set-based module discovery: Topics by Science.gov

Sample records for set-based module discovery

ConGEMs: Condensed Gene Co-Expression Module Discovery Through Rule-Based Clustering and Its Application to Carcinogenesis.

PubMed

Mallik, Saurav; Zhao, Zhongming

2017-12-28

For transcriptomic analysis, there are numerous microarray-based genomic data, especially those generated for cancer research. The typical analysis measures the difference between a cancer sample-group and a matched control group for each transcript or gene. Association rule mining is used to discover interesting item sets through rule-based methodology. Thus, it has advantages to find causal effect relationships between the transcripts. In this work, we introduce two new rule-based similarity measures-weighted rank-based Jaccard and Cosine measures-and then propose a novel computational framework to detect condensed gene co-expression modules ( C o n G E M s) through the association rule-based learning system and the weighted similarity scores. In practice, the list of evolved condensed markers that consists of both singular and complex markers in nature depends on the corresponding condensed gene sets in either antecedent or consequent of the rules of the resultant modules. In our evaluation, these markers could be supported by literature evidence, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway and Gene Ontology annotations. Specifically, we preliminarily identified differentially expressed genes using an empirical Bayes test. A recently developed algorithm-RANWAR-was then utilized to determine the association rules from these genes. Based on that, we computed the integrated similarity scores of these rule-based similarity measures between each rule-pair, and the resultant scores were used for clustering to identify the co-expressed rule-modules. We applied our method to a gene expression dataset for lung squamous cell carcinoma and a genome methylation dataset for uterine cervical carcinogenesis. Our proposed module discovery method produced better results than the traditional gene-module discovery measures. In summary, our proposed rule-based method is useful for exploring biomarker modules from transcriptomic data.
Assessment of composite motif discovery methods.

PubMed

Klepper, Kjetil; Sandve, Geir K; Abul, Osman; Johansen, Jostein; Drablos, Finn

2008-02-26

Computational discovery of regulatory elements is an important area of bioinformatics research and more than a hundred motif discovery methods have been published. Traditionally, most of these methods have addressed the problem of single motif discovery - discovering binding motifs for individual transcription factors. In higher organisms, however, transcription factors usually act in combination with nearby bound factors to induce specific regulatory behaviours. Hence, recent focus has shifted from single motifs to the discovery of sets of motifs bound by multiple cooperating transcription factors, so called composite motifs or cis-regulatory modules. Given the large number and diversity of methods available, independent assessment of methods becomes important. Although there have been several benchmark studies of single motif discovery, no similar studies have previously been conducted concerning composite motif discovery. We have developed a benchmarking framework for composite motif discovery and used it to evaluate the performance of eight published module discovery tools. Benchmark datasets were constructed based on real genomic sequences containing experimentally verified regulatory modules, and the module discovery programs were asked to predict both the locations of these modules and to specify the single motifs involved. To aid the programs in their search, we provided position weight matrices corresponding to the binding motifs of the transcription factors involved. In addition, selections of decoy matrices were mixed with the genuine matrices on one dataset to test the response of programs to varying levels of noise. Although some of the methods tested tended to score somewhat better than others overall, there were still large variations between individual datasets and no single method performed consistently better than the rest in all situations. The variation in performance on individual datasets also shows that the new benchmark datasets represents a suitable variety of challenges to most methods for module discovery.
An Iterative Time Windowed Signature Algorithm for Time Dependent Transcription Module Discovery

PubMed Central

Meng, Jia; Gao, Shou-Jiang; Huang, Yufei

2010-01-01

An algorithm for the discovery of time varying modules using genome-wide expression data is present here. When applied to large-scale time serious data, our method is designed to discover not only the transcription modules but also their timing information, which is rarely annotated by the existing approaches. Rather than assuming commonly defined time constant transcription modules, a module is depicted as a set of genes that are co-regulated during a specific period of time, i.e., a time dependent transcription module (TDTM). A rigorous mathematical definition of TDTM is provided, which is serve as an objective function for retrieving modules. Based on the definition, an effective signature algorithm is proposed that iteratively searches the transcription modules from the time series data. The proposed method was tested on the simulated systems and applied to the human time series microarray data during Kaposi's sarcoma-associated herpesvirus (KSHV) infection. The result has been verified by Expression Analysis Systematic Explorer. PMID:21552463
Development of Scientific Approach Based on Discovery Learning Module

NASA Astrophysics Data System (ADS)

Ellizar, E.; Hardeli, H.; Beltris, S.; Suharni, R.

2018-04-01

Scientific Approach is a learning process, designed to make the students actively construct their own knowledge through stages of scientific method. The scientific approach in learning process can be done by using learning modules. One of the learning model is discovery based learning. Discovery learning is a learning model for the valuable things in learning through various activities, such as observation, experience, and reasoning. In fact, the students’ activity to construct their own knowledge were not optimal. It’s because the available learning modules were not in line with the scientific approach. The purpose of this study was to develop a scientific approach discovery based learning module on Acid Based, also on electrolyte and non-electrolyte solution. The developing process of this chemistry modules use the Plomp Model with three main stages. The stages are preliminary research, prototyping stage, and the assessment stage. The subject of this research was the 10th and 11th Grade of Senior High School students (SMAN 2 Padang). Validation were tested by the experts of Chemistry lecturers and teachers. Practicality of these modules had been tested through questionnaire. The effectiveness had been tested through experimental procedure by comparing student achievement between experiment and control groups. Based on the findings, it can be concluded that the developed scientific approach discovery based learning module significantly improve the students’ learning in Acid-based and Electrolyte solution. The result of the data analysis indicated that the chemistry module was valid in content, construct, and presentation. Chemistry module also has a good practicality level and also accordance with the available time. This chemistry module was also effective, because it can help the students to understand the content of the learning material. That’s proved by the result of learning student. Based on the result can conclude that chemistry module based on discovery learning and scientific approach in electrolyte and non-electrolyte solution and Acid Based for the 10th and 11th grade of senior high school students were valid, practice, and effective.
Network-based approach to identify prognostic biomarkers for estrogen receptor-positive breast cancer treatment with tamoxifen.

PubMed

Liu, Rong; Guo, Cheng-Xian; Zhou, Hong-Hao

2015-01-01

This study aims to identify effective gene networks and prognostic biomarkers associated with estrogen receptor positive (ER+) breast cancer using human mRNA studies. Weighted gene coexpression network analysis was performed with a complex ER+ breast cancer transcriptome to investigate the function of networks and key genes in the prognosis of breast cancer. We found a significant correlation of an expression module with distant metastasis-free survival (HR = 2.25; 95% CI .21.03-4.88 in discovery set; HR = 1.78; 95% CI = 1.07-2.93 in validation set). This module contained genes enriched in the biological process of the M phase. From this module, we further identified and validated 5 hub genes (CDK1, DLGAP5, MELK, NUSAP1, and RRM2), the expression levels of which were strongly associated with poor survival. Highly expressed MELK indicated poor survival in luminal A and luminal B breast cancer molecular subtypes. This gene was also found to be associated with tamoxifen resistance. Results indicated that a network-based approach may facilitate the discovery of biomarkers for the prognosis of ER+ breast cancer and may also be used as a basis for establishing personalized therapies. Nevertheless, before the application of this approach in clinical settings, in vivo and in vitro experiments and multi-center randomized controlled clinical trials are still needed.
The promises and pitfalls of RNA-interference-based therapeutics

PubMed Central

Castanotto, Daniela; Rossi, John J.

2009-01-01

The discovery that gene expression can be controlled by the Watson–Crick base-pairing of small RNAs with messenger RNAs containing complementary sequence — a process known as RNA interference — has markedly advanced our understanding of eukaryotic gene regulation and function. The ability of short RNA sequences to modulate gene expression has provided a powerful tool with which to study gene function and is set to revolutionize the treatment of disease. Remarkably, despite being just one decade from its discovery, the phenomenon is already being used therapeutically in human clinical trials, and biotechnology companies that focus on RNA-interference-based therapeutics are already publicly traded. PMID:19158789
Global Landscape of a Co-Expressed Gene Network in Barley and its Application to Gene Discovery in Triticeae Crops

PubMed Central

Mochida, Keiichi; Uehara-Yamaguchi, Yukiko; Yoshida, Takuhiro; Sakurai, Tetsuya; Shinozaki, Kazuo

2011-01-01

Accumulated transcriptome data can be used to investigate regulatory networks of genes involved in various biological systems. Co-expression analysis data sets generated from comprehensively collected transcriptome data sets now represent efficient resources that are capable of facilitating the discovery of genes with closely correlated expression patterns. In order to construct a co-expression network for barley, we analyzed 45 publicly available experimental series, which are composed of 1,347 sets of GeneChip data for barley. On the basis of a gene-to-gene weighted correlation coefficient, we constructed a global barley co-expression network and classified it into clusters of subnetwork modules. The resulting clusters are candidates for functional regulatory modules in the barley transcriptome. To annotate each of the modules, we performed comparative annotation using genes in Arabidopsis and Brachypodium distachyon. On the basis of a comparative analysis between barley and two model species, we investigated functional properties from the representative distributions of the gene ontology (GO) terms. Modules putatively involved in drought stress response and cellulose biogenesis have been identified. These modules are discussed to demonstrate the effectiveness of the co-expression analysis. Furthermore, we applied the data set of co-expressed genes coupled with comparative analysis in attempts to discover potentially Triticeae-specific network modules. These results demonstrate that analysis of the co-expression network of the barley transcriptome together with comparative analysis should promote the process of gene discovery in barley. Furthermore, the insights obtained should be transferable to investigations of Triticeae plants. The associated data set generated in this analysis is publicly accessible at http://coexpression.psc.riken.jp/barley/. PMID:21441235
Immediate Dissemination of Student Discoveries to a Model Organism Database Enhances Classroom-Based Research Experiences

PubMed Central

Wiley, Emily A.; Stover, Nicholas A.

2014-01-01

Use of inquiry-based research modules in the classroom has soared over recent years, largely in response to national calls for teaching that provides experience with scientific processes and methodologies. To increase the visibility of in-class studies among interested researchers and to strengthen their impact on student learning, we have extended the typical model of inquiry-based labs to include a means for targeted dissemination of student-generated discoveries. This initiative required: 1) creating a set of research-based lab activities with the potential to yield results that a particular scientific community would find useful and 2) developing a means for immediate sharing of student-generated results. Working toward these goals, we designed guides for course-based research aimed to fulfill the need for functional annotation of the Tetrahymena thermophila genome, and developed an interactive Web database that links directly to the official Tetrahymena Genome Database for immediate, targeted dissemination of student discoveries. This combination of research via the course modules and the opportunity for students to immediately “publish” their novel results on a Web database actively used by outside scientists culminated in a motivational tool that enhanced students’ efforts to engage the scientific process and pursue additional research opportunities beyond the course. PMID:24591511
Immediate dissemination of student discoveries to a model organism database enhances classroom-based research experiences.

PubMed

Wiley, Emily A; Stover, Nicholas A

2014-01-01

Use of inquiry-based research modules in the classroom has soared over recent years, largely in response to national calls for teaching that provides experience with scientific processes and methodologies. To increase the visibility of in-class studies among interested researchers and to strengthen their impact on student learning, we have extended the typical model of inquiry-based labs to include a means for targeted dissemination of student-generated discoveries. This initiative required: 1) creating a set of research-based lab activities with the potential to yield results that a particular scientific community would find useful and 2) developing a means for immediate sharing of student-generated results. Working toward these goals, we designed guides for course-based research aimed to fulfill the need for functional annotation of the Tetrahymena thermophila genome, and developed an interactive Web database that links directly to the official Tetrahymena Genome Database for immediate, targeted dissemination of student discoveries. This combination of research via the course modules and the opportunity for students to immediately "publish" their novel results on a Web database actively used by outside scientists culminated in a motivational tool that enhanced students' efforts to engage the scientific process and pursue additional research opportunities beyond the course.
Discovery of error-tolerant biclusters from noisy gene expression data.

PubMed

Gupta, Rohit; Rao, Navneet; Kumar, Vipin

2011-11-24

An important analysis performed on microarray gene-expression data is to discover biclusters, which denote groups of genes that are coherently expressed for a subset of conditions. Various biclustering algorithms have been proposed to find different types of biclusters from these real-valued gene-expression data sets. However, these algorithms suffer from several limitations such as inability to explicitly handle errors/noise in the data; difficulty in discovering small bicliusters due to their top-down approach; inability of some of the approaches to find overlapping biclusters, which is crucial as many genes participate in multiple biological processes. Association pattern mining also produce biclusters as their result and can naturally address some of these limitations. However, traditional association mining only finds exact biclusters, which limits its applicability in real-life data sets where the biclusters may be fragmented due to random noise/errors. Moreover, as they only work with binary or boolean attributes, their application on gene-expression data require transforming real-valued attributes to binary attributes, which often results in loss of information. Many past approaches have tried to address the issue of noise and handling real-valued attributes independently but there is no systematic approach that addresses both of these issues together. In this paper, we first propose a novel error-tolerant biclustering model, 'ET-bicluster', and then propose a bottom-up heuristic-based mining algorithm to sequentially discover error-tolerant biclusters directly from real-valued gene-expression data. The efficacy of our proposed approach is illustrated by comparing it with a recent approach RAP in the context of two biological problems: discovery of functional modules and discovery of biomarkers. For the first problem, two real-valued S.Cerevisiae microarray gene-expression data sets are used to demonstrate that the biclusters obtained from ET-bicluster approach not only recover larger set of genes as compared to those obtained from RAP approach but also have higher functional coherence as evaluated using the GO-based functional enrichment analysis. The statistical significance of the discovered error-tolerant biclusters as estimated by using two randomization tests, reveal that they are indeed biologically meaningful and statistically significant. For the second problem of biomarker discovery, we used four real-valued Breast Cancer microarray gene-expression data sets and evaluate the biomarkers obtained using MSigDB gene sets. The results obtained for both the problems: functional module discovery and biomarkers discovery, clearly signifies the usefulness of the proposed ET-bicluster approach and illustrate the importance of explicitly incorporating noise/errors in discovering coherent groups of genes from gene-expression data.
Insight into structural requirements for selective and/or dual CXCR3 and CXCR4 allosteric modulators.

PubMed

Kolarič, Anja; Švajger, Urban; Tomašič, Tihomir; Brox, Regine; Frank, Theresa; Minovski, Nikola; Tschammer, Nuska; Anderluh, Marko

2018-05-11

Based on the previously published pyrazolopyridine-based hit compound for which negative allosteric modulation of both CXCR3 and CXCR4 receptors was disclosed, we designed, synthesized and biologically evaluated a set of novel, not only negative, but also positive allosteric modulators with preserved pyrazolopyridine core. Compound 9e is a dual negative modulator, inhibiting G protein activity of both receptors. For CXCR4 receptor para-substituted aromatic group of compounds distinguishes between negative and positive modulation. Para-methoxy substitution leads to functional antagonism, while para-chloro triggers agonism. Additionally, we discovered that chemotaxis is not completely correlated with G protein pathways. This is the first work in which we have on a series of compounds successfully demonstrated that it is possible to produce selective as well as dual-acting modulators of chemokine receptors, which is very promising for future research in the field of discovery of selective or dual modulators of chemokine receptors. Copyright © 2018 Elsevier Masson SAS. All rights reserved.
Trellis Tone Modulation Multiple-Access for Peer Discovery in D2D Networks

PubMed Central

Lim, Chiwoo; Kim, Sang-Hyo

2018-01-01

In this paper, a new non-orthogonal multiple-access scheme, trellis tone modulation multiple-access (TTMMA), is proposed for peer discovery of distributed device-to-device (D2D) communication. The range and capacity of discovery are important performance metrics in peer discovery. The proposed trellis tone modulation uses single-tone transmission and achieves a long discovery range due to its low Peak-to-Average Power Ratio (PAPR). The TTMMA also exploits non-orthogonal resource assignment to increase the discovery capacity. For the multi-user detection of superposed multiple-access signals, a message-passing algorithm with supplementary schemes are proposed. With TTMMA and its message-passing demodulation, approximately 1.5 times the number of devices are discovered compared to the conventional frequency division multiple-access (FDMA)-based discovery. PMID:29673167
Trellis Tone Modulation Multiple-Access for Peer Discovery in D2D Networks.

PubMed

Lim, Chiwoo; Jang, Min; Kim, Sang-Hyo

2018-04-17

In this paper, a new non-orthogonal multiple-access scheme, trellis tone modulation multiple-access (TTMMA), is proposed for peer discovery of distributed device-to-device (D2D) communication. The range and capacity of discovery are important performance metrics in peer discovery. The proposed trellis tone modulation uses single-tone transmission and achieves a long discovery range due to its low Peak-to-Average Power Ratio (PAPR). The TTMMA also exploits non-orthogonal resource assignment to increase the discovery capacity. For the multi-user detection of superposed multiple-access signals, a message-passing algorithm with supplementary schemes are proposed. With TTMMA and its message-passing demodulation, approximately 1.5 times the number of devices are discovered compared to the conventional frequency division multiple-access (FDMA)-based discovery.
The extraction of drug-disease correlations based on module distance in incomplete human interactome.

PubMed

Yu, Liang; Wang, Bingbo; Ma, Xiaoke; Gao, Lin

2016-12-23

Extracting drug-disease correlations is crucial in unveiling disease mechanisms, as well as discovering new indications of available drugs, or drug repositioning. Both the interactome and the knowledge of disease-associated and drug-associated genes remain incomplete. We present a new method to predict the associations between drugs and diseases. Our method is based on a module distance, which is originally proposed to calculate distances between modules in incomplete human interactome. We first map all the disease genes and drug genes to a combined protein interaction network. Then based on the module distance, we calculate the distances between drug gene sets and disease gene sets, and take the distances as the relationships of drug-disease pairs. We also filter possible false positive drug-disease correlations by p-value. Finally, we validate the top-100 drug-disease associations related to six drugs in the predicted results. The overlapping between our predicted correlations with those reported in Comparative Toxicogenomics Database (CTD) and literatures, and their enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways demonstrate our approach can not only effectively identify new drug indications, but also provide new insight into drug-disease discovery.
Effectiveness of Discovery Learning-Based Transformation Geometry Module

NASA Astrophysics Data System (ADS)

Febriana, R.; Haryono, Y.; Yusri, R.

2017-09-01

Development of transformation geometry module is conducted because the students got difficulties to understand the existing book. The purpose of the research was to find out the effectiveness of discovery learning-based transformation geometry module toward student’s activity. Model of the development was Plomp model consisting preliminary research, prototyping phase and assessment phase. The research was focused on assessment phase where it was to observe the designed product effectiveness. The instrument was observation sheet. The observed activities were visual activities, oral activities, listening activities, mental activities, emotional activities and motor activities. Based on the result of the research, it is found that visual activities, learning activities, writing activities, the student’s activity is in the criteria very effective. It can be concluded that the use of discovery learning-based transformation geometry module use can increase the positive student’s activity and decrease the negative activity.
Route to three-dimensional fragments using diversity-oriented synthesis

PubMed Central

Hung, Alvin W.; Ramek, Alex; Wang, Yikai; Kaya, Taner; Wilson, J. Anthony; Clemons, Paul A.; Young, Damian W.

2011-01-01

Fragment-based drug discovery (FBDD) has proven to be an effective means of producing high-quality chemical ligands as starting points for drug-discovery pursuits. The increasing number of clinical candidate drugs developed using FBDD approaches is a testament of the efficacy of this approach. The success of fragment-based methods is highly dependent on the identity of the fragment library used for screening. The vast majority of FBDD has centered on the use of sp2-rich aromatic compounds. An expanded set of fragments that possess more 3D character would provide access to a larger chemical space of fragments than those currently used. Diversity-oriented synthesis (DOS) aims to efficiently generate a set of molecules diverse in skeletal and stereochemical properties. Molecules derived from DOS have also displayed significant success in the modulation of function of various “difficult” targets. Herein, we describe the application of DOS toward the construction of a unique set of fragments containing highly sp3-rich skeletons for fragment-based screening. Using cheminformatic analysis, we quantified the shapes and physical properties of the new 3D fragments and compared them with a database containing known fragment-like molecules. PMID:21482811
Route to three-dimensional fragments using diversity-oriented synthesis.

PubMed

Hung, Alvin W; Ramek, Alex; Wang, Yikai; Kaya, Taner; Wilson, J Anthony; Clemons, Paul A; Young, Damian W

2011-04-26

Fragment-based drug discovery (FBDD) has proven to be an effective means of producing high-quality chemical ligands as starting points for drug-discovery pursuits. The increasing number of clinical candidate drugs developed using FBDD approaches is a testament of the efficacy of this approach. The success of fragment-based methods is highly dependent on the identity of the fragment library used for screening. The vast majority of FBDD has centered on the use of sp(2)-rich aromatic compounds. An expanded set of fragments that possess more 3D character would provide access to a larger chemical space of fragments than those currently used. Diversity-oriented synthesis (DOS) aims to efficiently generate a set of molecules diverse in skeletal and stereochemical properties. Molecules derived from DOS have also displayed significant success in the modulation of function of various "difficult" targets. Herein, we describe the application of DOS toward the construction of a unique set of fragments containing highly sp(3)-rich skeletons for fragment-based screening. Using cheminformatic analysis, we quantified the shapes and physical properties of the new 3D fragments and compared them with a database containing known fragment-like molecules.
WHAM!: a web-based visualization suite for user-defined analysis of metagenomic shotgun sequencing data.

