were unacceptable. By contrast, 186W metal was found to be a viable target material for 186Re production. Lastly, thick targets prepared with powdered 186W pressed between layers of graphite provided a particularly robust target configuration.« less

Deuteron irradiation of W and WO3 for production of high specific activity (186)Re: Challenges associated with thick target preparation.

PubMed

Balkin, Ethan R; Gagnon, Katherine; Strong, Kevin T; Smith, Bennett E; Dorman, Eric F; Emery, Robert C; Pauzauskie, Peter J; Fassbender, Michael E; Cutler, Cathy S; Ketring, Alan R; Jurisson, Silvia S; Wilbur, D Scott

2016-09-01

This investigation evaluated target fabrication and beam parameters for scale-up production of high specific activity (186)Re using deuteron irradiation of enriched (186)W via the (186)W(d,2n)(186)Re reaction. Thick W and WO3 targets were prepared, characterized and evaluated in deuteron irradiations. Full-thickness targets, as determined using SRIM, were prepared by uniaxially pressing powdered natural abundance W and WO3, or 96.86% enriched (186)W, into Al target supports. Alternatively, thick targets were prepared by pressing (186)W between two layers of graphite powder or by placing pre-sintered (1105°C, 12h) natural abundance WO3 pellets into an Al target support. Assessments of structural integrity were made on each target prepared. Prior to irradiation, material composition analyses were conducted using SEM, XRD, and Raman spectroscopy. Within a minimum of 24h post irradiation, gamma-ray spectroscopy was performed on all targets to assess production yields and radionuclidic byproducts. Problems were encountered with the structural integrity of some pressed W and WO3 pellets before and during irradiation, and target material characterization results could be correlated with the structural integrity of the pressed target pellets. Under the conditions studied, the findings suggest that all WO3 targets prepared and studied were unacceptable. By contrast, (186)W metal was found to be a viable target material for (186)Re production. Thick targets prepared with powdered (186)W pressed between layers of graphite provided a particularly robust target configuration. Copyright © 2016 Elsevier Ltd. All rights reserved.

Systems genetics for drug target discovery

PubMed Central

Penrod, Nadia M.; Cowper-Sal_lari, Richard; Moore, Jason H.

2011-01-01

The collection and analysis of genomic data has the potential to reveal novel druggable targets by providing insight into the genetic basis of disease. However, the number of drugs, targeting new molecular entities, approved by the US Food and Drug Administration (FDA) has not increased in the years since the collection of genomic data has become commonplace. The paucity of translatable results can be partly attributed to conventional analysis methods that test one gene at a time in an effort to identify disease-associated factors as candidate drug targets. By disengaging genetic factors from their position within the genetic regulatory system, much of the information stored within the genomic data set is lost. Here we discuss how genomic data is used to identify disease-associated genes or genomic regions, how disease-associated regions are validated as functional targets, and the role network analysis can play in bridging the gap between data generation and effective drug target identification. PMID:21862141

Dim target trajectory-associated detection in bright earth limb background

NASA Astrophysics Data System (ADS)

Chen, Penghui; Xu, Xiaojian; He, Xiaoyu; Jiang, Yuesong

2015-09-01

The intensive emission of earth limb in the field of view of sensors contributes much to the observation images. Due to the low signal-to-noise ratio (SNR), it is a challenge to detect small targets in earth limb background, especially for the detection of point-like targets from a single frame. To improve the target detection, track before detection (TBD) based on the frame sequence is performed. In this paper, a new technique is proposed to determine the target associated trajectories, which jointly carries out background removing, maximum value projection (MVP) and Hough transform. The background of the bright earth limb in the observation images is removed according to the profile characteristics. For a moving target, the corresponding pixels in the MVP image are shifting approximately regularly in time sequence. And the target trajectory is determined by Hough transform according to the pixel characteristics of the target and the clutter and noise. Comparing with traditional frame-by-frame methods, determining associated trajectories from MVP reduces the computation load. Numerical simulations are presented to demonstrate the effectiveness of the approach proposed.

Prescribed targets for titration of vasopressors in septic shock: a retrospective cohort study

PubMed Central

St-Arnaud, Charles; Éthier, Jean-François; Hamielec, Cindy; Bersten, Andrew; Guyatt, Gordon; Meade, Maureen; Zhou, Qi; Leclair, Marc-André; Patel, Alpesh

2013-01-01

Background Without robust clinical evidence to guide titration of vasopressors in septic shock, it is unclear how dosing of these potent medications occurs. We sought to measure the proportion of vasopressor prescriptions for septic shock that were missing explicit targets and to describe the targets that we identified. Methods We conducted a multicentre, retrospective cohort study involving 9 intensive care units (ICUs) located at 3 academic hospitals in Canada and Australia. We reviewed charts of consecutive patients aged 18 years or older who were admitted to the ICU for a presumptive diagnosis of sepsis. Other inclusion criteria were hypotension (systolic arterial pressure ≤ 90 mm Hg or mean arterial pressure [MAP] ≤ 65 mm Hg) and continuous infusion of vasopressors for at least 1 hour within the initial 48 hours of ICU stay, the period of observation for this study. Results We included data from 369 patient charts. At least 1 target was specified in 99% of charts. The most common targets were MAP measurements (73%). The median initial MAP target was 65 (range 55–90) mm Hg. In multivariable regression models, hospital site and older age of the patient, but not comorbidities of the patient, were associated with MAP targets. In 40% of patients, the treating team modified the initial target at least once. Interpretation This study suggests that an explicit blood pressure target accompanies nearly every vasopressor prescription and that patient characteristics have little influence on its value. Identification of a titration strategy that will maximize benefit and minimize harm constitutes a research priority. PMID:25077114

Monocyte to macrophage differentiation-associated (MMD) targeted by miR-140-5p regulates tumor growth in non-small cell lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Weina, E-mail: liweina228@163.com; He, Fei, E-mail: hesili1027@163.com

2014-07-18

Highlights: • Expression of MMD is increased in lung cancer tissues. • Knockdown of MMD inhibits growth of A549 and LLC cells in vitro and in vivo. • MMD is a direct functional target of miR-140-5p. • MiR-140-5p/MMD axis regulates Erk1/2 signaling. - Abstract: Monocyte to macrophage differentiation-associated (MMD) is identified in macrophages as a gene associated with the differentiation from monocytes to macrophages. Recent microarray analysis for non-small cell lung cancer (NSCLC) suggests that MMD is an important signature associated with relapse and survival among patients with NSCLC. Therefore, we speculate that MMD likely plays a role in lungmore » cancer. In this study, we found that the protein level of MMD was increased in lung cancer compared to benign lung tissues, and knockdown of MMD inhibited the growth of A549 and Lewis lung cancer cells (LLC) in vitro and in vivo. Integrated analysis demonstrated that MMD was a direct functional target of miR-140-5p. Furthermore, we found that miR-140-5p/MMD axis could affect the cell proliferation of lung cancer cells by regulating Erk signaling. Together, our results highlight the significance of miR-140-5p/MMD axis in lung cancer, and miR-140-5p/MMD axis could serve as new molecular targets for the therapy against lung cancer.« less

Psychopathy, attention, and oddball target detection: New insights from PCL-R facet scores.

PubMed

Anderson, Nathaniel E; Steele, Vaughn R; Maurer, J Michael; Bernat, Edward M; Kiehl, Kent A

2015-09-01

Psychopathy is a disorder accompanied by cognitive deficits including abnormalities in attention. Prior studies examining cognitive features of psychopaths using ERPs have produced some inconsistent results. We examined psychopathy-related differences in ERPs during an auditory oddball task in a sample of incarcerated adult males. We extend previous work by deriving ERPs with principal component analysis (PCA) and relate these to the four facets of Hare's Psychopathy Checklist Revised (PCL-R). Features of psychopathy were associated with increased target N1 amplitude (facets 1, 4), decreased target P3 amplitude (facet 1), and reduced slow wave amplitude for frequent standard stimuli (facets 1, 3, 4). We conclude that employing PCA and examining PCL-R facets improve sensitivity and help clarify previously reported associations. Furthermore, attenuated slow wave during standards may be a novel marker for psychopaths' abnormalities in attention. © 2015 Society for Psychophysiological Research.

Diagnosing criterion-level effects on memory: what aspects of memory are enhanced by repeated retrieval?

PubMed

Vaughn, Kalif E; Rawson, Katherine A

2011-09-01

Previous research has shown that increasing the criterion level (i.e., the number of times an item must be correctly retrieved during practice) improves subsequent memory, but which specific components of memory does increased criterion level enhance? In two experiments, we examined the extent to which the criterion level affects associative memory, target memory, and cue memory. Participants studied Lithuanian-English word pairs via cued recall with restudy until items were correctly recalled one to five times. In Experiment 1, participants took one of four recall tests and one of three recognition tests after a 2-day delay. In Experiment 2, participants took only recognition tests after a 1-week delay. In both experiments, increasing the criterion level enhanced associative memory, as indicated by enhanced performance on forward and backward cued-recall tests and on tests of associative recognition. An increased criterion level also improved target memory, as indicated by enhanced free recall and recognition of targets, and improved cue memory, as indicated by enhanced free recall and recognition of cues.

Targeted exome sequencing of Korean triple-negative breast cancer reveals homozygous deletions associated with poor prognosis of adjuvant chemotherapy-treated patients

PubMed Central

Jeong, Hae Min; Kim, Ryong Nam; Kwon, Mi Jeong; Oh, Ensel; Han, Jinil; Lee, Se Kyung; Choi, Jong-Sun; Park, Sara; Nam, Seok Jin; Gong, Gyung Yup; Nam, Jin Wu; Choi, Doo Ho; Lee, Hannah; Nam, Byung-Ho; Choi, Yoon-La; Shin, Young Kee

2017-01-01

Triple-negative breast cancer is characterized by the absence of estrogen and progesterone receptors and human epidermal growth factor receptor 2, and is associated with a poorer outcome than other subtypes of breast cancer. Moreover, there are no accurate prognostic genes or effective therapeutic targets, thereby necessitating continued intensive investigation. This study analyzed the genetic mutation landscape in 70 patients with triple-negative breast cancer by targeted exome sequencing of tumor and matched normal samples. Sequencing showed that more than 50% of these patients had deleterious mutations and homozygous deletions of DNA repair genes, such as ATM, BRCA1, BRCA2, WRN, and CHEK2. These findings suggested that a large number of patients with triple-negative breast cancer have impaired DNA repair function and that therefore a poly ADP-ribose polymerase inhibitor may be an effective drug in the treatment of this disease. Notably, homozygous deletion of three genes, EPHA5, MITF, and ACSL3, was significantly associated with an increased risk of recurrence or distant metastasis in adjuvant chemotherapy-treated patients. PMID:28977883

How do associative and phonemic overlap interact to boost illusory recollection?

PubMed

Hutchison, Keith A; Meade, Michelle L; Williams, Nikolas S; Manley, Krista D; McNabb, Jaimie C

2018-05-01

This project investigated the underlying mechanisms that boost false remember responses when participants receive study words that are both semantically and phonologically similar to a critical lure. Participants completed a memory task in which they were presented with a list of words all associated with a critical lure. Included within the list of semantic associates was a target that was either semantically associated (e.g., yawn) to the critical lure (e.g., sleep) or shared the initial (e.g., slam) or final (e.g., beep) phoneme(s) with the critical lure. After hearing the list, participants recalled each list item and indicated whether they just knew it was on the list or if they instead recollected specific contextual details of that item's presentation. We found that inserting an initial phonemic overlap target boosted experiences of recollection, but only when semantically related associates were presented beforehand. The results are consistent with models of spoken word recognition and show that established semantic context plus initial phonemic overlap play important roles in boosting false recollection.

Encoding and retrieval processes involved in the access of source information in the absence of item memory.

PubMed

Ball, B Hunter; DeWitt, Michael R; Knight, Justin B; Hicks, Jason L

2014-09-01

The current study sought to examine the relative contributions of encoding and retrieval processes in accessing contextual information in the absence of item memory using an extralist cuing procedure in which the retrieval cues used to query memory for contextual information were related to the target item but never actually studied. In Experiments 1 and 2, participants studied 1 category member (e.g., onion) from a variety of different categories and at test were presented with an unstudied category label (e.g., vegetable) to probe memory for item and source information. In Experiments 3 and 4, 1 member of unidirectional (e.g., credit or card) or bidirectional (e.g., salt or pepper) associates was studied, whereas the other unstudied member served as a test probe. When recall failed, source information was accessible only when items were processed deeply during encoding (Experiments 1 and 2) and when there was strong forward associative strength between the retrieval cue and target (Experiments 3 and 4). These findings suggest that a retrieval probe diagnostic of semantically related item information reinstantiates information bound in memory during encoding that results in reactivation of associated contextual information, contingent upon sufficient learning of the item itself and the association between the item and its context information.

Hypophosphatemia and its clinical implications in critically ill children: a retrospective study.

PubMed

Kilic, Omer; Demirkol, Demet; Ucsel, Raif; Citak, Agop; Karabocuoglu, Metin

2012-10-01

The aims of this study were to determine the prevalence of hypophosphatemia and to discuss the clinical implications of hypophosphatemia in critically ill children. A retrospective review of the medical records of children admitted to the pediatric intensive care unit from December 2006 to December 2007 was conducted. In 60.2% (n = 71) of the patients, any serum phosphorous level at admission and at the third day or seventh day after admission to pediatric intensive care unit was in hypophosphatemic range. Sepsis was present in 22.9% (n = 27) of the children studied and was associated with hypophosphatemia (P = .02). Hypophosphatemia was also associated with use of furosemide (P = .04), use of steroid (P = .04), use of β(2) agonist (P = .026), and use of an H(2) blocker (P = .004). There was a significant association between hypophosphatemia and the rate to attain target caloric requirements by enteral route (P = .007). The median time to attain target caloric requirements by enteral route was 2.9 ± 1.9 (0.2-10) days in the normophosphatemic group and 4.4 ± 2.8 (0.3-12) days in the hypophosphatemic group. In the multiple regression model, solely the rate to attain the target caloric requirements by enteral route demonstrated independent association with hypophosphatemia (P = .006; β = .27; 95% confidence interval, 0.02-0.09). Significant association was found between hypophosphatemia and the duration of mechanical ventilation and between hypophosphatemia and pediatric intensive care unit length of stay (P = .02 and P = .001, respectively). Critically ill pediatric patients are prone to hypophosphatemia, especially if they cannot be fed early by enteral route. Hypophosphatemia is associated with an increased duration of mechanical ventilation and increased length of stay in the pediatric intensive care unit, suggesting that active repletion might improve these parameters. Copyright © 2012 Elsevier Inc. All rights reserved.

The role of socio-economic and clinical factors on HbA1c in children and adolescents with type 1 diabetes: an Italian multicentre survey.

PubMed

Gesuita, Rosaria; Skrami, Edlira; Bonfanti, Riccardo; Cipriano, Paola; Ferrito, Lucia; Frongia, Paola; Iafusco, Dario; Iannilli, Antonio; Lombardo, Fortunato; Mozzillo, Enza; Paleari, Renata; Rabbone, Ivana; Sabbion, Alberto; Salvatoni, Alessandro; Scaramuzza, Andrea; Schiaffini, Riccardo; Sulli, Nicoletta; Toni, Sonia; Carle, Flavia; Cherubini, Valentino

2017-05-01

To identify the role of the family's socio-economic and clinical characteristics on metabolic control in children and adolescents with type 1 diabetes. In this cross-sectional, multicentre study, 768 subjects with type 1 diabetes under 18 years of age were consecutively recruited from January 2008 to February 2009. Target condition was considered for HbA 1c values <7.5% (<58 mmol/mol). A multiple correspondence analysis (MCA) was performed to analyze the association between the socio-economic and clinical characteristics of the participants. A logistic regression analysis was performed to identify factors associated with the subjects metabolic control. In both analyses, the family's socio-economic status was represented, measured by the Hollingshead Four-Factor Index of Social Status (SES) or by parental years of education. A total of 28.1% of subjects reached target HbA1c values. The MCA identified a strong association between at-target condition and several factors: high levels of SES or high levels of parental education, the use of the carbohydrate counting system, the use of insulin pumps, the use of the insulin delivery system over a short period of time, a normal body mass index. The logistic regression analysis showed that SES and the mother's years of education were significantly associated with the target condition [odds ratio (OR): 1.01, 95% confidence interval (CI): 1.01-1.03, p = 0.029; OR: 1.05, 95% CI: 1.01-1.10, p = 0.027, respectively). Personal, clinical, and family characteristics were found to be associated with HbA 1c target. Their identification can be crucial in addressing strategies to optimize metabolic control and improve diabetes management. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Temperament Is Associated With Outdoor Free Play in Young Children: A TARGet Kids! Study.

PubMed

Sharp, Julia R; Maguire, Jonathon L; Carsley, Sarah; Abdullah, Kawsari; Chen, Yang; Perrin, Eliana M; Parkin, Patricia C; Birken, Catherine S

Outdoor free play is important for preschoolers' physical activity, health, and development. Certain temperamental characteristics are associated with obesity, nutrition, and sedentary behaviors in preschoolers, but the relationship between temperament and outdoor play has not been examined. This study examined whether there is an association between temperament and outdoor play in young children. Healthy children aged 1 to 5 years recruited to The Applied Research Group for Kids (TARGet Kids!), a community-based primary care research network, from July 2008 to September 2013 were included. Parent-reported child temperament was assessed using the Childhood Behavior Questionnaire. Outdoor free play and other potential confounding variables were assessed through validated questionnaires. Multivariable linear regression was used to determine the association between temperament and outdoor play, adjusted for potential confounders. There were 3393 children with data on outdoor play. The association between negative affectivity and outdoor play was moderated by sex; in boys, for every 1-point increase in negative affectivity score, mean outdoor play decreased by 4.7 minutes per day. There was no significant association in girls. Surgency was associated with outdoor play; for every 1-point increase in surgency/extraversion, outdoor play increased by 4.6 minutes per day. Young children's temperamental characteristics were associated with their participation in outdoor free play. Consideration of temperament could enhance interventions and strategies to increase outdoor play in young children. Longitudinal studies are needed to elucidate the relationship between children's early temperament and physical activity. Copyright © 2017 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

Using more different and more familiar targets improves the detection of concealed information.

PubMed

Suchotzki, Kristina; De Houwer, Jan; Kleinberg, Bennett; Verschuere, Bruno

2018-04-01

When embedded among a number of plausible irrelevant options, the presentation of critical (e.g., crime-related or autobiographical) information is associated with a marked increase in response time (RT). This RT effect crucially depends on the inclusion of a target/non-target discrimination task with targets being a dedicated set of items that require a unique response (press YES; for all other items press NO). Targets may be essential because they share a feature - familiarity - with the critical items. Whereas irrelevant items have not been encountered before, critical items are known from the event or the facts of the investigation. Target items are usually learned before the test, and thereby made familiar to the participants. Hence, familiarity-based responding needs to be inhibited on the critical items and may therefore explain the RT increase on the critical items. This leads to the hypothesis that the more participants rely on familiarity, the more pronounced the RT increase on critical items may be. We explored two ways to increase familiarity-based responding: (1) Increasing the number of different target items, and (2) using familiar targets. In two web-based studies (n = 357 and n = 499), both the number of different targets and the use of familiar targets facilitated concealed information detection. The effect of the number of different targets was small yet consistent across both studies, the effect of target familiarity was large in both studies. Our results support the role of familiarity-based responding in the Concealed Information Test and point to ways on how to improve validity of the Concealed Information Test. Copyright © 2018 Elsevier B.V. All rights reserved.

Understanding the Key to Targeting the IGF Axis in Cancer: A Biomarker Assessment

PubMed Central

Lodhia, Kunal Amratlal; Tienchaiananda, Piyawan; Haluska, Paul

2015-01-01

Type 1 insulin like growth factor receptor (IGF-1R) targeted therapies showed compelling pre-clinical evidence; however, to date, this has failed to translate into patient benefit in Phase 2/3 trials in unselected patients. This was further complicated by the toxicity, including hyperglycemia, which largely results from the overlap between IGF and insulin signaling systems and associated feedback mechanisms. This has halted the clinical development of inhibitors targeting IGF signaling, which has limited the availability of biopsy samples for correlative studies to understand biomarkers of response. Indeed, a major factor contributing to lack of clinical benefit of IGF targeting agents has been difficulty in identifying patients with tumors driven by IGF signaling due to the lack of predictive biomarkers. In this review, we will describe the IGF system, rationale for targeting IGF signaling, the potential liabilities of targeting strategies, and potential biomarkers that may improve success. PMID:26217584

Comparative study of radiation emission without and with target in a 2.2 kJ plasma focus device

NASA Astrophysics Data System (ADS)

Khan, Muhammad Zubair; Ling, Yap Seong; San, Wong Chiow

2014-03-01

The radiation emission in a 2.2 kJ Mather-type dense plasma focus device is investigated using a five channel BPX65 PIN diode spectrometer. Estimated X-ray associated with the hollow anode without and with target in Argon gas medium is compared. At optimum conditions, the radiation emission from the system is found to be strongly influenced with target in hollow anode and the filling gas pressure. The maximum X-ray yield in 4π sr was obtained in case of hollow anode in argon gas medium with target "Lead" due to interaction of electron beam. Results indicated that an appropriate design of hollow anode with target could enhance the radiation emission by more intense interaction of expected electron beam with target. The outcomes are helpful in designing a plasma focus with enhanced X-ray radiation with improved shot to shot reproducibility in plasma focus device.

Plasma and memory B cell responses targeting O-specific polysaccharide (OSP) are associated with protection against Vibrio cholerae O1 infection among household contacts of cholera patients in Bangladesh.

PubMed

Aktar, Amena; Rahman, M Arifur; Afrin, Sadia; Akter, Aklima; Uddin, Taher; Yasmin, Tahirah; Sami, Md Israk Nur; Dash, Pinki; Jahan, Sultana Rownok; Chowdhury, Fahima; Khan, Ashraful I; LaRocque, Regina C; Charles, Richelle C; Bhuiyan, Taufiqur Rahman; Mandlik, Anjali; Kelly, Meagan; Kováč, Pavol; Xu, Peng; Calderwood, Stephen B; Harris, Jason B; Qadri, Firdausi; Ryan, Edward T

2018-04-01

The mediators of protection against cholera, a severe dehydrating illness of humans caused by Vibrio cholerae, are unknown. We have previously shown that plasma IgA as well as memory B IgG cells targeting lipopolysaccharide (LPS) of Vibrio cholerae O1 correlate with protection against V. cholerae O1 infection among household contacts of cholera patients. Protection against cholera is serogroup specific, and serogroup specificity is defined by the O-specific polysaccharide (OSP) component of LPS. Therefore, we prospectively followed household contacts of cholera patients to determine whether OSP-specific immune responses present at the time of enrollment are associated with protection against V. cholerae infection. In this study, we enrolled two hundred forty two household contacts of one hundred fifty index patients who were infected with Vibrio cholerae. We determined OSP-specific memory B cells and plasma IgA, IgG and IgM antibody responses on study entry (day 2). The presence of OSP-specific plasma IgA, IgM, and IgG antibody responses on study entry were associated with a decrease in the risk of infection in household contacts (IgA, p = 0.015; IgM, p = 0.01, and IgG, p = 0.024). In addition, the presence of OSP-specific IgG memory B cell responses in peripheral blood on study entry was also associated with a decreased risk of infection (44% reduction; 95% CI: 31.1 to 99.8) in contacts. No protection was associated with cholera toxin B subunit (CtxB)-specific memory B cell responses. These results suggest that immune responses that target OSP, both in plasma and memory responses, may be important in mediating protection against infection with V. cholerae O1.