PubMed

Devlin, Joseph C; Battaglia, Thomas; Blaser, Martin J; Ruggles, Kelly V

2018-06-25

Exploration of large data sets, such as shotgun metagenomic sequence or expression data, by biomedical experts and medical professionals remains as a major bottleneck in the scientific discovery process. Although tools for this purpose exist for 16S ribosomal RNA sequencing analysis, there is a growing but still insufficient number of user-friendly interactive visualization workflows for easy data exploration and figure generation. The development of such platforms for this purpose is necessary to accelerate and streamline microbiome laboratory research. We developed the Workflow Hub for Automated Metagenomic Exploration (WHAM!) as a web-based interactive tool capable of user-directed data visualization and statistical analysis of annotated shotgun metagenomic and metatranscriptomic data sets. WHAM! includes exploratory and hypothesis-based gene and taxa search modules for visualizing differences in microbial taxa and gene family expression across experimental groups, and for creating publication quality figures without the need for command line interface or in-house bioinformatics. WHAM! is an interactive and customizable tool for downstream metagenomic and metatranscriptomic analysis providing a user-friendly interface allowing for easy data exploration by microbiome and ecological experts to facilitate discovery in multi-dimensional and large-scale data sets.
Evaluation of students' perceptions on game based learning program using fuzzy set conjoint analysis

NASA Astrophysics Data System (ADS)

Sofian, Siti Siryani; Rambely, Azmin Sham

2017-04-01

An effectiveness of a game based learning (GBL) can be determined from an application of fuzzy set conjoint analysis. The analysis was used due to the fuzziness in determining individual perceptions. This study involved a survey collected from 36 students aged 16 years old of SMK Mersing, Johor who participated in a Mathematics Discovery Camp organized by UKM research group called PRISMatik. The aim of this research was to determine the effectiveness of the module delivered to cultivate interest in mathematics subject in the form of game based learning through different values. There were 11 games conducted for the participants and students' perceptions based on the evaluation of six criteria were measured. A seven-point Likert scale method was used to collect students' preferences and perceptions. This scale represented seven linguistic terms to indicate their perceptions on each module of GBLs. Score of perceptions were transformed into degree of similarity using fuzzy set conjoint analysis. It was found that Geometric Analysis Recreation (GEAR) module was able to increase participant preference corresponded to the six attributes generated. The computations were also made for the other 10 games conducted during the camp. Results found that interest, passion and team work were the strongest values obtained from GBL activities in this camp as participants stated very strongly agreed that these attributes fulfilled their preferences in every module. This was an indicator of efficiency for the program. The evaluation using fuzzy conjoint analysis implicated the successfulness of a fuzzy approach to evaluate students' perceptions toward GBL.
A machine-learned analysis of human gene polymorphisms modulating persisting pain points at major roles of neuroimmune processes.

PubMed

Kringel, Dario; Lippmann, Catharina; Parnham, Michael J; Kalso, Eija; Ultsch, Alfred; Lötsch, Jörn

2018-06-19

Human genetic research has implicated functional variants of more than one hundred genes in the modulation of persisting pain. Artificial intelligence and machine learning techniques may combine this knowledge with results of genetic research gathered in any context, which permits the identification of the key biological processes involved in chronic sensitization to pain. Based on published evidence, a set of 110 genes carrying variants reported to be associated with modulation of the clinical phenotype of persisting pain in eight different clinical settings was submitted to unsupervised machine-learning aimed at functional clustering. Subsequently, a mathematically supported subset of genes, comprising those most consistently involved in persisting pain, was analyzed by means of computational functional genomics in the Gene Ontology knowledgebase. Clustering of genes with evidence for a modulation of persisting pain elucidated a functionally heterogeneous set. The situation cleared when the focus was narrowed to a genetic modulation consistently observed throughout several clinical settings. On this basis, two groups of biological processes, the immune system and nitric oxide signaling, emerged as major players in sensitization to persisting pain, which is biologically highly plausible and in agreement with other lines of pain research. The present computational functional genomics-based approach provided a computational systems-biology perspective on chronic sensitization to pain. Human genetic control of persisting pain points to the immune system as a source of potential future targets for drugs directed against persisting pain. Contemporary machine-learned methods provide innovative approaches to knowledge discovery from previous evidence. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Molecular property diagnostic suite (MPDS): Development of disease-specific open source web portals for drug discovery.

PubMed

Nagamani, S; Gaur, A S; Tanneeru, K; Muneeswaran, G; Madugula, S S; Consortium, Mpds; Druzhilovskiy, D; Poroikov, V V; Sastry, G N

2017-11-01

Molecular property diagnostic suite (MPDS) is a Galaxy-based open source drug discovery and development platform. MPDS web portals are designed for several diseases, such as tuberculosis, diabetes mellitus, and other metabolic disorders, specifically aimed to evaluate and estimate the drug-likeness of a given molecule. MPDS consists of three modules, namely data libraries, data processing, and data analysis tools which are configured and interconnected to assist drug discovery for specific diseases. The data library module encompasses vast information on chemical space, wherein the MPDS compound library comprises 110.31 million unique molecules generated from public domain databases. Every molecule is assigned with a unique ID and card, which provides complete information for the molecule. Some of the modules in the MPDS are specific to the diseases, while others are non-specific. Importantly, a suitably altered protocol can be effectively generated for another disease-specific MPDS web portal by modifying some of the modules. Thus, the MPDS suite of web portals shows great promise to emerge as disease-specific portals of great value, integrating chemoinformatics, bioinformatics, molecular modelling, and structure- and analogue-based drug discovery approaches.
Validity and Practitality of Acid-Base Module Based on Guided Discovery Learning for Senior High School

NASA Astrophysics Data System (ADS)

Yerimadesi; Bayharti; Jannah, S. M.; Lufri; Festiyed; Kiram, Y.

2018-04-01

This Research and Development(R&D) aims to produce guided discovery learning based module on topic of acid-base and determine its validity and practicality in learning. Module development used Four D (4-D) model (define, design, develop and disseminate).This research was performed until development stage. Research’s instruments were validity and practicality questionnaires. Module was validated by five experts (three chemistry lecturers of Universitas Negeri Padang and two chemistry teachers of SMAN 9 Padang). Practicality test was done by two chemistry teachers and 30 students of SMAN 9 Padang. Kappa Cohen’s was used to analyze validity and practicality. The average moment kappa was 0.86 for validity and those for practicality were 0.85 by teachers and 0.76 by students revealing high category. It can be concluded that validity and practicality was proven for high school chemistry learning.
The sun sets on the Space Shuttle Discovery during post-flight processing in the Mate-Demate Device (MDD), following its landing at NASA DFRC in California

NASA Image and Video Library

2005-08-14

The sun sets on the Space Shuttle Discovery during post-flight processing in the Mate-Demate Device (MDD), following its landing at NASA's Dryden Flight Research Center in California. The gantry-like MDD structure is used for servicing the shuttle orbiters in preparation for their ferry flight back to the Kennedy Space Center in Florida, including mounting the shuttle atop NASA's modified Boeing 747 Shuttle Carrier Aircraft. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.
SABRE: a method for assessing the stability of gene modules in complex tissues and subject populations.

PubMed

Shannon, Casey P; Chen, Virginia; Takhar, Mandeep; Hollander, Zsuzsanna; Balshaw, Robert; McManus, Bruce M; Tebbutt, Scott J; Sin, Don D; Ng, Raymond T

2016-11-14

Gene network inference (GNI) algorithms can be used to identify sets of coordinately expressed genes, termed network modules from whole transcriptome gene expression data. The identification of such modules has become a popular approach to systems biology, with important applications in translational research. Although diverse computational and statistical approaches have been devised to identify such modules, their performance behavior is still not fully understood, particularly in complex human tissues. Given human heterogeneity, one important question is how the outputs of these computational methods are sensitive to the input sample set, or stability. A related question is how this sensitivity depends on the size of the sample set. We describe here the SABRE (Similarity Across Bootstrap RE-sampling) procedure for assessing the stability of gene network modules using a re-sampling strategy, introduce a novel criterion for identifying stable modules, and demonstrate the utility of this approach in a clinically-relevant cohort, using two different gene network module discovery algorithms. The stability of modules increased as sample size increased and stable modules were more likely to be replicated in larger sets of samples. Random modules derived from permutated gene expression data were consistently unstable, as assessed by SABRE, and provide a useful baseline value for our proposed stability criterion. Gene module sets identified by different algorithms varied with respect to their stability, as assessed by SABRE. Finally, stable modules were more readily annotated in various curated gene set databases. The SABRE procedure and proposed stability criterion may provide guidance when designing systems biology studies in complex human disease and tissues.
A systems-genetics approach and data mining tool to assist in the discovery of genes underlying complex traits in Oryza sativa.

PubMed

Ficklin, Stephen P; Feltus, Frank Alex

2013-01-01

Many traits of biological and agronomic significance in plants are controlled in a complex manner where multiple genes and environmental signals affect the expression of the phenotype. In Oryza sativa (rice), thousands of quantitative genetic signals have been mapped to the rice genome. In parallel, thousands of gene expression profiles have been generated across many experimental conditions. Through the discovery of networks with real gene co-expression relationships, it is possible to identify co-localized genetic and gene expression signals that implicate complex genotype-phenotype relationships. In this work, we used a knowledge-independent, systems genetics approach, to discover a high-quality set of co-expression networks, termed Gene Interaction Layers (GILs). Twenty-two GILs were constructed from 1,306 Affymetrix microarray rice expression profiles that were pre-clustered to allow for improved capture of gene co-expression relationships. Functional genomic and genetic data, including over 8,000 QTLs and 766 phenotype-tagged SNPs (p-value < = 0.001) from genome-wide association studies, both covering over 230 different rice traits were integrated with the GILs. An online systems genetics data-mining resource, the GeneNet Engine, was constructed to enable dynamic discovery of gene sets (i.e. network modules) that overlap with genetic traits. GeneNet Engine does not provide the exact set of genes underlying a given complex trait, but through the evidence of gene-marker correspondence, co-expression, and functional enrichment, site visitors can identify genes with potential shared causality for a trait which could then be used for experimental validation. A set of 2 million SNPs was incorporated into the database and serve as a potential set of testable biomarkers for genes in modules that overlap with genetic traits. Herein, we describe two modules found using GeneNet Engine, one with significant overlap with the trait amylose content and another with significant overlap with blast disease resistance.
A Systems-Genetics Approach and Data Mining Tool to Assist in the Discovery of Genes Underlying Complex Traits in Oryza sativa

PubMed Central

Ficklin, Stephen P.; Feltus, Frank Alex

2013-01-01

Many traits of biological and agronomic significance in plants are controlled in a complex manner where multiple genes and environmental signals affect the expression of the phenotype. In Oryza sativa (rice), thousands of quantitative genetic signals have been mapped to the rice genome. In parallel, thousands of gene expression profiles have been generated across many experimental conditions. Through the discovery of networks with real gene co-expression relationships, it is possible to identify co-localized genetic and gene expression signals that implicate complex genotype-phenotype relationships. In this work, we used a knowledge-independent, systems genetics approach, to discover a high-quality set of co-expression networks, termed Gene Interaction Layers (GILs). Twenty-two GILs were constructed from 1,306 Affymetrix microarray rice expression profiles that were pre-clustered to allow for improved capture of gene co-expression relationships. Functional genomic and genetic data, including over 8,000 QTLs and 766 phenotype-tagged SNPs (p-value < = 0.001) from genome-wide association studies, both covering over 230 different rice traits were integrated with the GILs. An online systems genetics data-mining resource, the GeneNet Engine, was constructed to enable dynamic discovery of gene sets (i.e. network modules) that overlap with genetic traits. GeneNet Engine does not provide the exact set of genes underlying a given complex trait, but through the evidence of gene-marker correspondence, co-expression, and functional enrichment, site visitors can identify genes with potential shared causality for a trait which could then be used for experimental validation. A set of 2 million SNPs was incorporated into the database and serve as a potential set of testable biomarkers for genes in modules that overlap with genetic traits. Herein, we describe two modules found using GeneNet Engine, one with significant overlap with the trait amylose content and another with significant overlap with blast disease resistance. PMID:23874666
MATRYOSHKA-R (RBO-3-2) Radiation Suite in the Service Module (SM)

NASA Image and Video Library

2009-03-14

ISS018-E-040944 (18 March 2009) --- Cosmonaut Yury Lonchakov, Expedition 18 flight engineer, works with the European Matroshka-R Phantom experiment in the Zvezda Service Module of the International Space Station while Space Shuttle Discovery (STS-119) remains docked with the station. Matroshka, the name for the traditional Russian set of nestling dolls, is an antroph-amorphous model of a human torso designed for radiation studies.
MATRYOSHKA-R (RBO-3-2) radiation suite in service module (SM)

NASA Image and Video Library

2009-03-18

ISS018-E-040992 (18 March 2009) --- Cosmonaut Yury Lonchakov, Expedition 18 flight engineer, works with the European Matroshka-R Phantom experiment in the Zvezda Service Module of the International Space Station while Space Shuttle Discovery (STS-119) remains docked with the station. Matroshka, the name for the traditional Russian set of nestling dolls, is an antroph-amorphous model of a human torso designed for radiation studies.
KSC-2010-4425

NASA Image and Video Library

2010-08-19

CAPE CANAVERAL, Fla. -- In Orbiter Processing Facility-3 at NASA's Kennedy Space Center in Florida, the clamshell doors of space shuttle Discovery's payload bay begin to close in preparation for the its move to the Vehicle Assembly Building next month. There, it will be attached to its external fuel tank and a set of solid rocket boosters for launch on the STS-133 mission to the International Space Station. Targeted to launch Nov. 1, STS-133 will carry the multipurpose logistics module, or PMM, packed with supplies and critical spare parts, as well as Robonaut 2, or R2, to the station. Discovery will leave the module behind so it can be used for microgravity experiments in fluid physics, materials science, biology and biotechnology. Photo credit: NASA/Kim Shiflett
KSC-2010-4423

NASA Image and Video Library

2010-08-19

CAPE CANAVERAL, Fla. -- In Orbiter Processing Facility-3 at NASA's Kennedy Space Center in Florida, the clamshell doors of space shuttle Discovery's payload bay begin to close in preparation for the its move to the Vehicle Assembly Building next month. There, it will be attached to its external fuel tank and a set of solid rocket boosters for launch on the STS-133 mission to the International Space Station. Targeted to launch Nov. 1, STS-133 will carry the multipurpose logistics module, or PMM, packed with supplies and critical spare parts, as well as Robonaut 2, or R2, to the station. Discovery will leave the module behind so it can be used for microgravity experiments in fluid physics, materials science, biology and biotechnology. Photo credit: NASA/Kim Shiflett
KSC-2010-4430

NASA Image and Video Library

2010-08-19

CAPE CANAVERAL, Fla. -- In Orbiter Processing Facility-3 at NASA's Kennedy Space Center in Florida, the clamshell doors of space shuttle Discovery's payload bay close completely in preparation for the its move to the Vehicle Assembly Building next month. There, it will be attached to its external fuel tank and a set of solid rocket boosters for launch on the STS-133 mission to the International Space Station. Targeted to launch Nov. 1, STS-133 will carry the multipurpose logistics module, or PMM, packed with supplies and critical spare parts, as well as Robonaut 2, or R2, to the station. Discovery will leave the module behind so it can be used for microgravity experiments in fluid physics, materials science, biology and biotechnology. Photo credit: NASA/Kim Shiflett
KSC-2010-4431

NASA Image and Video Library

2010-08-19

CAPE CANAVERAL, Fla. -- In Orbiter Processing Facility-3 at NASA's Kennedy Space Center in Florida, the clamshell doors of space shuttle Discovery's payload bay close completely in preparation for the its move to the Vehicle Assembly Building next month. There, it will be attached to its external fuel tank and a set of solid rocket boosters for launch on the STS-133 mission to the International Space Station. Targeted to launch Nov. 1, STS-133 will carry the multipurpose logistics module, or PMM, packed with supplies and critical spare parts, as well as Robonaut 2, or R2, to the station. Discovery will leave the module behind so it can be used for microgravity experiments in fluid physics, materials science, biology and biotechnology. Photo credit: NASA/Kim Shiflett
KSC-2010-4429

NASA Image and Video Library

2010-08-19

CAPE CANAVERAL, Fla. -- In Orbiter Processing Facility-3 at NASA's Kennedy Space Center in Florida, the clamshell doors of space shuttle Discovery's payload bay close completely in preparation for the its move to the Vehicle Assembly Building next month. There, it will be attached to its external fuel tank and a set of solid rocket boosters for launch on the STS-133 mission to the International Space Station. Targeted to launch Nov. 1, STS-133 will carry the multipurpose logistics module, or PMM, packed with supplies and critical spare parts, as well as Robonaut 2, or R2, to the station. Discovery will leave the module behind so it can be used for microgravity experiments in fluid physics, materials science, biology and biotechnology. Photo credit: NASA/Kim Shiflett
KSC-2010-4432

NASA Image and Video Library

2010-08-19

CAPE CANAVERAL, Fla. -- In Orbiter Processing Facility-3 at NASA's Kennedy Space Center in Florida, the clamshell doors of space shuttle Discovery's payload bay are closed completely in preparation for the its move to the Vehicle Assembly Building next month. There, it will be attached to its external fuel tank and a set of solid rocket boosters for launch on the STS-133 mission to the International Space Station. Targeted to launch Nov. 1, STS-133 will carry the multipurpose logistics module, or PMM, packed with supplies and critical spare parts, as well as Robonaut 2, or R2, to the station. Discovery will leave the module behind so it can be used for microgravity experiments in fluid physics, materials science, biology and biotechnology. Photo credit: NASA/Kim Shiflett
KSC-2010-4422

NASA Image and Video Library

2010-08-19

CAPE CANAVERAL, Fla. -- In Orbiter Processing Facility-3 at NASA's Kennedy Space Center in Florida, the clamshell doors of space shuttle Discovery's payload bay begin to close in preparation for the its move to the Vehicle Assembly Building next month. There, it will be attached to its external fuel tank and a set of solid rocket boosters for launch on the STS-133 mission to the International Space Station. Targeted to launch Nov. 1, STS-133 will carry the multipurpose logistics module, or PMM, packed with supplies and critical spare parts, as well as Robonaut 2, or R2, to the station. Discovery will leave the module behind so it can be used for microgravity experiments in fluid physics, materials science, biology and biotechnology. Photo credit: NASA/Kim Shiflett
KSC-2010-4424

NASA Image and Video Library

2010-08-19

CAPE CANAVERAL, Fla. -- In Orbiter Processing Facility-3 at NASA's Kennedy Space Center in Florida, the clamshell doors of space shuttle Discovery's payload bay begin to close in preparation for the its move to the Vehicle Assembly Building next month. There, it will be attached to its external fuel tank and a set of solid rocket boosters for launch on the STS-133 mission to the International Space Station. Targeted to launch Nov. 1, STS-133 will carry the multipurpose logistics module, or PMM, packed with supplies and critical spare parts, as well as Robonaut 2, or R2, to the station. Discovery will leave the module behind so it can be used for microgravity experiments in fluid physics, materials science, biology and biotechnology. Photo credit: NASA/Kim Shiflett
MATRYOSHKA-R (RBO-3-2) Radiation Suite in the Service Module (SM)

NASA Image and Video Library

2009-03-14

ISS018-E-040939 (18 March 2009) --- Cosmonaut Yury Lonchakov, Expedition 18 flight engineer, prepares to work with the European Matroshka-R Phantom experiment in the Zvezda Service Module of the International Space Station while Space Shuttle Discovery (STS-119) remains docked with the station. Matroshka, the name for the traditional Russian set of nestling dolls, is an antroph-amorphous model of a human torso designed for radiation studies.
Drug repositioning for enzyme modulator based on human metabolite-likeness.

PubMed

Lee, Yoon Hyeok; Choi, Hojae; Park, Seongyong; Lee, Boah; Yi, Gwan-Su

2017-05-31

Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs. We constructed a drug-metabolite structural similarity matrix, which contains 1,861 FDA-approved drugs and 1,110 human intermediary metabolites scored with the Tanimoto similarity. To verify the metabolite-likeness measure for drug repositioning, we analyzed 17 known antimetabolite drugs that resemble the innate metabolites of their eleven target enzymes as the gold standard positives. Highly scored drugs were selected as possible modulators of enzymes for their corresponding metabolites. Then, we assessed the performance of metabolite-likeness with a receiver operating characteristic analysis and compared it with other drug-target prediction methods. We set the similarity threshold for drug repositioning candidates of new enzyme modulators based on maximization of the Youden's index. We also carried out literature surveys for supporting the drug repositioning results based on the metabolite-likeness. In this paper, we applied metabolite-likeness to repurpose FDA-approved drugs to disease-associated enzyme modulators that resemble human innate metabolites. All antimetabolite drugs were mapped with their known 11 target enzymes with statistically significant similarity values to the corresponding metabolites. The comparison with other drug-target prediction methods showed the higher performance of metabolite-likeness for predicting enzyme modulators. After that, the drugs scored higher than similarity score of 0.654 were selected as possible modulators of enzymes for their corresponding metabolites. In addition, we showed that drug repositioning results of 10 enzymes were concordant with the literature evidence. This study introduced a method to predict the repositioning of known drugs to possible modulators of disease associated enzymes using human metabolite-likeness. We demonstrated that this approach works correctly with known antimetabolite drugs and showed that the proposed method has better performance compared to other drug target prediction methods in terms of enzyme modulators prediction. This study as a proof-of-concept showed how to apply metabolite-likeness to drug repositioning as well as potential in further expansion as we acquire more disease associated metabolite-target protein relations.
A human tissue-based functional assay platform to evaluate the immune function impact of small molecule inhibitors that target the immune system.

PubMed

St Pierre, Cristina; Guo, Jane; Shin, John D; Engstrom, Laura W; Lee, Hyun-Hee; Herbert, Alan; Surdi, Laura; Baker, James; Salmon, Michael; Shah, Sanjiv; Ellis, J Michael; Houshyar, Hani; Crackower, Michael A; Kleinschek, Melanie A; Jones, Dallas C; Hicks, Alexandra; Zaller, Dennis M; Alves, Stephen E; Ramadas, Ravisankar A

2017-01-01

While the immune system is essential for the maintenance of the homeostasis, health and survival of humans, aberrant immune responses can lead to chronic inflammatory and autoimmune disorders. Pharmacological modulation of drug targets in the immune system to ameliorate disease also carry a risk of immunosuppression that could lead to adverse outcomes. Therefore, it is important to understand the 'immune fingerprint' of novel therapeutics as they relate to current and, clinically used immunological therapies to better understand their potential therapeutic benefit as well as immunosuppressive ability that might lead to adverse events such as infection risks and cancer. Since the mechanistic investigation of pharmacological modulators in a drug discovery setting is largely compound- and mechanism-centric but not comprehensive in terms of immune system impact, we developed a human tissue based functional assay platform to evaluate the impact of pharmacological modulators on a range of innate and adaptive immune functions. Here, we demonstrate that it is possible to generate a qualitative and quantitative immune system impact of pharmacological modulators, which might help better understand and predict the benefit-risk profiles of these compounds in the treatment of immune disorders.
S187. SEARCHING FOR BRAIN CO-EXPRESSION MODULES THAT CONTRIBUTE DISPROPORTIONATELY TO THE COMMON POLYGENIC RISK FOR SCHIZOPHRENIA

PubMed Central

Costas, Javier; Paramo, Mario; Arrojo, Manuel

2018-01-01

Abstract Background Genomic research has revealed that schizophrenia is a highly polygenic disease. Recent estimates indicate that at least 71% of genomic segments of 1 Mb include one or more risk loci for schizophrenia (Loh et al., Nature Genet 2015). This extremely high polygenicity represents a challenge to decipher the biological basis of schizophrenia, as it is expected that any set of SNPs with enough size will be associated with the disorder. Among the different gene sets available for study (such as those from Gene Ontology, KEGG pathway, Reactome pathways or protein protein interaction datasets), those based on brain co-expression networks represent putative functional relationships in the relevant tissue. The aim of this work was to identify brain co-expression networks that contribute disproportionately to the common polygenic risk for schizophrenia to get more insight on schizophrenia etiopathology. Methods We analyzed a case -control dataset consisting of 582 schizophrenia patients from Galicia, NW Spain, and 591 ancestrally matched controls, genotyped with the Illumina PsychArray. Using as discovery sample the summary results from the largest GWAS of schizophrenia to date (Psychiatric Genomics Consortium, SCZ2), we generated polygenic risk scores (PRS) in our sample based on SNPs located at genes belonging to brain co-expression modules determined by the CommonMind Consortium (Fromer et al., Nature Neurosci 2016). PRS were generated using the clumping procedure of PLINK, considering several different thresholds to select SNPs from the discovery sample. In order to test if any specific module increased risk to schizophrenia more than expected by their size, we generated up to 10,000 random permutations of the same number of SNPs, matched by frequency, distance to nearest gene, number of SNPs in LD and gene density, using SNPsnap. Results As expected, most modules with enough number of independent SNPs belonging to them showed a significant increase in Nagelkerke’s R2 in our case-control sample after the addition of the module-specific PRS in a logistic regression model. Our permutation strategy revealed that most modules did not show an excess of risk, measured by increase in Nagelkerke’s R2, in comparison to equal number of SNPs with similar characteristics. But one module, M2c from Fromer et al., remained highly significant after multiple tests’ correction. Reactome pathways analysis revealed an over-representation of genes involved in “Neuronal System” and “Axon guidance” among genes from this module. Using the same protocol, we detected that the 84 genes from the neuronal system pathway at this module, representing less than 6% of the genes from the module, explained a higher level of risk than expected. “Voltage-gated Potassium channels” and “Neurexins and neuroligins” are overrepresented among the Neuronal System genes from module M2c. Discussion Here, we show that, in spite of the high polygenicity of schizophrenia, it is possible to identify gene sets contributing disproportionately to total risk, as it was the case for the M2c module from Fromer et al. These authors have previously reported that the M2c module was enriched in GWAS signals, as well as CNVs and rare variants associated with schizophrenia. Therefore, this module shows a disproportionately contribution to schizophrenia risk. Study supported by Grant PI14/01020 from Instituto de Salud Carlos III, Ministry of Health, Spanish Government.

Application of mass spectrometry technologies for the discovery of low-molecular weight modulators of enzymes and protein-protein interactions.

PubMed

Zehender, Hartmut; Mayr, Lorenz M

2007-10-01

In recent years, mass spectrometry has gained widespread use as an assay and screening technology in drug discovery because it enables sensitive, label-free detection of low-molecular weight modulators of biomolecules as well as sensitive and accurate detection of high-molecular weight modifications of biomolecules. Electrospray and matrix-assisted laser desorption ionization are the most widely used ionization techniques to identify chemical compounds interfering with enzymatic function, receptor-ligand binding or molecules modulating a protein-protein interaction of interest. Mass spectrometry based techniques are no longer restricted to screening in biochemical assay systems but have now become also applicable to imaging of biomolecules and chemical compounds in cell-based assay systems and even in highly complex tissue sections.
Motif-based analysis of large nucleotide data sets using MEME-ChIP

PubMed Central

Ma, Wenxiu; Noble, William S; Bailey, Timothy L

2014-01-01

MEME-ChIP is a web-based tool for analyzing motifs in large DNA or RNA data sets. It can analyze peak regions identified by ChIP-seq, cross-linking sites identified by cLIP-seq and related assays, as well as sets of genomic regions selected using other criteria. MEME-ChIP performs de novo motif discovery, motif enrichment analysis, motif location analysis and motif clustering, providing a comprehensive picture of the DNA or RNA motifs that are enriched in the input sequences. MEME-ChIP performs two complementary types of de novo motif discovery: weight matrix–based discovery for high accuracy; and word-based discovery for high sensitivity. Motif enrichment analysis using DNA or RNA motifs from human, mouse, worm, fly and other model organisms provides even greater sensitivity. MEME-ChIP’s interactive HTML output groups and aligns significant motifs to ease interpretation. this protocol takes less than 3 h, and it provides motif discovery approaches that are distinct and complementary to other online methods. PMID:24853928
Discovery and validation of a glioblastoma co-expressed gene module

PubMed Central

Dunwoodie, Leland J.; Poehlman, William L.; Ficklin, Stephen P.; Feltus, Frank Alexander

2018-01-01

Tumors exhibit complex patterns of aberrant gene expression. Using a knowledge-independent, noise-reducing gene co-expression network construction software called KINC, we created multiple RNAseq-based gene co-expression networks relevant to brain and glioblastoma biology. In this report, we describe the discovery and validation of a glioblastoma-specific gene module that contains 22 co-expressed genes. The genes are upregulated in glioblastoma relative to normal brain and lower grade glioma samples; they are also hypo-methylated in glioblastoma relative to lower grade glioma tumors. Among the proneural, neural, mesenchymal, and classical glioblastoma subtypes, these genes are most-highly expressed in the mesenchymal subtype. Furthermore, high expression of these genes is associated with decreased survival across each glioblastoma subtype. These genes are of interest to glioblastoma biology and our gene interaction discovery and validation workflow can be used to discover and validate co-expressed gene modules derived from any co-expression network. PMID:29541392
Discovery and validation of a glioblastoma co-expressed gene module.

PubMed

Dunwoodie, Leland J; Poehlman, William L; Ficklin, Stephen P; Feltus, Frank Alexander

2018-02-16

Tumors exhibit complex patterns of aberrant gene expression. Using a knowledge-independent, noise-reducing gene co-expression network construction software called KINC, we created multiple RNAseq-based gene co-expression networks relevant to brain and glioblastoma biology. In this report, we describe the discovery and validation of a glioblastoma-specific gene module that contains 22 co-expressed genes. The genes are upregulated in glioblastoma relative to normal brain and lower grade glioma samples; they are also hypo-methylated in glioblastoma relative to lower grade glioma tumors. Among the proneural, neural, mesenchymal, and classical glioblastoma subtypes, these genes are most-highly expressed in the mesenchymal subtype. Furthermore, high expression of these genes is associated with decreased survival across each glioblastoma subtype. These genes are of interest to glioblastoma biology and our gene interaction discovery and validation workflow can be used to discover and validate co-expressed gene modules derived from any co-expression network.
Spaceship Discovery's Crew and Cargo Lander Module Designs for Human Exploration of Mars

NASA Astrophysics Data System (ADS)

Benton, Mark G.

2008-01-01

The Spaceship Discovery design was first presented at STAIF 2006. This conceptual design space vehicle architecture for human solar system exploration includes two types of Mars exploration lander modules: A piloted crew lander, designated Lander Module 2 (LM2), and an autonomous cargo lander, designated Lander Module 3 (LM3). The LM2 and LM3 designs were first presented at AIAA Space 2007. The LM2 and LM3 concepts have recently been extensively redesigned. The specific objective of this paper is to present these revised designs. The LM2 and LM3 landers are based on a common design that can be configured to carry either crew or cargo. They utilize a combination of aerodynamic reentry, parachutes, and propulsive braking to decelerate from orbital velocity to a soft landing. The LM2 crew lander provides two-way transportation for a nominal three-person crew between Mars orbit and the surface, and provides life support for a 30-day contingency mission. It contains an ascent section to return the crew to orbit after completion of surface operations. The LM3 cargo lander provides one-way, autonomous transportation of cargo from Mars orbit to the surface and can be configured to carry a mix of consumables and equipment, or equipment only. Lander service life and endurance is based on the Spaceship Discovery conjunction-class Design Reference Mission 2. The LM3 is designed to extend the surface stay for three crew members in an LM2 crew lander such that two sets of crew and cargo landers enable human exploration of the surface for the bulk of the 454 day wait time at Mars, in two shifts of three crew members each. Design requirements, mission profiles, mass properties, performance data, and configuration layouts are presented for the LM2 crew and LM3 cargo landers. These lander designs are a proposed solution to the problem of safely transporting a human crew from Mars orbit to the surface, sustaining them for extended periods of time on the surface, and returning them safely to orbit. They are based on reliable and proven technology and build on an extensive heritage of successful unmanned probes. Safety, redundancy, and abort and rescue capabilities are stressed in the design and operations concepts. The designs share many common features, hardware, subsystems, and flight control modes to reduce development cost.
Module discovery by exhaustive search for densely connected, co-expressed regions in biomolecular interaction networks.

PubMed

Colak, Recep; Moser, Flavia; Chu, Jeffrey Shih-Chieh; Schönhuth, Alexander; Chen, Nansheng; Ester, Martin

2010-10-25

Computational prediction of functionally related groups of genes (functional modules) from large-scale data is an important issue in computational biology. Gene expression experiments and interaction networks are well studied large-scale data sources, available for many not yet exhaustively annotated organisms. It has been well established, when analyzing these two data sources jointly, modules are often reflected by highly interconnected (dense) regions in the interaction networks whose participating genes are co-expressed. However, the tractability of the problem had remained unclear and methods by which to exhaustively search for such constellations had not been presented. We provide an algorithmic framework, referred to as Densely Connected Biclustering (DECOB), by which the aforementioned search problem becomes tractable. To benchmark the predictive power inherent to the approach, we computed all co-expressed, dense regions in physical protein and genetic interaction networks from human and yeast. An automatized filtering procedure reduces our output which results in smaller collections of modules, comparable to state-of-the-art approaches. Our results performed favorably in a fair benchmarking competition which adheres to standard criteria. We demonstrate the usefulness of an exhaustive module search, by using the unreduced output to more quickly perform GO term related function prediction tasks. We point out the advantages of our exhaustive output by predicting functional relationships using two examples. We demonstrate that the computation of all densely connected and co-expressed regions in interaction networks is an approach to module discovery of considerable value. Beyond confirming the well settled hypothesis that such co-expressed, densely connected interaction network regions reflect functional modules, we open up novel computational ways to comprehensively analyze the modular organization of an organism based on prevalent and largely available large-scale datasets. Software and data sets are available at http://www.sfu.ca/~ester/software/DECOB.zip.
Integrative Analysis of Many Weighted Co-Expression Networks Using Tensor Computation

PubMed Central

Li, Wenyuan; Liu, Chun-Chi; Zhang, Tong; Li, Haifeng; Waterman, Michael S.; Zhou, Xianghong Jasmine

2011-01-01

The rapid accumulation of biological networks poses new challenges and calls for powerful integrative analysis tools. Most existing methods capable of simultaneously analyzing a large number of networks were primarily designed for unweighted networks, and cannot easily be extended to weighted networks. However, it is known that transforming weighted into unweighted networks by dichotomizing the edges of weighted networks with a threshold generally leads to information loss. We have developed a novel, tensor-based computational framework for mining recurrent heavy subgraphs in a large set of massive weighted networks. Specifically, we formulate the recurrent heavy subgraph identification problem as a heavy 3D subtensor discovery problem with sparse constraints. We describe an effective approach to solving this problem by designing a multi-stage, convex relaxation protocol, and a non-uniform edge sampling technique. We applied our method to 130 co-expression networks, and identified 11,394 recurrent heavy subgraphs, grouped into 2,810 families. We demonstrated that the identified subgraphs represent meaningful biological modules by validating against a large set of compiled biological knowledge bases. We also showed that the likelihood for a heavy subgraph to be meaningful increases significantly with its recurrence in multiple networks, highlighting the importance of the integrative approach to biological network analysis. Moreover, our approach based on weighted graphs detects many patterns that would be overlooked using unweighted graphs. In addition, we identified a large number of modules that occur predominately under specific phenotypes. This analysis resulted in a genome-wide mapping of gene network modules onto the phenome. Finally, by comparing module activities across many datasets, we discovered high-order dynamic cooperativeness in protein complex networks and transcriptional regulatory networks. PMID:21698123
MAVTgsa: An R Package for Gene Set (Enrichment) Analysis

DOE PAGES

Chien, Chih-Yi; Chang, Ching-Wei; Tsai, Chen-An; ...

2014-01-01

Gene semore » t analysis methods aim to determine whether an a priori defined set of genes shows statistically significant difference in expression on either categorical or continuous outcomes. Although many methods for gene set analysis have been proposed, a systematic analysis tool for identification of different types of gene set significance modules has not been developed previously. This work presents an R package, called MAVTgsa, which includes three different methods for integrated gene set enrichment analysis. (1) The one-sided OLS (ordinary least squares) test detects coordinated changes of genes in gene set in one direction, either up- or downregulation. (2) The two-sided MANOVA (multivariate analysis variance) detects changes both up- and downregulation for studying two or more experimental conditions. (3) A random forests-based procedure is to identify gene sets that can accurately predict samples from different experimental conditions or are associated with the continuous phenotypes. MAVTgsa computes the P values and FDR (false discovery rate) q -value for all gene sets in the study. Furthermore, MAVTgsa provides several visualization outputs to support and interpret the enrichment results. This package is available online.« less
Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65

PubMed Central

Huang, Xi-Ping; Karpiak, Joel; Kroeze, Wesley K.; Zhu, Hu; Chen, Xin; Moy, Sheryl S.; Saddoris, Kara A.; Nikolova, Viktoriya; Farrell, Martilias S.; Wang, Sheng; Mangano, Thomas J.; Deshpande, Deepak A.; Jiang, Alice; Penn, Raymond B.; Jin, Jian; Koller, Beverly H.; Kenakin, Terry; Shoichet, Brian K.; Roth, Bryan L.

2016-01-01

At least 120 non-olfactory G protein-coupled receptors in the human genome are ”orphans” for which endogenous ligands are unknown, and many have no selective ligands, hindering elucidation of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Yeast-based screens against GPR68 identified the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. Over 3000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators many of which were confirmed in functional assays. One potent GPR68 modulator—ogerin– suppressed recall in fear conditioning in wild-type, but not in GPR68 knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs. PMID:26550826
Network-Based Disease Module Discovery by a Novel Seed Connector Algorithm with Pathobiological Implications.

PubMed

Wang, Rui-Sheng; Loscalzo, Joseph

2018-05-20

Understanding the genetic basis of complex diseases is challenging. Prior work shows that disease-related proteins do not typically function in isolation. Rather, they often interact with each other to form a network module that underlies dysfunctional mechanistic pathways. Identifying such disease modules will provide insights into a systems-level understanding of molecular mechanisms of diseases. Owing to the incompleteness of our knowledge of disease proteins and limited information on the biological mediators of pathobiological processes, the key proteins (seed proteins) for many diseases appear scattered over the human protein-protein interactome and form a few small branches, rather than coherent network modules. In this paper, we develop a network-based algorithm, called the Seed Connector algorithm (SCA), to pinpoint disease modules by adding as few additional linking proteins (seed connectors) to the seed protein pool as possible. Such seed connectors are hidden disease module elements that are critical for interpreting the functional context of disease proteins. The SCA aims to connect seed disease proteins so that disease mechanisms and pathways can be decoded based on predicted coherent network modules. We validate the algorithm using a large corpus of 70 complex diseases and binding targets of over 200 drugs, and demonstrate the biological relevance of the seed connectors. Lastly, as a specific proof of concept, we apply the SCA to a set of seed proteins for coronary artery disease derived from a meta-analysis of large-scale genome-wide association studies and obtain a coronary artery disease module enriched with important disease-related signaling pathways and drug targets not previously recognized. Copyright © 2018 Elsevier Ltd. All rights reserved.
Evaluation of an Interactive Undergraduate Cosmology Curriculum

NASA Astrophysics Data System (ADS)

White, Aaron; Coble, Kimberly A.; Martin, Dominique; Hayes, Patrycia; Targett, Tom; Cominsky, Lynn R.

2018-06-01

The Big Ideas in Cosmology is an immersive set of web-based learning modules that integrates text, figures, and visualizations with short and long interactive tasks as well as labs that allow students to manipulate and analyze real cosmological data. This enables the transformation of general education astronomy and cosmology classes from primarily lecture and book-based courses to a format that builds important STEM skills, while engaging those outside the field with modern discoveries and a more realistic sense of practices and tools used by professional astronomers. Over two semesters, we field-tested the curriculum in general education cosmology classes at a state university in California [N ~ 80]. We administered pre- and post-instruction multiple-choice and open-ended content surveys as well as the CLASS, to gauge the effectiveness of the course and modules. Questions addressed included the structure, composition, and evolution of the universe, including students’ reasoning and “how we know.”Module development and evaluation was supported by NASA ROSES E/PO Grant #NNXl0AC89G, the Illinois Space Grant Consortium, the Fermi E/PO program, Sonoma State University’s Space Science Education and Public Outreach Group, and San Francisco State University. The modules are published by Great River Learning/Kendall-Hunt.
KSC-2010-4716

NASA Image and Video Library

2010-09-20

CAPE CANAVERAL, Fla. -- Bathed in bright xenon lights, space shuttle Discovery makes its nighttime trek, known as "rollout," from the Vehicle Assembly Building to Launch Pad 39A at NASA's Kennedy Space Center in Florida. It will take the shuttle, attached to its external fuel tank, twin solid rocket boosters and mobile launcher platform, about six hours to complete the move atop a crawler-transporter. Rollout sets the stage for Discovery's STS-133 crew to practice countdown and launch procedures during the Terminal Countdown Demonstration Test in mid-October. Targeted to liftoff Nov. 1, Discovery will take the Permanent Multipurpose Module (PMM) packed with supplies and critical spare parts, as well as Robonaut 2 (R2) to the International Space Station. Photo credit: NASA/Frankie Martin
KSC-2010-4707

NASA Image and Video Library

2010-09-20

CAPE CANAVERAL, Fla. -- Bathed in bright xenon lights, space shuttle Discovery makes its nighttime trek, known as "rollout," from the Vehicle Assembly Building to Launch Pad 39A at NASA's Kennedy Space Center in Florida. It will take the shuttle, attached to its external fuel tank, twin solid rocket boosters and mobile launcher platform, about six hours to complete the move atop a crawler-transporter. Rollout sets the stage for Discovery's STS-133 crew to practice countdown and launch procedures during the Terminal Countdown Demonstration Test in mid-October. Targeted to liftoff Nov. 1, Discovery will take the Permanent Multipurpose Module (PMM) packed with supplies and critical spare parts, as well as Robonaut 2 (R2) to the International Space Station. Photo credit: NASA/Jim Grossmann
Clustering Words to Match Conditions: An Algorithm for Stimuli Selection in Factorial Designs

ERIC Educational Resources Information Center

Guasch, Marc; Haro, Juan; Boada, Roger

2017-01-01

With the increasing refinement of language processing models and the new discoveries about which variables can modulate these processes, stimuli selection for experiments with a factorial design is becoming a tough task. Selecting sets of words that differ in one variable, while matching these same words into dozens of other confounding variables…
A New Algorithm for Identifying Cis-Regulatory Modules Based on Hidden Markov Model

PubMed Central

2017-01-01

The discovery of cis-regulatory modules (CRMs) is the key to understanding mechanisms of transcription regulation. Since CRMs have specific regulatory structures that are the basis for the regulation of gene expression, how to model the regulatory structure of CRMs has a considerable impact on the performance of CRM identification. The paper proposes a CRM discovery algorithm called ComSPS. ComSPS builds a regulatory structure model of CRMs based on HMM by exploring the rules of CRM transcriptional grammar that governs the internal motif site arrangement of CRMs. We test ComSPS on three benchmark datasets and compare it with five existing methods. Experimental results show that ComSPS performs better than them. PMID:28497059
KSC-2010-4426

NASA Image and Video Library

2010-08-19

CAPE CANAVERAL, Fla. -- In Orbiter Processing Facility-3 at NASA's Kennedy Space Center in Florida, the Ku-band antenna is stored in space shuttle Discovery's payload bay. The antenna, which resembles a mini-satellite dish, transmits audio, video and data between Earth and the shuttle. Next, the clamshell doors of the payload bay will close completely in preparation for its move to the Vehicle Assembly Building next month. There, it will be attached to its external fuel tank and a set of solid rocket boosters for launch on the STS-133 mission to the International Space Station. Targeted to launch Nov. 1, STS-133 will carry the multipurpose logistics module, or PMM, packed with supplies and critical spare parts, as well as Robonaut 2, or R2, to the station. Discovery will leave the module behind so it can be used for microgravity experiments in fluid physics, materials science, biology and biotechnology. Photo credit: NASA/Kim Shiflett
KSC-2010-4428

NASA Image and Video Library

2010-08-19

CAPE CANAVERAL, Fla. -- In Orbiter Processing Facility-3 at NASA's Kennedy Space Center in Florida, the Ku-band antenna is stored in space shuttle Discovery's payload bay. The antenna, which resembles a mini-satellite dish, transmits audio, video and data between Earth and the shuttle. Next, the clamshell doors of the payload bay will close completely in preparation for its move to the Vehicle Assembly Building next month. There, it will be attached to its external fuel tank and a set of solid rocket boosters for launch on the STS-133 mission to the International Space Station. Targeted to launch Nov. 1, STS-133 will carry the multipurpose logistics module, or PMM, packed with supplies and critical spare parts, as well as Robonaut 2, or R2, to the station. Discovery will leave the module behind so it can be used for microgravity experiments in fluid physics, materials science, biology and biotechnology. Photo credit: NASA/Kim Shiflett
KSC-2010-4427

NASA Image and Video Library

2010-08-19

CAPE CANAVERAL, Fla. -- In Orbiter Processing Facility-3 at NASA's Kennedy Space Center in Florida, the Ku-band antenna is stored in space shuttle Discovery's payload bay. The antenna, which resembles a mini-satellite dish, transmits audio, video and data between Earth and the shuttle. Next, the clamshell doors of the payload bay will close completely in preparation for its move to the Vehicle Assembly Building next month. There, it will be attached to its external fuel tank and a set of solid rocket boosters for launch on the STS-133 mission to the International Space Station. Targeted to launch Nov. 1, STS-133 will carry the multipurpose logistics module, or PMM, packed with supplies and critical spare parts, as well as Robonaut 2, or R2, to the station. Discovery will leave the module behind so it can be used for microgravity experiments in fluid physics, materials science, biology and biotechnology. Photo credit: NASA/Kim Shiflett
KSC-2010-5488

NASA Image and Video Library

2010-11-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center in Florida, xenon lights illuminate space shuttle Discovery on Launch Pad 39A following the retraction of the rotating service structure. The structure provides weather protection and access to the shuttle while it awaits lift off on the pad. Launch of Discovery on the STS-133 mission to the International Space Station is set for 3:29 p.m. on Nov. 4. During the 11-day mission, Discovery and its six crew members will deliver the Permanent Multipurpose Module, packed with supplies and critical spare parts, as well as Robonaut 2, to the orbiting laboratory. Discovery, which will fly its 39th mission, is scheduled to be retired following STS-133. This will be the 133rd Space Shuttle Program mission and the 35th shuttle voyage to the space station. For more information on STS-133, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Troy Cryder
Instructional and Learning Modes in Math. Module CMM:006:02.