Plasma and memory B cell responses targeting O-specific polysaccharide (OSP) are associated with protection against Vibrio cholerae O1 infection among household contacts of cholera patients in Bangladesh

PubMed Central

Aktar, Amena; Rahman, M. Arifur; Afrin, Sadia; Akter, Aklima; Uddin, Taher; Yasmin, Tahirah; Sami, Md. Israk Nur; Dash, Pinki; Jahan, Sultana Rownok; Chowdhury, Fahima; Khan, Ashraful I.; LaRocque, Regina C.; Charles, Richelle C.; Bhuiyan, Taufiqur Rahman; Mandlik, Anjali; Kelly, Meagan; Kováč, Pavol; Xu, Peng; Calderwood, Stephen B.; Harris, Jason B.; Ryan, Edward T.

2018-01-01

Background The mediators of protection against cholera, a severe dehydrating illness of humans caused by Vibrio cholerae, are unknown. We have previously shown that plasma IgA as well as memory B IgG cells targeting lipopolysaccharide (LPS) of Vibrio cholerae O1 correlate with protection against V. cholerae O1 infection among household contacts of cholera patients. Protection against cholera is serogroup specific, and serogroup specificity is defined by the O-specific polysaccharide (OSP) component of LPS. Therefore, we prospectively followed household contacts of cholera patients to determine whether OSP-specific immune responses present at the time of enrollment are associated with protection against V. cholerae infection. Methodology In this study, we enrolled two hundred forty two household contacts of one hundred fifty index patients who were infected with Vibrio cholerae. We determined OSP-specific memory B cells and plasma IgA, IgG and IgM antibody responses on study entry (day 2). Principle findings The presence of OSP-specific plasma IgA, IgM, and IgG antibody responses on study entry were associated with a decrease in the risk of infection in household contacts (IgA, p = 0.015; IgM, p = 0.01, and IgG, p = 0.024). In addition, the presence of OSP-specific IgG memory B cell responses in peripheral blood on study entry was also associated with a decreased risk of infection (44% reduction; 95% CI: 31.1 to 99.8) in contacts. No protection was associated with cholera toxin B subunit (CtxB)-specific memory B cell responses. Conclusion These results suggest that immune responses that target OSP, both in plasma and memory responses, may be important in mediating protection against infection with V. cholerae O1. PMID:29684006

Mother, Infant, and Household Factors Associated with the Type of Food Infants Receive in Developing Countries

PubMed Central

Yarnoff, Benjamin; Allaire, Benjamin; Detzel, Patrick

2014-01-01

Objectives: We explore the complex factors associated with infant feeding by analyzing what mother, infant, and household factors are associated with the types of food given to infants. We seek to quantify associations in order to inform public health policy about the importance of target populations for infant feeding programs. Methods: We used data from the Demographic Health Survey in 20 developing countries for multiple years to examine mother, infant, and household factors associated with six types of food given to infants (exclusive breastfeeding, non-exclusive breastfeeding, infant formula, milk liquids, non-milk liquids, and solid foods). We performed a seemingly unrelated regressions analysis with community-year fixed effects to account for correlation between food types and control for confounding factors associated with community resources, culture, time period, and geography in the pooled analysis. Results: We found that several mother, infant, and household characteristics were associated with each of the feeding types. Most notably, mother’s education, working status, and weight are significantly associated with the type of food given to infants. We provide quantified estimates of the association of each of these variables with six types of food given to infants. Conclusion: By identifying maternal characteristics associated with infant feeding and quantifying those associations, we help public health policymakers generate priorities for targeting infant feeding programs to specific populations that are at greatest risk. Higher educated, working mothers are best to target with exclusive breastfeeding programs for young infants. Mothers with lower education are best to target with complementary feeding programs in infants older than 1 year. Finally, while maternal weight is associated with higher levels of exclusive breastfeeding the association is too weak to merit targeting of breastfeeding programs to low-weight mothers. PMID:24616887

Negative regulation of ABA signaling by WRKY33 is critical for Arabidopsis immunity towards Botrytis cinerea 2100

PubMed Central

Liu, Shouan; Kracher, Barbara; Ziegler, Jörg; Birkenbihl, Rainer P; Somssich, Imre E

2015-01-01

The Arabidopsis mutant wrky33 is highly susceptible to Botrytis cinerea. We identified >1680 Botrytis-induced WRKY33 binding sites associated with 1576 Arabidopsis genes. Transcriptional profiling defined 318 functional direct target genes at 14 hr post inoculation. Comparative analyses revealed that WRKY33 possesses dual functionality acting either as a repressor or as an activator in a promoter-context dependent manner. We confirmed known WRKY33 targets involved in hormone signaling and phytoalexin biosynthesis, but also uncovered a novel negative role of abscisic acid (ABA) in resistance towards B. cinerea 2100. The ABA biosynthesis genes NCED3 and NCED5 were identified as direct targets required for WRKY33-mediated resistance. Loss-of-WRKY33 function resulted in elevated ABA levels and genetic studies confirmed that WRKY33 acts upstream of NCED3/NCED5 to negatively regulate ABA biosynthesis. This study provides the first detailed view of the genome-wide contribution of a specific plant transcription factor in modulating the transcriptional network associated with plant immunity. DOI: http://dx.doi.org/10.7554/eLife.07295.001 PMID:26076231

Colorectal Cancer Screening: Stool DNA and Other Noninvasive Modalities.

PubMed

Bailey, James R; Aggarwal, Ashish; Imperiale, Thomas F

2016-03-01

Colorectal cancer screening dates to the discovery of precancerous adenomatous tissue. Screening modalities and guidelines directed at prevention and early detection have evolved and resulted in a significant decrease in the prevalence and mortality of colorectal cancer via direct visualization or using specific markers. Despite continued efforts and an overall reduction in deaths attributed to colorectal cancer over the last 25 years, colorectal cancer remains one of the most common causes of malignancy-associated deaths. In attempt to further reduce the prevalence of colorectal cancer and associated deaths, continued improvement in screening quality and adherence remains key. Noninvasive screening modalities are actively being explored. Identification of specific genetic alterations in the adenoma-cancer sequence allow for the study and development of noninvasive screening modalities beyond guaiac-based fecal occult blood testing which target specific alterations or a panel of alterations. The stool DNA test is the first noninvasive screening tool that targets both human hemoglobin and specific genetic alterations. In this review we discuss stool DNA and other commercially available noninvasive colorectal cancer screening modalities in addition to other targets which previously have been or are currently under study.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fan, Qi; Wang, Xuedi; Zhang, Hanguang

Highlights: Black-Right-Pointing-Pointer Cat S is highly expressed in HCC cells with high metastatic potential. Black-Right-Pointing-Pointer Knockdown of Cat S inhibits growth and invasion of HCC cells. Black-Right-Pointing-Pointer Knockdown of Cat S inhibits HCC-associated angiogenesis. Black-Right-Pointing-Pointer Cat S might be a potential target for HCC therapy. -- Abstract: Cathepsin S (Cat S) plays an important role in tumor invasion and metastasis by its ability to degrade extracellular matrix (ECM). Our previous study suggested there could be a potential association between Cat S and hepatocellular carcinoma (HCC) metastasis. The present study was designed to determine the role of Cat S in HCCmore » cell growth, invasion and angiogenesis, using RNA interference technology. Small interfering RNA (siRNA) sequences for the Cat S gene were synthesized and transfected into human HCC cell line MHCC97-H. The Cat S gene targeted siRNA-mediated knockdown of Cat S expression, leading to potent suppression of MHCC97-H cell proliferation, invasion and angiogenesis. These data suggest that Cat S might be a potential target for HCC therapy.« less

Culture-Independent Identification of Periodontitis-Associated Porphyromonas and Tannerella Populations by Targeted Molecular Analysis

PubMed Central

de Lillo, A.; Booth, V.; Kyriacou, L.; Weightman, A. J.; Wade, W. G.

2004-01-01

Periodontitis is the commonest bacterial disease of humans and is the major cause of adult tooth loss. About half of the oral microflora is unculturable; and 16S rRNA PCR, cloning, and sequencing techniques have demonstrated the high level of species richness of the oral microflora. In the present study, a PCR primer set specific for the genera Porphyromonas and Tannerella was designed and used to analyze the bacterial populations in subgingival plaque samples from inflamed shallow and deep sites in subjects with periodontitis and shallow sites in age- and sex-matched controls. A total of 308 clones were sequenced and found to belong to one of six Porphyromonas or Tannerella species or phylotypes, one of which, Porphyromonas P3, was novel. Tannerella forsythensis was found in significantly higher proportions in patients than in controls. Porphyromonas catoniae and Tannerella phylotype BU063 appeared to be associated with shallow sites. Targeted culture-independent molecular ecology studies have a valuable role to play in the identification of bacterial targets for further investigations of the pathogenesis of bacterial infections. PMID:15583276

Characterizing Blood Metabolomics Profiles Associated with Self-Reported Food Intakes in Female Twins

PubMed Central

Pallister, Tess; Jennings, Amy; Mohney, Robert P.; Yarand, Darioush; Mangino, Massimo; Cassidy, Aedin; MacGregor, Alexander; Spector, Tim D.; Menni, Cristina

2016-01-01

Using dietary biomarkers in nutritional epidemiological studies may better capture exposure and improve the level at which diet-disease associations can be established and explored. Here, we aimed to identify and evaluate reproducibility of novel biomarkers of reported habitual food intake using targeted and non-targeted metabolomic blood profiling in a large twin cohort. Reported intakes of 71 food groups, determined by FFQ, were assessed against 601 fasting blood metabolites in over 3500 adult female twins from the TwinsUK cohort. For each metabolite, linear regression analysis was undertaken in the discovery group (excluding MZ twin pairs discordant [≥1 SD apart] for food group intake) with each food group as a predictor adjusting for age, batch effects, BMI, family relatedness and multiple testing (1.17x10-6 = 0.05/[71 food groups x 601 detected metabolites]). Significant results were then replicated (non-targeted: P<0.05; targeted: same direction) in the MZ discordant twin group and results from both analyses meta-analyzed. We identified and replicated 180 significant associations with 39 food groups (P<1.17x10-6), overall consisting of 106 different metabolites (74 known and 32 unknown), including 73 novel associations. In particular we identified trans-4-hydroxyproline as a potential marker of red meat intake (0.075[0.009]; P = 1.08x10-17), ergothioneine as a marker of mushroom consumption (0.181[0.019]; P = 5.93x10-22), and three potential markers of fruit consumption (top association: apple and pears): including metabolites derived from gut bacterial transformation of phenolic compounds, 3-phenylpropionate (0.024[0.004]; P = 1.24x10-8) and indolepropionate (0.026[0.004]; P = 2.39x10-9), and threitol (0.033[0.003]; P = 1.69x10-21). With the largest nutritional metabolomics dataset to date, we have identified 73 novel candidate biomarkers of food intake for potential use in nutritional epidemiological studies. We compiled our findings into the DietMetab database (http://www.twinsuk.ac.uk/dietmetab-data/), an online tool to investigate our top associations. PMID:27355821

Characterizing Blood Metabolomics Profiles Associated with Self-Reported Food Intakes in Female Twins.

PubMed

Pallister, Tess; Jennings, Amy; Mohney, Robert P; Yarand, Darioush; Mangino, Massimo; Cassidy, Aedin; MacGregor, Alexander; Spector, Tim D; Menni, Cristina

2016-01-01

Using dietary biomarkers in nutritional epidemiological studies may better capture exposure and improve the level at which diet-disease associations can be established and explored. Here, we aimed to identify and evaluate reproducibility of novel biomarkers of reported habitual food intake using targeted and non-targeted metabolomic blood profiling in a large twin cohort. Reported intakes of 71 food groups, determined by FFQ, were assessed against 601 fasting blood metabolites in over 3500 adult female twins from the TwinsUK cohort. For each metabolite, linear regression analysis was undertaken in the discovery group (excluding MZ twin pairs discordant [≥1 SD apart] for food group intake) with each food group as a predictor adjusting for age, batch effects, BMI, family relatedness and multiple testing (1.17x10-6 = 0.05/[71 food groups x 601 detected metabolites]). Significant results were then replicated (non-targeted: P<0.05; targeted: same direction) in the MZ discordant twin group and results from both analyses meta-analyzed. We identified and replicated 180 significant associations with 39 food groups (P<1.17x10-6), overall consisting of 106 different metabolites (74 known and 32 unknown), including 73 novel associations. In particular we identified trans-4-hydroxyproline as a potential marker of red meat intake (0.075[0.009]; P = 1.08x10-17), ergothioneine as a marker of mushroom consumption (0.181[0.019]; P = 5.93x10-22), and three potential markers of fruit consumption (top association: apple and pears): including metabolites derived from gut bacterial transformation of phenolic compounds, 3-phenylpropionate (0.024[0.004]; P = 1.24x10-8) and indolepropionate (0.026[0.004]; P = 2.39x10-9), and threitol (0.033[0.003]; P = 1.69x10-21). With the largest nutritional metabolomics dataset to date, we have identified 73 novel candidate biomarkers of food intake for potential use in nutritional epidemiological studies. We compiled our findings into the DietMetab database (http://www.twinsuk.ac.uk/dietmetab-data/), an online tool to investigate our top associations.

Genomic profiles of lung cancer associated with idiopathic pulmonary fibrosis.

PubMed

Hwang, Ji An; Kim, Deokhoon; Chun, Sung-Min; Bae, SooHyun; Song, Joon Seon; Kim, Mi Young; Koo, Hyun Jung; Song, Jin Woo; Kim, Woo Sung; Lee, Jae Cheol; Kim, Hyeong Ryul; Choi, Chang-Min; Jang, Se Jin

2018-01-01

Little is known about the pathogenesis or molecular profiles of idiopathic pulmonary fibrosis-associated lung cancer (IPF-LC). This study was performed to investigate the genomic profiles of IPF-LC and to explore the possibility of defining potential therapeutic targets in IPF-LC. We assessed genomic profiles of IPF-LC by using targeted exome sequencing (OncoPanel version 2) in 35 matched tumour/normal pairs surgically resected between 2004 and 2014. Germline and somatic variant calling was performed with GATK HaplotypeCaller and MuTect with GATK SomaticIndelocator, respectively. Copy number analysis was conducted with CNVkit, with focal events determined by Genomic Identification of Significant Targets in Cancer 2.0, and pathway analysis (KEGG) with DAVID. Germline mutations in TERT (rs2736100, n = 33) and CDKN1A (rs2395655, n = 27) associated with idiopathic pulmonary fibrosis risk were detected in most samples. A total of 410 somatic mutations were identified, with an average of 11.7 per tumour, including 69 synonymous, 177 missense, 17 nonsense, 1 nonstop and 11 splice-site mutations, and 135 small coding indels. Spectra of the somatic mutations revealed predominant C > T transitions despite an extensive smoking history in most patients, suggesting a potential association between APOBEC-related mutagenesis and the development of IPF-LC. TP53 (22/35, 62.9%) and BRAF (6/35, 17.1%) were found to be significantly mutated in IPF-LC. Recurrent focal amplifications in three chromosomal loci (3q26.33, 7q31.2, and 12q14.3) and 9p21.3 deletion were identified, and genes associated with the JAK-STAT signalling pathway were significantly amplified in IPF-LC (P = 0.012). This study demonstrates that IPF-LC is genetically characterized by the presence of somatic mutations reflecting a variety of environmental exposures on the background of specific germline mutations, and is associated with potentially targetable alterations such as BRAF mutations. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Identification, Characterization, and Functional Validation of Drought-responsive MicroRNAs in Subtropical Maize Inbreds

PubMed Central

Aravind, Jayaraman; Rinku, Sharma; Pooja, Banduni; Shikha, Mittal; Kaliyugam, Shiriga; Mallikarjuna, Mallana Gowdra; Kumar, Arun; Rao, Atmakuri Ramakrishna; Nepolean, Thirunavukkarasu

2017-01-01

MicroRNA-mediated gene regulation plays a crucial role in controlling drought tolerance. In the present investigation, 13 drought-associated miRNA families consisting of 65 members and regulating 42 unique target mRNAs were identified from drought-associated microarray expression data in maize and were subjected to structural and functional characterization. The largest number of members (14) was found in the zma-miR166 and zma-miR395 families, with several targets. However, zma-miR160, zma-miR390, zma-miR393, and zma-miR2275 each showed a single target. Twenty-three major drought-responsive cis-regulatory elements were found in the upstream regions of miRNAs. Many drought-related transcription factors, such as GAMYB, HD-Zip III, and NAC, were associated with the target mRNAs. Furthermore, two contrasting subtropical maize genotypes (tolerant: HKI-1532 and sensitive: V-372) were used to understand the miRNA-assisted regulation of target mRNA under drought stress. Approximately 35 and 31% of miRNAs were up-regulated in HKI-1532 and V-372, respectively. The up-regulation of target mRNAs was as high as 14.2% in HKI-1532 but was only 2.38% in V-372. The expression patterns of miRNA-target mRNA pairs were classified into four different types: Type I- up-regulation, Type II- down-regulation, Type III- neutral regulation, and Type IV- opposite regulation. HKI-1532 displayed 46 Type I, 13 Type II, and 23 Type III patterns, whereas V-372 had mostly Type IV interactions (151). A low level of negative regulations of miRNA associated with a higher level of mRNA activity in the tolerant genotype helped to maintain crucial biological functions such as ABA signaling, the auxin response pathway, the light-responsive pathway and endosperm expression under stress conditions, thereby leading to drought tolerance. Our study identified candidate miRNAs and mRNAs operating in important pathways under drought stress conditions, and these candidates will be useful in the development of drought-tolerant maize hybrids. PMID:28626466

Contribution of NIH funding to new drug approvals 2010–2016

PubMed Central

Beierlein, Jennifer M.; Khanuja, Navleen Surjit; McNamee, Laura M.; Ledley, Fred D.

2018-01-01

This work examines the contribution of NIH funding to published research associated with 210 new molecular entities (NMEs) approved by the Food and Drug Administration from 2010–2016. We identified >2 million publications in PubMed related to the 210 NMEs (n = 131,092) or their 151 known biological targets (n = 1,966,281). Of these, >600,000 (29%) were associated with NIH-funded projects in RePORTER. This funding included >200,000 fiscal years of NIH project support (1985–2016) and project costs >$100 billion (2000–2016), representing ∼20% of the NIH budget over this period. NIH funding contributed to every one of the NMEs approved from 2010–2016 and was focused primarily on the drug targets rather than on the NMEs themselves. There were 84 first-in-class products approved in this interval, associated with >$64 billion of NIH-funded projects. The percentage of fiscal years of project funding identified through target searches, but not drug searches, was greater for NMEs discovered through targeted screening than through phenotypic methods (95% versus 82%). For targeted NMEs, funding related to targets preceded funding related to the NMEs, consistent with the expectation that basic research provides validated targets for targeted screening. This analysis, which captures basic research on biological targets as well as applied research on NMEs, suggests that the NIH contribution to research associated with new drug approvals is greater than previously appreciated and highlights the risk of reducing federal funding for basic biomedical research. PMID:29440428

A HapMap harvest of insights into the genetics of common disease

PubMed Central

Manolio, Teri A.; Brooks, Lisa D.; Collins, Francis S.

2008-01-01

The International HapMap Project was designed to create a genome-wide database of patterns of human genetic variation, with the expectation that these patterns would be useful for genetic association studies of common diseases. This expectation has been amply fulfilled with just the initial output of genome-wide association studies, identifying nearly 100 loci for nearly 40 common diseases and traits. These associations provided new insights into pathophysiology, suggesting previously unsuspected etiologic pathways for common diseases that will be of use in identifying new therapeutic targets and developing targeted interventions based on genetically defined risk. In addition, HapMap-based discoveries have shed new light on the impact of evolutionary pressures on the human genome, suggesting multiple loci important for adapting to disease-causing pathogens and new environments. In this review we examine the origin, development, and current status of the HapMap; its prospects for continued evolution; and its current and potential future impact on biomedical science. PMID:18451988

Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study.

PubMed

Dewey, Frederick E; Murray, Michael F; Overton, John D; Habegger, Lukas; Leader, Joseph B; Fetterolf, Samantha N; O'Dushlaine, Colm; Van Hout, Cristopher V; Staples, Jeffrey; Gonzaga-Jauregui, Claudia; Metpally, Raghu; Pendergrass, Sarah A; Giovanni, Monica A; Kirchner, H Lester; Balasubramanian, Suganthi; Abul-Husn, Noura S; Hartzel, Dustin N; Lavage, Daniel R; Kost, Korey A; Packer, Jonathan S; Lopez, Alexander E; Penn, John; Mukherjee, Semanti; Gosalia, Nehal; Kanagaraj, Manoj; Li, Alexander H; Mitnaul, Lyndon J; Adams, Lance J; Person, Thomas N; Praveen, Kavita; Marcketta, Anthony; Lebo, Matthew S; Austin-Tse, Christina A; Mason-Suares, Heather M; Bruse, Shannon; Mellis, Scott; Phillips, Robert; Stahl, Neil; Murphy, Andrew; Economides, Aris; Skelding, Kimberly A; Still, Christopher D; Elmore, James R; Borecki, Ingrid B; Yancopoulos, George D; Davis, F Daniel; Faucett, William A; Gottesman, Omri; Ritchie, Marylyn D; Shuldiner, Alan R; Reid, Jeffrey G; Ledbetter, David H; Baras, Aris; Carey, David J

2016-12-23

The DiscovEHR collaboration between the Regeneron Genetics Center and Geisinger Health System couples high-throughput sequencing to an integrated health care system using longitudinal electronic health records (EHRs). We sequenced the exomes of 50,726 adult participants in the DiscovEHR study to identify ~4.2 million rare single-nucleotide variants and insertion/deletion events, of which ~176,000 are predicted to result in a loss of gene function. Linking these data to EHR-derived clinical phenotypes, we find clinical associations supporting therapeutic targets, including genes encoding drug targets for lipid lowering, and identify previously unidentified rare alleles associated with lipid levels and other blood level traits. About 3.5% of individuals harbor deleterious variants in 76 clinically actionable genes. The DiscovEHR data set provides a blueprint for large-scale precision medicine initiatives and genomics-guided therapeutic discovery. Copyright © 2016, American Association for the Advancement of Science.

Meta-review of protein network regulating obesity between validated obesity candidate genes in the white adipose tissue of high-fat diet-induced obese C57BL/6J mice.

PubMed

Kim, Eunjung; Kim, Eun Jung; Seo, Seung-Won; Hur, Cheol-Goo; McGregor, Robin A; Choi, Myung-Sook

2014-01-01

Worldwide obesity and related comorbidities are increasing, but identifying new therapeutic targets remains a challenge. A plethora of microarray studies in diet-induced obesity models has provided large datasets of obesity associated genes. In this review, we describe an approach to examine the underlying molecular network regulating obesity, and we discuss interactions between obesity candidate genes. We conducted network analysis on functional protein-protein interactions associated with 25 obesity candidate genes identified in a literature-driven approach based on published microarray studies of diet-induced obesity. The obesity candidate genes were closely associated with lipid metabolism and inflammation. Peroxisome proliferator activated receptor gamma (Pparg) appeared to be a core obesity gene, and obesity candidate genes were highly interconnected, suggesting a coordinately regulated molecular network in adipose tissue. In conclusion, the current network analysis approach may help elucidate the underlying molecular network regulating obesity and identify anti-obesity targets for therapeutic intervention.