ERIC Educational Resources Information Center

Rexroat, Melvin E.

This is the second module in a series on mathematics methods and materials for preservice elementary teachers. This module focuses on three instructional and learning modes: expository, guided discovery, and inquiry (pure discovery). Objectives for the module are listed, the prerequisites are stated, pre- and post-assessment standards are…

Many Paths toward Discovery: A Module for Teaching How Science Works

ERIC Educational Resources Information Center

Price, Rebecca M.; Perez, Kathryn E.

2018-01-01

Improving students' understanding of how science works requires explicit instruction. Here, we test the efficacy of a module based on two previously published activities (the "Cube Puzzle" and the case study "Asteroids and Dinosaurs") that teach how science works to college science majors. Students also use the How Science…
KSC-2011-1624

NASA Image and Video Library

2011-02-24

CAPE CANAVERAL, Fla. -- Swarms of people are at the Kennedy Space Center Visitor Complex in Florida to watch space shuttle Discovery lift off on its final scheduled mission from Launch Pad 39A. Liftoff is set for 4:50 p.m. EST on Feb. 24. Discovery and its six-member STS-133 crew will deliver the Permanent Multipurpose Module, packed with supplies and critical spare parts, as well as Robonaut 2, the dexterous humanoid astronaut helper, to the International Space Station. Discovery, which will fly its 39th mission, is scheduled to be retired following STS-133. This will be the 133rd Space Shuttle Program mission and the 35th shuttle voyage to the space station. For more information on the STS-133 mission, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Jack Pfaller
KSC-2011-1625

NASA Image and Video Library

2011-02-24

CAPE CANAVERAL, Fla. -- Swarms of people are at the Kennedy Space Center Visitor Complex in Florida to watch space shuttle Discovery lift off on its final scheduled mission from Launch Pad 39A. Liftoff is set for 4:50 p.m. EST on Feb. 24. Discovery and its six-member STS-133 crew will deliver the Permanent Multipurpose Module, packed with supplies and critical spare parts, as well as Robonaut 2, the dexterous humanoid astronaut helper, to the International Space Station. Discovery, which will fly its 39th mission, is scheduled to be retired following STS-133. This will be the 133rd Space Shuttle Program mission and the 35th shuttle voyage to the space station. For more information on the STS-133 mission, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Jack Pfaller
KSC-2011-1623

NASA Image and Video Library

2011-02-24

CAPE CANAVERAL, Fla. -- Swarms of people are at the Kennedy Space Center Visitor Complex in Florida to watch space shuttle Discovery lift off on its final scheduled mission from Launch Pad 39A. Liftoff is set for 4:50 p.m. EST on Feb. 24. Discovery and its six-member STS-133 crew will deliver the Permanent Multipurpose Module, packed with supplies and critical spare parts, as well as Robonaut 2, the dexterous humanoid astronaut helper, to the International Space Station. Discovery, which will fly its 39th mission, is scheduled to be retired following STS-133. This will be the 133rd Space Shuttle Program mission and the 35th shuttle voyage to the space station. For more information on the STS-133 mission, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Jack Pfaller
KSC-2011-1622

NASA Image and Video Library

2011-02-24

CAPE CANAVERAL, Fla. -- Swarms of people are at the Kennedy Space Center Visitor Complex in Florida to watch space shuttle Discovery lift off on its final scheduled mission from Launch Pad 39A. Liftoff is set for 4:50 p.m. EST on Feb. 24. Discovery and its six-member STS-133 crew will deliver the Permanent Multipurpose Module, packed with supplies and critical spare parts, as well as Robonaut 2, the dexterous humanoid astronaut helper, to the International Space Station. Discovery, which will fly its 39th mission, is scheduled to be retired following STS-133. This will be the 133rd Space Shuttle Program mission and the 35th shuttle voyage to the space station. For more information on the STS-133 mission, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Jack Pfaller
KSC-2011-1626

NASA Image and Video Library

2011-02-24

CAPE CANAVERAL, Fla. -- Swarms of people are at the Kennedy Space Center Visitor Complex in Florida to watch space shuttle Discovery lift off on its final scheduled mission from Launch Pad 39A. Liftoff is set for 4:50 p.m. EST on Feb. 24. Discovery and its six-member STS-133 crew will deliver the Permanent Multipurpose Module, packed with supplies and critical spare parts, as well as Robonaut 2, the dexterous humanoid astronaut helper, to the International Space Station. Discovery, which will fly its 39th mission, is scheduled to be retired following STS-133. This will be the 133rd Space Shuttle Program mission and the 35th shuttle voyage to the space station. For more information on the STS-133 mission, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Jack Pfaller
Hierarchical virtual screening approaches in small molecule drug discovery.

PubMed

Kumar, Ashutosh; Zhang, Kam Y J

2015-01-01

Virtual screening has played a significant role in the discovery of small molecule inhibitors of therapeutic targets in last two decades. Various ligand and structure-based virtual screening approaches are employed to identify small molecule ligands for proteins of interest. These approaches are often combined in either hierarchical or parallel manner to take advantage of the strength and avoid the limitations associated with individual methods. Hierarchical combination of ligand and structure-based virtual screening approaches has received noteworthy success in numerous drug discovery campaigns. In hierarchical virtual screening, several filters using ligand and structure-based approaches are sequentially applied to reduce a large screening library to a number small enough for experimental testing. In this review, we focus on different hierarchical virtual screening strategies and their application in the discovery of small molecule modulators of important drug targets. Several virtual screening studies are discussed to demonstrate the successful application of hierarchical virtual screening in small molecule drug discovery. Copyright © 2014 Elsevier Inc. All rights reserved.
STS-96 Mission Highlights. Part 2

NASA Technical Reports Server (NTRS)

1999-01-01

In this second part of a three-part video mission-highlights set, on-orbit spacecrew activities performed on the STS-96 Space Shuttle Orbiter Discovery and the International Space Station are reviewed. The flight crew consists of Kent V. Rominger, Commander; Rick D. Husband, Pilot; and Mission Specialists Ellen Ochoa, Tamara E. Jernigan, Daniel T. Barry, Julie Payette (Canadian), and Valery Ivanovich Tokarev (Russian). The primary goals of this mission were to work on logistics and resupply the International Space Station. This second part in the mission series features video from Flight Day 4-7 (FD 4-7). FD 4 of STS-96 presents astronauts Tammy Jernigan and Dan Barry completing the second longest space walk in shuttle history. Footage includes Jernigan and Barry transferring and installing two cranes from the shuttle's payload bay to locations on the outside of the station. The astronauts enter the International Space Station delivering supplies and prepare the outpost to receive its first resident crew, scheduled to arrive in early 2000 on FD 5. The video also captures the crew involved in logistics transfer activities within the Discovery/ISS orbiting complex. FD 6 includes footage of Valery Tokarev and Canadian astronaut Julie Payette charging out the final six battery recharge controller units for two of Zarya's power-producing batteries and all crew members' involvement in logistics transfer activities from the SPACEHAB module to designated locations in the International Space Station. With the transfer work of FD 6 all but complete, the astronauts conduct some additional work, installing parts of a wireless strain gauge system that will help engineers track the effects of adding modules to the station throughout its assembly. Moving the few remaining items from Discovery to the ISS, then closing a series of hatches within the station's modules leading back to the shuttle are the primary activities contained in FD 7. Final coverage features Discovery's astronauts finishing their work inside the International Space Station, closing all of the hatches and readying the shuttle's small thrusters to be fired to raise the entire complex's orbit in preparation for the undocking and departure set for FD 8.
Pharmacophore-based design and discovery of (-)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis.

PubMed

Xie, Qiong; Zheng, Zhaoxi; Shao, Biyun; Fu, Wei; Xia, Zheng; Li, Wei; Sun, Jian; Zheng, Wei; Zhang, Weiwei; Sheng, Wei; Zhang, Qihong; Chen, Hongzhuan; Wang, Hao; Qiu, Zhuibai

2017-12-01

Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer's disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (-)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate 43 was highly potent (IC 50 31.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. 43 also showed amyloid-β (Aβ) lowering effects (51.9% decrease of Aβ 42 ) superior to phenserine (31% decrease of total Aβ) in SH-SY5Y-APP 695 cells at 50 µM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.
Discovering discovery patterns with Predication-based Semantic Indexing.

PubMed

Cohen, Trevor; Widdows, Dominic; Schvaneveldt, Roger W; Davies, Peter; Rindflesch, Thomas C

2012-12-01

In this paper we utilize methods of hyperdimensional computing to mediate the identification of therapeutically useful connections for the purpose of literature-based discovery. Our approach, named Predication-based Semantic Indexing, is utilized to identify empirically sequences of relationships known as "discovery patterns", such as "drug x INHIBITS substance y, substance y CAUSES disease z" that link pharmaceutical substances to diseases they are known to treat. These sequences are derived from semantic predications extracted from the biomedical literature by the SemRep system, and subsequently utilized to direct the search for known treatments for a held out set of diseases. Rapid and efficient inference is accomplished through the application of geometric operators in PSI space, allowing for both the derivation of discovery patterns from a large set of known TREATS relationships, and the application of these discovered patterns to constrain search for therapeutic relationships at scale. Our results include the rediscovery of discovery patterns that have been constructed manually by other authors in previous research, as well as the discovery of a set of previously unrecognized patterns. The application of these patterns to direct search through PSI space results in better recovery of therapeutic relationships than is accomplished with models based on distributional statistics alone. These results demonstrate the utility of efficient approximate inference in geometric space as a means to identify therapeutic relationships, suggesting a role of these methods in drug repurposing efforts. In addition, the results provide strong support for the utility of the discovery pattern approach pioneered by Hristovski and his colleagues. Copyright © 2012 Elsevier Inc. All rights reserved.
Discovering discovery patterns with predication-based Semantic Indexing

PubMed Central

Cohen, Trevor; Widdows, Dominic; Schvaneveldt, Roger W.; Davies, Peter; Rindflesch, Thomas C.

2012-01-01

In this paper we utilize methods of hyperdimensional computing to mediate the identification of therapeutically useful connections for the purpose of literature-based discovery. Our approach, named Predication-based Semantic Indexing, is utilized to identify empirically sequences of relationships known as “discovery patterns”, such as “drug x INHIBITS substance y, substance y CAUSES disease z” that link pharmaceutical substances to diseases they are known to treat. These sequences are derived from semantic predications extracted from the biomedical literature by the SemRep system, and subsequently utilized to direct the search for known treatments for a held out set of diseases. Rapid and efficient inference is accomplished through the application of geometric operators in PSI space, allowing for both the derivation of discovery patterns from a large set of known TREATS relationships, and the application of these discovered patterns to constrain search for therapeutic relationships at scale. Our results include the rediscovery of discovery patterns that have been constructed manually by other authors in previous research, as well as the discovery of a set of previously unrecognized patterns. The application of these patterns to direct search through PSI space results in better recovery of therapeutic relationships than is accomplished with models based on distributional statistics alone. These results demonstrate the utility of efficient approximate inference in geometric space as a means to identify therapeutic relationships, suggesting a role of these methods in drug repurposing efforts. In addition, the results provide strong support for the utility of the discovery pattern approach pioneered by Hristovski and his colleagues. PMID:22841748
Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics | Office of Cancer Genomics

Cancer.gov

High cancer death rates indicate the need for new anticancer therapeutic agents. Approaches to discovering new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds through phenotypic compound library screening and target deconvolution by predictive chemogenomics.
Contributions of Academic Labs to the Discovery and Development of Chemical Biology Tools

PubMed Central

Huryn, Donna M.; Resnick, Lynn O.; Wipf, Peter

2013-01-01

The academic setting provides an environment that may foster success in the discovery of certain types of small molecule tools, while proving less suitable in others. For example, small molecule probes for poorly understood systems, those that exploit a specific resident expertise, and those whose commercial return is not apparent are ideally suited to be pursued in a university setting. In this perspective, we highlight five projects that emanated from academic research groups and generated valuable tool compounds that have been used to interrogate biological phenomena: Reactive oxygen species (ROS) sensors, GPR30 agonists and antagonists, selective CB2 agonists, Hsp70 modulators and beta-amyloid PET imaging agents. By continuing to take advantage of the unique expertise resident in university settings, and the ability to pursue novel projects that may have great scientific value, but limited or no immediate commercial value, probes from academic research groups continue to provide useful tools and generate a long-term resource for biomedical researchers. PMID:23672690
Contributions of academic laboratories to the discovery and development of chemical biology tools.

PubMed

Huryn, Donna M; Resnick, Lynn O; Wipf, Peter

2013-09-26

The academic setting provides an environment that may foster success in the discovery of certain types of small molecule tools while proving less suitable in others. For example, small molecule probes for poorly understood systems, those that exploit a specific resident expertise, and those whose commercial return is not apparent are ideally suited to be pursued in a university setting. In this review, we highlight five projects that emanated from academic research groups and generated valuable tool compounds that have been used to interrogate biological phenomena: reactive oxygen species (ROS) sensors, GPR30 agonists and antagonists, selective CB2 agonists, Hsp70 modulators, and β-amyloid PET imaging agents. By taking advantage of the unique expertise resident in university settings and the ability to pursue novel projects that may have great scientific value but with limited or no immediate commercial value, probes from academic research groups continue to provide useful tools and generate a long-term resource for biomedical researchers.
The development of a valid discovery-based learning module to improve students' mathematical connection

NASA Astrophysics Data System (ADS)

Kuneni, Erna; Mardiyana, Pramudya, Ikrar

2017-08-01

Geometry is the most important branch in mathematics. The purpose of teaching this material is to develop students' level of thinking for a better understanding. Otherwise, geometry in particular, has contributed students' failure in mathematics examinations. This problem occurs due to special feature in geometry which has complexity of correlation among its concept. This relates to mathematical connection. It is still difficult for students to improve this ability. This is because teachers' lack in facilitating students towards it. Eventhough, facilitating students can be in the form of teaching material. A learning module can be a solution because it consists of series activities that should be taken by students to achieve a certain goal. A series activities in this case is adopted by the phases of discovery-based learning model. Through this module, students are facilitated to discover concept by deep instruction and guidance. It can build the mathematical habits of mind and also strengthen the mathematical connection. Method used in this research was ten stages of research and development proposed by Bord and Gall. The research purpose is to create a valid learning module to improve students' mathematical connection in teaching quadrilateral. The retrieved valid module based on media expert judgment is 2,43 for eligibility chart aspect, 2,60 for eligibility presentation aspect, and 3,00 for eligibility contents aspect. Then the retrieved valid module based on material expert judgment is 3,10 for eligibility content aspect, 2,87 for eligibility presentation aspect, and 2,80 for eligibility language and legibility aspect.
Identifying candidate driver genes by integrative ovarian cancer genomics data

NASA Astrophysics Data System (ADS)

Lu, Xinguo; Lu, Jibo

2017-08-01

Integrative analysis of molecular mechanics underlying cancer can distinguish interactions that cannot be revealed based on one kind of data for the appropriate diagnosis and treatment of cancer patients. Tumor samples exhibit heterogeneity in omics data, such as somatic mutations, Copy Number Variations CNVs), gene expression profiles and so on. In this paper we combined gene co-expression modules and mutation modulators separately in tumor patients to obtain the candidate driver genes for resistant and sensitive tumor from the heterogeneous data. The final list of modulators identified are well known in biological processes associated with ovarian cancer, such as CCL17, CACTIN, CCL16, CCL22, APOB, KDF1, CCL11, HNF1B, LRG1, MED1 and so on, which can help to facilitate the discovery of biomarkers, molecular diagnostics, and drug discovery.
Attack of the Killer Fungus: A Hypothesis-Driven Lab Module †

PubMed Central

Sato, Brian K.

2013-01-01

Discovery-driven experiments in undergraduate laboratory courses have been shown to increase student learning and critical thinking abilities. To this end, a lab module involving worm capture by a nematophagous fungus was developed. The goals of this module are to enhance scientific understanding of the regulation of worm capture by soil-dwelling fungi and for students to attain a set of established learning goals, including the ability to develop a testable hypothesis and search for primary literature for data analysis, among others. Students in a ten-week majors lab course completed the lab module and generated novel data as well as data that agrees with the published literature. In addition, learning gains were achieved as seen through a pre-module and post-module test, student self-assessment, class exam, and lab report. Overall, this lab module enables students to become active participants in the scientific method while contributing to the understanding of an ecologically relevant model organism. PMID:24358387
PyGOLD: a python based API for docking based virtual screening workflow generation.

PubMed

Patel, Hitesh; Brinkjost, Tobias; Koch, Oliver

2017-08-15

Molecular docking is one of the successful approaches in structure based discovery and development of bioactive molecules in chemical biology and medicinal chemistry. Due to the huge amount of computational time that is still required, docking is often the last step in a virtual screening approach. Such screenings are set as workflows spanned over many steps, each aiming at different filtering task. These workflows can be automatized in large parts using python based toolkits except for docking using the docking software GOLD. However, within an automated virtual screening workflow it is not feasible to use the GUI in between every step to change the GOLD configuration file. Thus, a python module called PyGOLD was developed, to parse, edit and write the GOLD configuration file and to automate docking based virtual screening workflows. The latest version of PyGOLD, its documentation and example scripts are available at: http://www.ccb.tu-dortmund.de/koch or http://www.agkoch.de. PyGOLD is implemented in Python and can be imported as a standard python module without any further dependencies. oliver.koch@agkoch.de, oliver.koch@tu-dortmund.de. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
Separate class true discovery rate degree of association sets for biomarker identification.

PubMed

Crager, Michael R; Ahmed, Murat

2014-01-01

In 2008, Efron showed that biological features in a high-dimensional study can be divided into classes and a separate false discovery rate (FDR) analysis can be conducted in each class using information from the entire set of features to assess the FDR within each class. We apply this separate class approach to true discovery rate degree of association (TDRDA) set analysis, which is used in clinical-genomic studies to identify sets of biomarkers having strong association with clinical outcome or state while controlling the FDR. Careful choice of classes based on prior information can increase the identification power of the separate class analysis relative to the overall analysis.
Two new Blazhko stars: XZ UMi and VX Scl

NASA Astrophysics Data System (ADS)

Skarka, M.; Dolinsky, J.; Jurysek, J.; Honkova, K.; Masek, M.; Liska, J.; Zejda, M.

2016-02-01

A brief report about a discovery of modulation in two RRab Lyrae stars XZ UMi and VX Scl is presented. The suspicion of modulation comes from our observations, but the modulation periods (41.1d for XZ UMi and 67.3d for VX Scl) were estimated based on the analysis of NSVS (XZ UMi) and SuperWASP data (VX Scl). Both stars show indications of period change. The peaks close to the basic pulsation frequency of VX Scl could be the signs of possible double modulation.

Current perspectives in fragment-based lead discovery (FBLD)

PubMed Central

Lamoree, Bas; Hubbard, Roderick E.

2017-01-01

It is over 20 years since the first fragment-based discovery projects were disclosed. The methods are now mature for most ‘conventional’ targets in drug discovery such as enzymes (kinases and proteases) but there has also been growing success on more challenging targets, such as disruption of protein–protein interactions. The main application is to identify tractable chemical startpoints that non-covalently modulate the activity of a biological molecule. In this essay, we overview current practice in the methods and discuss how they have had an impact in lead discovery – generating a large number of fragment-derived compounds that are in clinical trials and two medicines treating patients. In addition, we discuss some of the more recent applications of the methods in chemical biology – providing chemical tools to investigate biological molecules, mechanisms and systems. PMID:29118093
NASA SMD E/PO Community Addresses the needs of the Higher Ed Community: Introducing Slide sets for the Introductory Earth and Space Science Instructor

NASA Astrophysics Data System (ADS)

Buxner, S.; Meinke, B. K.; Brain, D.; Schneider, N. M.; Schultz, G. R.; Smith, D. A.; Grier, J.; Shipp, S. S.

2014-12-01

The NASA Science Mission Directorate (SMD) Science Education and Public Outreach (E/PO) community and Forums work together to bring the cutting-edge discoveries of NASA Astrophysics and Planetary Science missions to the introductory astronomy college classroom. These mission- and grant-based E/PO programs are uniquely poised to foster collaboration between scientists with content expertise and educators with pedagogy expertise. We present two new opportunities for college instructors to bring the latest NASA discoveries in Space Science into their classrooms. The NASA Science Mission Directorate (SMD) Astrophysics Education and Public Outreach Forum is coordinating the development of a pilot series of slide sets to help Astronomy 101 instructors incorporate new discoveries in their classrooms. The "Astro 101 slide sets" are presentations 5-7 slides in length on a new development or discovery from a NASA Astrophysics mission relevant to topics in introductory astronomy courses. We intend for these slide sets to help Astronomy 101 instructors include new developments (discoveries not yet in their textbooks) into the broader context of the course. In a similar effort to keep the astronomy classroom apprised of the fast moving field of planetary science, the Division of Planetary Sciences (DPS) has developed the Discovery slide sets, which are 3-slide presentations that can be incorporated into college lectures. The slide sets are targeted at the Introductory Astronomy undergraduate level. Each slide set consists of three slides which cover a description of the discovery, a discussion of the underlying science, and a presentation of the big picture implications of the discovery, with a fourth slide includes links to associated press releases, images, and primary sources. Topics span all subdisciplines of planetary science, and sets are available in Farsi and Spanish. The NASA SMD Planetary Science Forum has recently partnered with the DPS to continue producing the Discovery slides and connect them to NASA mission science.
Empowering pharmacoinformatics by linked life science data

NASA Astrophysics Data System (ADS)

Goldmann, Daria; Zdrazil, Barbara; Digles, Daniela; Ecker, Gerhard F.