General practice variation in spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease in Denmark: a population-based observational study

PubMed Central

2013-01-01

Background Spirometry testing is essential to confirm an obstructive lung disease, but studies have reported that a large proportion of patients diagnosed with COPD or asthma have no history of spirometry testing. Also, it has been shown that many patients are prescribed medication for obstructive lung disease without a relevant diagnosis or spirometry test registered. General practice characteristics have been reported to influence diagnosis and management of several chronic diseases. However, these findings are inconsistent, and it is uncertain whether practice characteristics influence spirometry testing among patients receiving medication for obstructive lung disease. The aim of this study was therefore to examine if practice characteristics are associated with spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease. Methods A national register-based cohort study was performed. All patients over 18 years receiving first-time prescriptions for medication targeting obstructive lung disease in 2008 were identified and detailed patient-specific data on sociodemographic status and spirometry tests were extracted. Information on practice characteristics like number of doctors, number of patients per doctor, training practice status, as well as age and gender of the general practitioners was linked to each medication user. Results Partnership practices had a higher odds ratio (OR) of performing spirometry compared with single-handed practices (OR 1.24, CI 1.09-1.40). We found a significant association between increasing general practitioner age and decreasing spirometry testing. This tendency was most pronounced among partnership practices, where doctors over 65 years had the lowest odds of spirometry testing (OR 0.25, CI 0.10-0.61). Training practice status was significantly associated with spirometry testing among single-handed practices (OR 1.40, CI 1.10-1.79). Conclusion Some of the variation in spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease was associated with practice characteristics. This variation in performance may indicate a potential for quality improvement. PMID:23923987

Network-based study reveals potential infection pathways of hepatitis-C leading to various diseases.

PubMed

Mukhopadhyay, Anirban; Maulik, Ujjwal

2014-01-01

Protein-protein interaction network-based study of viral pathogenesis has been gaining popularity among computational biologists in recent days. In the present study we attempt to investigate the possible pathways of hepatitis-C virus (HCV) infection by integrating the HCV-human interaction network, human protein interactome and human genetic disease association network. We have proposed quasi-biclique and quasi-clique mining algorithms to integrate these three networks to identify infection gateway host proteins and possible pathways of HCV pathogenesis leading to various diseases. Integrated study of three networks, namely HCV-human interaction network, human protein interaction network, and human proteins-disease association network reveals potential pathways of infection by the HCV that lead to various diseases including cancers. The gateway proteins have been found to be biologically coherent and have high degrees in human interactome compared to the other virus-targeted proteins. The analyses done in this study provide possible targets for more effective anti-hepatitis-C therapeutic involvement.

Network-Based Study Reveals Potential Infection Pathways of Hepatitis-C Leading to Various Diseases

PubMed Central

Mukhopadhyay, Anirban; Maulik, Ujjwal

2014-01-01

Protein-protein interaction network-based study of viral pathogenesis has been gaining popularity among computational biologists in recent days. In the present study we attempt to investigate the possible pathways of hepatitis-C virus (HCV) infection by integrating the HCV-human interaction network, human protein interactome and human genetic disease association network. We have proposed quasi-biclique and quasi-clique mining algorithms to integrate these three networks to identify infection gateway host proteins and possible pathways of HCV pathogenesis leading to various diseases. Integrated study of three networks, namely HCV-human interaction network, human protein interaction network, and human proteins-disease association network reveals potential pathways of infection by the HCV that lead to various diseases including cancers. The gateway proteins have been found to be biologically coherent and have high degrees in human interactome compared to the other virus-targeted proteins. The analyses done in this study provide possible targets for more effective anti-hepatitis-C therapeutic involvement. PMID:24743187

Identification of genes highly downregulated in pancreatic cancer through a meta-analysis of microarray datasets: implications for discovery of novel tumor-suppressor genes and therapeutic targets.

PubMed

Goonesekere, Nalin C W; Andersen, Wyatt; Smith, Alex; Wang, Xiaosheng

2018-02-01

The lack of specific symptoms at early tumor stages, together with a high biological aggressiveness of the tumor contribute to the high mortality rate for pancreatic cancer (PC), which has a 5-year survival rate of about 7%. Recent failures of targeted therapies inhibiting kinase activity in clinical trials have highlighted the need for new approaches towards combating this deadly disease. In this study, we have identified genes that are significantly downregulated in PC, through a meta-analysis of large number of microarray datasets. We have used qRT-PCR to confirm the downregulation of selected genes in a panel of PC cell lines. This study has yielded several novel candidate tumor-suppressor genes (TSGs) including GNMT, CEL, PLA2G1B and SERPINI2. We highlight the role of GNMT, a methyl transferase associated with the methylation potential of the cell, and CEL, a lipase, as potential therapeutic targets. We have uncovered genetic links to risk factors associated with PC such as smoking and obesity. Genes important for patient survival and prognosis are also discussed, and we confirm the dysregulation of metabolic pathways previously observed in PC. While many of the genes downregulated in our dataset are associated with protein products normally produced by the pancreas for excretion, we have uncovered some genes whose downregulation appear to play a more causal role in PC. These genes will assist in providing a better understanding of the disease etiology of PC, and in the search for new therapeutic targets and biomarkers.

Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival.

PubMed

Lin, Zhiqiang; Zhou, Pingzhu; von Gise, Alexander; Gu, Fei; Ma, Qing; Chen, Jinghai; Guo, Haidong; van Gorp, Pim R R; Wang, Da-Zhi; Pu, William T

2015-01-02

Yes-associated protein (YAP), the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEA (transcriptional enhancer activator)-domain sequence-specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. To identify direct YAP targets that mediate its mitogenic and antiapoptotic effects in the heart. We identified direct YAP targets by combining differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP-bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase, as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEA-domain occupied a conserved enhancer within the first intron of Pik3cb, and this enhancer drove YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the phosphoinositol-3-kinase-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in Yap loss-of-function was significantly rescued by adeno-associated virus-mediated Pik3cb expression. Pik3cb is a crucial direct target of YAP, through which the YAP activates phosphoinositol-3-kinase-AKT pathway and regulates cardiomyocyte proliferation and survival. © 2014 American Heart Association, Inc.

Targeting von Willebrand Factor in Ischaemic Stroke: Focus on Clinical Evidence.

PubMed

Buchtele, Nina; Schwameis, Michael; Gilbert, James C; Schörgenhofer, Christian; Jilma, Bernd

2018-06-01

Despite great efforts in stroke research, disability and recurrence rates in ischaemic stroke remain unacceptably high. To address this issue, one potential target for novel therapeutics is the glycoprotein von Willebrand factor (vWF), which increases in thrombogenicity especially under high shear rates as it bridges between vascular sub-endothelial collagen and platelets. The rationale for vWF as a potential target in stroke comes from four bodies of evidence. (1) Animal models which recapitulate the pathogenesis of stroke and validate the concept of targeting vWF for stroke prevention and the use of the vWF cleavage enzyme ADAMTS13 in acute stroke treatment. (2) Extensive epidemiologic data establishing the prognostic role of vWF in the clinical setting showing that high vWF levels are associated with an increased risk of first stroke, stroke recurrence or stroke-associated mortality. As such, vWF levels may be a suitable marker for further risk stratification to potentially fine-tune current risk prediction models which are mainly based on clinical and imaging data. (3) Genetic studies showing an association between vWF levels and stroke risk on genomic levels. Finally, (4) studies of patients with primary disorders of excess or deficiency of function in the vWF axis (e.g. thrombotic thrombocytopenic purpura and von Willebrand disease, respectively) which demonstrate the crucial role of vWF in atherothrombosis. Therapeutic inhibition of VWF by novel agents appears particularly promising for secondary prevention of stroke recurrence in specific sub-groups of patients such as those suffering from large artery atherosclerosis, as designated according to the TOAST classification. Schattauer GmbH Stuttgart.

A leap into the chemical space of protein-protein interaction inhibitors.

PubMed

Villoutreix, B O; Labbé, C M; Lagorce, D; Laconde, G; Sperandio, O

2012-01-01

Protein-protein interactions (PPI) are involved in vital cellular processes and are therefore associated to a growing number of diseases. But working with them as therapeutic targets comes with some major hurdles that require substantial mutations from our way to design drugs on historical targets such as enzymes and G-Protein Coupled Receptor (GPCR). Among the numerous ways we could improve our methodologies to maximize the potential of developing new chemical entities on PPI targets, is the fundamental question of what type of compounds should we use to identify the first hits and among which chemical space should we navigate to optimize them to the drug candidate stage. In this review article, we cover different aspects on PPI but with the aim to gain some insights into the specific nature of the chemical space of PPI inhibitors. We describe the work of different groups to highlight such properties and discuss their respective approach. We finally discuss a case study in which we describe the properties of a set of 115 PPI inhibitors that we compare to a reference set of 1730 enzyme inhibitors. This case study highlights interesting properties such as the unfortunate price that still needs to be paid by PPI inhibitors in terms of molecular weight, hydrophobicity, and aromaticity in order to reach a critical level of activity. But it also shows that not all PPI targets are equivalent, and that some PPI targets can demonstrate a better druggability by illustrating the better drug likeness of their associated inhibitors.

Identification of lactoferricin B intracellular targets using an Escherichia coli proteome chip.

PubMed

Tu, Yu-Hsuan; Ho, Yu-Hsuan; Chuang, Ying-Chih; Chen, Po-Chung; Chen, Chien-Sheng

2011-01-01

Lactoferricin B (LfcinB) is a well-known antimicrobial peptide. Several studies have indicated that it can inhibit bacteria by affecting intracellular activities, but the intracellular targets of this antimicrobial peptide have not been identified. Therefore, we used E. coli proteome chips to identify the intracellular target proteins of LfcinB in a high-throughput manner. We probed LfcinB with E. coli proteome chips and further conducted normalization and Gene Ontology (GO) analyses. The results of the GO analyses showed that the identified proteins were associated with metabolic processes. Moreover, we validated the interactions between LfcinB and chip assay-identified proteins with fluorescence polarization (FP) assays. Sixteen proteins were identified, and an E. coli interaction database (EcID) analysis revealed that the majority of the proteins that interact with these 16 proteins affected the tricarboxylic acid (TCA) cycle. Knockout assays were conducted to further validate the FP assay results. These results showed that phosphoenolpyruvate carboxylase was a target of LfcinB, indicating that one of its mechanisms of action may be associated with pyruvate metabolism. Thus, we used pyruvate assays to conduct an in vivo validation of the relationship between LfcinB and pyruvate level in E. coli. These results showed that E. coli exposed to LfcinB had abnormal pyruvate amounts, indicating that LfcinB caused an accumulation of pyruvate. In conclusion, this study successfully revealed the intracellular targets of LfcinB using an E. coli proteome chip approach.

Identification of Lactoferricin B Intracellular Targets Using an Escherichia coli Proteome Chip

PubMed Central

Chen, Po-Chung; Chen, Chien-Sheng

2011-01-01

Lactoferricin B (LfcinB) is a well-known antimicrobial peptide. Several studies have indicated that it can inhibit bacteria by affecting intracellular activities, but the intracellular targets of this antimicrobial peptide have not been identified. Therefore, we used E. coli proteome chips to identify the intracellular target proteins of LfcinB in a high-throughput manner. We probed LfcinB with E. coli proteome chips and further conducted normalization and Gene Ontology (GO) analyses. The results of the GO analyses showed that the identified proteins were associated with metabolic processes. Moreover, we validated the interactions between LfcinB and chip assay-identified proteins with fluorescence polarization (FP) assays. Sixteen proteins were identified, and an E. coli interaction database (EcID) analysis revealed that the majority of the proteins that interact with these 16 proteins affected the tricarboxylic acid (TCA) cycle. Knockout assays were conducted to further validate the FP assay results. These results showed that phosphoenolpyruvate carboxylase was a target of LfcinB, indicating that one of its mechanisms of action may be associated with pyruvate metabolism. Thus, we used pyruvate assays to conduct an in vivo validation of the relationship between LfcinB and pyruvate level in E. coli. These results showed that E. coli exposed to LfcinB had abnormal pyruvate amounts, indicating that LfcinB caused an accumulation of pyruvate. In conclusion, this study successfully revealed the intracellular targets of LfcinB using an E. coli proteome chip approach. PMID:22164243

Chromosomal Targeting by the Type III-A CRISPR-Cas System Can Reshape Genomes in Staphylococcus aureus

PubMed Central

Guan, Jing; Wang, Wanying

2017-01-01

ABSTRACT CRISPR-Cas (clustered regularly interspaced short palindromic repeat [CRISPR]-CRISPR-associated protein [Cas]) systems can provide protection against invading genetic elements by using CRISPR RNAs (crRNAs) as a guide to locate and degrade the target DNA. CRISPR-Cas systems have been classified into two classes and five types according to the content of cas genes. Previous studies have indicated that CRISPR-Cas systems can avoid viral infection and block plasmid transfer. Here we show that chromosomal targeting by the Staphylococcus aureus type III-A CRISPR-Cas system can drive large-scale genome deletion and alteration within integrated staphylococcal cassette chromosome mec (SCCmec). The targeting activity of the CRISPR-Cas system is associated with the complementarity between crRNAs and protospacers, and 10- to 13-nucleotide truncations of spacers partially block CRISPR attack and more than 13-nucleotide truncation can fully abolish targeting, suggesting that a minimal length is required to license cleavage. Avoiding base pairings in the upstream region of protospacers is also necessary for CRISPR targeting. Successive trinucleotide complementarity between the 5′ tag of crRNAs and protospacers can disrupt targeting. Our findings reveal that type III-A CRISPR-Cas systems can modulate bacterial genome stability and may serve as a high-efficiency tool for deleting resistance or virulence genes in bacteria. IMPORTANCE Staphylococcus aureus is a pathogen that can cause a wide range of infections in humans. Studies have suggested that CRISPR-Cas systems can drive the loss of integrated mobile genetic elements (MGEs) by chromosomal targeting. Here we demonstrate that CRISPR-mediated cleavage contributes to the partial deletion of integrated SCCmec in methicillin-resistant S. aureus (MRSA), which provides a strategy for the treatment of MRSA infections. The spacer within artificial CRISPR arrays should contain more than 25 nucleotides for immunity, and consecutive trinucleotide pairings between a selected target and the 5′ tag of crRNA can block targeting. These findings add to our understanding of the molecular mechanisms of the type III-A CRISPR-Cas system and provide a novel strategy for the exploitation of engineered CRISPR immunity against integrated MGEs in bacteria for clinical and industrial applications. PMID:29152580

Chromosomal Targeting by the Type III-A CRISPR-Cas System Can Reshape Genomes in Staphylococcus aureus.

PubMed

Guan, Jing; Wang, Wanying; Sun, Baolin

2017-01-01

CRISPR-Cas (clustered regularly interspaced short palindromic repeat [CRISPR]-CRISPR-associated protein [Cas]) systems can provide protection against invading genetic elements by using CRISPR RNAs (crRNAs) as a guide to locate and degrade the target DNA. CRISPR-Cas systems have been classified into two classes and five types according to the content of cas genes. Previous studies have indicated that CRISPR-Cas systems can avoid viral infection and block plasmid transfer. Here we show that chromosomal targeting by the Staphylococcus aureus type III-A CRISPR-Cas system can drive large-scale genome deletion and alteration within integrated staphylococcal cassette chromosome mec (SCC mec ). The targeting activity of the CRISPR-Cas system is associated with the complementarity between crRNAs and protospacers, and 10- to 13-nucleotide truncations of spacers partially block CRISPR attack and more than 13-nucleotide truncation can fully abolish targeting, suggesting that a minimal length is required to license cleavage. Avoiding base pairings in the upstream region of protospacers is also necessary for CRISPR targeting. Successive trinucleotide complementarity between the 5' tag of crRNAs and protospacers can disrupt targeting. Our findings reveal that type III-A CRISPR-Cas systems can modulate bacterial genome stability and may serve as a high-efficiency tool for deleting resistance or virulence genes in bacteria. IMPORTANCE Staphylococcus aureus is a pathogen that can cause a wide range of infections in humans. Studies have suggested that CRISPR-Cas systems can drive the loss of integrated mobile genetic elements (MGEs) by chromosomal targeting. Here we demonstrate that CRISPR-mediated cleavage contributes to the partial deletion of integrated SCC mec in methicillin-resistant S. aureus (MRSA), which provides a strategy for the treatment of MRSA infections. The spacer within artificial CRISPR arrays should contain more than 25 nucleotides for immunity, and consecutive trinucleotide pairings between a selected target and the 5' tag of crRNA can block targeting. These findings add to our understanding of the molecular mechanisms of the type III-A CRISPR-Cas system and provide a novel strategy for the exploitation of engineered CRISPR immunity against integrated MGEs in bacteria for clinical and industrial applications.

Sequence diversity of the leukotoxin (lktA) gene in caprine and ovine strains of Mannheimia haemolytica.

PubMed

Vougidou, C; Sandalakis, V; Psaroulaki, A; Petridou, E; Ekateriniadou, L

2013-04-20

Mannheimia haemolytica is the aetiological agent of pneumonic pasteurellosis in small ruminants. The primary virulence factor of the bacterium is a leukotoxin (LktA), which induces apoptosis in susceptible cells via mitochondrial targeting. It has been previously shown that certain lktA alleles are associated either with cattle or sheep. The objective of the present study was to investigate lktA sequence variation among ovine and caprine M haemolytica strains isolated from pneumonic lungs, revealing any potential adaptation for the caprine host, for which there is no available data. Furthermore, we investigated amino acid variation in the N-terminal part of the sequences and its effect on targeting mitochondria. Data analysis showed that the prevalent caprine genotype differed at a single non-synonymous site from a previously described uncommon bovine allele, whereas the ovine sequences represented new, distinct alleles. N-terminal sequence differences did not affect the mitochondrial targeting ability of the isolates; interestingly enough in one case, mitochondrial matrix targeting was indicated rather than membrane association, suggesting an alternative LktA trafficking pattern.

Marine protected area and the spatial distribution of the gill net fishery in Copacabana, Rio de Janeiro, RJ, Brazil.

PubMed

Amorim, R B; Monteiro-Neto, C

2016-02-01

This study characterizes the gill net fishery at Colônia de Pescadores Z13 (CPZ13), in Copacabana, Rio de Janeiro, and its relationship with the marine protected area 'Monumento Natural do Arquipélago das Ilhas Cagarras - MoNa Cagarras', describing the fleet and fishing gears, identifying fishing spots, species and their associations by gillnet type. From June 2012 to May 2013, every Tuesday to Sunday, gill net landings were monitored and fishers interviewed regarding their catch. Small boats (dory whaleboats) are used to set three types of gillnets: "Corvineira" (target species - whitemouth croaker), "linguadeira" (target species - flounders) and "rede-alta" (target species - bluefish). Fifty-nine species within 37 families were captured at 14 fishing spots, showing association with bottom type and distance from shore. The use of fisher's local ecological knowledge defines gear placement at specific sites targeting fisheries resources. All fishing sites are not within the limits of MoNa Cagarras but would benefit from management plans including an MPA buffering zone.

Interaction of cellular proteins with BCL-xL targeted to cytoplasmic inclusion bodies in adenovirus infected cells.

PubMed

Subramanian, T; Vijayalingam, S; Kuppuswamy, M; Chinnadurai, G

2015-09-01

Adenovirus-mediated apoptosis was suppressed when cellular anti-apoptosis proteins (BCL-2 and BCL-xL) were substituted for the viral E1B-19K. For unbiased proteomic analysis of proteins targeted by BCL-xL in adenovirus-infected cells and to visualize the interactions with target proteins, BCL-xL was targeted to cytosolic inclusion bodies utilizing the orthoreovirus µNS protein sequences. The chimeric protein was localized in non-canonical cytosolic factory-like sites and promoted survival of virus-infected cells. The BCL-xL-associated proteins were isolated from the cytosolic inclusion bodies in adenovirus-infected cells and analyzed by LC-MS. These proteins included BAX, BAK, BID, BIK and BIM as well as mitochondrial proteins such as prohibitin 2, ATP synthase and DNA-PKcs. Our studies suggested that in addition to the interaction with various pro-apoptotic proteins, the association with certain mitochondrial proteins such as DNA-PKcs and prohibitins might augment the survival function of BCL-xL in virus infected cells. Copyright © 2015 Elsevier Inc. All rights reserved.

Retro-Active Emotion: Do Negative Emotional Stimuli Disrupt Consolidation in Working Memory?

PubMed

Kandemir, Güven; Akyürek, Elkan G; Nieuwenstein, Mark R

2017-01-01

While many studies have shown that a task-irrelevant emotionally arousing stimulus can interfere with the processing of a shortly following target, it remains unclear whether an emotional stimulus can also retro-actively interrupt the ongoing processing of an earlier target. In two experiments, we examined whether the presentation of a negative emotionally arousing picture can disrupt working memory consolidation of a preceding visual target. In both experiments, the effects of negative emotional pictures were compared with the effects of neutral pictures. In Experiment 1, the pictures were entirely task-irrelevant whereas in Experiment 2 the pictures were associated with a 2-alternative forced choice task that required participants to respond to the color of a frame surrounding the pictures. The results showed that the appearance of the pictures did not interfere with target consolidation when the pictures were task-irrelevant, whereas such interference was observed when the pictures were associated with a 2-AFC task. Most importantly, however, the results showed no effects of whether the picture had neutral or emotional content. Implications for further research are discussed.

Daily relations among affect, urge, targeted naltrexone, and alcohol use in young adults.

PubMed

Bold, Krysten W; Fucito, Lisa M; Corbin, William R; DeMartini, Kelly S; Leeman, Robert F; Kranzler, Henry R; O'Malley, Stephanie S

2016-10-01

Heavy drinking among young adults is a serious public health problem. Naltrexone, an opioid antagonist, has been shown to reduce drinking in young adults compared to placebo and can be taken on a targeted (i.e., as needed) basis. Understanding risk factors for drinking and naltrexone effects within-person in young adults may help to optimize the use of targeted naltrexone. The current study was a secondary analysis of daily diary data from 127 (n = 40 female) young adults (age 18-25) enrolled in a double-blind clinical trial of daily (25 mg) plus targeted (25 mg) naltrexone versus placebo. Hierarchical linear models were used to examine the effects of daily affect, urge, and taking targeted medication on same-day risk of drinking to intoxication (defined as estimated blood-alcohol-concentration, BAC ≥ .08 g%). Results indicated urge significantly mediated within-person positive affect-drinking relations on a daily level. Specifically, positive affect was associated with greater urge to drink, which in turn was associated with greater odds of BAC ≥ .08 g%. Furthermore, days of greater positive affect and urge were associated with taking a targeted dose of medication, which reduced the likelihood of intoxication by nearly 23% in the naltrexone group compared to placebo. Gender and family history of alcohol dependence were examined as moderators of these daily level effects. These results provide further evidence of naltrexone's ability to reduce alcohol consumption in young adults and identify potential within-person risk processes related to heavy drinking that could inform alcohol-related interventions for this population. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Knowledge, attitude, and uptake related to human papillomavirus vaccination among young women in Germany recruited via a social media site.

PubMed

Remschmidt, Cornelius; Walter, Dietmar; Schmich, Patrick; Wetzstein, Matthias; Deleré, Yvonne; Wichmann, Ole

2014-01-01

Many industrialized countries have introduced human papillomavirus (HPV) vaccination of young women, but vaccine uptake often remains suboptimal. This study aimed to investigate whether a social media site like Facebook is an appropriate tool to assess knowledge, attitude and uptake related to HPV vaccination in young women in Germany. Between December 2012 and January 2013 two different targeting strategies were implemented on Facebook, providing a link to an online questionnaire. Advertisements were displayed to female Facebook users aged 18-25 years living in Germany. During the simple targeting strategy, advertisements comprised health-related images along with various short titles and text messages. During the focused strategy, advertisements were targeted to users who in addition had certain fashion brands or pop stars listed on their profiles. The targeting strategies were compared with respect to participant characteristics. Univariate and multivariate analyses were used to identify factors associated with HPV vaccine uptake. A total of 1161 women participated. The two targeting strategies resulted in significant differences regarding educational status and migrant background. Overall, awareness of HPV was high, but only 53% received at least one vaccine dose. In multivariate analysis, HPV vaccine uptake was independently associated with a physician's recommendation and trust in vaccine effectiveness. Concerns of adverse effects were negatively associated with vaccine uptake. Social network recruitment permits fast and convenient access to young people. Sample characteristics can be manipulated by adjusting targeting strategies. There is further need for promoting knowledge of HPV vaccination among young women. Physicians have a major role in the vaccination decision-making process of young women.

Knowledge, attitude, and uptake related to human papillomavirus vaccination among young women in Germany recruited via a social media site

PubMed Central

Remschmidt, Cornelius; Walter, Dietmar; Schmich, Patrick; Wetzstein, Matthias; Deleré, Yvonne; Wichmann, Ole

2014-01-01

Background: Many industrialized countries have introduced human papillomavirus (HPV) vaccination of young women, but vaccine uptake often remains suboptimal. This study aimed to investigate whether a social media site like Facebook is an appropriate tool to assess knowledge, attitude and uptake related to HPV vaccination in young women in Germany. Methods: Between December 2012 and January 2013 two different targeting strategies were implemented on Facebook, providing a link to an online questionnaire. Advertisements were displayed to female Facebook users aged 18–25 years living in Germany. During the simple targeting strategy, advertisements comprised health-related images along with various short titles and text messages. During the focused strategy, advertisements were targeted to users who in addition had certain fashion brands or pop stars listed on their profiles. The targeting strategies were compared with respect to participant characteristics. Univariate and multivariate analyses were used to identify factors associated with HPV vaccine uptake. Results: A total of 1161 women participated. The two targeting strategies resulted in significant differences regarding educational status and migrant background. Overall, awareness of HPV was high, but only 53% received at least one vaccine dose. In multivariate analysis, HPV vaccine uptake was independently associated with a physician's recommendation and trust in vaccine effectiveness. Concerns of adverse effects were negatively associated with vaccine uptake. Discussion: Social network recruitment permits fast and convenient access to young people. Sample characteristics can be manipulated by adjusting targeting strategies. There is further need for promoting knowledge of HPV vaccination among young women. Physicians have a major role in the vaccination decision-making process of young women. PMID:25483492

l-Theanine and caffeine improve target-specific attention to visual stimuli by decreasing mind wandering: a human functional magnetic resonance imaging study.

PubMed

Kahathuduwa, Chanaka N; Dhanasekara, Chathurika S; Chin, Shao-Hua; Davis, Tyler; Weerasinghe, Vajira S; Dassanayake, Tharaka L; Binks, Martin

2018-01-01

Oral intake of l-theanine and caffeine supplements is known to be associated with faster stimulus discrimination, possibly via improving attention to stimuli. We hypothesized that l-theanine and caffeine may be bringing about this beneficial effect by increasing attention-related neural resource allocation to target stimuli and decreasing deviation of neural resources to distractors. We used functional magnetic resonance imaging (fMRI) to test this hypothesis. Solutions of 200mg of l-theanine, 160mg of caffeine, their combination, or the vehicle (distilled water; placebo) were administered in a randomized 4-way crossover design to 9 healthy adult men. Sixty minutes after administration, a 20-minute fMRI scan was performed while the subjects performed a visual color stimulus discrimination task. l-Theanine and l-theanine-caffeine combination resulted in faster responses to targets compared with placebo (∆=27.8milliseconds, P=.018 and ∆=26.7milliseconds, P=.037, respectively). l-Theanine was associated with decreased fMRI responses to distractor stimuli in brain regions that regulate visual attention, suggesting that l-theanine may be decreasing neural resource allocation to process distractors, thus allowing to attend to targets more efficiently. l-Theanine-caffeine combination was associated with decreased fMRI responses to target stimuli as compared with distractors in several brain regions that typically show increased activation during mind wandering. Factorial analysis suggested that l-theanine and caffeine seem to have a synergistic action in decreasing mind wandering. Therefore, our hypothesis is that l-theanine and caffeine may be decreasing deviation of attention to distractors (including mind wandering); thus, enhancing attention to target stimuli was confirmed. Copyright © 2017 Elsevier Inc. All rights reserved.

Recovering from conflict in romantic relationships: a developmental perspective.

PubMed

Salvatore, Jessica E; Kuo, Sally I-Chun; Steele, Ryan D; Simpson, Jeffry A; Collins, W Andrew

2011-03-01

This study adopted a developmental perspective on recovery from conflict in romantic relationships. Participants were 73 young adults (target participants), studied since birth, and their romantic partners. A novel observational coding scheme was used to evaluate each participant's degree of conflict recovery, operationalized as the extent to which the participant disengaged from conflict during a 4-min "cool-down" task immediately following a 10-min conflict discussion. Conflict recovery was systematically associated with developmental and dyadic processes. Targets who were rated as securely attached more times in infancy recovered from conflict better, as did their romantic partners. Concurrently, having a romantic partner who displayed better recovery predicted more positive relationship emotions and greater relationship satisfaction. Prospectively, target participants' early attachment security and their partners' degree of conflict recovery interacted to predict relationship stability 2 years later, such that having a partner who recovered from conflict better buffered targets with insecure histories.

Role of Molecular Dynamics and Related Methods in Drug Discovery.

PubMed

De Vivo, Marco; Masetti, Matteo; Bottegoni, Giovanni; Cavalli, Andrea

2016-05-12

Molecular dynamics (MD) and related methods are close to becoming routine computational tools for drug discovery. Their main advantage is in explicitly treating structural flexibility and entropic effects. This allows a more accurate estimate of the thermodynamics and kinetics associated with drug-target recognition and binding, as better algorithms and hardware architectures increase their use. Here, we review the theoretical background of MD and enhanced sampling methods, focusing on free-energy perturbation, metadynamics, steered MD, and other methods most consistently used to study drug-target binding. We discuss unbiased MD simulations that nowadays allow the observation of unsupervised ligand-target binding, assessing how these approaches help optimizing target affinity and drug residence time toward improved drug efficacy. Further issues discussed include allosteric modulation and the role of water molecules in ligand binding and optimization. We conclude by calling for more prospective studies to attest to these methods' utility in discovering novel drug candidates.

The association between community environment and cognitive function: a systematic review.

PubMed

Wu, Yu-Tzu; Prina, A Matthew; Brayne, Carol

2015-03-01

The aim of this study is to review the published evidence on the association between community environment and cognitive function in older people, focusing on the findings and a critique of the existing studies. A literature search was conducted to identify studies linking the community environment and cognitive function in older people. The results and methodological factors, including the definition of community, individual level characteristics and the measurements of cognitive function and community environment were extracted from each study. The measurements of community environment were mainly categorized into two types: compositional, generated by aggregating individual and household data (community-level socioeconomic status, deprivation index) and contextual, targeting at the features of built or social environment in local areas (green space, street conditions, crime rate). Fourteen of the fifteen studies used compositional measurements such as community-level socioeconomic status and deprivation index and significant associations were found in eleven studies. Some individual level factors (ethnicity, genotype and socioeconomic status) were found to modify the association between community environment and cognitive function. Few contextual measurements were included in the existing studies. A conceptual framework for the pathway from community environment to cognitive function of older people is provided in this review. To disentangle the additional effect of place from individual risk factors and investigate the casual direction of community environment and cognition in later life, longitudinal studies with measurements targeting built and social environments of community and change of cognitive functions over time need to be included in future studies.

Measurement of thick target neutron yield from the reaction (p+181 Ta) with projectiles in the range of 6-20 MeV

NASA Astrophysics Data System (ADS)

Paul, Sabyasachi; Sahoo, G. S.; Tripathy, S. P.; Sharma, S. C.; Joshi, D. S.; Bandyopadhyay, T.

2018-02-01

181Ta is a commonly used backing material for many targets in nuclear reaction studies. When the target thickness is less than the range of bombarded projectiles, the interaction via Ta(p,n) reactions in the backing can be a significant source of background. In this study, the neutron spectral yields from the reaction of protons of different energies (between 6 to 20 MeV) with a thick Ta target were determined using CR-39 detectors. The results from this study can be used as a correction factor in such situations. The parameters of registered tracks in CR-39 were analysed using an in-house image analysing program autoTRAK_n and then to derive the associated dose values. The spectral yields obtained experimentally were compared with those obtained from the theoretical calculations. The neutron yield was found to increase with increase in projectile energy mainly due to the opening of reaction channels from (p, n) to (p, 3n).

Airborne target tracking algorithm against oppressive decoys in infrared imagery

NASA Astrophysics Data System (ADS)

Sun, Xiechang; Zhang, Tianxu

2009-10-01

This paper presents an approach for tracking airborne target against oppressive infrared decoys. Oppressive decoy lures infrared guided missile by its high infrared radiation. Traditional tracking algorithms have degraded stability even come to tracking failure when airborne target continuously throw out many decoys. The proposed approach first determines an adaptive tracking window. The center of the tracking window is set at a predicted target position which is computed based on uniform motion model. Different strategies are applied for determination of tracking window size according to target state. The image within tracking window is segmented and multi features of candidate targets are extracted. The most similar candidate target is associated to the tracking target by using a decision function, which calculates a weighted sum of normalized feature differences between two comparable targets. Integrated intensity ratio of association target and tracking target, and target centroid are examined to estimate target state in the presence of decoys. The tracking ability and robustness of proposed approach has been validated by processing available real-world and simulated infrared image sequences containing airborne targets and oppressive decoys.

PREFACE: 1st Tensor Polarized Solid Target Workshop

NASA Astrophysics Data System (ADS)

2014-10-01

These are the proceedings of the first Tensor Spin Observables Workshop that was held in March 2014 at the Thomas Jefferson National Accelerator Facility in Newport News, Virginia. The conference was convened to study the physics that can be done with the recently approved E12-13-011 polarized target. A tensor polarized target holds the potential of initiating a new generation of tensor spin physics at Jefferson Lab. Experiments which utilize tensor polarized targets can help clarify how nuclear properties arise from partonic degrees of freedom, provide unique insight into short-range correlations and quark angular momentum, and also help pin down the polarization of the quark sea with a future Electron Ion Collider. This three day workshop was focused on tensor spin observables and the associated tensor target development. The workshop goals were to stimulate progress in the theoretical treatment of polarized spin-1 systems, foster the development of new proposals, and to reach a consensus on the optimal polarized target configuration for the tensor spin program. The workshop was sponsored by the University of New Hampshire, the Jefferson Science Associates, Florida International University, and Jefferson Lab. It was organized by Karl Slifer (chair), Patricia Solvignon, and Elena Long of the University of New Hampshire, Douglas Higinbotham and Christopher Keith of Jefferson Lab, and Misak Sargsian of the Florida International University. These proceedings represent the effort put forth by the community to begin exploring the possibilities that a high-luminosity, high-tensor polarized solid target can offer.

Potential role of DNA methylation as a facilitator of target search processes for transcription factors through interplay with methyl-CpG-binding proteins.

PubMed

Kemme, Catherine A; Marquez, Rolando; Luu, Ross H; Iwahara, Junji

2017-07-27

Eukaryotic genomes contain numerous non-functional high-affinity sequences for transcription factors. These sequences potentially serve as natural decoys that sequester transcription factors. We have previously shown that the presence of sequences similar to the target sequence could substantially impede association of the transcription factor Egr-1 with its targets. In this study, using a stopped-flow fluorescence method, we examined the kinetic impact of DNA methylation of decoys on the search process of the Egr-1 zinc-finger protein. We analyzed its association with an unmethylated target site on fluorescence-labeled DNA in the presence of competitor DNA duplexes, including Egr-1 decoys. DNA methylation of decoys alone did not affect target search kinetics. In the presence of the MeCP2 methyl-CpG-binding domain (MBD), however, DNA methylation of decoys substantially (∼10-30-fold) accelerated the target search process of the Egr-1 zinc-finger protein. This acceleration did not occur when the target was also methylated. These results suggest that when decoys are methylated, MBD proteins can block them and thereby allow Egr-1 to avoid sequestration in non-functional locations. This effect may occur in vivo for DNA methylation outside CpG islands (CGIs) and could facilitate localization of some transcription factors within regulatory CGIs, where DNA methylation is rare. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Drug Target Prediction and Repositioning Using an Integrated Network-Based Approach

PubMed Central

Emig, Dorothea; Ivliev, Alexander; Pustovalova, Olga; Lancashire, Lee; Bureeva, Svetlana; Nikolsky, Yuri; Bessarabova, Marina

2013-01-01

The discovery of novel drug targets is a significant challenge in drug development. Although the human genome comprises approximately 30,000 genes, proteins encoded by fewer than 400 are used as drug targets in the treatment of diseases. Therefore, novel drug targets are extremely valuable as the source for first in class drugs. On the other hand, many of the currently known drug targets are functionally pleiotropic and involved in multiple pathologies. Several of them are exploited for treating multiple diseases, which highlights the need for methods to reliably reposition drug targets to new indications. Network-based methods have been successfully applied to prioritize novel disease-associated genes. In recent years, several such algorithms have been developed, some focusing on local network properties only, and others taking the complete network topology into account. Common to all approaches is the understanding that novel disease-associated candidates are in close overall proximity to known disease genes. However, the relevance of these methods to the prediction of novel drug targets has not yet been assessed. Here, we present a network-based approach for the prediction of drug targets for a given disease. The method allows both repositioning drug targets known for other diseases to the given disease and the prediction of unexploited drug targets which are not used for treatment of any disease. Our approach takes as input a disease gene expression signature and a high-quality interaction network and outputs a prioritized list of drug targets. We demonstrate the high performance of our method and highlight the usefulness of the predictions in three case studies. We present novel drug targets for scleroderma and different types of cancer with their underlying biological processes. Furthermore, we demonstrate the ability of our method to identify non-suspected repositioning candidates using diabetes type 1 as an example. PMID:23593264

Semantic processing of unattended parafoveal words.

PubMed

Di Pace, E; Longoni, A M; Zoccolotti, P

1991-08-01

The influence that a context word presented either foveally or parafoveally, may exert on the processing of a subsequent target word was studied in a semantic decision task. Fourteen subjects participated in the experiment. They were presented with word-nonword pairs (prime). One member of the pair (which the subjects had to attend to) appeared centrally, the other parafoveally. The prime was followed by a target at two inter-stimulus intervals (ISI; 200 and 2000 msec). The word stimulus of the pair could be semantically related or unrelated to the target. The subjects' task was to classify the target as animal or not animal by pressing one of two buttons as quickly as possible. When the target word was semantically associated with the foveal (attended) word the reaction times were faster for both ISIs; when it was associated with the parafoveal (unattended) word in the prime pair, there were facilitatory effects only in the short ISI condition. A second experiment was run in order to evaluate the possibility that the obtained results were due to identification of the parafoveal stimulus. The same prime-target pairs of experiment 1 (without the target stimuli) were used. The prime-target pairs were presented to fourteen subjects who were requested to name the foveal (attended) stimulus and subsequently, if possible, the parafoveal (unattended) one. Even in this condition, percentage of identification of the unattended word was only 15%, suggesting that previous findings were not due to identification of unattended stimuli. Results are discussed in relation to Posner and Snyder's (1975) dual coding theory.

Predictors of clinical outcome in emphysema patients with atelectasis following endoscopic valve therapy: A retrospective study.

PubMed

Gompelmann, Daniela; Hofbauer, Tobias; Gerovasili, Vasiliki; Eberhardt, Ralf; Lim, Hyun-Ju; Herth, Felix; Heussel, Claus-Peter

2016-10-01

The aim of endoscopic valve therapy in patients with emphysema is complete lobar atelectasis of the most emphysematous lobe. However, even after the radiological advent of atelectasis, great variability in clinical outcomes can be observed. The baseline clinical measures (vital capacity (VC), forced expiratory flow in 1 s (FEV1 ), residual volume (RV) and 6-min walk test (6-MWT)) and computed tomography variables (low attenuation volume (LAV) of the target lobe, LAV% of the target and the ipsilateral untreated lobe and LAV of the target lobe to LAV of the target lung and to LAV of the total lung) of 77 patients with complete atelectasis following valve therapy were retrospectively examined to determine their impact on patient´s outcome (changes in VC, FEV1 , RV and 6-MWT from baseline to the time of atelectasis). Low attenuation volume of the target lobe to LAV of the target lung predicts a significant FEV1 improvement in patients with complete lobar atelectasis following valve therapy. A 10% difference in that computed tomography predictor was associated with a 82-mL improvement in FEV1 (P = 0.006). Lower 6-MWT scores, low VC and high RV at baseline were significantly associated with greater improvement in the respective parameter (all P < 0.001). Low attenuation volume of the target lobe to LAV of the target lung and baseline clinical measures seem to significantly predict clinical outcomes in patients with complete lobar atelectasis following valve treatment. © 2016 Asian Pacific Society of Respirology.

Toxicity and Carcinogenicity Studies of Ginkgo biloba extract in Rat and Mouse: Liver, Thyroid, and Nose are Targets

PubMed Central

Rider, Cynthia V.; Nyska, Abraham; Cora, Michelle C.; Kissling, Grace E.; Smith, Cynthia; Travlos, Gregory S.; Hejtmancik, Milton R.; Fomby, Laurene M.; Colleton, Curtis A.; Ryan, Michael J.; Kooistra, Linda; Morrison, James P.; Chan, Po C.

2014-01-01

Ginkgo biloba extract (GBE) is a popular herbal supplement that is used to improve circulation and brain function. In spite of widespread human exposure to relatively high doses over potentially long periods of time, there is a paucity of data from animal studies regarding the toxicity and carcinogenicity associated with GBE. In order to fill this knowledge gap, three-month and two-year toxicity and carcinogenicity studies with GBE administered by oral gavage to B6C3F1/N mice and F344/N rats were performed as part of the National Toxicology Program’s Dietary Supplements and Herbal Medicines Initiative. The targets of GBE treatment were the liver, thyroid, and nose. These targets were consistent across exposure period, sex, and species, albeit with varying degrees of effect observed among studies. Key findings included a notably high incidence of hepatoblastomas in male and female mice and evidence of carcinogenic potential in the thyroid gland of both mice and rats. Various nonneoplastic lesions were observed beyond control levels in the liver, thyroid gland, and nose of rats and mice administered GBE. Although these results cannot be directly extrapolated to humans, the findings fill an important data gap in assessing risk associated with GBE use. PMID:23960164

Familial breast cancer - targeted therapy in secondary and tertiary prevention.

PubMed

Kast, Karin; Rhiem, Kerstin

2015-02-01

The introduction of an increasing number of individualized molecular targeted therapies into clinical routine mirrors their importance in modern cancer prevention and treatment. Well-known examples for targeted agents are the monoclonal antibody trastuzumab and the selective estrogen receptor modulator tamoxifen. The identification of an unaltered gene in tumor tissue in colon cancer (KRAS) is a predictor for the patient's response to targeted therapy with a monoclonal antibody (cetuximab). Targeted therapy for hereditary breast and ovarian cancer has become a reality with the approval of olaparib for platin-sensitive late relapsed BRCA-associated ovarian cancer in December 2014. This manuscript reviews the status quo of poly-ADP-ribose polymerase inhibitors (PARPi) in the therapy of breast and ovarian cancer as well as the struggle for carboplatin as a potential standard of care for triple-negative and, in particular, BRCA-associated breast cancer. Details of the mechanism of action with information on tumor development are provided, and an outlook for further relevant research is given. The efficacy of agents against molecular targets together with the identification of an increasing number of cancer-associated genes will open the floodgates to a new era of treatment decision-making based on molecular tumor profiles. Current clinical trials involving patients with BRCA-associated cancer explore the efficacy of the molecular targeted therapeutics platinum and PARPi.

RovS and its associated signaling peptide form a cell-to-cell communication system required for Streptococcus agalactiae pathogenesis.

PubMed

Pérez-Pascual, David; Gaudu, Philippe; Fleuchot, Betty; Besset, Colette; Rosinski-Chupin, Isabelle; Guillot, Alain; Monnet, Véronique; Gardan, Rozenn

2015-01-20

Bacteria can communicate with each other to coordinate their biological functions at the population level. In a previous study, we described a cell-to-cell communication system in streptococci that involves a transcriptional regulator belonging to the Rgg family and short hydrophobic peptides (SHPs) that act as signaling molecules. Streptococcus agalactiae, an opportunistic pathogenic bacterium responsible for fatal infections in neonates and immunocompromised adults, has one copy of the shp/rgg locus. The SHP-associated Rgg is called RovS in S. agalactiae. In this study, we found that the SHP/RovS cell-to-cell communication system is active in the strain NEM316 of S. agalactiae, and we identified different partners that are involved in this system, such as the Eep peptidase, the PptAB, and the OppA1-F oligopeptide transporters. We also identified a new target gene controlled by this system and reexamined the regulation of a previously proposed target gene, fbsA, in the context of the SHP-associated RovS system. Furthermore, our results are the first to indicate the SHP/RovS system specificity to host liver and spleen using a murine model, which demonstrates its implication in streptococci virulence. Finally, we observed that SHP/RovS regulation influences S. agalactiae's ability to adhere to and invade HepG2 hepatic cells. Hence, the SHP/RovS cell-to-cell communication system appears to be an essential mechanism that regulates pathogenicity in S. agalactiae and represents an attractive target for the development of new therapeutic strategies. Rgg regulators and their cognate pheromones, called small hydrophobic peptides (SHPs), are present in nearly all streptococcal species. The general pathways of the cell-to-cell communication system in which Rgg and SHP take part are well understood. However, many other players remain unidentified, and the direct targets of the system, as well as its link to virulence, remain unclear. Here, we identified the different players involved in the SHP/Rgg system in S. agalactiae, which is the leading agent of severe infections in human newborns. We have identified a direct target of the Rgg regulator in S. agalactiae (called RovS) and examined a previously proposed target, all in the context of associated SHP. For the first time, we have also demonstrated the implication of the SHP/RovS mechanism in virulence, as well as its host organ specificity. Thus, this cell-to-cell communication system may represent a future target for S. agalactiae disease treatment. Copyright © 2015 Pérez-Pascual et al.

NURSE STAFFING AND RENAL ANAEMIA OUTCOMES IN HAEMODIALYSIS CARE.

PubMed

Erlingmark, Julia; Hedström, Mariann; Lindberg, Magnus

2016-09-01

Current trends in renal anaemia management place greater emphasis, and thus increased workload, on the role of the nurse in haemodialysis settings. However, there is little evidence that demonstrates the relationship between nurse staffing and patient outcomes. To describe nurse staffing in haemodialysis settings, its relationship with target levels of renal anaemia management and to describe target level achievement for different ways of organising anaemia management. Cross-sectional audit. Forty (out of 78) haemodialysis centres in Sweden reported quality assurance data. The numbers of bedside registered nurses, licensed nurse assistants and patients undergoing haemodialysis during a predefined morning shift; type of anaemia management and achieved target levels of anaemia management. The mean patient:registered nurse ratio was 2.4 and the mean patient:nurse assistant ratio was 12.8. There were no significant relationships between registered nurse staffing and target level achievement. On average, 45.6% of the patients had haemoglobin within the target levels at centres applying nurse-driven anaemia management, compared with 47.3% at physician-driven centres. These cross-sectional data suggest that renal anaemia outcomes are unrelated to the patient:registered nurse ratio. There is, however, room for improvement in renal anaemia management in the units included in this study, particularly the achievement of target levels of haemoglobin and transferrin saturation. © 2016 European Dialysis and Transplant Nurses Association/European Renal Care Association.