2017-03-01

With the public availability of large data sources such as ChEMBLdb and the Open PHACTS Discovery Platform, retrieval of data sets for certain protein targets of interest with consistent assay conditions is no longer a time consuming process. Especially the use of workflow engines such as KNIME or Pipeline Pilot allows complex queries and enables to simultaneously search for several targets. Data can then directly be used as input to various ligand- and structure-based studies. In this contribution, using in-house projects on P-gp inhibition, transporter selectivity, and TRPV1 modulation we outline how the incorporation of linked life science data in the daily execution of projects allowed to expand our approaches from conventional Hansch analysis to complex, integrated multilayer models.
Chloride channels as drug targets

PubMed Central

Verkman, Alan S.; Galietta, Luis J. V.

2013-01-01

Chloride channels represent a relatively under-explored target class for drug discovery as elucidation of their identity and physiological roles has lagged behind that of many other drug targets. Chloride channels are involved in a wide range of biological functions, including epithelial fluid secretion, cell-volume regulation, neuroexcitation, smooth-muscle contraction and acidification of intracellular organelles. Mutations in several chloride channels cause human diseases, including cystic fibrosis, macular degeneration, myotonia, kidney stones, renal salt wasting and hyperekplexia. Chloride-channel modulators have potential applications in the treatment of some of these disorders, as well as in secretory diarrhoeas, polycystic kidney disease, osteoporosis and hypertension. Modulators of GABAA (γ-aminobutyric acid A) receptor chloride channels are in clinical use and several small-molecule chloride-channel modulators are in preclinical development and clinical trials. Here, we discuss the broad opportunities that remain in chloride-channel-based drug discovery. PMID:19153558
Microwave-Assisted Esterification: A Discovery-Based Microscale Laboratory Experiment

ERIC Educational Resources Information Center

Reilly, Maureen K.; King, Ryan P.; Wagner, Alexander J.; King, Susan M.

2014-01-01

An undergraduate organic chemistry laboratory experiment has been developed that features a discovery-based microscale Fischer esterification utilizing a microwave reactor. Students individually synthesize a unique ester from known sets of alcohols and carboxylic acids. Each student identifies the best reaction conditions given their particular…
KSC-2011-1628

NASA Image and Video Library

2011-02-24

CAPE CANAVERAL, Fla. -- Folks from across the country camped out in communities surrounding NASA's Kennedy Space Center in Florida to witness space shuttle Discovery make history by lifting off on its final scheduled mission from Launch Pad 39A. Seen here, is State Road 406, also known as the A. Max Brewer Causeway, in Titusville, Fla. Liftoff is set for 4:50 p.m. EST on Feb. 24. Discovery and its six-member STS-133 crew will deliver the Permanent Multipurpose Module, packed with supplies and critical spare parts, as well as Robonaut 2, the dexterous humanoid astronaut helper, to the International Space Station. Discovery, which will fly its 39th mission, is scheduled to be retired following STS-133. This will be the 133rd Space Shuttle Program mission and the 35th shuttle voyage to the space station. For more information on the STS-133 mission, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Jack Pfaller
KSC-2011-1630

NASA Image and Video Library

2011-02-24

CAPE CANAVERAL, Fla. -- Folks from across the country camped out in communities surrounding NASA's Kennedy Space Center in Florida to witness space shuttle Discovery make history by lifting off on its final scheduled mission from Launch Pad 39A. Seen here, is State Road 406, also known as the A. Max Brewer Causeway, in Titusville, Fla. Liftoff is set for 4:50 p.m. EST on Feb. 24. Discovery and its six-member STS-133 crew will deliver the Permanent Multipurpose Module, packed with supplies and critical spare parts, as well as Robonaut 2, the dexterous humanoid astronaut helper, to the International Space Station. Discovery, which will fly its 39th mission, is scheduled to be retired following STS-133. This will be the 133rd Space Shuttle Program mission and the 35th shuttle voyage to the space station. For more information on the STS-133 mission, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Jack Pfaller
KSC-2011-1627

NASA Image and Video Library

2011-02-24

CAPE CANAVERAL, Fla. -- Folks from across the country camped out in communities surrounding NASA's Kennedy Space Center in Florida to witness space shuttle Discovery make history by lifting off on its final scheduled mission from Launch Pad 39A. Seen here, is State Road 406, also known as the A. Max Brewer Causeway, in Titusville, Fla. Liftoff is set for 4:50 p.m. EST on Feb. 24. Discovery and its six-member STS-133 crew will deliver the Permanent Multipurpose Module, packed with supplies and critical spare parts, as well as Robonaut 2, the dexterous humanoid astronaut helper, to the International Space Station. Discovery, which will fly its 39th mission, is scheduled to be retired following STS-133. This will be the 133rd Space Shuttle Program mission and the 35th shuttle voyage to the space station. For more information on the STS-133 mission, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Jack Pfaller
The effectiveness of game and recreational activity to motivate high achievers and low achievers: Evaluation using fuzzy conjoint analysis

NASA Astrophysics Data System (ADS)

Sofian, Siti Siryani; Rambely, Azmin Sham

2018-04-01

Students' evaluation is important in order to determine the effectiveness of a learning program. A game and recreational activity (GaRA) is a problem-based learning (PBL) method that engages students in a learning process through games and activity. The effectiveness of GaRA can be determined from an application of fuzzy conjoint analysis (FCA) to diminish fuzziness in determining individual perceptions. This study involves a survey collected from 68 students participating in a Mathematics Discovery Camp organized by a UKM research group, named PRISMatik, from two different schools. The aim of this research was to determine the effectiveness of modules delivered to motivate students towards mathematics subject in the form of GaRA through different factors. There were six games conducted for the participants and their perceptions based on the evaluation of six criterias were measured. A seven-point Likert scale, which indicates seven linguistic terms, was used to collect students' preferences and perceptions on each module of GaRAs. Scores of perceptions were transformed into degrees of similarity using fuzzy set conjoint analysis. Results found that interest, effort and team work was the strongest values obtained from GaRA modules in this camp as participants indicated their strong agreement that these criteria fulfilled their preferences in most module. Participants also stated that almost all attributes fulfilled their preference in each module regardless their individual academic achievement. Thus the method demonstrated that modules delivered through PBL approach has effectively motivated students through six attributes introduced. The evaluation using FCA implicated the successfulness of a fuzzy approach to evaluate fuzziness obtained in the Likert-scale and has shown its ability in ranking the attributes from most preferred to least preferred.
Doing that thing that scientists do: A discovery-driven module on protein purification and characterization for the undergraduate biochemistry laboratory classroom.

PubMed

Garrett, Teresa A; Osmundson, Joseph; Isaacson, Marisa; Herrera, Jennifer

2015-01-01

In traditional introductory biochemistry laboratory classes students learn techniques for protein purification and analysis by following provided, established, step-by-step procedures. Students are exposed to a variety of biochemical techniques but are often not developing procedures or collecting new, original data. In this laboratory module, students develop research skills through work on an original research project and gain confidence in their ability to design and execute an experiment while faculty can enhance their scholarly pursuits through the acquisition of original data in the classroom laboratory. Students are prepared for a 6-8 week discovery-driven project on the purification of the Escherichia coli cytidylate kinase (CMP kinase) through in class problems and other laboratory exercises on bioinformatics and protein structure analysis. After a minimal amount of guidance on how to perform the CMP kinase in vitro enzyme assay, SDS-PAGE, and the basics of protein purification, students, working in groups of three to four, develop a protein purification protocol based on the scientific literature and investigate some aspect of CMP kinase that interests them. Through this process, students learn how to implement a new but perhaps previously worked out procedure to answer their research question. In addition, they learn the importance of keeping a clear and thorough laboratory notebook and how to interpret their data and use that data to inform the next set of experiments. Following this module, students had increased confidence in their ability to do basic biochemistry techniques and reported that the "self-directed" nature of this lab increased their engagement in the project. © 2015 The International Union of Biochemistry and Molecular Biology.
PERSONAL AND CIRCUMSTANTIAL FACTORS INFLUENCING THE ACT OF DISCOVERY.

ERIC Educational Resources Information Center

OSTRANDER, EDWARD R.

HOW STUDENTS SAY THEY LEARN WAS INVESTIGATED. INTERVIEWS WITH A RANDOM SAMPLE OF 74 WOMEN STUDENTS POSED QUESTIONS ABOUT THE NATURE, FREQUENCY, PATTERNS, AND CIRCUMSTANCES UNDER WHICH ACTS OF DISCOVERY TAKE PLACE IN THE ACADEMIC SETTING. STUDENTS WERE ASSIGNED DISCOVERY RATINGS BASED ON READINGS OF TYPESCRIPTS. EACH STUDENT WAS CLASSIFIED AND…
Light-addressable measurements of cellular oxygen consumption rates in microwell arrays based on phase-based phosphorescence lifetime detection

PubMed Central

Huang, Shih-Hao; Hsu, Yu-Hsuan; Wu, Chih-Wei; Wu, Chang-Jer

2012-01-01

A digital light modulation system that utilizes a modified commercial digital micromirror device (DMD) projector, which is equipped with a UV light-emitting diode as a light modulation source, has been developed to spatially direct excited light toward a microwell array device to detect the oxygen consumption rate (OCR) of single cells via phase-based phosphorescence lifetime detection. The microwell array device is composed of a combination of two components: an array of glass microwells containing Pt(II) octaethylporphine (PtOEP) as the oxygen-sensitive luminescent layer and a microfluidic module with pneumatically actuated glass lids set above the microwells to controllably seal the microwells of interest. By controlling the illumination pattern on the DMD, the modulated excitation light can be spatially projected to only excite the sealed microwell for cellular OCR measurements. The OCR of baby hamster kidney-21 fibroblast cells cultivated on the PtOEP layer within a sealed microwell has been successfully measured at 104 ± 2.96 amol s−1 cell−1. Repeatable and consistent measurements indicate that the oxygen measurements did not adversely affect the physiological state of the measured cells. The OCR of the cells exhibited a good linear relationship with the diameter of the microwells, ranging from 400 to 1000 μm and containing approximately 480 to 1200 cells within a microwell. In addition, the OCR variation of single cells in situ infected by Dengue virus with a different multiplicity of infection was also successfully measured in real-time. This proposed platform provides the potential for a wide range of biological applications in cell-based biosensing, toxicology, and drug discovery. PMID:24348889
Examination of a Junction-Box Adhesion Test for Use in Photovoltaic Module Qualification: Preprint

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

Miller, D. C.; Wohlgemuth, J. H.

2012-08-01

Engineering robust adhesion of the junction-box (j-box) is a hurdle typically encountered by photovoltaic (PV) module manufacturers during product development. There are historical incidences of adverse effects (e.g., fires) caused when the j-box/adhesive/module system has failed in the field. The addition of a weight to the j-box during the 'damp heat' IEC qualification test is proposed to verify the basic robustness of its adhesion system. The details of the proposed test will be described, in addition to the preliminary results obtained using representative materials and components. The described discovery experiments examine moisture-cured silicone, foam tape, and hot-melt adhesives used inmore » conjunction with PET or glass module 'substrates.' To be able to interpret the results, a set of material-level characterizations was performed, including thermogravimetric analysis, differential scanning calorimetry, and dynamic mechanical analysis. PV j-boxes were adhered to a substrate, loaded with a prescribed weight, and then placed inside an environmental chamber (at 85C, 85% relative humidity). Some systems did not remain attached through the discovery experiments. Observed failure modes include delamination (at the j-box/adhesive or adhesive/substrate interface) and phase change/creep. The results are discussed in the context of the application requirements, in addition to the plan for the formal experiment supporting the proposed modification to the qualification test.« less
Systems-based biological concordance and predictive reproducibility of gene set discovery methods in cardiovascular disease.

PubMed

Azuaje, Francisco; Zheng, Huiru; Camargo, Anyela; Wang, Haiying

2011-08-01

The discovery of novel disease biomarkers is a crucial challenge for translational bioinformatics. Demonstration of both their classification power and reproducibility across independent datasets are essential requirements to assess their potential clinical relevance. Small datasets and multiplicity of putative biomarker sets may explain lack of predictive reproducibility. Studies based on pathway-driven discovery approaches have suggested that, despite such discrepancies, the resulting putative biomarkers tend to be implicated in common biological processes. Investigations of this problem have been mainly focused on datasets derived from cancer research. We investigated the predictive and functional concordance of five methods for discovering putative biomarkers in four independently-generated datasets from the cardiovascular disease domain. A diversity of biosignatures was identified by the different methods. However, we found strong biological process concordance between them, especially in the case of methods based on gene set analysis. With a few exceptions, we observed lack of classification reproducibility using independent datasets. Partial overlaps between our putative sets of biomarkers and the primary studies exist. Despite the observed limitations, pathway-driven or gene set analysis can predict potentially novel biomarkers and can jointly point to biomedically-relevant underlying molecular mechanisms. Copyright © 2011 Elsevier Inc. All rights reserved.
KSC-2009-2938

NASA Image and Video Library

2009-05-05

CAPE CANAVERAL, Fla. – In the Space Station Processing Facility at NASA's Kennedy Space Center in Florida, technicians place equipment in the Resupply Stowage Platform, or RSP, to be installed in the multi-purpose logistics module Leonardo. The module is part of the payload for space shuttle Discovery's STS-128 mission. Discovery will carry science and storage racks to the International Space Station . Launch of Discovery is targeted for Aug. 6. Photo credit: NASA/Kim Shiflett
Improved accuracy of supervised CRM discovery with interpolated Markov models and cross-species comparison

PubMed Central

Kazemian, Majid; Zhu, Qiyun; Halfon, Marc S.; Sinha, Saurabh

2011-01-01

Despite recent advances in experimental approaches for identifying transcriptional cis-regulatory modules (CRMs, ‘enhancers’), direct empirical discovery of CRMs for all genes in all cell types and environmental conditions is likely to remain an elusive goal. Effective methods for computational CRM discovery are thus a critically needed complement to empirical approaches. However, existing computational methods that search for clusters of putative binding sites are ineffective if the relevant TFs and/or their binding specificities are unknown. Here, we provide a significantly improved method for ‘motif-blind’ CRM discovery that does not depend on knowledge or accurate prediction of TF-binding motifs and is effective when limited knowledge of functional CRMs is available to ‘supervise’ the search. We propose a new statistical method, based on ‘Interpolated Markov Models’, for motif-blind, genome-wide CRM discovery. It captures the statistical profile of variable length words in known CRMs of a regulatory network and finds candidate CRMs that match this profile. The method also uses orthologs of the known CRMs from closely related genomes. We perform in silico evaluation of predicted CRMs by assessing whether their neighboring genes are enriched for the expected expression patterns. This assessment uses a novel statistical test that extends the widely used Hypergeometric test of gene set enrichment to account for variability in intergenic lengths. We find that the new CRM prediction method is superior to existing methods. Finally, we experimentally validate 12 new CRM predictions by examining their regulatory activity in vivo in Drosophila; 10 of the tested CRMs were found to be functional, while 6 of the top 7 predictions showed the expected activity patterns. We make our program available as downloadable source code, and as a plugin for a genome browser installed on our servers. PMID:21821659
High-Throughput Screening Using iPSC-Derived Neuronal Progenitors to Identify Compounds Counteracting Epigenetic Gene Silencing in Fragile X Syndrome.

PubMed

Kaufmann, Markus; Schuffenhauer, Ansgar; Fruh, Isabelle; Klein, Jessica; Thiemeyer, Anke; Rigo, Pierre; Gomez-Mancilla, Baltazar; Heidinger-Millot, Valerie; Bouwmeester, Tewis; Schopfer, Ulrich; Mueller, Matthias; Fodor, Barna D; Cobos-Correa, Amanda

2015-10-01

Fragile X syndrome (FXS) is the most common form of inherited mental retardation, and it is caused in most of cases by epigenetic silencing of the Fmr1 gene. Today, no specific therapy exists for FXS, and current treatments are only directed to improve behavioral symptoms. Neuronal progenitors derived from FXS patient induced pluripotent stem cells (iPSCs) represent a unique model to study the disease and develop assays for large-scale drug discovery screens since they conserve the Fmr1 gene silenced within the disease context. We have established a high-content imaging assay to run a large-scale phenotypic screen aimed to identify compounds that reactivate the silenced Fmr1 gene. A set of 50,000 compounds was tested, including modulators of several epigenetic targets. We describe an integrated drug discovery model comprising iPSC generation, culture scale-up, and quality control and screening with a very sensitive high-content imaging assay assisted by single-cell image analysis and multiparametric data analysis based on machine learning algorithms. The screening identified several compounds that induced a weak expression of fragile X mental retardation protein (FMRP) and thus sets the basis for further large-scale screens to find candidate drugs or targets tackling the underlying mechanism of FXS with potential for therapeutic intervention. © 2015 Society for Laboratory Automation and Screening.
Making the Introductory Meteorology Class Relevant in a Minority Serving Community College

NASA Astrophysics Data System (ADS)

Marchese, P. J.; Tremberger, G.; Bluestone, C.

2008-12-01

Queensborough Community College (QCC), a constituent campus of the City University of New York (CUNY), has modified the introductory Meteorology Class lecture and lab to include active learning activities and discovery based learning. The modules were developed at QCC and other 4 year colleges and designed to introduce basic physical concepts important in meteorology. The modules consisted of either interactive lecture demonstrations or discovery-based activities. The discovery based activities are intended to have students become familiar with scientific investigation. Students engage in formulating hypotheses, developing and carrying out experiments, and analyzing scientific data. These activities differ from traditional lab experiments in that they avoid "cookbook" procedures and emphasize having the students learn about physical concepts by applying the scientific method. During the interactive lecture demonstrations the instructor describes an experiment/phenomenon that is to be demonstrated in class. Students discuss the phenomenon based on their experiences and make a prediction about the outcome. The class then runs the experiment, makes observations, and compares the expected results to the actual outcome. As a result of these activities students in the introductory Meteorology class scored higher in exams questions measuring conceptual understanding, as well as factual knowledge. Lower scoring students demonstrated the greatest benefit, while the better students had little (or no) changes. All students also had higher self-efficacy scores after the intervention, compared to an unmodified class.
Aptamers as tools for target prioritization and lead identification.

PubMed

Burgstaller, Petra; Girod, Anne; Blind, Michael

2002-12-15

The increasing number of potential drug target candidates has driven the development of novel technologies designed to identify functionally important targets and enhance the subsequent lead discovery process. Highly specific synthetic nucleic acid ligands--also known as aptamers--offer a new exciting route in the drug discovery process by linking target validation directly with HTS. Recently, aptamers have proven to be valuable tools for modulating the function of endogenous cellular proteins in their natural environment. A set of technologies has been developed to use these sophisticated ligands for the validation of potential drug targets in disease models. Moreover, aptamers that are specific antagonists of protein function can act as substitute interaction partners in HTS assays to facilitate the identification of small-molecule lead compounds.
KSC-07pd2373

NASA Image and Video Library

2007-08-24

KENNEDY SPACE CENTER, FLA. -- A close-up view of the LO2 feed line bracket with the BX265foam insulation and super lightweight ablator, or SLA, cork insulation removed. The BX265 foam insulation will later be reapplied without the SLA. The tank is scheduled to fly on Space Shuttle Discovery in October 2007 on mission STS-120. Discovery's crew will add the module Harmony that will serve as a port for installing additional international laboratories. Harmony will be the first expansion of the living and working space on the complex since the Russian Pirs airlock was installed in 2001. The mission also will move the first set of solar arrays installed on the station to a permanent location on the complex and redeploy them. Photo credit: NASA/Jim Grossmann

KSC-01pp1474

NASA Image and Video Library

2001-08-10

KENNEDY SPACE CENTER, Fla. -- A helicopter provides a unique view of the launch of Space Shuttle Discovery from Launch Pad 39A on mission STS-105. Liftoff occurred at 5:10:14 p.m. EDT. As Discovery soars into the sky it casts a shadow from the setting sun. Below the smoke column rises the 525-foot-high Vehicle Assembly Building, a landmark at Kennedy Space Center. To the left is the Banana Creek and in the foreground are the marshlands of the Merritt Island National Wildlife Refuge, which shares a boundary with Kennedy. Besides the Shuttle crew of four, Discovery carries the Expedition Three crew who will replace Expedition Two on the Space Station. The mission includes the third flight of an Italian-built Multi-Purpose Logistics Module delivering additional scientific racks, equipment and supplies for the Space Station and the Early Ammonia Servicer (EAS) tank. The EAS, which will be attached to the Station during two spacewalks, contains spare ammonia for the Station’s cooling system. The three-member Expedition Two crew will be returning to Earth aboard Discovery after a five-month stay on the Station
Plasma proteomic analysis reveals altered protein abundances in cardiovascular disease.