Inflammation-Mediated Regulation of MicroRNA Expression in Transplanted Pancreatic Islets

PubMed Central

Bravo-Egana, Valia; Rosero, Samuel; Klein, Dagmar; Jiang, Zhijie; Vargas, Nancy; Tsinoremas, Nicholas; Doni, Marco; Podetta, Michele; Ricordi, Camillo; Molano, R. Damaris; Pileggi, Antonello; Pastori, Ricardo L.

2012-01-01

Nonspecific inflammation in the transplant microenvironment results in β-cell dysfunction and death influencing negatively graft outcome. MicroRNA (miRNA) expression and gene target regulation in transplanted islets are not yet well characterized. We evaluated the impact of inflammation on miRNA expression in transplanted rat islets. Islets exposed in vitro to proinflammatory cytokines and explanted syngeneic islet grafts were evaluated by miRNA arrays. A subset of 26 islet miRNAs was affected by inflammation both in vivo and in vitro. Induction of miRNAs was dependent on NF-κB, a pathway linked with cytokine-mediated islet cell death. RT-PCR confirmed expression of 8 miRNAs. The association between these miRNAs and mRNA target-predicting algorithms in genome-wide RNA studies of β-cell inflammation identified 238 potential miRNA gene targets. Several genes were ontologically associated with regulation of insulin signaling and secretion, diabetes, and islet physiology. One of the most activated miRNAs was miR-21. Overexpression of miR-21 in insulin-secreting MIN6 cells downregulated endogenous expression of the tumor suppressor Pdcd4 and of Pclo, a Ca2+ sensor protein involved in insulin secretion. Bioinformatics identified both as potential targets. The integrated analysis of miRNA and mRNA expression profiles revealed potential targets that may identify molecular targets for therapeutic interventions. PMID:22655170

Genome-wide Target Enrichment-aided Chip Design: a 66 K SNP Chip for Cashmere Goat.

PubMed

Qiao, Xian; Su, Rui; Wang, Yang; Wang, Ruijun; Yang, Ting; Li, Xiaokai; Chen, Wei; He, Shiyang; Jiang, Yu; Xu, Qiwu; Wan, Wenting; Zhang, Yaolei; Zhang, Wenguang; Chen, Jiang; Liu, Bin; Liu, Xin; Fan, Yixing; Chen, Duoyuan; Jiang, Huaizhi; Fang, Dongming; Liu, Zhihong; Wang, Xiaowen; Zhang, Yanjun; Mao, Danqing; Wang, Zhiying; Di, Ran; Zhao, Qianjun; Zhong, Tao; Yang, Huanming; Wang, Jian; Wang, Wen; Dong, Yang; Chen, Xiaoli; Xu, Xun; Li, Jinquan

2017-08-17

Compared with the commercially available single nucleotide polymorphism (SNP) chip based on the Bead Chip technology, the solution hybrid selection (SHS)-based target enrichment SNP chip is not only design-flexible, but also cost-effective for genotype sequencing. In this study, we propose to design an animal SNP chip using the SHS-based target enrichment strategy for the first time. As an update to the international collaboration on goat research, a 66 K SNP chip for cashmere goat was created from the whole-genome sequencing data of 73 individuals. Verification of this 66 K SNP chip with the whole-genome sequencing data of 436 cashmere goats showed that the SNP call rates was between 95.3% and 99.8%. The average sequencing depth for target SNPs were 40X. The capture regions were shown to be 200 bp that flank target SNPs. This chip was further tested in a genome-wide association analysis of cashmere fineness (fiber diameter). Several top hit loci were found marginally associated with signaling pathways involved in hair growth. These results demonstrate that the 66 K SNP chip is a useful tool in the genomic analyses of cashmere goats. The successful chip design shows that the SHS-based target enrichment strategy could be applied to SNP chip design in other species.

Drug-targeting methodologies with applications: A review

PubMed Central

Kleinstreuer, Clement; Feng, Yu; Childress, Emily

2014-01-01

Targeted drug delivery to solid tumors is a very active research area, focusing mainly on improved drug formulation and associated best delivery methods/devices. Drug-targeting has the potential to greatly improve drug-delivery efficacy, reduce side effects, and lower the treatment costs. However, the vast majority of drug-targeting studies assume that the drug-particles are already at the target site or at least in its direct vicinity. In this review, drug-delivery methodologies, drug types and drug-delivery devices are discussed with examples in two major application areas: (1) inhaled drug-aerosol delivery into human lung-airways; and (2) intravascular drug-delivery for solid tumor targeting. The major problem addressed is how to deliver efficiently the drug-particles from the entry/infusion point to the target site. So far, most experimental results are based on animal studies. Concerning pulmonary drug delivery, the focus is on the pros and cons of three inhaler types, i.e., pressurized metered dose inhaler, dry powder inhaler and nebulizer, in addition to drug-aerosol formulations. Computational fluid-particle dynamics techniques and the underlying methodology for a smart inhaler system are discussed as well. Concerning intravascular drug-delivery for solid tumor targeting, passive and active targeting are reviewed as well as direct drug-targeting, using optimal delivery of radioactive microspheres to liver tumors as an example. The review concludes with suggestions for future work, considereing both pulmonary drug targeting and direct drug delivery to solid tumors in the vascular system. PMID:25516850

Mammalian target of rapamycin inhibitors, temsirolimus and torin 1, attenuate stemness-associated properties and expression of mesenchymal markers promoted by phorbol-myristate-acetate and oncostatin-M in glioblastoma cells.

PubMed

Chandrika, Goparaju; Natesh, Kumar; Ranade, Deepak; Chugh, Ashish; Shastry, Padma

2017-03-01

The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway is crucial for tumor survival, proliferation, and progression, making it an attractive target for therapeutic intervention. In glioblastoma, activated mammalian target of rapamycin promotes invasive phenotype and correlates with poor patient survival. A wide range of mammalian target of rapamycin inhibitors are currently being evaluated for cytotoxicity and anti-proliferative activity in various tumor types but are not explored sufficiently for controlling tumor invasion and recurrence. We recently reported that mammalian target of rapamycin inhibitors-rapamycin, temsirolimus, torin 1, and PP242-suppressed invasion and migration promoted by tumor necrosis factor-alpha and phorbol-myristate-acetate in glioblastoma cells. As aggressive invasion and migration of tumors are associated with mesenchymal and stem-like cell properties, this study aimed to examine the effect of mammalian target of rapamycin inhibitors on these features in glioblastoma cells. We demonstrate that temsirolimus and torin 1 effectively reduced the constitutive as well as phorbol-myristate-acetate/oncostatin-M-induced expression of mesenchymal markers (fibronectin, vimentin, and YKL40) and neural stem cell markers (Sox2, Oct4, nestin, and mushashi1). The inhibitors significantly abrogated the neurosphere-forming capacity induced by phorbol-myristate-acetate and oncostatin-M. Furthermore, we demonstrate that the drugs dephosphorylated signal transducer and activator transcription factor 3, a major regulator of mesenchymal and neural stem cell markers implicating the role of signal transducer and activator transcription factor 3 in the inhibitory action of these drugs. The findings demonstrate the potential of mammalian target of rapamycin inhibitors as "stemness-inhibiting drugs" and a promising therapeutic approach to target glioma stem cells.

Location and color biases have different influences on selective attention.

PubMed

Fecteau, Jillian H; Korjoukov, Ilia; Roelfsema, Pieter R

2009-05-01

Are locations or colors more effective cues in biasing attention? We addressed this question with a visual search task that featured an associative priming manipulation. The observers indicated which target appeared in a search array. Unknown to them, one target appeared at the same location more often and a second target appeared in the same color more often. Both location and color biases facilitated performance, but location biases benefited the selection of all targets, whereas color biases only benefited the associated target letter. The generalized benefit of location biases suggests that locations are more effective cues to attention.

Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23.

PubMed

McGovern, Amanda; Schoenfelder, Stefan; Martin, Paul; Massey, Jonathan; Duffus, Kate; Plant, Darren; Yarwood, Annie; Pratt, Arthur G; Anderson, Amy E; Isaacs, John D; Diboll, Julie; Thalayasingam, Nishanthi; Ospelt, Caroline; Barton, Anne; Worthington, Jane; Fraser, Peter; Eyre, Stephen; Orozco, Gisela

2016-11-01

The identification of causal genes from genome-wide association studies (GWAS) is the next important step for the translation of genetic findings into biologically meaningful mechanisms of disease and potential therapeutic targets. Using novel chromatin interaction detection techniques and allele specific assays in T and B cell lines, we provide compelling evidence that redefines causal genes at the 6q23 locus, one of the most important loci that confers autoimmunity risk. Although the function of disease-associated non-coding single nucleotide polymorphisms (SNPs) at 6q23 is unknown, the association is generally assigned to TNFAIP3, the closest gene. However, the DNA fragment containing the associated SNPs interacts through chromatin looping not only with TNFAIP3, but also with IL20RA, located 680 kb upstream. The risk allele of the most likely causal SNP, rs6927172, is correlated with both a higher frequency of interactions and increased expression of IL20RA, along with a stronger binding of both the NFκB transcription factor and chromatin marks characteristic of active enhancers in T-cells. Our results highlight the importance of gene assignment for translating GWAS findings into biologically meaningful mechanisms of disease and potential therapeutic targets; indeed, monoclonal antibody therapy targeting IL-20 is effective in the treatment of rheumatoid arthritis and psoriasis, both with strong GWAS associations to this region.

Distinct regions of triadin are required for targeting and retention at the junctional domain of the sarcoplasmic reticulum.

PubMed

Rossi, Daniela; Bencini, Cristina; Maritati, Marina; Benini, Francesca; Lorenzini, Stefania; Pierantozzi, Enrico; Scarcella, Angela Maria; Paolini, Cecilia; Protasi, Feliciano; Sorrentino, Vincenzo

2014-03-01

Ca2+ release, which is necessary for muscle contraction, occurs at the j-SR (junctional domain of the sarcoplasmic reticulum). It requires the assembly of a large multiprotein complex containing the RyR (ryanodine receptor) and additional proteins, including triadin and calsequestrin. The signals which drive these proteins to the j-SR and how they assemble to form this multiprotein complex are poorly understood. To address aspects of these questions we studied the localization, dynamic properties and molecular interactions of triadin. We identified three regions, named TR1 (targeting region 1), TR2 and TR3, that contribute to the localization of triadin at the j-SR. FRAP experiments showed that triadin is stably associated with the j-SR and that this association is mediated by TR3. Protein pull-down experiments indicated that TR3 contains binding sites for calsequestrin-1 and that triadin clustering can be enhanced by binding to calsequestrin-1. These findings were confirmed by FRET experiments. Interestingly, the stable association of triadin to the j-SR was significantly decreased in myotubes from calsequestrin-1 knockout mice. Taken together, these results identify three regions in triadin that mediate targeting to the j-SR and reveal a role for calsequestrin-1 in promoting the stable association of triadin to the multiprotein complex associated with RyR.

A review of the ligands and related targeting strategies for active targeting of paclitaxel to tumours.

PubMed

Li, Juan; Wang, Fengshan; Sun, Deqing; Wang, Rongmei

2016-08-01

It has been 30 years since the discovery of the anti-tumour property of paclitaxel (PTX), which has been successfully applied in clinic for the treatment of carcinomas of the lungs, breast and ovarian. However, PTX is poorly soluble in water and has no targeting and selectivity to tumour tissue. Recent advances in active tumour targeting of PTX delivery vehicles have addressed some of the issues related to lack of solubility in water and non-specific toxicities associated with PTX. These PTX delivery vehicles are designed for active targeting to specific cancer cells by the addition of ligands for recognition by specific receptors/antigens on cancer cells. This article will focus on various ligands and related targeting strategies serving as potential tools for active targeting of PTX to tumour tissues, illustrating their use in different tumour models. This review also highlights the need of further studies on the discovery of receptors in different cells of specific organ and ligands with binding efficiency to these specific receptors.

[Effects of mere subliminal exposure on trait judgments and the role of stereotyped knowledge].

PubMed

Yamada, Ayumi

2004-06-01

This study investigated the effects of repeated exposures to male and female targets on trait impressions and the role of stereotyped knowledge for the target's social category in impression formation process. The participants were repeatedly exposed to slides of male and female faces for subliminal durations. For each of 12 pairs containing both previously presented slide and newly presented slide, the participants made forced-choice liking judgments (Experiment 1), trait judgments (Experiment 2) and recognition judgments (Experiments 1 and 2). It was found that participants' attitude toward the targets became more positive, even though target recognition was not significantly greater than the chance level. Yet, when the dimension of judgment was stereotypically associated with the target's social category, exposure effects were obtained for the targets whose social category and its dimension were inferentially matched, but not obtained for the targets whose social category and its dimension were not inferentially matched. Some theoretical implications of the role of social category information in the mere exposure phenomenon are discussed.

Event-Related Potentials Indicate Different Processes to Mediate Categorical and Associative Priming in Person Recognition

ERIC Educational Resources Information Center

Wiese, Holger; Schweinberger, Stefan R.

2008-01-01

Whether representations of people are stored in associative networks based on co-occurrence or are stored in terms of more abstract semantic categories is a controversial question. In the present study, participants performed fame decisions to unfamiliar or famous target faces (Experiment 1) or names (Experiment 2), which were primed, either by…

Bug-in-Ear Coaching: Impacts on Early Childhood Educators' Practices and Associations with Toddlers' Expressive Communication

ERIC Educational Resources Information Center

Ottley, Jennifer Riggie; Hanline, Mary Frances

2014-01-01

Many early childhood educators struggle to meet the communication needs of children with delays and disabilities. The purpose of this study was to examine the functional relation between bug-in-ear coaching and the frequency of educators' correct use of targeted communication strategies, as well as associations with children's expressive…

The Association between Exposure to "Tips" and Smoking-Related Outcomes among Adolescents in the United States

ERIC Educational Resources Information Center

Zhao, Xiaoquan; Cai, Xiaomei

2016-01-01

The Tips From Former Smokers ("Tips") campaign in the United States primarily targets adult smokers, but considers adolescents an important secondary audience. This study examines the association between exposure to Tips and smoking outcomes in the adolescent population in the United States. We analyzed data from the 2013 National Youth…

Long-Term Interference at the Semantic Level: Evidence from Blocked-Cyclic Picture Matching

ERIC Educational Resources Information Center

Wei, Tao; Schnur, Tatiana T.

2016-01-01

Processing semantically related stimuli creates interference across various domains of cognition, including language and memory. In this study, we identify the locus and mechanism of interference when retrieving meanings associated with words and pictures. Subjects matched a probe stimulus (e.g., cat) to its associated target picture (e.g., yarn)…

Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis.

PubMed

Popkirov, Stoyan; Ayzenberg, Ilya; Hahn, Stefanie; Bauer, Jan; Denno, Yvonne; Rieckhoff, Nicole; Radzimski, Christiane; Hans, Volkmar H; Berg, Sebastian; Roghmann, Florian; Noldus, Joachim; Bien, Christian G; Skodda, Sabine; Wellmer, Jörg; Stöcker, Winfried; Krogias, Christos; Gold, Ralf; Schlegel, Uwe; Probst, Christian; Komorowski, Lars; Miske, Ramona; Kleiter, Ingo

2017-05-29

Onconeural antibodies are associated with cancer and paraneoplastic encephalitis. While their pathogenic role is still largely unknown, their high diagnostic value is undisputed. In this study we describe the discovery of a novel target of autoimmunity in an index case of paraneoplastic encephalitis associated with urogenital cancer.A 75-year-old man with a history of invasive bladder carcinoma 6 years ago with multiple recurrences and a newly discovered renal cell carcinoma presented with seizures and progressive cognitive decline followed by super-refractory status epilepticus. Clinical and ancillary findings including brain biopsy suggested paraneoplastic encephalitis. Immunohistochemistry of the brain biopsy was used to characterize the inflammatory response. Indirect immunofluorescence assay (IFA) was used for autoantibody screening. The autoantigen was identified by histo-immunoprecipitation and mass spectrometry and was validated by expressing the recombinant antigen in HEK293 cells and neutralization tests. Sera from 125 control patients were screened using IFA to test for the novel autoantibodies.IFA analysis of serum revealed a novel autoantibody against brain tissue. An intracellular enzyme, Rho-associated protein kinase 2 (ROCK2), was identified as target-antigen. ROCK2 was expressed in affected brain tissue and archival bladder tumor samples of this patient. Brain histopathology revealed appositions of cytotoxic CD8 + T cells on ROCK2-positive neurons. ROCK2 antibodies were not found in the sera of 20 patients with bladder cancer and 17 with renal cancer, both without neurological symptoms, 49 healthy controls, and 39 patients with other antineuronal autoantibodies. In conclusion, novel onconeural antibodies targeting ROCK2 are associated with paraneoplastic encephalitis and should be screened for when paraneoplastic neurological syndromes, especially in patients with urogenital cancers, occur.

Semantic congruence affects hippocampal response to repetition of visual associations.

PubMed

McAndrews, Mary Pat; Girard, Todd A; Wilkins, Leanne K; McCormick, Cornelia

2016-09-01

Recent research has shown complementary engagement of the hippocampus and medial prefrontal cortex (mPFC) in encoding and retrieving associations based on pre-existing or experimentally-induced schemas, such that the latter supports schema-congruent information whereas the former is more engaged for incongruent or novel associations. Here, we attempted to explore some of the boundary conditions in the relative involvement of those structures in short-term memory for visual associations. The current literature is based primarily on intentional evaluation of schema-target congruence and on study-test paradigms with relatively long delays between learning and retrieval. We used a continuous recognition paradigm to investigate hippocampal and mPFC activation to first and second presentations of scene-object pairs as a function of semantic congruence between the elements (e.g., beach-seashell versus schoolyard-lamp). All items were identical at first and second presentation and the context scene, which was presented 500ms prior to the appearance of the target object, was incidental to the task which required a recognition response to the central target only. Very short lags 2-8 intervening stimuli occurred between presentations. Encoding the targets with congruent contexts was associated with increased activation in visual cortical regions at initial presentation and faster response time at repetition, but we did not find enhanced activation in mPFC relative to incongruent stimuli at either presentation. We did observe enhanced activation in the right anterior hippocampus, as well as regions in visual and lateral temporal and frontal cortical regions, for the repetition of incongruent scene-object pairs. This pattern demonstrates rapid and incidental effects of schema processing in hippocampal, but not mPFC, engagement during continuous recognition. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lower mean blood glucose during short-term intensive insulin therapy is associated with long-term glycemic remission in patients with newly diagnosed type 2 diabetes: Evidence-based recommendations for standardization.

PubMed

Liu, Liehua; Liu, Juan; Xu, Lijuan; Ke, Weijian; Wan, Xuesi; Li, Hai; He, Xiaoying; Wang, Liangjiao; Cao, Xiaopei; Xiao, Haipeng; Li, Yanbing

2017-11-30

Optimal glycemic targets during short-term intensive insulin therapy in patients with newly diagnosed type 2 diabetes are not standardized. The present study was carried out to determine the optimal glycemic targets during therapy by analyzing the impacts of glucose levels on therapeutic outcomes. A total of 95 individuals with newly diagnosed type 2 diabetes were enrolled. Short-term intensive insulin therapy was carried out using an insulin pump to achieve and maintain glycemic targets (fasting blood glucose ≤6.0 mmol/L, 2-h postprandial blood glucose ≤7.8 mmol/L) for 14 days, with daily eight-point capillary blood glucose profiles recorded. Patients were followed up for 1 year after discharge. In most participants, the mean blood glucose and glycemic excursion parameters during the therapy were controlled within the normal range. Mean blood glucose was independently associated with amelioration of acute insulin response (r = -0.25, P = 0.015) and 1-year remission (odds ratio 0.12, 95% confidence interval 0.034-0.426), but negatively associated with more level 1 hypoglycemia (r = -0.34, P = 0.001), although major hypoglycemia was rare. Among mean blood glucose tertiles, patients in the middle (68.7%) and lower (75.0%) tertiles had a higher 1-year remission rate compared with the upper tertile (32.3%, both P < 0.001), whereas only the middle tertile did not have increased hypoglycemia compared with the upper tertile (8.1 ± 5.4 vs 7.2 ± 3.9 events/person, P = 0.48). Stricter glycemic control during short-term intensive insulin therapy produced more remission despite self-manageable hypoglycemia. Based on glycemic parameters in the middle mean tertile, we propose new glycemic targets that are approximately 0.4 mmol/L lower than current the targets, as long-term benefit outweighs short-term risks. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Mitosis Is a Source of Potential Markers for Screening and Survival and Therapeutic Targets in Cervical Cancer

PubMed Central

Espinosa, Ana María; Alfaro, Ana; Roman-Basaure, Edgar; Guardado-Estrada, Mariano; Palma, Ícela; Serralde, Cyntia; Medina, Ingrid; Juárez, Eligia; Bermúdez, Miriam; Márquez, Edna; Borges-Ibáñez, Manuel; Muñoz-Cortez, Sergio; Alcántara-Vázquez, Avissai; Alonso, Patricia; Curiel-Valdez, José; Kofman, Susana; Villegas, Nicolas; Berumen, Jaime

2013-01-01

The effect of preventive human papillomavirus (HPV) vaccination on the reduction of the cervical cancer (CC) burden will not be known for 30 years. Therefore, it’s still necessary to improve the procedures for CC screening and treatment. The objective of this study was to identify and characterize cellular targets that could be considered potential markers for screening or therapeutic targets. A pyramidal strategy was used. Initially the expression of 8,638 genes was compared between 43 HPV16-positive CCs and 12 healthy cervical epitheliums using microarrays. A total of 997 genes were deregulated, and 21 genes that showed the greatest deregulation were validated using qRT-PCR. The 6 most upregulated genes (CCNB2, CDC20, PRC1, SYCP2, NUSAP1, CDKN3) belong to the mitosis pathway. They were further explored in 29 low-grade cervical intraepithelial neoplasias (CIN1) and 21 high-grade CIN (CIN2/3) to investigate whether they could differentiate CC and CIN2/3 (CIN2+) from CIN1 and controls. CCNB2, PRC1, and SYCP2 were mostly associated with CC and CDC20, NUSAP1, and CDKN3 were also associated with CIN2/3. The sensitivity and specificity of CDKN3 and NUSAP1 to detect CIN2+ was approximately 90%. The proteins encoded by all 6 genes were shown upregulated in CC by immunohistochemistry. The association of these markers with survival was investigated in 42 CC patients followed up for at least 42 months. Only CDKN3 was associated with poor survival and it was independent from clinical stage (HR = 5.9, 95%CI = 1.4–23.8, p = 0.01). CDKN3 and NUSAP1 may be potential targets for the development of screening methods. Nevertheless, further studies with larger samples are needed to define the optimal sensitivity and specificity. Inhibition of mitosis is a well-known strategy to combat cancers. Therefore, CDKN3 may be not only a screening and survival marker but a potential therapeutic target in CC. However, whether it’s indispensable for tumor growth remains to be demonstrated. PMID:23405241

Third-line Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

PubMed

Wells, J Connor; Stukalin, Igor; Norton, Craig; Srinivas, Sandy; Lee, Jae Lyun; Donskov, Frede; Bjarnason, Georg A; Yamamoto, Haru; Beuselinck, Benoit; Rini, Brian I; Knox, Jennifer J; Agarwal, Neeraj; Ernst, D Scott; Pal, Sumanta K; Wood, Lori A; Bamias, Aristotelis; Alva, Ajjai S; Kanesvaran, Ravindran; Choueiri, Toni K; Heng, Daniel Y C

2017-02-01

The use of third-line targeted therapy (TTT) in metastatic renal cell carcinoma (mRCC) is not well characterized and varies due to the lack of robust data to guide treatment decisions. This study examined the use of third-line therapy in a large international population. To evaluate the use and efficacy of targeted therapy in a third-line setting. Twenty-five international cancer centers provided consecutive data on 4824 mRCC patients who were treated with an approved targeted therapy. One thousand and twelve patients (21%) received TTT and were included in the analysis. Patients were analyzed for overall survival (OS) and progression-free survival using Kaplan-Meier curves, and were evaluated for overall response. Cox regression analyses were used to determine the statistical association between OS and the six factors included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. Subgroup analysis was performed on patients stratified by their IMDC prognostic risk status. Everolimus was the most prevalent third-line therapy (27.5%), but sunitinib, sorafenib, pazopanib, temsirolimus, and axitinib were all utilized in over ≥9% of patients. Patients receiving any TTT had an OS of 12.4 mo, a progression-free survival of 3.9 mo, and 61.1% of patients experienced an overall response of stable disease or better. Patients not receiving TTT had an OS of 2.1 mo. Patients with favorable- (7.2%) or intermediate-risk (65.3%) disease had the highest OS with TTT, 29.9 mo and 15.5 mo, respectively, while poor-risk (27.5%) patients survived 5.5 mo. Results are limited by the retrospective nature of the study. TTT remains highly heterogeneous. The IMDC prognostic criteria can be used to stratify third-line patients. TTT use in favorable- and intermediate-risk patients was associated with the greatest OS. Patients with favorable- and intermediate-prognostic criteria disease treated with third-line targeted therapy have an associated longer overall survival compared with those with poor risk disease. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

A Study of the Factors Associated with Successful Technology Transfer and their Applicability to Air Force Technology Transfers.

DTIC Science & Technology

1995-09-01

transfer project. (D) 8a Organization has a technology transfer organization. (D,A) 10a Marketing and advertising of technologies targeted to relevant...Entrepreneurial (D) Developer: 10A: Marketing and advertising of technologies targeted to relevant industries. Most developers indicate that they marketed...regard to marketing and advertising . 10B: Technology maturation supported by internal units or by contracting out. Technology maturation is the

Neuronal Functions Associated with Endo- and Exocytotic Events-cum-Molecular Trafficking May Be Cell Maturation-Dependent: Lessons Learned from Studies on Botulism

DTIC Science & Technology

2011-01-01

Clostridium botulinum type A progenitor toxins . Infect Immun 64:1589–1594 Li L, Singh BR (1999) Structure -function relationship of clostridial...experimental design and demonstration of the validity of the targeted neurologic therapeutic delivery approach based on recombinant botulinum toxin ...Endocytosis Exocytosis Molecular trafficking Cell maturation Botulism Targeted therapeutic Background Botulinum neurotoxins (BoNTs) are produced by

Prognostic benefit of optimum left ventricular lead position in cardiac resynchronization therapy: follow-up of the TARGET Study Cohort (Targeted Left Ventricular Lead Placement to guide Cardiac Resynchronization Therapy).

PubMed

Kydd, Anna C; Khan, Fakhar Z; Watson, William D; Pugh, Peter J; Virdee, Munmohan S; Dutka, David P

2014-06-01

This study was conducted to assess the impact of left ventricular (LV) lead position on longer-term survival after cardiac resynchronization therapy (CRT). An optimal LV lead position in CRT is associated with improved clinical outcome. A strategy of speckle-tracking echocardiography can be used to guide the implanter to the site of latest activation and away from segments of low strain amplitude (scar). Long-term, prospective survival data according to LV lead position in CRT are limited. Data from a follow-up registry of 250 consecutive patients receiving CRT between June 2008 and July 2010 were studied. The study population comprised patients recruited to the derivation group and the subsequent TARGET (Targeted Left Ventricular Lead Placement to guide Cardiac Resynchronization Therapy) randomized, controlled trial. Final LV lead position was described, in relation to the pacing site determined by pre-procedure speckle-tracking echocardiography, as optimal (concordant/adjacent) or suboptimal (remote). All-cause mortality was recorded at follow-up. An optimal LV lead position (n = 202) conferred LV remodeling response superior to that of a suboptimal lead position (change in LV end-systolic volume: -24 ± 15% vs. -12 ± 17% [p < 0.001]; change in ejection fraction: +7 ± 8% vs. +4 ± 7% [p = 0.02]). During long-term follow-up (median: 39 months; range: <1 to 61 months), an optimal LV lead position was associated with improved survival (log-rank p = 0.003). A suboptimal LV lead placement independently predicted all-cause mortality (hazard ratio: 1.8; p = 0.024). An optimal LV lead position at the site of latest mechanical activation, avoiding low strain amplitude (scar), was associated with superior CRT response and improved survival that persisted during follow-up. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Impact of transgenic soybean expressing Cry1Ac and Cry1F proteins on the non-target arthropod community associated with soybean in Brazil

PubMed Central

2018-01-01

Field-scale studies that examine the potential for adverse effects of Bt crop technology on non-target arthropods may supplement data from laboratory studies to support an environmental risk assessment. A three year field study was conducted in Brazil to evaluate potential for adverse effects of cultivating soybean event DAS-81419-2 that produces the Cry1Ac and Cry1F proteins. To do so, we examined the diversity and abundance of non-target arthropods (NTAs) in Bt soybean in comparison with its non-Bt near isoline, with and without conventional insecticide applications, in three Brazilian soybean producing regions. Non-target arthropod abundance was surveyed using Moericke traps (yellow pan) and pitfall trapping. Total abundance (N), richness (S), Shannon-Wiener (H’), Simpson’s (D) and Pielou’s evenness (J) values for arthropod samples were calculated for each treatment and sampling period (soybean growth stages). A faunistic analysis was used to select the most representative NTAs which were used to describe the NTA community structure associated with soybean, and to test for effects due to the treatments effects via application of the Principal Response Curve (PRC) method. Across all years and sites, a total of 254,054 individuals from 190 taxa were collected by Moericke traps, while 29,813 individuals from 100 taxa were collected using pitfall traps. Across sites and sampling dates, the abundance and diversity measurements of representative NTAs were not significantly affected by Bt soybean as compared with non-sprayed non-Bt soybean. Similarly, community analyses and repeated measures ANOVA, when applicable, indicated that neither Bt soybean nor insecticide sprays altered the structure of the NTA communities under study. These results support the conclusion that transgenic soybean event DAS-81419-2 producing Cry1Ac and Cry1F toxins does not adversely affect the NTA community associated with soybean. PMID:29394266

Effects of ongoing task context and target typicality on prospective memory performance: the importance of associative cueing

NASA Technical Reports Server (NTRS)

Nowinski, Jessica Lang; Dismukes, Key R.

2005-01-01

Two experiments examined whether prospective memory performance is influenced by contextual cues. In our automatic activation model, any information available at encoding and retrieval should aid recall of the prospective task. The first experiment demonstrated an effect of the ongoing task context; performance was better when information about the ongoing task present at retrieval was available at encoding. Performance was also improved by a strong association between the prospective memory target as it was presented at retrieval and the intention as it was encoded. Experiment 2 demonstrated boundary conditions of the ongoing task context effect, which implicate the association between the ongoing and prospective tasks formed at encoding as the source of the context effect. The results of this study are consistent with predictions based on automatic activation of intentions.

The Benefits of Targeted Memory Reactivation for Consolidation in Sleep are Contingent on Memory Accuracy and Direct Cue-Memory Associations

PubMed Central

Cairney, Scott A.; Lindsay, Shane; Sobczak, Justyna M.; Paller, Ken A.; Gaskell, M. Gareth

2016-01-01

Study Objectives: To investigate how the effects of targeted memory reactivation (TMR) are influenced by memory accuracy prior to sleep and the presence or absence of direct cue-memory associations. Methods: 30 participants associated each of 50 pictures with an unrelated word and then with a screen location in two separate tasks. During picture-location training, each picture was also presented with a semantically related sound. The sounds were therefore directly associated with the picture locations but indirectly associated with the words. During a subsequent nap, half of the sounds were replayed in slow wave sleep (SWS). The effect of TMR on memory for the picture locations (direct cue-memory associations) and picture-word pairs (indirect cue-memory associations) was then examined. Results: TMR reduced overall memory decay for recall of picture locations. Further analyses revealed a benefit of TMR for picture locations recalled with a low degree of accuracy prior to sleep, but not those recalled with a high degree of accuracy. The benefit of TMR for low accuracy memories was predicted by time spent in SWS. There was no benefit of TMR for memory of the picture-word pairs, irrespective of memory accuracy prior to sleep. Conclusions: TMR provides the greatest benefit to memories recalled with a low degree of accuracy prior to sleep. The memory benefits of TMR may also be contingent on direct cue-memory associations. Citation: Cairney SA, Lindsay S, Sobczak JM, Paller KA, Gaskell MG. The benefits of targeted memory reactivation for consolidation in sleep are contingent on memory accuracy and direct cue-memory associations. SLEEP 2016;39(5):1139–1150. PMID:26856905

Recent Progress and Advances in HGF/MET-Targeted Therapeutic Agents for Cancer Treatment

PubMed Central

Zhang, Yilong; Jain, Rajul K.; Zhu, Min

2015-01-01

The hepatocyte growth factor (HGF): MET axis is a ligand-mediated receptor tyrosine kinase pathway that is involved in multiple cellular functions, including proliferation, survival, motility, and morphogenesis. Aberrancy in the HGF/MET pathway has been reported in multiple tumor types and is associated with tumor stage and prognosis. Thus, targeting the HGF/MET pathway has become a potential therapeutic strategy in oncology development in the last two decades. A number of novel therapeutic agents—either as therapeutic proteins or small molecules that target the HGF/MET pathway—have been tested in patients with different tumor types in clinical studies. In this review, recent progress in HGF/MET pathway-targeted therapy for cancer treatment, the therapeutic potential of HGF/MET-targeted agents, and challenges in the development of such agents will be discussed. PMID:28536405

Neutron measurements from beam-target reactions at the ELISE neutral beam test facility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xufei, X., E-mail: xiexufei@pku.edu.cn; Fan, T.; Nocente, M.

2014-11-15

Measurements of 2.5 MeV neutron emission from beam-target reactions performed at the ELISE neutral beam test facility are presented in this paper. The measurements are used to study the penetration of a deuterium beam in a copper dump, based on the observation of the time evolution of the neutron counting rate from beam-target reactions with a liquid scintillation detector. A calculation based on a local mixing model of deuterium deposition in the target up to a concentration of 20% at saturation is used to evaluate the expected neutron yield for comparison with data. The results are of relevance to understandmore » neutron emission associated to beam penetration in a solid target, with applications to diagnostic systems for the SPIDER and MITICA Neutral Beam Injection prototypes.« less

Comprehensive genotyping in dyslipidemia: mendelian dyslipidemias caused by rare variants and Mendelian randomization studies using common variants.

PubMed

Tada, Hayato; Kawashiri, Masa-Aki; Yamagishi, Masakazu

2017-04-01

Dyslipidemias, especially hyper-low-density lipoprotein cholesterolemia and hypertriglyceridemia, are important causal risk factors for coronary artery disease. Comprehensive genotyping using the 'next-generation sequencing' technique has facilitated the investigation of Mendelian dyslipidemias, in addition to Mendelian randomization studies using common genetic variants associated with plasma lipids and coronary artery disease. The beneficial effects of low-density lipoprotein cholesterol-lowering therapies on coronary artery disease have been verified by many randomized controlled trials over the years, and subsequent genetic studies have supported these findings. More recently, Mendelian randomization studies have preceded randomized controlled trials. When the on-target/off-target effects of rare variants and common variants exhibit the same direction, novel drugs targeting molecules identified by investigations of rare Mendelian lipid disorders could be promising. Such a strategy could aid in the search for drug discovery seeds other than those for dyslipidemias.

An analytical and experimental study of the behavior of semi-infinite metal targets under hypervelocity impact

NASA Technical Reports Server (NTRS)

Chakrapani, B.; Rand, J. L.

1971-01-01

The material strength and strain rate effects associated with the hypervelocity impact problem were considered. A yield criterion involving the second and third invariants of the stress deviator and a strain rate sensitive constitutive equation were developed. The part of total deformation which represents change in shape is attributable to the stress deviator. Constitutive equation is a means for analytically describing the mechanical response of a continuum under study. The accuracy of the yield criterion was verified utilizing the published two and three dimensional experimental data. The constants associated with the constitutive equation were determined from one dimensional quasistatic and dynamic experiments. Hypervelocity impact experiments were conducted on semi-infinite targets of 1100 aluminum, 6061 aluminum alloy, mild steel, and commercially pure lead using spherically shaped and normally incident pyrex projectiles.

Metastasis-associated long noncoding RNAs in gastrointestinal cancer: Implications for novel biomarkers and therapeutic targets

PubMed Central

Zhang, Fei-Fei; Luo, Yu-Hao; Wang, Hui; Zhao, Liang

2016-01-01

Long non-coding RNAs (lncRNAs), a newly discovered class of ncRNA molecules, have been widely accepted as crucial regulators of various diseases including cancer. Increasing numbers of studies have demonstrated that lncRNAs are involved in diverse physiological and pathophysiological processes, such as cell cycle progression, chromatin remodeling, gene transcription, and posttranscriptional processing. Aberrant expression of lncRNAs frequently occurs in gastrointestinal cancer and plays emerging roles in cancer metastasis. In this review, we focus on and outline the regulatory functions of recently identified metastasis-associated lncRNAs, and evaluate the potential roles of lncRNAs as novel diagnostic biomarkers and therapeutic targets in gastrointestinal cancer. PMID:27818589

Amplification and quantification of cold-associated microRNAs in the Colorado potato beetle (Leptinotarsa decemlineata) agricultural pest.

PubMed

Morin, M D; Frigault, J J; Lyons, P J; Crapoulet, N; Boquel, S; Storey, K B; Morin, P Jr

2017-10-01

The Colorado potato beetle [Leptinotarsa decemlineata (Say)] is an important insect pest that can inflict considerable damage to potato plants. This insect can survive extended periods of cold exposure, and yet the molecular switches underlying this phenomenon have not been fully elucidated. A better characterization of this process would highlight novel vulnerabilities associated with L. decemlineata that could serve as targets for the management of this devastating pest. Using high-throughput sequencing, the current work reveals a cold-associated signature group of microRNAs (miRNAs) in control (15 °C) and -5 °C-exposed L. decemlineata. The results show 42 differentially expressed miRNAs following cold exposure including miR-9a-3p, miR-210-3p, miR-276-5p and miR-277-3p. Functional analysis of predicted targets associated with these cold-responsive miRNAs notably linked these changes with vital metabolic and cellular processes. Overall, this study highlights the miRNAs probably responsible for facilitating cold adaptation in L. decemlineata and implicates miRNAs as a key molecular target to consider in the development of novel pest management strategies against these insects. © 2017 The Royal Entomological Society.

Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia

PubMed Central

Park, Jung Eun; Yuen, Hiu Fung; Zhou, Jian Biao; Al-aidaroos, Abdul Qader O; Guo, Ke; Valk, Peter J; Zhang, Shu Dong; Chng, Wee Joo; Hong, Cheng William; Mills, Ken; Zeng, Qi

2013-01-01

FLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 expression is upregulated by the FLT3-STAT5 signalling pathway in leukaemia cells, leading an activation of AP-1 transcription factors via ERK and JNK pathways. PRL-3-depleted AML cells showed a significant decrease in cell growth. Clinically, high PRL-3 mRNA expression was associated with FLT3-ITD mutations in four independent AML datasets with 1158 patients. Multivariable Cox-regression analysis on our Cohort 1 with 221 patients identified PRL-3 as a novel prognostic marker independent of other clinical parameters. Kaplan–Meier analysis showed high PRL-3 mRNA expression was significantly associated with poorer survival among 491 patients with normal karyotype. Targeting PRL-3 reversed the oncogenic effects in FLT3-ITD AML models in vitro and in vivo. Herein, we suggest that PRL-3 could serve as a prognostic marker to predict poorer survival and as a promising novel therapeutic target for AML patients. PMID:23929599

Mobile Apps for Teaching Intubation: Scoping Review and Critical Analysis in eLearning

PubMed Central

2017-01-01

Background Airway management is a core skill in anesthesia ensuring adequate oxygenation and delivery of inhalational agents for the patient. Objective The goals of this study were to critically evaluate the quality of airway management apps and target revised Bloom's Taxonomy cognitive levels. Methods An electronic search using the keywords “airway” and “airway management” was conducted in May 2015 across the App Store, Google Play, BlackBerry World, and Windows Store. Apps were included in the study if their content was related to airway management. App content and characteristics were extracted into a standard form and evaluated. Results A total of 65 apps met the inclusion criteria, and 73% (47/65) of apps were developed by companies or industry. Anesthesiology trainees were the target audience in only 20% (13/65) of apps. Bag mask ventilation and laryngeal mask airways were covered in only 20% (13/65) of apps. Only 2 apps were supported in the scientific literature. For Bloom’s Taxonomy, 37% (24/65) of apps targeted knowledge, 5% (3/65) comprehension, 22% (14/65) application, 28% (18/65) analysis, 9% (6/65) evaluation, and 0% synthesis. Multivariate analysis identified cost of apps, size of apps (MB), and apps targeting trainees and paramedics to be associated with higher levels of cognitive processing of revised Bloom’s Taxonomy. Conclusions Apps developed for teaching intubation target lower levels of cognitive processing and are largely not validated by research. Cost, app size, and targeted user are associated with higher cognitive levels. Trainees and all users should be aware of the paucity of the published evidence behind the efficacy of some of these apps. PMID:28874335

Mobile Apps for Teaching Intubation: Scoping Review and Critical Analysis in eLearning.

PubMed

Matava, Clyde; Leo, Anne-Marie; Alam, Fahad

2017-09-05

Airway management is a core skill in anesthesia ensuring adequate oxygenation and delivery of inhalational agents for the patient. The goals of this study were to critically evaluate the quality of airway management apps and target revised Bloom's Taxonomy cognitive levels. An electronic search using the keywords "airway" and "airway management" was conducted in May 2015 across the App Store, Google Play, BlackBerry World, and Windows Store. Apps were included in the study if their content was related to airway management. App content and characteristics were extracted into a standard form and evaluated. A total of 65 apps met the inclusion criteria, and 73% (47/65) of apps were developed by companies or industry. Anesthesiology trainees were the target audience in only 20% (13/65) of apps. Bag mask ventilation and laryngeal mask airways were covered in only 20% (13/65) of apps. Only 2 apps were supported in the scientific literature. For Bloom's Taxonomy, 37% (24/65) of apps targeted knowledge, 5% (3/65) comprehension, 22% (14/65) application, 28% (18/65) analysis, 9% (6/65) evaluation, and 0% synthesis. Multivariate analysis identified cost of apps, size of apps (MB), and apps targeting trainees and paramedics to be associated with higher levels of cognitive processing of revised Bloom's Taxonomy. Apps developed for teaching intubation target lower levels of cognitive processing and are largely not validated by research. Cost, app size, and targeted user are associated with higher cognitive levels. Trainees and all users should be aware of the paucity of the published evidence behind the efficacy of some of these apps. ©Clyde Matava, Anne-Marie Leo, Fahad Alam. Originally published in JMIR Medical Education (http://mededu.jmir.org), 05.09.2017.

State-Targeted Funding and Technical Assistance to Increase Access to Medication Treatment for Opioid Use Disorder.

PubMed

Abraham, Amanda J; Andrews, Christina M; Grogan, Colleen M; Pollack, Harold A; D'Aunno, Thomas; Humphreys, Keith; Friedmann, Peter D

2018-04-01

As the United States grapples with an opioid epidemic, expanding access to effective treatment for opioid use disorder is a major public health priority. Identifying effective policy tools that can be used to expand access to care is critically important. This article examines the relationship between state-targeted funding and technical assistance and adoption of three medications for treating opioid use disorder: oral naltrexone, injectable naltrexone, and buprenorphine. This study draws from the 2013-2014 wave of the National Drug Abuse Treatment System Survey, a nationally representative, longitudinal study of substance use disorder treatment programs. The sample includes data from 695 treatment programs (85.5% response rate) and representatives from single-state agencies in 49 states and Washington, D.C. (98% response rate). Logistic regression was used to examine the relationships of single-state agency targeted funding and technical assistance to availability of opioid use disorder medications among treatment programs. State-targeted funding was associated with increased program-level adoption of oral naltrexone (adjusted odds ratio [AOR]=3.14, 95% confidence interval [CI]=1.49-6.60, p=.004) and buprenorphine (AOR=2.47, 95% CI=1.31-4.67, p=.006). Buprenorphine adoption was also correlated with state technical assistance to support medication provision (AOR=1.18, 95% CI=1.00-1.39, p=.049). State-targeted funding for medications may be a viable policy lever for increasing access to opioid use disorder medications. Given the historically low rates of opioid use disorder medication adoption in treatment programs, single-state agency targeted funding is a potentially important tool to reduce mortality and morbidity associated with opioid disorders and misuse.

Discovery of Transcriptional Targets Regulated by Nuclear Receptors Using a Probabilistic Graphical Model

PubMed Central

Lee, Mikyung; Huang, Ruili; Tong, Weida

2016-01-01

Nuclear receptors (NRs) are ligand-activated transcriptional regulators that play vital roles in key biological processes such as growth, differentiation, metabolism, reproduction, and morphogenesis. Disruption of NRs can result in adverse health effects such as NR-mediated endocrine disruption. A comprehensive understanding of core transcriptional targets regulated by NRs helps to elucidate their key biological processes in both toxicological and therapeutic aspects. In this study, we applied a probabilistic graphical model to identify the transcriptional targets of NRs and the biological processes they govern. The Tox21 program profiled a collection of approximate 10 000 environmental chemicals and drugs against a panel of human NRs in a quantitative high-throughput screening format for their NR disruption potential. The Japanese Toxicogenomics Project, one of the most comprehensive efforts in the field of toxicogenomics, generated large-scale gene expression profiles on the effect of 131 compounds (in its first phase of study) at various doses, and different durations, and their combinations. We applied author-topic model to these 2 toxicological datasets, which consists of 11 NRs run in either agonist and/or antagonist mode (18 assays total) and 203 in vitro human gene expression profiles connected by 52 shared drugs. As a result, a set of clusters (topics), which consists of a set of NRs and their associated target genes were determined. Various transcriptional targets of the NRs were identified by assays run in either agonist or antagonist mode. Our results were validated by functional analysis and compared with TRANSFAC data. In summary, our approach resulted in effective identification of associated/affected NRs and their target genes, providing biologically meaningful hypothesis embedded in their relationships. PMID:26643261

Inferring protein domains associated with drug side effects based on drug-target interaction network.