PubMed

Lygirou, Vasiliki; Latosinska, Agnieszka; Makridakis, Manousos; Mullen, William; Delles, Christian; Schanstra, Joost P; Zoidakis, Jerome; Pieske, Burkert; Mischak, Harald; Vlahou, Antonia

2018-04-17

Cardiovascular disease (CVD) describes the pathological conditions of the heart and blood vessels. Despite the large number of studies on CVD and its etiology, its key modulators remain largely unknown. To this end, we performed a comprehensive proteomic analysis of blood plasma, with the scope to identify disease-associated changes after placing them in the context of existing knowledge, and generate a well characterized dataset for further use in CVD multi-omics integrative analysis. LC-MS/MS was employed to analyze plasma from 32 subjects (19 cases of various CVD phenotypes and 13 controls) in two steps: discovery (13 cases and 8 controls) and test (6 cases and 5 controls) set analysis. Following label-free quantification, the detected proteins were correlated to existing plasma proteomics datasets (plasma proteome database; PPD) and functionally annotated (Cytoscape, Ingenuity Pathway Analysis). Differential expression was defined based on identification confidence (≥ 2 peptides per protein), statistical significance (Mann-Whitney p value ≤ 0.05) and a minimum of twofold change. Peptides detected in at least 50% of samples per group were considered, resulting in a total of 3796 identified proteins (838 proteins based on ≥ 2 peptides). Pathway annotation confirmed the functional relevance of the findings (representation of complement cascade, fibrin clot formation, platelet degranulation, etc.). Correlation of the relative abundance of the proteins identified in the discovery set with their reported concentrations in the PPD was significant, confirming the validity of the quantification method. The discovery set analysis revealed 100 differentially expressed proteins between cases and controls, 39 of which were verified (≥ twofold change) in the test set. These included proteins already studied in the context of CVD (such as apolipoprotein B, alpha-2-macroglobulin), as well as novel findings (such as low density lipoprotein receptor related protein 2 [LRP2], protein SZT2) for which a mechanism of action is suggested. This proteomic study provides a comprehensive dataset to be used for integrative and functional studies in the field. The observed protein changes reflect known CVD-related processes (e.g. lipid uptake, inflammation) but also novel hypotheses for further investigation including a potential pleiotropic role of LPR2 but also links of SZT2 to CVD.
Relational Network for Knowledge Discovery through Heterogeneous Biomedical and Clinical Features

PubMed Central

Chen, Huaidong; Chen, Wei; Liu, Chenglin; Zhang, Le; Su, Jing; Zhou, Xiaobo

2016-01-01

Biomedical big data, as a whole, covers numerous features, while each dataset specifically delineates part of them. “Full feature spectrum” knowledge discovery across heterogeneous data sources remains a major challenge. We developed a method called bootstrapping for unified feature association measurement (BUFAM) for pairwise association analysis, and relational dependency network (RDN) modeling for global module detection on features across breast cancer cohorts. Discovered knowledge was cross-validated using data from Wake Forest Baptist Medical Center’s electronic medical records and annotated with BioCarta signaling signatures. The clinical potential of the discovered modules was exhibited by stratifying patients for drug responses. A series of discovered associations provided new insights into breast cancer, such as the effects of patient’s cultural background on preferences for surgical procedure. We also discovered two groups of highly associated features, the HER2 and the ER modules, each of which described how phenotypes were associated with molecular signatures, diagnostic features, and clinical decisions. The discovered “ER module”, which was dominated by cancer immunity, was used as an example for patient stratification and prediction of drug responses to tamoxifen and chemotherapy. BUFAM-derived RDN modeling demonstrated unique ability to discover clinically meaningful and actionable knowledge across highly heterogeneous biomedical big data sets. PMID:27427091
Relational Network for Knowledge Discovery through Heterogeneous Biomedical and Clinical Features

NASA Astrophysics Data System (ADS)

Chen, Huaidong; Chen, Wei; Liu, Chenglin; Zhang, Le; Su, Jing; Zhou, Xiaobo

2016-07-01

Biomedical big data, as a whole, covers numerous features, while each dataset specifically delineates part of them. “Full feature spectrum” knowledge discovery across heterogeneous data sources remains a major challenge. We developed a method called bootstrapping for unified feature association measurement (BUFAM) for pairwise association analysis, and relational dependency network (RDN) modeling for global module detection on features across breast cancer cohorts. Discovered knowledge was cross-validated using data from Wake Forest Baptist Medical Center’s electronic medical records and annotated with BioCarta signaling signatures. The clinical potential of the discovered modules was exhibited by stratifying patients for drug responses. A series of discovered associations provided new insights into breast cancer, such as the effects of patient’s cultural background on preferences for surgical procedure. We also discovered two groups of highly associated features, the HER2 and the ER modules, each of which described how phenotypes were associated with molecular signatures, diagnostic features, and clinical decisions. The discovered “ER module”, which was dominated by cancer immunity, was used as an example for patient stratification and prediction of drug responses to tamoxifen and chemotherapy. BUFAM-derived RDN modeling demonstrated unique ability to discover clinically meaningful and actionable knowledge across highly heterogeneous biomedical big data sets.
Education modules using EnviroAtlas (#2)

EPA Science Inventory

Session Title #1: Exploration and Discovery through Maps: Teaching Science with Technology. Online maps have the power to spark student interest and bring students closer to their local natural environments. EnviroAtlas is an interactive, web-based tool that was designed by the...
Education modules using EnviroAtlas

EPA Science Inventory

Proposal #1: Exploration and Discovery through Maps: Teaching Science with Technology (Elementary)Online maps have the power to bring students closer to their local natural environments. EnviroAtlas is an interactive, web-based tool that was designed by the EPA and its partners ...
Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2.

PubMed

Eggert, Erik; Hillig, Roman C; Koehr, Silke; Stöckigt, Detlef; Weiske, Jörg; Barak, Naomi; Mowat, Jeffrey; Brumby, Thomas; Christ, Clara D; Ter Laak, Antonius; Lang, Tina; Fernandez-Montalvan, Amaury E; Badock, Volker; Weinmann, Hilmar; Hartung, Ingo V; Barsyte-Lovejoy, Dalia; Szewczyk, Magdalena; Kennedy, Steven; Li, Fengling; Vedadi, Masoud; Brown, Peter J; Santhakumar, Vijayaratnam; Arrowsmith, Cheryl H; Stellfeld, Timo; Stresemann, Carlo

2016-05-26

Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood. Utilization of highly potent and selective chemical probes for target validation has emerged as a concept which circumvents possible limitations of knockdown experiments and, in particular, could result in an improved exploration of drug targets with a complex underlying biology. Here, we report the development of a potent, selective, and cell-active, substrate-competitive inhibitor of SMYD2, which is the first reported inhibitor suitable for in vivo target validation studies in rodents.
Design of small-molecule epigenetic modulators

PubMed Central

Pachaiyappan, Boobalan

2013-01-01

The field of epigenetics has expanded rapidly to reveal multiple new targets for drug discovery. The functional elements of the epigenomic machinery can be catagorized as writers, erasers and readers, and together these elements control cellular gene expression and homeostasis. It is increasingly clear that aberrations in the epigenome can underly a variety of diseases, and thus discovery of small molecules that modulate the epigenome in a specific manner is a viable approach to the discovery of new therapeutic agents. In this Digest, the components of epigenetic control of gene expression will be briefly summarized, and efforts to identify small molecules that modulate epigenetic processes will be described. PMID:24300735
Changing paradigm from one target one ligand towards multi target directed ligand design for key drug targets of Alzheimer disease: An important role of Insilco methods in multi target directed ligands design.

PubMed

Kumar, Akhil; Tiwari, Ashish; Sharma, Ashok

2018-03-15

Alzheimer disease (AD) is now considered as a multifactorial neurodegenerative disorder and rapidly increasing to an alarming situation and causing higher death rate. One target one ligand hypothesis is not able to provide complete solution of AD due to multifactorial nature of disease and one target one drug seems to fail to provide better treatment against AD. Moreover, current available treatments are limited and most of the upcoming treatments under clinical trials are based on modulating single target. So the current AD drug discovery research shifting towards new approach for better solution that simultaneously modulate more than one targets in the neurodegenerative cascade. This can be achieved by network pharmacology, multi-modal therapies, multifaceted, and/or the more recently proposed term "multi-targeted designed drugs. Drug discovery project is tedious, costly and long term project. Moreover, multi target AD drug discovery added extra challenges such as good binding affinity of ligands for multiple targets, optimal ADME/T properties, no/less off target side effect and crossing of the blood brain barrier. These hurdles may be addressed by insilico methods for efficient solution in less time and cost as computational methods successfully applied to single target drug discovery project. Here we are summarizing some of the most prominent and computationally explored single target against AD and further we discussed successful example of dual or multiple inhibitors for same targets. Moreover we focused on ligand and structure based computational approach to design MTDL against AD. However is not an easy task to balance dual activity in a single molecule but computational approach such as virtual screening docking, QSAR, simulation and free energy are useful in future MTDLs drug discovery alone or in combination with fragment based method. However, rational and logical implementations of computational drug designing methods are capable of assisting AD drug discovery and play an important role in optimizing multi-target drug discovery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Infrared and Raman Spectroscopy: A Discovery-Based Activity for the General Chemistry Curriculum

ERIC Educational Resources Information Center

Borgsmiller, Karen L.; O'Connell, Dylan J.; Klauenberg, Kathryn M.; Wilson, Peter M.; Stromberg, Christopher J.

2012-01-01

A discovery-based method is described for incorporating the concepts of IR and Raman spectroscopy into the general chemistry curriculum. Students use three sets of springs to model the properties of single, double, and triple covalent bonds. Then, Gaussian 03W molecular modeling software is used to illustrate the relationship between bond…
Genomics, "Discovery Science," Systems Biology, and Causal Explanation: What Really Works?

PubMed

Davidson, Eric H

2015-01-01

Diverse and non-coherent sets of epistemological principles currently inform research in the general area of functional genomics. Here, from the personal point of view of a scientist with over half a century of immersion in hypothesis driven scientific discovery, I compare and deconstruct the ideological bases of prominent recent alternatives, such as "discovery science," some productions of the ENCODE project, and aspects of large data set systems biology. The outputs of these types of scientific enterprise qualitatively reflect their radical definitions of scientific knowledge, and of its logical requirements. Their properties emerge in high relief when contrasted (as an example) to a recent, system-wide, predictive analysis of a developmental regulatory apparatus that was instead based directly on hypothesis-driven experimental tests of mechanism.
Cloud-based solution to identify statistically significant MS peaks differentiating sample categories.

PubMed

Ji, Jun; Ling, Jeffrey; Jiang, Helen; Wen, Qiaojun; Whitin, John C; Tian, Lu; Cohen, Harvey J; Ling, Xuefeng B

2013-03-23

Mass spectrometry (MS) has evolved to become the primary high throughput tool for proteomics based biomarker discovery. Until now, multiple challenges in protein MS data analysis remain: large-scale and complex data set management; MS peak identification, indexing; and high dimensional peak differential analysis with the concurrent statistical tests based false discovery rate (FDR). "Turnkey" solutions are needed for biomarker investigations to rapidly process MS data sets to identify statistically significant peaks for subsequent validation. Here we present an efficient and effective solution, which provides experimental biologists easy access to "cloud" computing capabilities to analyze MS data. The web portal can be accessed at http://transmed.stanford.edu/ssa/. Presented web application supplies large scale MS data online uploading and analysis with a simple user interface. This bioinformatic tool will facilitate the discovery of the potential protein biomarkers using MS.
atBioNet--an integrated network analysis tool for genomics and biomarker discovery.

PubMed

Ding, Yijun; Chen, Minjun; Liu, Zhichao; Ding, Don; Ye, Yanbin; Zhang, Min; Kelly, Reagan; Guo, Li; Su, Zhenqiang; Harris, Stephen C; Qian, Feng; Ge, Weigong; Fang, Hong; Xu, Xiaowei; Tong, Weida

2012-07-20

Large amounts of mammalian protein-protein interaction (PPI) data have been generated and are available for public use. From a systems biology perspective, Proteins/genes interactions encode the key mechanisms distinguishing disease and health, and such mechanisms can be uncovered through network analysis. An effective network analysis tool should integrate different content-specific PPI databases into a comprehensive network format with a user-friendly platform to identify key functional modules/pathways and the underlying mechanisms of disease and toxicity. atBioNet integrates seven publicly available PPI databases into a network-specific knowledge base. Knowledge expansion is achieved by expanding a user supplied proteins/genes list with interactions from its integrated PPI network. The statistically significant functional modules are determined by applying a fast network-clustering algorithm (SCAN: a Structural Clustering Algorithm for Networks). The functional modules can be visualized either separately or together in the context of the whole network. Integration of pathway information enables enrichment analysis and assessment of the biological function of modules. Three case studies are presented using publicly available disease gene signatures as a basis to discover new biomarkers for acute leukemia, systemic lupus erythematosus, and breast cancer. The results demonstrated that atBioNet can not only identify functional modules and pathways related to the studied diseases, but this information can also be used to hypothesize novel biomarkers for future analysis. atBioNet is a free web-based network analysis tool that provides a systematic insight into proteins/genes interactions through examining significant functional modules. The identified functional modules are useful for determining underlying mechanisms of disease and biomarker discovery. It can be accessed at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm285284.htm.
Inhibition of Retinoblastoma Protein Inactivation

DTIC Science & Technology

2016-09-01

Retinoblastoma protein, E2F transcription factor, high throughput screen, drug discovery, x-ray crystallography 16. SECURITY CLASSIFICATION OF: 17...developed a method to perform fragment based screening by x-ray crystallography . 2.0 KEYWORDS Retinoblastoma (Rb) pathway, E2F transcription factor...cancer, cell-cycle inhibition, activation, modulation, inhibition, high throughput screening, fragment-based screening, x-ray crystallography
Immediate Dissemination of Student Discoveries to a Model Organism Database Enhances Classroom-Based Research Experiences

ERIC Educational Resources Information Center

Wiley, Emily A.; Stover, Nicholas A.

2014-01-01

Use of inquiry-based research modules in the classroom has soared over recent years, largely in response to national calls for teaching that provides experience with scientific processes and methodologies. To increase the visibility of in-class studies among interested researchers and to strengthen their impact on student learning, we have…
Design of small molecule epigenetic modulators.

PubMed

Pachaiyappan, Boobalan; Woster, Patrick M

2014-01-01

The field of epigenetics has expanded rapidly to reveal multiple new targets for drug discovery. The functional elements of the epigenomic machinery can be categorized as writers, erasers and readers, and together these elements control cellular gene expression and homeostasis. It is increasingly clear that aberrations in the epigenome can underly a variety of diseases, and thus discovery of small molecules that modulate the epigenome in a specific manner is a viable approach to the discovery of new therapeutic agents. In this Digest, the components of epigenetic control of gene expression will be briefly summarized, and efforts to identify small molecules that modulate epigenetic processes will be described. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.
discovery toolset for Emulytics v. 1.0

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

Fritz, David; Crussell, Jonathan

The discovery toolset for Emulytics enables the construction of high-fidelity emulation models of systems. The toolset consists of a set of tools and techniques to automatically go from network discovery of operational systems to emulating those complex systems. Our toolset combines data from host discovery and network mapping tools into an intermediate representation that can then be further refined. Once the intermediate representation reaches the desired state, our toolset supports emitting the Emulytics models with varying levels of specificity based on experiment needs.
KSC-2011-1629

NASA Image and Video Library

2011-02-24

CAPE CANAVERAL, Fla. -- Folks from across the country camped out in communities surrounding NASA's Kennedy Space Center in Florida to witness space shuttle Discovery make history by lifting off on its final scheduled mission from Launch Pad 39A. Seen here is Sand Point Park near U. S. Highway 1 and State Road 406, also known as the A. Max Brewer Causeway, in Titusville, Fla. Liftoff is set for 4:50 p.m. EST on Feb. 24. Discovery and its six-member STS-133 crew will deliver the Permanent Multipurpose Module, packed with supplies and critical spare parts, as well as Robonaut 2, the dexterous humanoid astronaut helper, to the International Space Station. Discovery, which will fly its 39th mission, is scheduled to be retired following STS-133. This will be the 133rd Space Shuttle Program mission and the 35th shuttle voyage to the space station. For more information on the STS-133 mission, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Jack Pfaller
KSC-07pd2371

NASA Image and Video Library

2007-08-24

KENNEDY SPACE CENTER, FLA. -- The super lightweight ablator, or SLA, cork insulation has been removed from the external tank and a United Space Alliance external tank technician sands off the residue from the LO2 feed line bracket. The BX265 foam insulation will later be reapplied without the SLA. The tank is scheduled to fly on Space Shuttle Discovery in October 2007 on mission STS-120. Discovery's crew will add the module Harmony that will serve as a port for installing additional international laboratories. Harmony will be the first expansion of the living and working space on the complex since the Russian Pirs airlock was installed in 2001. The mission also will move the first set of solar arrays installed on the station to a permanent location on the complex and redeploy them. Photo credit: NASA/Jim Grossmann
KSC-07pd2370

NASA Image and Video Library

2007-08-24

KENNEDY SPACE CENTER, FLA. -- Now that the foam insulation is removed from the external tank, the crack in the super lightweight ablator, or SLA, cork insulation is visible as had been observed previously by X-rays. The BX265 foam insulation will later be reapplied without the SLA. The tank is scheduled to fly on Space Shuttle Discovery in October 2007 on mission STS-120. Discovery's crew will add the module Harmony that will serve as a port for installing additional international laboratories. Harmony will be the first expansion of the living and working space on the complex since the Russian Pirs airlock was installed in 2001. The mission also will move the first set of solar arrays installed on the station to a permanent location on the complex and redeploy them. Photo credit: NASA/Jim Grossmann

KSC-08pd1041

NASA Image and Video Library

2008-04-26

CAPE CANAVERAL, Fla. -- In the Vehicle Assembly Building at NASA's Kennedy Space Center, space shuttle Discovery, looking like a giant bat, hangs suspended above the transfer aisle. The crane holding it will lift Discovery to the upper levels and lower it into high bay 3. In the bay, Discovery will be mated to the external tank and solid rocket boosters for launch on the upcoming STS-124 mission to the International Space Station. On the mission, the STS-124 crew will transport the Japanese Experiment Module - Pressurized Module and the Japanese Remote Manipulator System to the space station. Launch of Discovery is targeted for May 31 Photo credit: NASA/Jim Grossmann
Extraction of consensus protein patterns in regions containing non-proline cis peptide bonds and their functional assessment.

PubMed

Exarchos, Konstantinos P; Exarchos, Themis P; Rigas, Georgios; Papaloukas, Costas; Fotiadis, Dimitrios I

2011-05-10

In peptides and proteins, only a small percentile of peptide bonds adopts the cis configuration. Especially in the case of amide peptide bonds, the amount of cis conformations is quite limited thus hampering systematic studies, until recently. However, lately the emerging population of databases with more 3D structures of proteins has produced a considerable number of sequences containing non-proline cis formations (cis-nonPro). In our work, we extract regular expression-type patterns that are descriptive of regions surrounding the cis-nonPro formations. For this purpose, three types of pattern discovery are performed: i) exact pattern discovery, ii) pattern discovery using a chemical equivalency set, and iii) pattern discovery using a structural equivalency set. Afterwards, using each pattern as predicate, we search the Eukaryotic Linear Motif (ELM) resource to identify potential functional implications of regions with cis-nonPro peptide bonds. The patterns extracted from each type of pattern discovery are further employed, in order to formulate a pattern-based classifier, which is used to discriminate between cis-nonPro and trans-nonPro formations. In terms of functional implications, we observe a significant association of cis-nonPro peptide bonds towards ligand/binding functionalities. As for the pattern-based classification scheme, the highest results were obtained using the structural equivalency set, which yielded 70% accuracy, 77% sensitivity and 63% specificity.
Reasoning About Nature: Graduate students and teachers integrating historic and modern science in high school math and science classes

NASA Astrophysics Data System (ADS)

Davis, J. B.; Rigsby, C. A.; Muston, C.; Robinson, Z.; Morehead, A.; Stellwag, E. J.; Shinpaugh, J.; Thompson, A.; Teller, J.

2010-12-01

Graduate students and faculty at East Carolina University are working with area high schools to address the common science and mathematics deficiencies of many high school students. Project RaN (Reasoning about Nature), an interdisciplinary science/math/education research project, addresses these deficiencies by focusing on the history of science and the relationship between that history and modern scientific thought and practice. The geological sciences portion of project RaN has three specific goals: (1) to elucidate the relationships among the history of scientific discovery, the geological sciences, and modern scientific thought; (2) to develop, and utilize in the classroom, instructional modules that are relevant to the modern geological sciences curriculum and that relate fundamental scientific discoveries and principles to multiple disciplines and to modern societal issues; and (3) to use these activity-based modules to heighten students’ interest in science disciplines and to generate enthusiasm for doing science in both students and instructors. The educational modules that result from this linkage of modern and historical scientific thought are activity-based, directly related to the National Science Standards for the high school sciences curriculum, and adaptable to fit each state’s standard course of study for the sciences and math. They integrate historic sciences and mathematics with modern science, contain relevant background information on both the concept(s) and scientist(s) involved, present questions that compel students to think more deeply (both qualitatively and quantitatively) about the subject matter, and include threads that branch off to related topics. Modules on topics ranging from the density to cladistics to Kepler’s laws of planetary motion have been developed and tested. Pre- and post-module data suggest that both students and teachers benefit from these interdisciplinary historically based classroom experiences.
A system view and analysis of essential hypertension.

PubMed

Botzer, Alon; Grossman, Ehud; Moult, John; Unger, Ron

2018-05-01

The goal of this study was to investigate genes associated with essential hypertension from a system perspective, making use of bioinformatic tools to gain insights that are not evident when focusing at a detail-based resolution. Using various databases (pathways, Genome Wide Association Studies, knockouts etc.), we compiled a set of about 200 genes that play a major role in hypertension and identified the interactions between them. This enabled us to create a protein-protein interaction network graph, from which we identified key elements, based on graph centrality analysis. Enriched gene regulatory elements (transcription factors and microRNAs) were extracted by motif finding techniques and knowledge-based tools. We found that the network is composed of modules associated with functions such as water retention, endothelial vasoconstriction, sympathetic activity and others. We identified the transcription factor SP1 and the two microRNAs miR27 (a and b) and miR548c-3p that seem to play a major role in regulating the network as they exert their control over several modules and are not restricted to specific functions. We also noticed that genes involved in metabolic diseases (e.g. insulin) are central to the network. We view the blood-pressure regulation mechanism as a system-of-systems, composed of several contributing subsystems and pathways rather than a single module. The system is regulated by distributed elements. Understanding this mode of action can lead to a more precise treatment and drug target discovery. Our analysis suggests that insulin plays a primary role in hypertension, highlighting the tight link between essential hypertension and diseases associated with the metabolic syndrome.
Strain-induced dimensionality crossover of precursor modulations in Ni2MnGa

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

Nie, Zhihua; Wang, Yandong; Shang, Shunli

2015-01-01

Precursor modulations often occur in functional materials like magnetic shape memory alloys, ferroelectrics, and superconductors. In this letter, we have revealed the underlying mechanism of the precursor modulations in ferromagnetic shape memory alloys Ni2MnGa by combining synchrotron-based x-ray diffraction experiments and first-principles phonon calculations. We discovered the precursor modulations along [011] direction can be eliminated with [001] uniaxial loading, while the precursor modulations or premartensite can be totally suppressed by hydrostatic pressure condition. The TA2 phonon anomaly is sensitive to stress induced lattice strain, and the entire TA2 branch is stabilized along the directions where precursor modulations are eliminated bymore » external stress. Our discovery bridges precursor modulations and phonon anomalies, and sheds light on the microscopic mechanism of the two-step superelasticity in precursor martensite.« less
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Economically Depressed Areas Strand: Human Development: Module III-E-3: Resources for the Economically Depressed Family.

ERIC Educational Resources Information Center

Boogaert, John

This competency-based preservice home economics teacher education module on resources for the economically depressed area family is the third in a set of three modules on human development in economically depressed areas. (This set is part of a larger set of sixty-seven modules on the Management Approach to Teaching Consumer and Homemaking…
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Consumer Approach Strand: Housing. Module I-B-6: Maintenance Procedures for Surfaces and Appliances.