PubMed

Iwata, Hiroaki; Mizutani, Sayaka; Tabei, Yasuo; Kotera, Masaaki; Goto, Susumu; Yamanishi, Yoshihiro

2013-01-01

Most phenotypic effects of drugs are involved in the interactions between drugs and their target proteins, however, our knowledge about the molecular mechanism of the drug-target interactions is very limited. One of challenging issues in recent pharmaceutical science is to identify the underlying molecular features which govern drug-target interactions. In this paper, we make a systematic analysis of the correlation between drug side effects and protein domains, which we call "pharmacogenomic features," based on the drug-target interaction network. We detect drug side effects and protein domains that appear jointly in known drug-target interactions, which is made possible by using classifiers with sparse models. It is shown that the inferred pharmacogenomic features can be used for predicting potential drug-target interactions. We also discuss advantages and limitations of the pharmacogenomic features, compared with the chemogenomic features that are the associations between drug chemical substructures and protein domains. The inferred side effect-domain association network is expected to be useful for estimating common drug side effects for different protein families and characteristic drug side effects for specific protein domains.

Long-term adaptation to change in implicit contextual learning.

PubMed

Zellin, Martina; von Mühlenen, Adrian; Müller, Hermann J; Conci, Markus

2014-08-01

The visual world consists of spatial regularities that are acquired through experience in order to guide attentional orienting. For instance, in visual search, detection of a target is faster when a layout of nontarget items is encountered repeatedly, suggesting that learned contextual associations can guide attention (contextual cuing). However, scene layouts sometimes change, requiring observers to adapt previous memory representations. Here, we investigated the long-term dynamics of contextual adaptation after a permanent change of the target location. We observed fast and reliable learning of initial context-target associations after just three repetitions. However, adaptation of acquired contextual representations to relocated targets was slow and effortful, requiring 3 days of training with overall 80 repetitions. A final test 1 week later revealed equivalent effects of contextual cuing for both target locations, and these were comparable to the effects observed on day 1. That is, observers learned both initial target locations and relocated targets, given extensive training combined with extended periods of consolidation. Thus, while implicit contextual learning efficiently extracts statistical regularities of our environment at first, it is rather insensitive to change in the longer term, especially when subtle changes in context-target associations need to be acquired.

Cue-independent forgetting by intentional suppression - Evidence for inhibition as the mechanism of intentional forgetting.

PubMed

Wang, Yingying; Cao, Zhijun; Zhu, Zijian; Cai, Huaqian; Wu, Yanhong

2015-10-01

People are able to intentionally forget unwanted memories through voluntary suppression, as revealed by the Think/No-think (TNT) paradigm. However, the nature of intentional forgetting is controversial. Findings that forgetting is independent of retrieval cues suggest that inhibitory control underlies intentional forgetting, but this result is also in line with an interference account. To resolve this controversy, we have directly contrasted the cue-independent characteristic of suppression versus interference. A double-cue paradigm was used, in which two different cues were associated with the same target during initial memory formation. Only one cue-target association received further interference/suppression training. In the test phase, when both cues were used to retrieve the target, we found that interference caused memory impairment that was restricted to the trained cue-target association, while suppression induced forgetting that generalized to the independent cue-target association. Therefore, the effect of suppression differs from that of interference. The cue-independent forgetting by voluntary suppression indicates that the target memory itself is inhibited, providing evidence that the underlying mechanism of suppression-induced forgetting is inhibitory control. Copyright © 2015 Elsevier B.V. All rights reserved.

Enteropeptidase: A Gene Associated with a Starvation Human Phenotype and a Novel Target for Obesity Treatment

PubMed Central

Braud, Sandrine; Ciufolini, Marco A.; Harosh, Itzik

2012-01-01

Background Obesity research focuses essentially on gene targets associated with the obese phenotype. None of these targets have yet provided a viable drug therapy. Focusing instead on genes that are involved in energy absorption and that are associated with a “human starvation phenotype”, we have identified enteropeptidase (EP), a gene associated with congenital enteropeptidase deficiency, as a novel target for obesity treatment. The advantages of this target are that the gene is expressed exclusively in the brush border of the intestine; it is peripheral and not redundant. Methodology/Principal Findings Potent and selective EP inhibitors were designed around a boroarginine or borolysine motif. Oral administration of these compounds to mice restricted the bioavailability of dietary energy, and in a long-term treatment it significantly diminished the rate of increase in body weight, despite ad libitum food intake. No adverse reactions of the type seen with lipase inhibitors, such as diarrhea or steatorrhea, were observed. This validates EP as a novel, druggable target for obesity treatment. Conclusions In vivo testing of novel boroarginine or borolysine-based EP inhibitors validates a novel approach to the treatment of obesity. PMID:23185382

Antibody targeting of HER2/HER3 signaling overcomes heregulin-induced resistance to PI3K inhibition in prostate cancer.

PubMed

Poovassery, Jayakumar S; Kang, Jeffrey C; Kim, Dongyoung; Ober, Raimund J; Ward, E Sally

2015-07-15

Dysregulated expression and/or mutations of the various components of the phosphoinositide 3-kinase (PI3K)/Akt pathway occur with high frequency in prostate cancer and are associated with the development and progression of castration resistant tumors. However, small molecule kinase inhibitors that target this signaling pathway have limited efficacy in inhibiting tumor growth, primarily due to compensatory survival signals through receptor tyrosine kinases (RTKs). Although members of the epidermal growth factor receptor (EGFR), or HER, family of RTKs are strongly implicated in the development and progression of prostate cancer, targeting individual members of this family such as EGFR or HER2 has resulted in limited success in clinical trials. Multiple studies indicate a critical role for HER3 in the development of resistance against both HER-targeted therapies and PI3K/Akt pathway inhibitors. In this study, we found that the growth inhibitory effect of GDC-0941, a class I PI3K inhibitor, is markedly reduced in the presence of heregulin. Interestingly, this effect is more pronounced in cells lacking phosphatase and tensin homolog function. Heregulin-mediated resistance to GDC-0941 is associated with reactivation of Akt downstream of HER3 phosphorylation. Importantly, combined blockade of HER2 and HER3 signaling by an anti-HER2/HER3 bispecific antibody or a mixture of anti-HER2 and anti-HER3 antibodies restores sensitivity to GDC-0941 in heregulin-treated androgen-dependent and -independent prostate cancer cells. These studies indicate that the combination of PI3K inhibitors with HER2/HER3 targeting antibodies may constitute a promising therapeutic strategy for prostate cancer. © 2014 UICC.

Study of Plasma Liner Driven Magnetized Target Fusion Via Advanced Simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Samulyak, Roman V.; Brookhaven National Lab.; Parks, Paul

The feasibility of the plasma liner driven Magnetized Target Fusion (MTF) via terascale numerical simulations will be assessed. In the MTF concept, a plasma liner, formed by merging of a number (60 or more) of radial, highly supersonic plasma jets, implodes on the target in the form of two compact plasma toroids, and compresses it to conditions of the fusion ignition. By avoiding major difficulties associated with both the traditional laser driven inertial confinement fusion and solid liner driven MTF, the plasma liner driven MTF potentially provides a low-cost and fast R&D path towards the demonstration of practical fusion energy.more » High fidelity numerical simulations of full nonlinear models associated with the plasma liner MTF using state-of-art numerical algorithms and terascale computing are necessary in order to resolve uncertainties and provide guidance for future experiments. At Stony Brook University, we have developed unique computational capabilities that ideally suite the MTF problem. The FronTier code, developed in collaboration with BNL and LANL under DOE funding including SciDAC for the simulation of 3D multi-material hydro and MHD flows, has beenbenchmarked and used for fundamental and engineering problems in energy science applications. We have performed 3D simulations of converging supersonic plasma jets, their merger and the formation of the plasma liner, and a study of the corresponding oblique shock problem. We have studied the implosion of the plasma liner on the magnetized plasma target by resolving Rayleigh-Taylor instabilities in 2D and 3D and other relevant physics and estimate thermodynamic conditions of the target at the moment of maximum compression and the hydrodynamic efficiency of the method.« less

Computational analysis of ribonomics datasets identifies long non-coding RNA targets of γ-herpesviral miRNAs.

PubMed

Sethuraman, Sunantha; Thomas, Merin; Gay, Lauren A; Renne, Rolf

2018-05-29

Ribonomics experiments involving crosslinking and immuno-precipitation (CLIP) of Ago proteins have expanded the understanding of the miRNA targetome of several organisms. These techniques, collectively referred to as CLIP-seq, have been applied to identifying the mRNA targets of miRNAs expressed by Kaposi's Sarcoma-associated herpes virus (KSHV) and Epstein-Barr virus (EBV). However, these studies focused on identifying only those RNA targets of KSHV and EBV miRNAs that are known to encode proteins. Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are also targeted by miRNAs. In this study, we performed a systematic re-analysis of published datasets from KSHV- and EBV-driven cancers. We used CLIP-seq data from lymphoma cells or EBV-transformed B cells, and a crosslinking, ligation and sequencing of hybrids dataset from KSHV-infected endothelial cells, to identify novel lncRNA targets of viral miRNAs. Here, we catalog the lncRNA targetome of KSHV and EBV miRNAs, and provide a detailed in silico analysis of lncRNA-miRNA binding interactions. Viral miRNAs target several hundred lncRNAs, including a subset previously shown to be aberrantly expressed in human malignancies. In addition, we identified thousands of lncRNAs to be putative targets of human miRNAs, suggesting that miRNA-lncRNA interactions broadly contribute to the regulation of gene expression.

Distinct Functional Connectivities Predict Clinical Response with Emotion Regulation Therapy

PubMed Central

Fresco, David M.; Roy, Amy K.; Adelsberg, Samantha; Seeley, Saren; García-Lesy, Emmanuel; Liston, Conor; Mennin, Douglas S.

2017-01-01

Despite the success of available medical and psychosocial treatments, a sizable subgroup of individuals with commonly co-occurring disorders, generalized anxiety disorder (GAD) and major depressive disorder (MDD), fail to make sufficient treatment gains thereby prolonging their deficits in life functioning and satisfaction. Clinically, these patients often display temperamental features reflecting heightened sensitivity to underlying motivational systems related to threat/safety and reward/loss (e.g., somatic anxiety) as well as inordinate negative self-referential processing (e.g., worry, rumination). This profile may reflect disruption in two important neural networks associated with emotional/motivational salience (e.g., salience network) and self-referentiality (e.g., default network, DN). Emotion Regulation Therapy (ERT) was developed to target this hypothesized profile and its neurobehavioral markers. In the present study, 22 GAD patients (with and without MDD) completed resting state MRI scans before receiving 16 sessions of ERT. To test study these hypotheses, we examined the associations between baseline patterns of intrinsic functional connectivity (iFC) of the insula and of hubs within the DN (anterior and dorsal medial prefrontal cortex [MPFC] and posterior cingulate cortex [PCC]) and treatment-related changes in worry, somatic anxiety symptoms and decentering. Results suggest that greater treatment linked reductions in worry were associated with iFC clusters in both the insular and parietal cortices. Greater treatment linked gains in decentering, a metacognitive process that involves the capacity to observe items that arise in the mind with healthy psychological distance that is targeted by ERT, was associated with iFC clusters in the anterior and posterior DN. The current study adds to the growing body of research implicating disruptions in the default and salience networks as promising targets of treatment for GAD with and without co-occurring MDD. PMID:28316567

Molecular aspects of allergens in atopic dermatitis

PubMed Central

Campana, Raffaela; Dzoro, Sheron; Mittermann, Irene; Fedenko, Elena; Elisyutina, Olga; Khaitov, Musa; Karaulov, Alexander; Valenta, Rudolf

2017-01-01

Purpose of review Molecular allergology uses pure, mainly recombinant and structurally defined allergen molecules and allergen-derived epitopes to study mechanisms of IgE-associated allergy, to diagnose, and even predict the development of allergic manifestations and to treat and prevent IgE-associated allergies. Atopic dermatitis, a chronic inflammatory skin disease is almost always associated with IgE sensitization to allergens. However, also non-IgE-mediated pathomechanisms seem to be operative in atopic dermatitis and it is often difficult to identify the disease-causing allergens. Here we review recent work showing the usefulness of molecular allergology to study mechanisms of atopic dermatitis, for diagnosis and eventually for treatment and prevention of atopic dermatitis. Recent findings IgE sensitization to airborne, food-derived, microbial allergens, and autoallergens has been found to be associated with atopic dermatitis. Using defined allergen molecules and non-IgE-reactive allergen derivatives, evidence could be provided for the existence of IgE- and non-IgE-mediated mechanisms of inflammation in atopic dermatitis. Furthermore, effects of epicutaneous allergen administration on systemic allergen-specific immune responses have been studied. Multi-allergen tests containing micro-arrayed allergen molecules have been shown to be useful for the identification of culprit allergens in atopic dermatitis and may improve the management of atopic dermatitis by allergen-specific immunotherapy, allergen avoidance, and IgE-targeting therapies in a personalized medicine approach. Summary Molecular allergology allows for dissection of the pathomechanisms of atopic dermatitis, provides new forms of allergy diagnosis for identification of disease-causing allergens, and opens the door to new forms of management by allergen-specific and T cells-targeting or IgE-targeting interventions in a personalized medicine approach. PMID:28622169

Evaluating treatment outcomes and durations among cases of smear-positive pulmonary tuberculosis in Yemen: a prospective follow-up study.

PubMed

Jaber, Ammar Ali Saleh; Khan, Amer Hayat; Sulaiman, Syed Azhar Syed

2017-01-01

Evaluating outcomes after tuberculosis (TB) treatment can help identify the primary reasons for treatment success or failure. However, Yemen has a treatment success rate that remains below the World Health Organization's target. This study aimed to identify factors that were associated with unsuccessful treatment and prolonged treatment (>1 year). Newly diagnosed cases of smear-positive pulmonary TB were prospectively followed at two centers (Taiz and Alhodidah, Yemen) between April 2014 and March 2015. Standardized forms were used to obtain information from the patients regarding their socio-demographic and clinical characteristics, treatment duration, and TB-related information. Multivariate logistic regression analyses were performed to identify factors that were associated with unsuccessful treatment and prolonged treatment (>1 year). The study included data from 273 cases of newly diagnosed TB, with treatment being successful in 227 cases (83.1%) and unsuccessful in 46 cases (16.9%). Among the 46 patients with unsuccessful treatment, 29 patients (10.6%) stopped treatment, 6 patients (2.2%) transferred to another facility, 6 patients (2.2%) experienced treatment failure, and 5 patients (1.8%) died. The multivariate logistic regression analyses revealed that unsuccessful treatment was associated with female sex, illiterate status, and the presence of comorbidities. Prolonged treatment durations were associated with living in a rural area, smoking, chewing khat, a cough that lasted for >3 weeks at the beginning of treatment, and bilateral cavities during radiography. These results confirm that the treatment success rate in Yemen is lower than the World Health Organization's target for smear-positive pulmonary tuberculosis. Targeting the risk factors that we identified may help improve treatment outcomes. Furthermore, it may not be prudent to re-treat patients using first-line TB drugs after an initial treatment failure.

Predictors of HbA1c levels in patients initiating metformin.

PubMed

Martono, Doti P; Hak, Eelko; Lambers Heerspink, Hiddo; Wilffert, Bob; Denig, Petra

2016-12-01

The aim was to assess demographic and clinical factors as predictors of short (6 months) and long term (18 months) HbA1c levels in diabetes patients initiating metformin treatment. We conducted a cohort study including type 2 diabetes patients who received their first metformin prescription between 2007 and 2013 in the Groningen Initiative to Analyze Type 2 Diabetes Treatment (GIANTT) database. The primary outcome was HbA1c level at follow-up adjusted for baseline HbA1c; the secondary outcome was failing to achieve the target HbA1c level of 53 mmol/mol. Associations were analyzed by linear and logistic regression. Multiple imputation was used for missing data. Additional analyses stratified by dose and adherence level were conducted. The cohort included 6050 patients initiating metformin. Baseline HbA1c at target consistently predicted better HbA1c outcomes. Longer diabetes duration and lower total cholesterol level at baseline were predictors for higher HbA1c levels at 6 months. At 18 months, cholesterol level was not a predictor. Longer diabetes duration was also associated with not achieving the target HbA1c at follow-up. The association for longer diabetes duration was especially seen in patients starting on low dose treatment. No consistent associations were found for comorbidity and comedication. Diabetes duration was a relevant predictor of HbA1c levels after 6 and 18 months of follow-up in patients initiating metformin treatment. Given the study design, no causal inference can be made. Our study suggests that prompt treatment intensification may be needed in patients who have a longer diabetes duration at treatment initiation.

Postnatal Cardiac Gene Editing Using CRISPR/Cas9 With AAV9-Mediated Delivery of Short Guide RNAs Results in Mosaic Gene Disruption.

PubMed

Johansen, Anne Katrine; Molenaar, Bas; Versteeg, Danielle; Leitoguinho, Ana Rita; Demkes, Charlotte; Spanjaard, Bastiaan; de Ruiter, Hesther; Akbari Moqadam, Farhad; Kooijman, Lieneke; Zentilin, Lorena; Giacca, Mauro; van Rooij, Eva

2017-10-27

CRISPR/Cas9 (clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9)-based DNA editing has rapidly evolved as an attractive tool to modify the genome. Although CRISPR/Cas9 has been extensively used to manipulate the germline in zygotes, its application in postnatal gene editing remains incompletely characterized. To evaluate the feasibility of CRISPR/Cas9-based cardiac genome editing in vivo in postnatal mice. We generated cardiomyocyte-specific Cas9 mice and demonstrated that Cas9 expression does not affect cardiac function or gene expression. As a proof-of-concept, we delivered short guide RNAs targeting 3 genes critical for cardiac physiology, Myh6 , Sav1 , and Tbx20 , using a cardiotropic adeno-associated viral vector 9. Despite a similar degree of DNA disruption and subsequent mRNA downregulation, only disruption of Myh6 was sufficient to induce a cardiac phenotype, irrespective of short guide RNA exposure or the level of Cas9 expression. DNA sequencing analysis revealed target-dependent mutations that were highly reproducible across mice resulting in differential rates of in- and out-of-frame mutations. Finally, we applied a dual short guide RNA approach to effectively delete an important coding region of Sav1 , which increased the editing efficiency. Our results indicate that the effect of postnatal CRISPR/Cas9-based cardiac gene editing using adeno-associated virus serotype 9 to deliver a single short guide RNA is target dependent. We demonstrate a mosaic pattern of gene disruption, which hinders the application of the technology to study gene function. Further studies are required to expand the versatility of CRISPR/Cas9 as a robust tool to study novel cardiac gene functions in vivo. © 2017 American Heart Association, Inc.

Association of single nucleotide polymorphisms in a glutamate receptor gene (GRM8) with theta power of event-related oscillations and alcohol dependence.

PubMed

Chen, Andrew C H; Tang, Yongqiang; Rangaswamy, Madhavi; Wang, Jen C; Almasy, Laura; Foroud, Tatiana; Edenberg, Howard J; Hesselbrock, Victor; Nurnberger, John; Kuperman, Samuel; O'Connor, Sean J; Schuckit, Marc A; Bauer, Lance O; Tischfield, Jay; Rice, John P; Bierut, Laura; Goate, Alison; Porjesz, Bernice

2009-04-05

Evidence suggests the P3 amplitude of the event-related potential and its underlying superimposed event-related oscillations (EROs), primarily in the theta (4-5 Hz) and delta (1-3 Hz) frequencies, as endophenotypes for the risk of alcoholism and other disinhibitory disorders. Major neurochemical substrates contributing to theta and delta rhythms and P3 involve strong GABAergic, cholinergic and glutamatergic system interactions. The aim of this study was to test the potential associations between single nucleotide polymorphisms (SNPs) in glutamate receptor genes and ERO quantitative traits. GRM8 was selected because it maps at chromosome 7q31.3-q32.1 under the peak region where we previously identified significant linkage (peak LOD = 3.5) using a genome-wide linkage scan of the same phenotype (event-related theta band for the target visual stimuli). Neural activities recorded from scalp electrodes during a visual oddball task in which rare target elicited P3s were analyzed in a subset of the Collaborative Study on the Genetics of Alcoholism (COGA) sample comprising 1,049 Caucasian subjects from 209 families (with 472 DSM-IV alcohol dependent individuals). The family-based association test (FBAT) detected significant association (P < 0.05) with multiple SNPs in the GRM8 gene and event-related theta power to target visual stimuli, and also with alcohol dependence, even after correction for multiple comparisons by false discovery rate (FDR). Our results suggest that variation in GRM8 may be involved in modulating event-related theta oscillations during information processing and also in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders. (c) 2008 Wiley-Liss, Inc.

High vascular delivery of EGF, but low receptor binding rate is observed in AsPC-1 tumors as compared to normal pancreas.

PubMed

Samkoe, Kimberley S; Sexton, Kristian; Tichauer, Kenneth M; Hextrum, Shannon K; Pardesi, Omar; Davis, Scott C; O'Hara, Julia A; Hoopes, P Jack; Hasan, Tayyaba; Pogue, Brian W

2012-08-01

Cellular receptor targeted imaging agents present the potential to target extracellular molecular expression in cancerous lesions; however, the image contrast in vivo does not reflect the magnitude of overexpression expected from in vitro data. Here, the in vivo delivery and binding kinetics of epidermal growth factor receptor (EGFR) was determined for normal pancreas and AsPC-1 orthotopic pancreatic tumors known to overexpress EGFR. EGFR in orthotopic xenograft AsPC-1 tumors was targeted with epidermal growth factor (EGF) conjugated with IRDye800CW. The transfer rate constants (k(e), K₁₂, k₂₁, k₂₃, and k₃₂) associated with a three-compartment model describing the vascular delivery, leakage rate and binding of targeted agents were determined experimentally. The plasma excretion rate, k (e), was determined from extracted blood plasma samples. K₁₂, k₂₁, and k₃₂ were determined from ex vivo tissue washing studies at time points ≥ 24 h. The measured in vivo uptake of IRDye800CW-EGF and a non-targeted tracer dye, IRDye700DX-carboxylate, injected simultaneously was used to determined k₂₃. The vascular exchange of IRDye800CW-EGF in the orthotopic tumor (K₁₂ and k₂₁) was higher than in the AsPC-1 tumor as compared to normal pancreas, suggesting that more targeted agent can be taken up in tumor tissue. However, the cellular associated (binding) rate constant (k₂₃) was slightly lower for AsPC-1 pancreatic tumor (4.1 × 10(-4) s(-1)) than the normal pancreas (5.5 × 10(-4) s(-1)), implying that less binding is occurring. Higher vascular delivery but low cellular association in the AsPC-1 tumor compared to the normal pancreas may be indicative of low receptor density due to low cellular content. This attribute of the AsPC-1 tumor may indicate one contributing cause of the difficulty in treating pancreatic tumors with cellular targeted agents.

Child-targeted TV advertising and preschoolers' consumption of high-sugar breakfast cereals.

PubMed

Longacre, Meghan R; Drake, Keith M; Titus, Linda J; Harris, Jennifer; Cleveland, Lauren P; Langeloh, Gail; Hendricks, Kristy; Dalton, Madeline A

2017-01-01

Breakfast cereals represent the most highly advertised packaged food on child-targeted television, and most ads are for cereals high in sugar. This study examined whether children's TV exposure to child-targeted, high-sugar breakfast cereal (SBC) ads was associated with their consumption of those SBC brands. Parents of 3- to 5-year-old children were recruited from pediatric and Women, Infants, and Children (WIC) clinics in Southern New Hampshire, USA, and completed a cross-sectional survey between April-December 2013. Parents reported their child's consumption of SBC brands; whether their child had watched any of 11 kids' channels in the past week; their child's TV viewing time; and socio-demographics. Children's exposure to child-targeted SBC TV ads was calculated by combining TV channel and viewing time with advertising data for SBC ads aired on kids' TV channels during the same timeframe. Five hundred forty-eight parents completed surveys; 52.7% had an annual household income of $50,000 or less. Children's mean age was 4.4 years, 51.6% were female, and 72.5% were non-Hispanic white. In the past week, 56.9% (N = 312) of children ate SBCs advertised on kids' channels. Overall, 40.6% of children were exposed to child-targeted SBC TV ads in the past week. In fully adjusted analyses, the number of SBC brands children consumed was positively associated with their exposure to child-targeted SBC ads. Children consumed 14% (RR = 1.14, 95% CI: 1.02, 1.27) more SBC brands for every 10 SBC ads seen in the past 7 days. Exposure to child-targeted SBC TV advertising is positively associated with SBC brand consumption among preschool-aged children. These findings support recommendations to limit the marketing of high-sugar foods to young children. Copyright © 2016 Elsevier Ltd. All rights reserved.

Factors Associated with Shooting Accuracy and Wounding Rate of Four Managed Wild Deer Species in the UK, Based on Anonymous Field Records from Deer Stalkers

PubMed Central

Aebischer, Nicholas J.; Wheatley, Christopher J.; Rose, Hugh R.

2014-01-01

The amount of wounding during routine culling is an important factor in the welfare of wild deer. Little information exists on factors determining shooting accuracy and wounding rates under field conditions in the UK. In this study, 102 anonymous stalkers collected data on the outcomes and circumstances of 2281 shots. Using hot-deck imputation and generalised linear mixed modelling, we related the probability that a shot hit its target, and the probability that the shot killed the deer if it was hit, to 28 variables describing the circumstances of the shot. Overall, 96% of deer were hit, of which 93% were killed outright. A reduced probability of hitting the target was associated with an uncomfortable firing position, too little time available, shooting off elbows or freehand, taking the head or upper neck as point of aim, a heavily obscured target, a distant target, shooting at females, lack of shooting practice and a basic (or no) stalker qualification. An increase in the likelihood of wounding was associated with an uncomfortable firing position, shooting with insufficient time, a distant target (only when time was not sufficient), a bullet weight below 75 grains, a target concealed in thicket or on the move and an area rarely stalked. To maximise stalking success and deer welfare, we recommend that stalkers ensure a comfortable firing position, use a gun rest, aim at the chest, use bullets heavier than 75 grains, avoid taking a rushed shot, shoot a distant animal only if there is plenty of time, fire only when the target is stationary, avoid shooting at an obscured animal, take care when the ground is unfamiliar, and do shooting practice at least once a month. The high miss rate of basic-level stalkers suggests that training should include additional firing practice under realistic shooting conditions. PMID:25334012

Proteomic and Bioinformatic Studies for the Characterization of Response to Pemetrexed in Platinum Drug Resistant Ovarian Cancer.

PubMed

Severi, Leda; Losi, Lorena; Fonda, Sergio; Taddia, Laura; Gozzi, Gaia; Marverti, Gaetano; Magni, Fulvio; Chinello, Clizia; Stella, Martina; Sheouli, Jalid; Braicu, Elena I; Genovese, Filippo; Lauriola, Angela; Marraccini, Chiara; Gualandi, Alessandra; D'Arca, Domenico; Ferrari, Stefania; Costi, Maria P

2018-01-01

Proteomics and bioinformatics are a useful combined technology for the characterization of protein expression level and modulation associated with the response to a drug and with its mechanism of action. The folate pathway represents an important target in the anticancer drugs therapy. In the present study, a discovery proteomics approach was applied to tissue samples collected from ovarian cancer patients who relapsed after the first-line carboplatin-based chemotherapy and were treated with pemetrexed (PMX), a known folate pathway targeting drug. The aim of the work is to identify the proteomic profile that can be associated to the response to the PMX treatment in pre-treatement tissue. Statistical metrics of the experimental Mass Spectrometry (MS) data were combined with a knowledge-based approach that included bioinformatics and a literature review through ProteinQuest™ tool, to design a protein set of reference (PSR). The PSR provides feedback for the consistency of MS proteomic data because it includes known validated proteins. A panel of 24 proteins with levels that were significantly different in pre-treatment samples of patients who responded to the therapy vs. the non-responder ones, was identified. The differences of the identified proteins were explained for the patients with different outcomes and the known PMX targets were further validated. The protein panel herein identified is ready for further validation in retrospective clinical trials using a targeted proteomic approach. This study may have a general relevant impact on biomarker application for cancer patients therapy selection.

Attempted Training of Alcohol Approach and Drinking Identity Associations in US Undergraduate Drinkers: Null Results from Two Studies

PubMed Central

Lindgren, Kristen P.; Wiers, Reinout W.; Teachman, Bethany A.; Gasser, Melissa L.; Westgate, Erin C.; Cousijn, Janna; Enkema, Matthew C.; Neighbors, Clayton

2015-01-01

There is preliminary evidence that approach avoid training can shift implicit alcohol associations and improve treatment outcomes. We sought to replicate and extend those findings in US undergraduate social drinkers (Study 1) and at-risk drinkers (Study 2). Three adaptations of the approach avoid task (AAT) were tested. The first adaptation – the approach avoid training – was a replication and targeted implicit alcohol approach associations. The remaining two adaptations – the general identity and personalized identity trainings – targeted implicit drinking identity associations, which are robust predictors of hazardous drinking in US undergraduates. Study 1 included 300 undergraduate social drinkers. They were randomly assigned to real or sham training conditions for one of the three training adaptations, and completed two training sessions, spaced one week apart. Study 2 included 288 undergraduates at risk for alcohol use disorders. The same training procedures were used, but the two training sessions occurred within a single week. Results were not as expected. Across both studies, the approach avoid training yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes. The general identity training also yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes with one exception; individuals who completed real training demonstrated no changes in drinking refusal self-efficacy whereas individuals who completed sham training had reductions in self-efficacy. Finally, across both studies, the personalized identity training yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes. Despite having relatively large samples and using a well-validated training task, study results indicated all three training adaptations were ineffective at this dose in US undergraduates. These findings are important because training studies are costly and labor-intensive. Future research may benefit from focusing on more severe populations, pairing training with other interventions, increasing training dose, and increasing gamification of training tasks. PMID:26241316

Long-term memory biases auditory spatial attention.

PubMed

Zimmermann, Jacqueline F; Moscovitch, Morris; Alain, Claude

2017-10-01

Long-term memory (LTM) has been shown to bias attention to a previously learned visual target location. Here, we examined whether memory-predicted spatial location can facilitate the detection of a faint pure tone target embedded in real world audio clips (e.g., soundtrack of a restaurant). During an initial familiarization task, participants heard audio clips, some of which included a lateralized target (p = 50%). On each trial participants indicated whether the target was presented from the left, right, or was absent. Following a 1 hr retention interval, participants were presented with the same audio clips, which now all included a target. In Experiment 1, participants showed memory-based gains in response time and d'. Experiment 2 showed that temporal expectations modulate attention, with greater memory-guided attention effects on performance when temporal context was reinstated from learning (i.e., when timing of the target within audio clips was not changed from initially learned timing). Experiment 3 showed that while conscious recall of target locations was modulated by exposure to target-context associations during learning (i.e., better recall with higher number of learning blocks), the influence of LTM associations on spatial attention was not reduced (i.e., number of learning blocks did not affect memory-guided attention). Both Experiments 2 and 3 showed gains in performance related to target-context associations, even for associations that were not explicitly remembered. Together, these findings indicate that memory for audio clips is acquired quickly and is surprisingly robust; both implicit and explicit LTM for the location of a faint target tone modulated auditory spatial attention. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Targeted Metabolomics Demonstrates Distinct and Overlapping Maternal Metabolites Associated With BMI, Glucose, and Insulin Sensitivity During Pregnancy Across Four Ancestry Groups.

PubMed

Jacob, Saya; Nodzenski, Michael; Reisetter, Anna C; Bain, James R; Muehlbauer, Michael J; Stevens, Robert D; Ilkayeva, Olga R; Lowe, Lynn P; Metzger, Boyd E; Newgard, Christopher B; Scholtens, Denise M; Lowe, William L

2017-07-01

We used targeted metabolomics in pregnant mothers to compare maternal metabolite associations with maternal BMI, glycemia, and insulin sensitivity. Targeted metabolomic assays of clinical metabolites, amino acids, and acylcarnitines were performed on fasting and 1-h postglucose serum samples from European ancestry, Afro-Caribbean, Thai, and Mexican American mothers (400 from each ancestry group) who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and underwent an oral glucose tolerance test at ∼28 weeks gestation. K-means clustering, which identified patterns of metabolite levels across ancestry groups, demonstrated that, at both fasting and 1-h, levels of the majority of metabolites were similar across ancestry groups. Meta-analyses demonstrated association of a broad array of fasting and 1-h metabolites, including lipids and amino acids and their metabolites, with maternal BMI, glucose levels, and insulin sensitivity before and after adjustment for the different phenotypes. At fasting and 1 h, a mix of metabolites was identified that were common across phenotypes or associated with only one or two phenotypes. Partial correlation estimates, which allowed comparison of the strength of association of different metabolites with maternal phenotypes, demonstrated that metabolites most strongly associated with different phenotypes included some that were common across as well as unique to each phenotype. Maternal BMI and glycemia have metabolic signatures that are both shared and unique to each phenotype. These signatures largely remain consistent across different ancestry groups and may contribute to the common and independent effects of these two phenotypes on adverse pregnancy outcomes. © 2017 by the American Diabetes Association.

Novel drug target identification for the treatment of dementia using multi-relational association mining.

PubMed

Nguyen, Thanh-Phuong; Priami, Corrado; Caberlotto, Laura

2015-07-08

Dementia is a neurodegenerative condition of the brain in which there is a progressive and permanent loss of cognitive and mental performance. Despite the fact that the number of people with dementia worldwide is steadily increasing and regardless of the advances in the molecular characterization of the disease, current medical treatments for dementia are purely symptomatic and hardly effective. We present a novel multi-relational association mining method that integrates the huge amount of scientific data accumulated in recent years to predict potential novel targets for innovative therapeutic treatment of dementia. Owing to the ability of processing large volumes of heterogeneous data, our method achieves a high performance and predicts numerous drug targets including several serine threonine kinase and a G-protein coupled receptor. The predicted drug targets are mainly functionally related to metabolism, cell surface receptor signaling pathways, immune response, apoptosis, and long-term memory. Among the highly represented kinase family and among the G-protein coupled receptors, DLG4 (PSD-95), and the bradikynin receptor 2 are highlighted also for their proposed role in memory and cognition, as described in previous studies. These novel putative targets hold promises for the development of novel therapeutic approaches for the treatment of dementia.

Novel drug target identification for the treatment of dementia using multi-relational association mining

PubMed Central

Nguyen, Thanh-Phuong; Priami, Corrado; Caberlotto, Laura

2015-01-01

Dementia is a neurodegenerative condition of the brain in which there is a progressive and permanent loss of cognitive and mental performance. Despite the fact that the number of people with dementia worldwide is steadily increasing and regardless of the advances in the molecular characterization of the disease, current medical treatments for dementia are purely symptomatic and hardly effective. We present a novel multi-relational association mining method that integrates the huge amount of scientific data accumulated in recent years to predict potential novel targets for innovative therapeutic treatment of dementia. Owing to the ability of processing large volumes of heterogeneous data, our method achieves a high performance and predicts numerous drug targets including several serine threonine kinase and a G-protein coupled receptor. The predicted drug targets are mainly functionally related to metabolism, cell surface receptor signaling pathways, immune response, apoptosis, and long-term memory. Among the highly represented kinase family and among the G-protein coupled receptors, DLG4 (PSD-95), and the bradikynin receptor 2 are highlighted also for their proposed role in memory and cognition, as described in previous studies. These novel putative targets hold promises for the development of novel therapeutic approaches for the treatment of dementia. PMID:26154857

Identification of a Novel De Novo Heterozygous Deletion in the SOX10 Gene in Waardenburg Syndrome Type II Using Next-Generation Sequencing.

PubMed

Li, Haonan; Jin, Peng; Hao, Qian; Zhu, Wei; Chen, Xia; Wang, Ping

2017-11-01

Waardenburg syndrome (WS) is a rare autosomal dominant disorder associated with pigmentation abnormalities and sensorineural hearing loss. In this study, we investigated the genetic cause of WSII in a patient and evaluated the reliability of the targeted next-generation exome sequencing method for the genetic diagnosis of WS. Clinical evaluations were conducted on the patient and targeted next-generation sequencing (NGS) was used to identify the candidate genes responsible for WSII. Multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative polymerase chain reaction (qPCR) were performed to confirm the targeted NGS results. Targeted NGS detected the entire deletion of the coding sequence (CDS) of the SOX10 gene in the WSII patient. MLPA results indicated that all exons of the SOX10 heterozygous deletion were detected; no aberrant copy number in the PAX3 and microphthalmia-associated transcription factor (MITF) genes was found. Real-time qPCR results identified the mutation as a de novo heterozygous deletion. This is the first report of using a targeted NGS method for WS candidate gene sequencing; its accuracy was verified by using the MLPA and qPCR methods. Our research provides a valuable method for the genetic diagnosis of WS.

SME filter approach to multiple target tracking with false and missing measurements

NASA Astrophysics Data System (ADS)

Lee, Yong J.; Kamen, Edward W.

1993-10-01

The symmetric measurement equation (SME) filter for track maintenance in multiple target tracking is extended to the general case when there are an arbitrary unknown number of false and missing position measurements in the measurement set at any time point. It is assumed that the number N of targets is known a priori and that the target motions consist of random perturbations of constant-velocity trajectories. The key idea in the paper is to generate a new measurement vector from sums-of-products of the elements of 'feasible' N-element data vectors that pass a thresholding operation in the sums-of-products framework. Via this construction, the data association problem is completely avoided, and in addition, there is no need to identify which target measurements may correspond to false returns or which target measurements may be missing. A computer simulation of SME filter performance is given, including a comparison with the associated filter (a benchmark) and the joint probabilistic data association (JPDA) filter.

Contribution of NIH funding to new drug approvals 2010-2016.

PubMed

Galkina Cleary, Ekaterina; Beierlein, Jennifer M; Khanuja, Navleen Surjit; McNamee, Laura M; Ledley, Fred D

2018-03-06

This work examines the contribution of NIH funding to published research associated with 210 new molecular entities (NMEs) approved by the Food and Drug Administration from 2010-2016. We identified >2 million publications in PubMed related to the 210 NMEs ( n = 131,092) or their 151 known biological targets ( n = 1,966,281). Of these, >600,000 (29%) were associated with NIH-funded projects in RePORTER. This funding included >200,000 fiscal years of NIH project support (1985-2016) and project costs >$100 billion (2000-2016), representing ∼20% of the NIH budget over this period. NIH funding contributed to every one of the NMEs approved from 2010-2016 and was focused primarily on the drug targets rather than on the NMEs themselves. There were 84 first-in-class products approved in this interval, associated with >$64 billion of NIH-funded projects. The percentage of fiscal years of project funding identified through target searches, but not drug searches, was greater for NMEs discovered through targeted screening than through phenotypic methods (95% versus 82%). For targeted NMEs, funding related to targets preceded funding related to the NMEs, consistent with the expectation that basic research provides validated targets for targeted screening. This analysis, which captures basic research on biological targets as well as applied research on NMEs, suggests that the NIH contribution to research associated with new drug approvals is greater than previously appreciated and highlights the risk of reducing federal funding for basic biomedical research. Copyright © 2018 the Author(s). Published by PNAS.

American Lung Association

MedlinePlus

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Anger-irritability as a mediator of ADHD risk for adolescent alcohol use and the contribution of coping skills

PubMed Central

Harty, Seth C.; Gnagy, Elizabeth M.; Pelham, William E.; Molina, Brooke S. G.

2017-01-01

Background Research on susceptibility to alcohol use disorder within the Attention-Deficit/Hyperactivity Disorder (ADHD) population has begun to expand examination of putative moderators and mediators in order to develop effective treatments. Specific dysregulated emotions have been separately associated with ADHD and with alcohol use difficulties. The current study is the first to conjointly study these variables by testing anger-irritability as a mediator of ADHD risk for adolescent alcohol use. Methods Frequency of binge drinking, drunkenness, and alcohol problems were examined for 142 children with ADHD followed into adolescence and compared to 100 demographically similar youth without ADHD. Parent-rated anger-irritability was tested as a mediator. Behavioral and cognitive coping skills, which are key clinical treatment targets, were studied as moderators of these associations. Results Childhood ADHD was positively associated with anger-irritability and the drinking outcomes in adolescence. Anger-irritability mediated the association between ADHD and alcohol use problems, but not binge drinking or drunkenness. Behavioral and cognitive, but not avoidant, coping played a moderating role, but only of the association between childhood ADHD and anger-irritability. Conclusions Active coping strategies by adolescents with ADHD may reduce the vulnerability to alcohol problems through a reduction of negative emotions. Future research on additional mediators and treatments that target these skills is encouraged. PMID:27991655

Parents with mental health problems and their children in a German population based sample: Results of the BELLA study.

PubMed

Plass-Christl, Angela; Haller, Anne-Catherine; Otto, Christiane; Barkmann, Claus; Wiegand-Grefe, Silke; Hölling, Heike; Schulte-Markwort, Michael; Ravens-Sieberer, Ulrike; Klasen, Fionna

2017-01-01

Mental health problems (MHP) of parents are associated with an increased risk of psychological and developmental difficulties in their children. This study aims at analyzing population-based data of parents with MHP and their children and the effects of associated risk factors in order to further targeted preventive and therapeutic interventions. The BELLA study is the mental health module of the German National Health Interview and Examination Survey among Children and Adolescents. MHP in parents and in their children as well as associated risk factors were examined in a sample of N = 1158 parents with children aged 11 to 17 years. Parental MHP were identified in 18.6% of the sample. Risk factors associated with parental MHP were low SES, parental unemployment, stressful life events, parental daily strain, parental chronic disease, and child MHP. A rate of 19.1% of the children of parents with MHP reported MHP themselves, the corresponding rate among children of parents without MHP was 7.7%. In multiple regression analyses the risk for children of parents with MHP to report MHP themselves was almost two times higher than the risk of children of parents without MHP. Other significant associations with child MHP included gender, the parents' age, and stressful life events. Parental MHP constitute a significant risk for the mental health of their children. Targeted screening methods and preventive interventions are needed.

A Small Molecule that Targets r(CGG)exp and Improves Defects in Fragile X-Associated Tremor Ataxia Syndrome

PubMed Central

Disney, Matthew D.; Liu, Biao; Yang, Wang-Yong; Sellier, Chantal; Tran, Tuan; Charlet-Berguerand, Nicolas; Childs-Disney, Jessica L.

2012-01-01

The development of small molecule chemical probes or therapeutics that target RNA remains a significant challenge despite the great interest in such compounds. The most significant barrier to compound development is a lack of knowledge of the chemical and RNA motif spaces that interact specifically. Herein, we describe a bioactive small molecule probe that targets expanded r(CGG) repeats, or r(CGG)exp , that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium, binds the 5’CGG/3’GGC motifs in r(CGG)exp and disrupts a toxic r(CGG)exp -protein complex in vitro. Structure-activity relationships (SAR) studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition to r(CGG)exp . Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)exp -protein aggregates. This approach may establish a general strategy to identify lead ligands that target RNA while also providing a chemical probe to dissect the varied mechanisms by which r(CGG)exp promotes toxicity. PMID:22948243

A small molecule that targets r(CGG)(exp) and improves defects in fragile X-associated tremor ataxia syndrome.

PubMed

Disney, Matthew D; Liu, Biao; Yang, Wang-Yong; Sellier, Chantal; Tran, Tuan; Charlet-Berguerand, Nicolas; Childs-Disney, Jessica L

2012-10-19

The development of small molecule chemical probes or therapeutics that target RNA remains a significant challenge despite the great interest in such compounds. The most significant barrier to compound development is defining which chemical and RNA motif spaces interact specifically. Herein, we describe a bioactive small molecule probe that targets expanded r(CGG) repeats, or r(CGG)(exp), that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium binds the 5'CGG/3'GGC motifs in r(CGG)(exp) and disrupts a toxic r(CGG)(exp)-protein complex in vitro. Structure-activity relationship studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition of r(CGG)(exp). Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)(exp)-containing nuclear foci. This approach may establish a general strategy to identify lead ligands that target RNA while also providing a chemical probe to dissect the varied mechanisms by which r(CGG)(exp) promotes toxicity.

Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair-deficiency and Lynch syndrome.

PubMed

Maletzki, Claudia; Huehns, Maja; Bauer, Ingrid; Ripperger, Tim; Mork, Maureen M; Vilar, Eduardo; Klöcking, Sabine; Zettl, Heike; Prall, Friedrich; Linnebacher, Michael

2017-07-01

Mismatch-repair deficient (MMR-D) malignancies include Lynch Syndrome (LS), which is secondary to germline mutations in one of the MMR genes, and the rare childhood-form of constitutional mismatch repair-deficiency (CMMR-D); caused by bi-allelic MMR gene mutations. A hallmark of LS-associated cancers is microsatellite instability (MSI), characterized by coding frameshift mutations (cFSM) in target genes. By contrast, tumors arising in CMMR-D patients are thought to display a somatic mutation pattern differing from LS. This study has the main goal to identify cFSM in MSI target genes relevant in CMMR-D and to compare the spectrum of common somatic mutations, including alterations in DNA polymerases POLE and D1 between LS and CMMR-D. CMMR-D-associated tumors harbored more somatic mutations compared to LS cases, especially in the TP53 gene and in POLE and POLD1, where novel mutations were additionally identified. Strikingly, MSI in classical mononucleotide markers BAT40 and CAT25 was frequent in CMMR-D cases. MSI-target gene analysis revealed mutations in CMMR-D-associated tumors, some of them known to be frequently hit in LS, such as RNaseT2, HT001, and TGFβR2. Our results imply a general role for these cFSM as potential new drivers of MMR-D tumorigenesis. © 2017 Wiley Periodicals, Inc.

Epstein-Barr virus miR-BART20-5p regulates cell proliferation and apoptosis by targeting BAD.

PubMed

Kim, Hyoji; Choi, Hoyun; Lee, Suk Kyeong

2015-01-28

Although Epstein-Barr virus (EBV) BamHI A rightward transcript (BART) microRNAs (miRNAs) are ubiquitously expressed in EBV-associated tumors, the role of most BART miRNAs is unclear. In this study, we showed that Bcl-2-associated death promoter (BAD) expression was significantly lower in EBV-infected AGS-EBV cells than in EBV-negative AGS cells and investigated whether BART miRNAs target BAD. Using bioinformatics analysis, five BART miRNAs showing seed match with the 3' untranslated region (3'-UTR) of BAD were selected. Of these, only miR-BART20-5p reduced BAD expression when individually transfected into AGS cells. A luciferase assay revealed that miR-BART20-5p directly targets BAD. The expression of BAD mRNA and protein was decreased by miR-BART20-5p and increased by an inhibitor of miR-BART20-5p. PE-Annexin V staining and cell proliferation assays showed that miR-BART20-5p reduced apoptosis and enhanced cell growth. Furthermore, miR-BART20-5p increased chemoresistance to 5-fluorouracil and docetaxel. Our data suggest that miR-BART20-5p contributes to tumorigenesis of EBV-associated gastric carcinoma by directly targeting the 3'-UTR of BAD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.