ERIC Educational Resources Information Center

Hennings, Patricia

This competency-based preservice home economics teacher education module on maintenance procedures for surfaces and appliances is the sixth in a set of six modules on consumer education related to housing. (This set is part of a larger set of sixty-seven modules on the Management Approach to Teaching Consumer and Homemaking Education [MATCHE]--see…
Applications of chemogenomic library screening in drug discovery.

PubMed

Jones, Lyn H; Bunnage, Mark E

2017-04-01

The allure of phenotypic screening, combined with the industry preference for target-based approaches, has prompted the development of innovative chemical biology technologies that facilitate the identification of new therapeutic targets for accelerated drug discovery. A chemogenomic library is a collection of selective small-molecule pharmacological agents, and a hit from such a set in a phenotypic screen suggests that the annotated target or targets of that pharmacological agent may be involved in perturbing the observable phenotype. In this Review, we describe opportunities for chemogenomic screening to considerably expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Other applications are explored, including drug repositioning, predictive toxicology and the discovery of novel pharmacological modalities.
A bioinformatics knowledge discovery in text application for grid computing

PubMed Central

Castellano, Marcello; Mastronardi, Giuseppe; Bellotti, Roberto; Tarricone, Gianfranco

2009-01-01

Background A fundamental activity in biomedical research is Knowledge Discovery which has the ability to search through large amounts of biomedical information such as documents and data. High performance computational infrastructures, such as Grid technologies, are emerging as a possible infrastructure to tackle the intensive use of Information and Communication resources in life science. The goal of this work was to develop a software middleware solution in order to exploit the many knowledge discovery applications on scalable and distributed computing systems to achieve intensive use of ICT resources. Methods The development of a grid application for Knowledge Discovery in Text using a middleware solution based methodology is presented. The system must be able to: perform a user application model, process the jobs with the aim of creating many parallel jobs to distribute on the computational nodes. Finally, the system must be aware of the computational resources available, their status and must be able to monitor the execution of parallel jobs. These operative requirements lead to design a middleware to be specialized using user application modules. It included a graphical user interface in order to access to a node search system, a load balancing system and a transfer optimizer to reduce communication costs. Results A middleware solution prototype and the performance evaluation of it in terms of the speed-up factor is shown. It was written in JAVA on Globus Toolkit 4 to build the grid infrastructure based on GNU/Linux computer grid nodes. A test was carried out and the results are shown for the named entity recognition search of symptoms and pathologies. The search was applied to a collection of 5,000 scientific documents taken from PubMed. Conclusion In this paper we discuss the development of a grid application based on a middleware solution. It has been tested on a knowledge discovery in text process to extract new and useful information about symptoms and pathologies from a large collection of unstructured scientific documents. As an example a computation of Knowledge Discovery in Database was applied on the output produced by the KDT user module to extract new knowledge about symptom and pathology bio-entities. PMID:19534749
A bioinformatics knowledge discovery in text application for grid computing.

PubMed

Castellano, Marcello; Mastronardi, Giuseppe; Bellotti, Roberto; Tarricone, Gianfranco

2009-06-16

A fundamental activity in biomedical research is Knowledge Discovery which has the ability to search through large amounts of biomedical information such as documents and data. High performance computational infrastructures, such as Grid technologies, are emerging as a possible infrastructure to tackle the intensive use of Information and Communication resources in life science. The goal of this work was to develop a software middleware solution in order to exploit the many knowledge discovery applications on scalable and distributed computing systems to achieve intensive use of ICT resources. The development of a grid application for Knowledge Discovery in Text using a middleware solution based methodology is presented. The system must be able to: perform a user application model, process the jobs with the aim of creating many parallel jobs to distribute on the computational nodes. Finally, the system must be aware of the computational resources available, their status and must be able to monitor the execution of parallel jobs. These operative requirements lead to design a middleware to be specialized using user application modules. It included a graphical user interface in order to access to a node search system, a load balancing system and a transfer optimizer to reduce communication costs. A middleware solution prototype and the performance evaluation of it in terms of the speed-up factor is shown. It was written in JAVA on Globus Toolkit 4 to build the grid infrastructure based on GNU/Linux computer grid nodes. A test was carried out and the results are shown for the named entity recognition search of symptoms and pathologies. The search was applied to a collection of 5,000 scientific documents taken from PubMed. In this paper we discuss the development of a grid application based on a middleware solution. It has been tested on a knowledge discovery in text process to extract new and useful information about symptoms and pathologies from a large collection of unstructured scientific documents. As an example a computation of Knowledge Discovery in Database was applied on the output produced by the KDT user module to extract new knowledge about symptom and pathology bio-entities.
KSC-2009-4560

NASA Image and Video Library

2009-08-09

CAPE CANAVERAL, Fla. – On Launch Pad 39A, the payload ground-handling mechanism moves back after placing the multi-purpose logistics module Leonardo in space shuttle Discovery's payload bay. Leonardo is the primary payload on Discovery's STS-128 mission to the International Space Station. Beneath the module is the Lightweight Multi-Purpose Experiment Support Structure Carrier. Discovery will deliver 33,000 pounds of equipment to the station, including science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch is targeted for late August. Photo credit: NASA/Jack Pfaller
The current state of GPCR-based drug discovery to treat metabolic disease.

PubMed

Sloop, Kyle W; Emmerson, Paul J; Statnick, Michael A; Willard, Francis S

2018-02-02

One approach of modern drug discovery is to identify agents that enhance or diminish signal transduction cascades in various cell types and tissues by modulating the activity of GPCRs. This strategy has resulted in the development of new medicines to treat many conditions, including cardiovascular disease, psychiatric disorders, HIV/AIDS, certain forms of cancer and Type 2 diabetes mellitus (T2DM). These successes justify further pursuit of GPCRs as disease targets and provide key learning that should help guide identifying future therapeutic agents. This report reviews the current landscape of GPCR drug discovery with emphasis on efforts aimed at developing new molecules for treating T2DM and obesity. We analyse historical efforts to generate GPCR-based drugs to treat metabolic disease in terms of causal factors leading to success and failure in this endeavour. © 2018 The British Pharmacological Society.
Modulating Calcium Signals to Boost AON Exon Skipping for DMD

DTIC Science & Technology

2017-10-01

NINDS $488,500/y Title: Rapid Phenotyping for Rare Variant Discovery in Autism This project is intended to use web-based recruiting to greatly...expand DNA samples available for genetic analysis to determine the heterogeneous genetic causes of autism . ACTIVE P30 AR057230-01 (Spencer
Seafloor Science and Remotely Operated Vehicle (SSROV) Day Camp: A Week-Long, Hands-On STEM Summer Camp

NASA Astrophysics Data System (ADS)

Wheat, C. G.; Fournier, T.; Monahan, K.; Paul, C.

2015-12-01

RETINA (Robotic Exploration Technologies IN Astrobiology) has developed a program geared towards stimulating our youth with innovative and relevant hands-on learning modules under a STEM umbrella. Given the breadth of potential science and engineering topics that excite children, the RETINA Program focuses on interactive participation in the design and development of simple robotic and sensor systems, providing a range of challenges to engage students through project-based learning (PBL). Thus, young students experience scientific discovery through the use and understanding of technology. This groundwork serves as the foundation for SSROV Camp, a week-long, summer day camp for 6th-8th grade students. The camp is centered on the sensors and platforms that guide seafloor exploration and discovery and builds upon the notion that transformative discoveries in the deep sea result from either sampling new environments or making new measurements with sensors adapted to this extreme environment. These technical and scientific needs are folded into the curriculum. Each of the first four days of the camp includes four team-based, hands-on technical challenges, communication among peer groups, and competition. The fifth day includes additional activities, culminating in camper-led presentations to describe a planned mission based on a given geologic setting. Presentations include hypotheses, operational requirements and expected data products. SSROV Camp was initiated last summer for three sessions, two in Monterey, CA and one in Oxford, MS. Campers from both regions grasped key elements of the program, based on written responses to questions before and after the camp. On average, 32% of the pre-test questions were answered correctly compared with 80% of the post-test questions. Additional confirmation of gains in campers' knowledge, skills, and critical thinking on environmental issues and engineering problems were apparent during the "jeopardy" competition, nightly homework, and mission presentations. On the basis of this successful effort, we hope to expand to other towns.
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Economically Depressed Areas Strand: Management. Module III-F-3: Marketing Practices in Relation to Low Income Clientele.

ERIC Educational Resources Information Center

California State Univ., Fresno. Dept. of Home Economics.

This competency-based preservice home economics teacher education module on marketing practices in relation to low income clientele is the third in a set of three modules on management in economically depressed areas (EDAs). (This set is part of a larger set of sixty-seven modules on the Management Approach to Teaching Consumer and Homemaking…
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Economically Depressed Areas Strand: Foods and Nutrition. Module III-C-1: Food Availability in Economically Depressed Areas.

ERIC Educational Resources Information Center

California State Univ., Fresno. Dept. of Home Economics.

This competency-based preservice home economics teacher education module on food availability in economically depressed areas (EDA) is the first in a set of three modules on foods and nutrition in economically depressed areas. (This set is part of a larger set of sixty-seven modules on the Management Approach to Teaching Consumer and Homemaking…
Antibody-enabled small-molecule drug discovery.

PubMed

Lawson, Alastair D G

2012-06-29

Although antibody-based therapeutics have become firmly established as medicines for serious diseases, the value of antibodies as tools in the early stages of small-molecule drug discovery is only beginning to be realized. In particular, antibodies may provide information to reduce risk in small-molecule drug discovery by enabling the validation of targets and by providing insights into the design of small-molecule screening assays. Moreover, antibodies can act as guides in the quest for small molecules that have the ability to modulate protein-protein interactions, which have traditionally only been considered to be tractable targets for biological drugs. The development of small molecules that have similar therapeutic effects to current biologics has the potential to benefit a broader range of patients at earlier stages of disease.
Concordant integrative gene set enrichment analysis of multiple large-scale two-sample expression data sets.

PubMed

Lai, Yinglei; Zhang, Fanni; Nayak, Tapan K; Modarres, Reza; Lee, Norman H; McCaffrey, Timothy A

2014-01-01

Gene set enrichment analysis (GSEA) is an important approach to the analysis of coordinate expression changes at a pathway level. Although many statistical and computational methods have been proposed for GSEA, the issue of a concordant integrative GSEA of multiple expression data sets has not been well addressed. Among different related data sets collected for the same or similar study purposes, it is important to identify pathways or gene sets with concordant enrichment. We categorize the underlying true states of differential expression into three representative categories: no change, positive change and negative change. Due to data noise, what we observe from experiments may not indicate the underlying truth. Although these categories are not observed in practice, they can be considered in a mixture model framework. Then, we define the mathematical concept of concordant gene set enrichment and calculate its related probability based on a three-component multivariate normal mixture model. The related false discovery rate can be calculated and used to rank different gene sets. We used three published lung cancer microarray gene expression data sets to illustrate our proposed method. One analysis based on the first two data sets was conducted to compare our result with a previous published result based on a GSEA conducted separately for each individual data set. This comparison illustrates the advantage of our proposed concordant integrative gene set enrichment analysis. Then, with a relatively new and larger pathway collection, we used our method to conduct an integrative analysis of the first two data sets and also all three data sets. Both results showed that many gene sets could be identified with low false discovery rates. A consistency between both results was also observed. A further exploration based on the KEGG cancer pathway collection showed that a majority of these pathways could be identified by our proposed method. This study illustrates that we can improve detection power and discovery consistency through a concordant integrative analysis of multiple large-scale two-sample gene expression data sets.
Computational Tools for Allosteric Drug Discovery: Site Identification and Focus Library Design.

PubMed

Huang, Wenkang; Nussinov, Ruth; Zhang, Jian

2017-01-01

Allostery is an intrinsic phenomenon of biological macromolecules involving regulation and/or signal transduction induced by a ligand binding to an allosteric site distinct from a molecule's active site. Allosteric drugs are currently receiving increased attention in drug discovery because drugs that target allosteric sites can provide important advantages over the corresponding orthosteric drugs including specific subtype selectivity within receptor families. Consequently, targeting allosteric sites, instead of orthosteric sites, can reduce drug-related side effects and toxicity. On the down side, allosteric drug discovery can be more challenging than traditional orthosteric drug discovery due to difficulties associated with determining the locations of allosteric sites and designing drugs based on these sites and the need for the allosteric effects to propagate through the structure, reach the ligand binding site and elicit a conformational change. In this study, we present computational tools ranging from the identification of potential allosteric sites to the design of "allosteric-like" modulator libraries. These tools may be particularly useful for allosteric drug discovery.
Description of web-enhanced virtual character simulation system to standardize patient hand-offs.

PubMed

Filichia, Lori; Halan, Shivashankar; Blackwelder, Ethan; Rossen, Brent; Lok, Benjamin; Korndorffer, James; Cendan, Juan

2011-04-01

The 80-h work week has increased discontinuity of patient care resulting in reports of increased medication errors and preventable adverse events. Graduate medical programs are addressing these shortcomings in a number of ways. We have developed a computer simulation platform called the Virtual People Factory (VPF), which allows us to capture and simulate the dialogue between a real user and a virtual character. We have converted the system to reflect a physician in the process of "checking-out" a patient to a covering physician. The responses are tracked and matched to educator-defined information termed "discoveries." Our proof of concept represented a typical post-operative patient with tachycardia. The system is web enabled. So far, 26 resident users at two institutions have completed the module. The critical discovery of tachycardia was identified by 62% of users. Residents spend 85% of the time asking intraoperative, postoperative, and past medical history questions. The system improves over time such that there is a near-doubling of questions that yield appropriate answers between users 13 and 22. Users who identified the virtual patient's underlying tachycardia expressed more concern and were more likely to order further testing for the patient in a post-module questionnaire (P = 0.13 and 0.08, respectively, NS). The VPF system can capture unique details about the hand-off interchange. The system improves with sequential users such that better matching of questions and answers occurs within the initial 25 users allowing rapid development of new modules. A catalog of hand-off modules could be easily developed. Wide-scale web-based deployment was uncomplicated. Identification of the critical findings appropriately translated to user concern for the patient though our series was too small to reach significance. Performance metrics based on the identification of critical discoveries could be used to assess readiness of the user to carry off a successful hand-off. Copyright © 2011 Elsevier Inc. All rights reserved.

KSC-07pd2368

NASA Image and Video Library

2007-08-24

KENNEDY SPACE CENTER, FLA. -- A United Space Alliance external tank technician maps out the cutting area of the liquid oxygen (LO2) feed line bracket where BX265 foam insulation and super lightweight ablator, or SLA, cork insulation is to be removed. The BX265 foam insulation will later be reapplied without the SLA. The tank is scheduled to fly on Space Shuttle Discovery in October 2007 on mission STS-120. Discovery's crew will add the module Harmony that will serve as a port for installing additional international laboratories. Harmony will be the first expansion of the living and working space on the complex since the Russian Pirs airlock was installed in 2001. The mission also will move the first set of solar arrays installed on the station to a permanent location on the complex and redeploy them. Photo credit: NASA/Jim Grossmann
KSC-07pd2369

NASA Image and Video Library

2007-08-24

KENNEDY SPACE CENTER, FLA. -- A United Space Alliance external tank technician has completed the removal of a layer of BX265 foam insulation from the LO2 feed line bracket on the external tank. The BX265 foam insulation will later be reapplied without the super lightweight ablator, or SLA, cork insulation. The tank is scheduled to fly on Space Shuttle Discovery in October 2007 on mission STS-120. Discovery's crew will add the module Harmony that will serve as a port for installing additional international laboratories. Harmony will be the first expansion of the living and working space on the complex since the Russian Pirs airlock was installed in 2001. The mission also will move the first set of solar arrays installed on the station to a permanent location on the complex and redeploy them. Photo credit: NASA/Jim Grossmann
Dry selection and wet evaluation for the rational discovery of new anthelmintics

NASA Astrophysics Data System (ADS)

Marrero-Ponce, Yovani; Castañeda, Yeniel González; Vivas-Reyes, Ricardo; Vergara, Fredy Máximo; Arán, Vicente J.; Castillo-Garit, Juan A.; Pérez-Giménez, Facundo; Torrens, Francisco; Le-Thi-Thu, Huong; Pham-The, Hai; Montenegro, Yolanda Vera; Ibarra-Velarde, Froylán

2017-09-01

Helminths infections remain a major problem in medical and public health. In this report, atom-based 2D bilinear indices, a TOMOCOMD-CARDD (QuBiLs-MAS module) molecular descriptor family and linear discriminant analysis (LDA) were used to find models that differentiate among anthelmintic and non-anthelmintic compounds. Two classification models obtained by using non-stochastic and stochastic 2D bilinear indices, classified correctly 86.64% and 84.66%, respectively, in the training set. Equation 1(2) correctly classified 141(135) out of 165 [85.45%(81.82%)] compounds in external validation set. Another LDA models were performed in order to get the most likely mechanism of action of anthelmintics. The model shows an accuracy of 86.84% in the training set and 94.44% in the external prediction set. Finally, we carry out an experiment to predict the biological profile of our 'in-house' collections of indole, indazole, quinoxaline and cinnoline derivatives (∼200 compounds). Subsequently, we selected a group of nine of the theoretically most active structures. Then, these chemicals were tested in an in vitro assay and one good candidate (VA5-5c) as fasciolicide compound (100% of reduction at concentrations of 50 and 10 mg/L) was discovered.
Hypotheses generation as supervised link discovery with automated class labeling on large-scale biomedical concept networks

PubMed Central

2012-01-01

Computational approaches to generate hypotheses from biomedical literature have been studied intensively in recent years. Nevertheless, it still remains a challenge to automatically discover novel, cross-silo biomedical hypotheses from large-scale literature repositories. In order to address this challenge, we first model a biomedical literature repository as a comprehensive network of biomedical concepts and formulate hypotheses generation as a process of link discovery on the concept network. We extract the relevant information from the biomedical literature corpus and generate a concept network and concept-author map on a cluster using Map-Reduce frame-work. We extract a set of heterogeneous features such as random walk based features, neighborhood features and common author features. The potential number of links to consider for the possibility of link discovery is large in our concept network and to address the scalability problem, the features from a concept network are extracted using a cluster with Map-Reduce framework. We further model link discovery as a classification problem carried out on a training data set automatically extracted from two network snapshots taken in two consecutive time duration. A set of heterogeneous features, which cover both topological and semantic features derived from the concept network, have been studied with respect to their impacts on the accuracy of the proposed supervised link discovery process. A case study of hypotheses generation based on the proposed method has been presented in the paper. PMID:22759614
The sun rises on the Space Shuttle Discovery as it rests on the runway at Edwards Air Force Base, California, after a safe landing August 9, 2005

NASA Image and Video Library

2005-08-09

The sun rises on the Space Shuttle Discovery as it rests on the runway at Edwards Air Force Base, California, after a safe landing August 9, 2005 to complete the STS-114 mission. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT this morning, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.
Improved accuracy of supervised CRM discovery with interpolated Markov models and cross-species comparison.

PubMed

Kazemian, Majid; Zhu, Qiyun; Halfon, Marc S; Sinha, Saurabh

2011-12-01

Despite recent advances in experimental approaches for identifying transcriptional cis-regulatory modules (CRMs, 'enhancers'), direct empirical discovery of CRMs for all genes in all cell types and environmental conditions is likely to remain an elusive goal. Effective methods for computational CRM discovery are thus a critically needed complement to empirical approaches. However, existing computational methods that search for clusters of putative binding sites are ineffective if the relevant TFs and/or their binding specificities are unknown. Here, we provide a significantly improved method for 'motif-blind' CRM discovery that does not depend on knowledge or accurate prediction of TF-binding motifs and is effective when limited knowledge of functional CRMs is available to 'supervise' the search. We propose a new statistical method, based on 'Interpolated Markov Models', for motif-blind, genome-wide CRM discovery. It captures the statistical profile of variable length words in known CRMs of a regulatory network and finds candidate CRMs that match this profile. The method also uses orthologs of the known CRMs from closely related genomes. We perform in silico evaluation of predicted CRMs by assessing whether their neighboring genes are enriched for the expected expression patterns. This assessment uses a novel statistical test that extends the widely used Hypergeometric test of gene set enrichment to account for variability in intergenic lengths. We find that the new CRM prediction method is superior to existing methods. Finally, we experimentally validate 12 new CRM predictions by examining their regulatory activity in vivo in Drosophila; 10 of the tested CRMs were found to be functional, while 6 of the top 7 predictions showed the expected activity patterns. We make our program available as downloadable source code, and as a plugin for a genome browser installed on our servers. © The Author(s) 2011. Published by Oxford University Press.
Principal component analysis-based unsupervised feature extraction applied to in silico drug discovery for posttraumatic stress disorder-mediated heart disease.

PubMed

Taguchi, Y-h; Iwadate, Mitsuo; Umeyama, Hideaki

2015-04-30

Feature extraction (FE) is difficult, particularly if there are more features than samples, as small sample numbers often result in biased outcomes or overfitting. Furthermore, multiple sample classes often complicate FE because evaluating performance, which is usual in supervised FE, is generally harder than the two-class problem. Developing sample classification independent unsupervised methods would solve many of these problems. Two principal component analysis (PCA)-based FE, specifically, variational Bayes PCA (VBPCA) was extended to perform unsupervised FE, and together with conventional PCA (CPCA)-based unsupervised FE, were tested as sample classification independent unsupervised FE methods. VBPCA- and CPCA-based unsupervised FE both performed well when applied to simulated data, and a posttraumatic stress disorder (PTSD)-mediated heart disease data set that had multiple categorical class observations in mRNA/microRNA expression of stressed mouse heart. A critical set of PTSD miRNAs/mRNAs were identified that show aberrant expression between treatment and control samples, and significant, negative correlation with one another. Moreover, greater stability and biological feasibility than conventional supervised FE was also demonstrated. Based on the results obtained, in silico drug discovery was performed as translational validation of the methods. Our two proposed unsupervised FE methods (CPCA- and VBPCA-based) worked well on simulated data, and outperformed two conventional supervised FE methods on a real data set. Thus, these two methods have suggested equivalence for FE on categorical multiclass data sets, with potential translational utility for in silico drug discovery.
Enhancing the chemical selectivity in discovery-based analysis with tandem ionization time-of-flight mass spectrometry detection for comprehensive two-dimensional gas chromatography.

PubMed

Freye, Chris E; Moore, Nicholas R; Synovec, Robert E

2018-02-16

The complementary information provided by tandem ionization time-of-flight mass spectrometry (TI-TOFMS) is investigated for comparative discovery-based analysis, when coupled with comprehensive two-dimensional gas chromatography (GC × GC). The TI conditions implemented were a hard ionization energy (70 eV) concurrently collected with a soft ionization energy (14 eV). Tile-based Fisher ratio (F-ratio) analysis is used to analyze diesel fuel spiked with twelve analytes at a nominal concentration of 50 ppm. F-ratio analysis is a supervised discovery-based technique that compares two different sample classes, in this case spiked and unspiked diesel, to reduce the complex GC × GC-TI-TOFMS data into a hit list of class distinguishing analyte features. Hit lists of the 70 eV and 14 eV data sets, and the single hit list produced when the two data sets are fused together, are all investigated. For the 70 eV hit list, eleven of the twelve analytes were found in the top thirteen hits. For the 14 eV hit list, nine of the twelve analytes were found in the top nine hits, with the other three analytes either not found or well down the hit list. As expected, the F-ratios per m/z used to calculate each average F-ratio per hit were generally smaller fragment ions for the 70 eV data set, while the larger fragment ions were emphasized in the 14 eV data set, supporting the notion that complementary information was provided. The discovery rate was improved when F-ratio analysis was performed on the fused data sets resulted in eleven of the twelve analytes being at the top of the single hit list. Using PARAFAC, analytes that were "discovered" were deconvoluted in order to obtain their identification via match values (MV). Location of the analytes and the "F-ratio spectra" obtained from F-ratio analysis were used to guide the deconvolution. Eight of the twelve analytes where successfully deconvoluted and identified using the in-house library for the 70 eV data set. PARAFAC deconvolution of the two separate data sets provided increased confidence in identification of "discovered" analytes. Herein, we explore the limit of analyte discovery and limit of analyte identification, and demonstrate a general workflow for the investigation of key chemical features in complex samples. Copyright © 2018 Elsevier B.V. All rights reserved.
KSC-07pd2825

NASA Image and Video Library

2007-10-09

KENNEDY SPACE CENTER, FLA. -- At Launch Pad 39A, space shuttle Discovery's payload bay doors are closed around the U.S. Node 2 module, named Harmony. The name was chosen from an academic competition involving more than 2,200 U. S. students in kindergarten through high school. The module will be delivered to the International Space Station aboard Discovery on the 14-day STS-120 mission. An orbiter's payload bay door closure at the pad is a milestone signaling that the launch date is near. Discovery's launch is targeted for Oct. 23 at 11:38 a.m. EDT. Photo credit: NASA/George Shelton
KSC-07pd2824

NASA Image and Video Library

2007-10-09

KENNEDY SPACE CENTER, FLA. -- At Launch Pad 39A, space shuttle Discovery's payload bay doors are nearly closed around the U.S. Node 2 module, named Harmony. The name was chosen from an academic competition involving more than 2,200 U. S. students in kindergarten through high school. The module will be delivered to the International Space Station aboard Discovery on the 14-day STS-120 mission. An orbiter's payload bay door closure at the pad is a milestone signaling that the launch date is near. Discovery's launch is targeted for Oct. 23 at 11:38 a.m. EDT. Photo credit: NASA/George Shelton
KSC-07pd2820

NASA Image and Video Library

2007-10-09

KENNEDY SPACE CENTER, FLA. -- At Launch Pad 39A, preparations are under way to close space shuttle Discovery's payload bay doors around the U.S. Node 2 module, named Harmony. The name was chosen from an academic competition involving more than 2,200 U. S. students in kindergarten through high school. The module will be delivered to the International Space Station aboard Discovery on the 14-day STS-120 mission. An orbiter's payload bay door closure at the pad is a milestone signaling that the launch date is near. Discovery's launch is targeted for Oct. 23 at 11:38 a.m. EDT. Photo credit: NASA/George Shelton
KSC-07pd2823

NASA Image and Video Library

2007-10-09

KENNEDY SPACE CENTER, FLA. -- At Launch Pad 39A, space shuttle Discovery's payload bay doors slowly enclose the U.S. Node 2 module, named Harmony. The name was chosen from an academic competition involving more than 2,200 U. S. students in kindergarten through high school. The module will be delivered to the International Space Station aboard Discovery on the 14-day STS-120 mission. An orbiter's payload bay door closure at the pad is a milestone signaling that the launch date is near. Discovery's launch is targeted for Oct. 23 at 11:38 a.m. EDT. Photo credit: NASA/George Shelton
KSC-07pd2822

NASA Image and Video Library

2007-10-09

KENNEDY SPACE CENTER, FLA. -- At Launch Pad 39A, space shuttle Discovery's payload bay doors are partially closed around the U.S. Node 2 module, named Harmony. The name was chosen from an academic competition involving more than 2,200 U. S. students in kindergarten through high school. The module will be delivered to the International Space Station aboard Discovery on the 14-day STS-120 mission. An orbiter's payload bay door closure at the pad is a milestone signaling that the launch date is near. Discovery's launch is targeted for Oct. 23 at 11:38 a.m. EDT. Photo credit: NASA/George Shelton
KSC-07pd2821

NASA Image and Video Library

2007-10-09

KENNEDY SPACE CENTER, FLA. -- At Launch Pad 39A, space shuttle Discovery's payload bay doors begin to close around the U.S. Node 2 module, named Harmony. The name was chosen from an academic competition involving more than 2,200 U. S. students in kindergarten through high school. The module will be delivered to the International Space Station aboard Discovery on the 14-day STS-120 mission. An orbiter's payload bay door closure at the pad is a milestone signaling that the launch date is near. Discovery's launch is targeted for Oct. 23 at 11:38 a.m. EDT. Photo credit: NASA/George Shelton
Navigating the Functional Landscape of Transcription Factors via Non-Negative Tensor Factorization Analysis of MEDLINE Abstracts

PubMed Central

Roy, Sujoy; Yun, Daqing; Madahian, Behrouz; Berry, Michael W.; Deng, Lih-Yuan; Goldowitz, Daniel; Homayouni, Ramin

2017-01-01

In this study, we developed and evaluated a novel text-mining approach, using non-negative tensor factorization (NTF), to simultaneously extract and functionally annotate transcriptional modules consisting of sets of genes, transcription factors (TFs), and terms from MEDLINE abstracts. A sparse 3-mode term × gene × TF tensor was constructed that contained weighted frequencies of 106,895 terms in 26,781 abstracts shared among 7,695 genes and 994 TFs. The tensor was decomposed into sub-tensors using non-negative tensor factorization (NTF) across 16 different approximation ranks. Dominant entries of each of 2,861 sub-tensors were extracted to form term–gene–TF annotated transcriptional modules (ATMs). More than 94% of the ATMs were found to be enriched in at least one KEGG pathway or GO category, suggesting that the ATMs are functionally relevant. One advantage of this method is that it can discover potentially new gene–TF associations from the literature. Using a set of microarray and ChIP-Seq datasets as gold standard, we show that the precision of our method for predicting gene–TF associations is significantly higher than chance. In addition, we demonstrate that the terms in each ATM can be used to suggest new GO classifications to genes and TFs. Taken together, our results indicate that NTF is useful for simultaneous extraction and functional annotation of transcriptional regulatory networks from unstructured text, as well as for literature based discovery. A web tool called Transcriptional Regulatory Modules Extracted from Literature (TREMEL), available at http://binf1.memphis.edu/tremel, was built to enable browsing and searching of ATMs. PMID:28894735
Inhibition of Retinoblastoma Protein Inactivation

DTIC Science & Technology

2017-11-01

SUBJECT TERMS cell cycle, Retinoblastoma protein, E2F transcription factor, high throughput screen, drug discovery, x-ray crystallography 16. SECURITY...screening by x-ray crystallography . 2.0 KEYWORDS Retinoblastoma (Rb) pathway, E2F transcription factor, cancer, cell-cycle inhibition, activation...modulation, inhibition, high throughput screening, fragment-based screening, x-ray crystallography . 3.0 ACCOMPLISHMENTS Summary: We
TechXcite: Discover Engineering--A New STEM Curriculum

ERIC Educational Resources Information Center

Sallee, Jeff; Schmitt-McQuitty, Lynn; Swint, Sherry; Meek, Amanda; Ybarra, Gary; Dalton, Rodger

2015-01-01

TechXcite is an engineering-focused, discovery-based after-school science, technology, engineering, and math (STEM) program. The free curriculum is downloadable from http://techxcite.pratt.duke.edu/ and is comprised of eight Modules, each with four to five 45-minute activities that exercise the science and math learned in school by using…
Active Learning in an Introductory Meteorology Class

NASA Astrophysics Data System (ADS)

Marchese, P. J.; Bluestone, C.

2007-12-01

Active learning modules were introduced to the primarily minority population in the introductory meteorology class at Queensborough Community College (QCC). These activities were developed at QCC and other 4 year colleges and designed to reinforce basic meteorological concepts. The modules consisted of either Interactive Lecture Demonstrations (ILD) or discovery-based activities. During the ILD the instructor would describe an experiment that would be demonstrated in class. Students would predict what the outcome would be and compare their expected results to the actual outcome of the experiment. In the discovery-based activities students would learn about physical concepts by performing basic experiments. These activities differed from the traditional lab in that it avoided "cookbook" procedures and emphasized having the students learn about the concept using the scientific method. As a result of these activities student scores measuring conceptual understanding, as well as factual knowledge, increased as compared to student scores in a more affluent community college. Students also had higher self- efficacy scores. Lower scoring students demonstrated the greatest benefit, while the better students had little (or no) changes.
Real-Time Discovery Services over Large, Heterogeneous and Complex Healthcare Datasets Using Schema-Less, Column-Oriented Methods

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

Begoli, Edmon; Dunning, Ted; Charlie, Frasure

We present a service platform for schema-leess exploration of data and discovery of patient-related statistics from healthcare data sets. The architecture of this platform is motivated by the need for fast, schema-less, and flexible approaches to SQL-based exploration and discovery of information embedded in the common, heterogeneously structured healthcare data sets and supporting components (electronic health records, practice management systems, etc.) The motivating use cases described in the paper are clinical trials candidate discovery, and a treatment effectiveness analysis. Following the use cases, we discuss the key features and software architecture of the platform, the underlying core components (Apache Parquet,more » Drill, the web services server), and the runtime profiles and performance characteristics of the platform. We conclude by showing dramatic speedup with some approaches, and the performance tradeoffs and limitations of others.« less
OPTICAL STUDIES OF 13 HARD X-RAY SELECTED CATACLYSMIC BINARIES FROM THE SWIFT-BAT SURVEY

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

Halpern, Jules P.; Thorstensen, John R.

2015-12-15

From a set of 13 cataclysmic binaries that were discovered in the Swift Burst Alert Telescope (BAT) survey, we conducted time-resolved optical spectroscopy and/or time-series photometry of 11, with the goal of measuring their orbital periods and searching for spin periods. Seven of the objects in this study are new optical identifications. Orbital periods are found for seven targets, ranging from 81 minutes to 20.4 hr. PBC J0706.7+0327 is an AM Herculis star (polar) based on its emission-line variations and large amplitude photometric modulation on the same period. Swift J2341.0+7645 may be a polar, although the evidence here is lessmore » secure. Coherent pulsations are detected from two objects, Swift J0503.7−2819 (975 s) and Swift J0614.0+1709 (1412 s and 1530 s, spin and beat periods, respectively), indicating that they are probable intermediate polars (DQ Herculis stars). For two other stars, longer spin periods are tentatively suggested. We also present the discovery of a 2.00 hr X-ray modulation from RX J2015.6+3711, possibly a contributor to Swift J2015.9+3715, and likely a polar.« less

Systems and methods for knowledge discovery in spatial data

DOEpatents

Obradovic, Zoran; Fiez, Timothy E.; Vucetic, Slobodan; Lazarevic, Aleksandar; Pokrajac, Dragoljub; Hoskinson, Reed L.

2005-03-08

Systems and methods are provided for knowledge discovery in spatial data as well as to systems and methods for optimizing recipes used in spatial environments such as may be found in precision agriculture. A spatial data analysis and modeling module is provided which allows users to interactively and flexibly analyze and mine spatial data. The spatial data analysis and modeling module applies spatial data mining algorithms through a number of steps. The data loading and generation module obtains or generates spatial data and allows for basic partitioning. The inspection module provides basic statistical analysis. The preprocessing module smoothes and cleans the data and allows for basic manipulation of the data. The partitioning module provides for more advanced data partitioning. The prediction module applies regression and classification algorithms on the spatial data. The integration module enhances prediction methods by combining and integrating models. The recommendation module provides the user with site-specific recommendations as to how to optimize a recipe for a spatial environment such as a fertilizer recipe for an agricultural field.
Computer-based teaching module design: principles derived from learning theories.

PubMed

Lau, K H Vincent

2014-03-01

The computer-based teaching module (CBTM), which has recently gained prominence in medical education, is a teaching format in which a multimedia program serves as a single source for knowledge acquisition rather than playing an adjunctive role as it does in computer-assisted learning (CAL). Despite empirical validation in the past decade, there is limited research into the optimisation of CBTM design. This review aims to summarise research in classic and modern multimedia-specific learning theories applied to computer learning, and to collapse the findings into a set of design principles to guide the development of CBTMs. Scopus was searched for: (i) studies of classic cognitivism, constructivism and behaviourism theories (search terms: 'cognitive theory' OR 'constructivism theory' OR 'behaviourism theory' AND 'e-learning' OR 'web-based learning') and their sub-theories applied to computer learning, and (ii) recent studies of modern learning theories applied to computer learning (search terms: 'learning theory' AND 'e-learning' OR 'web-based learning') for articles published between 1990 and 2012. The first search identified 29 studies, dominated in topic by the cognitive load, elaboration and scaffolding theories. The second search identified 139 studies, with diverse topics in connectivism, discovery and technical scaffolding. Based on their relative representation in the literature, the applications of these theories were collapsed into a list of CBTM design principles. Ten principles were identified and categorised into three levels of design: the global level (managing objectives, framing, minimising technical load); the rhetoric level (optimising modality, making modality explicit, scaffolding, elaboration, spaced repeating), and the detail level (managing text, managing devices). This review examined the literature in the application of learning theories to CAL to develop a set of principles that guide CBTM design. Further research will enable educators to take advantage of this unique teaching format as it gains increasing importance in medical education. © 2014 John Wiley & Sons Ltd.
Unified Software Solution for Efficient SPR Data Analysis in Drug Research

PubMed Central

Dahl, Göran; Steigele, Stephan; Hillertz, Per; Tigerström, Anna; Egnéus, Anders; Mehrle, Alexander; Ginkel, Martin; Edfeldt, Fredrik; Holdgate, Geoff; O’Connell, Nichole; Kappler, Bernd; Brodte, Annette; Rawlins, Philip B.; Davies, Gareth; Westberg, Eva-Lotta; Folmer, Rutger H. A.; Heyse, Stephan

2016-01-01

Surface plasmon resonance (SPR) is a powerful method for obtaining detailed molecular interaction parameters. Modern instrumentation with its increased throughput has enabled routine screening by SPR in hit-to-lead and lead optimization programs, and SPR has become a mainstream drug discovery technology. However, the processing and reporting of SPR data in drug discovery are typically performed manually, which is both time-consuming and tedious. Here, we present the workflow concept, design and experiences with a software module relying on a single, browser-based software platform for the processing, analysis, and reporting of SPR data. The efficiency of this concept lies in the immediate availability of end results: data are processed and analyzed upon loading the raw data file, allowing the user to immediately quality control the results. Once completed, the user can automatically report those results to data repositories for corporate access and quickly generate printed reports or documents. The software module has resulted in a very efficient and effective workflow through saved time and improved quality control. We discuss these benefits and show how this process defines a new benchmark in the drug discovery industry for the handling, interpretation, visualization, and sharing of SPR data. PMID:27789754
msCompare: A Framework for Quantitative Analysis of Label-free LC-MS Data for Comparative Candidate Biomarker Studies*

PubMed Central

Hoekman, Berend; Breitling, Rainer; Suits, Frank; Bischoff, Rainer; Horvatovich, Peter

2012-01-01

Data processing forms an integral part of biomarker discovery and contributes significantly to the ultimate result. To compare and evaluate various publicly available open source label-free data processing workflows, we developed msCompare, a modular framework that allows the arbitrary combination of different feature detection/quantification and alignment/matching algorithms in conjunction with a novel scoring method to evaluate their overall performance. We used msCompare to assess the performance of workflows built from modules of publicly available data processing packages such as SuperHirn, OpenMS, and MZmine and our in-house developed modules on peptide-spiked urine and trypsin-digested cerebrospinal fluid (CSF) samples. We found that the quality of results varied greatly among workflows, and interestingly, heterogeneous combinations of algorithms often performed better than the homogenous workflows. Our scoring method showed that the union of feature matrices of different workflows outperformed the original homogenous workflows in some cases. msCompare is open source software (https://trac.nbic.nl/mscompare), and we provide a web-based data processing service for our framework by integration into the Galaxy server of the Netherlands Bioinformatics Center (http://galaxy.nbic.nl/galaxy) to allow scientists to determine which combination of modules provides the most accurate processing for their particular LC-MS data sets. PMID:22318370
Argo_CUDA: Exhaustive GPU based approach for motif discovery in large DNA datasets.

PubMed

Vishnevsky, Oleg V; Bocharnikov, Andrey V; Kolchanov, Nikolay A

2018-02-01

The development of chromatin immunoprecipitation sequencing (ChIP-seq) technology has revolutionized the genetic analysis of the basic mechanisms underlying transcription regulation and led to accumulation of information about a huge amount of DNA sequences. There are a lot of web services which are currently available for de novo motif discovery in datasets containing information about DNA/protein binding. An enormous motif diversity makes their finding challenging. In order to avoid the difficulties, researchers use different stochastic approaches. Unfortunately, the efficiency of the motif discovery programs dramatically declines with the query set size increase. This leads to the fact that only a fraction of top "peak" ChIP-Seq segments can be analyzed or the area of analysis should be narrowed. Thus, the motif discovery in massive datasets remains a challenging issue. Argo_Compute Unified Device Architecture (CUDA) web service is designed to process the massive DNA data. It is a program for the detection of degenerate oligonucleotide motifs of fixed length written in 15-letter IUPAC code. Argo_CUDA is a full-exhaustive approach based on the high-performance GPU technologies. Compared with the existing motif discovery web services, Argo_CUDA shows good prediction quality on simulated sets. The analysis of ChIP-Seq sequences revealed the motifs which correspond to known transcription factor binding sites.
Strain-induced dimensionality crossover of precursor modulations in Ni{sub 2}MnGa

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

Nie, Zhihua, E-mail: zhihua-nie@yahoo.com, E-mail: ydwang@neu.edu.cn; Wang, Yandong, E-mail: zhihua-nie@yahoo.com, E-mail: ydwang@neu.edu.cn; Shang, Shunli

2015-01-12

Precursor modulations often occur in functional materials like magnetic shape memory alloys, ferroelectrics, and superconductors. In this letter, we have revealed the underlying mechanism of the precursor modulations in ferromagnetic shape memory alloys Ni{sub 2}MnGa by combining synchrotron-based x-ray diffraction experiments and first-principles phonon calculations. We discovered the precursor modulations along [011] direction can be eliminated with [001] uniaxial loading, while the precursor modulations or premartensite can be totally suppressed by hydrostatic pressure condition. The TA{sub 2} phonon anomaly is sensitive to stress induced lattice strain, and the entire TA{sub 2} branch is stabilized along the directions where precursor modulationsmore » are eliminated by external stress. Our discovery bridges precursor modulations and phonon anomalies, and sheds light on the microscopic mechanism of the two-step superelasticity in precursor martensite.« less
Towards microfluidic technology-based MALDI-MS platforms for drug discovery: a review.

PubMed

Winkle, Richard F; Nagy, Judit M; Cass, Anthony Eg; Sharma, Sanjiv

2008-11-01

Microfluidic methods have found applications in various disciplines. It has been predicted that the microfluidic technology would be useful in performing routine steps in drug discovery ranging from target identification to lead optimisation in which the number of compounds evaluated in this regard determines the success of combinatorial screening. The sheer size of the parameter space that can be explored often poses an enormous challenge. We set out to find how close we are towards the use of integrated matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-MS) microfluidic systems for drug discovery. In this article we review the latest applications of microfluidic technology in the area of MALDI-MS and drug discovery. Our literature survey revealed microfluidic technologies-based approaches for various stages of drug discovery; however, they are in still in developmental stages. Furthermore, we speculate on how these technologies could be used in the future.
7TM X-ray structures for class C GPCRs as new drug-discovery tools. 1. mGluR5.

PubMed

Topiol, Sid; Sabio, Michael

2016-01-15

We illustrate, with a focus on mGluR5, how the recently published, first X-ray structures of mGluR 7TM domains, specifically those of mGluR1 and mGluR5 complexed with negative allosteric modulators (NAMs), will begin to influence ligand- (e.g., drug- or sweetener-) discovery efforts involving class C GPCRs. With an extensive docking study allowing full ligand flexibility and full side chain flexibility of all residues in the ligand-binding cavity, we have predicted and analyzed the binding modes of a variety of structurally diverse mGluR5 NAM ligands, showing how the X-ray structures serve to effectively rationalize each ligand's binding characteristics. We demonstrated that the features that are inherent in our earlier overlay model are preserved in the protein structure-based docking models. We identified structurally diverse compounds, which potentially act as mGluR NAMs, and revealed binding-site differences by performing high-throughput docking using a database of approximately six million structures of commercially available compounds and the mGluR1 and mGluR5 X-ray structures. By comparing the 7TM domains of the mGluR5 and mGluR1 X-rays structures, we identified selectivity factors within group I of the mGluRs. Similarly, using homology models that we built for mGluR2 and mGluR4, we have identified the factors leading to the selectivity between group I and groups II and III for ligands occupying the deepest portion of the mGluR5 binding cavity. Finally, we have proposed a structure-based explanation of the pharmacological switching within a set of positive allosteric modulators (PAMs) and their corresponding, very close NAM analogs. Copyright © 2015 Elsevier Ltd. All rights reserved.
A Strange Fish Indeed: The "Discovery" of a Living Fossil

ERIC Educational Resources Information Center

Grant, Robert H.

2005-01-01

Through a series of fictionalized diary entries based on Marjorie Courtenay-Latimer's own writings, this case recounts the "discovery" in South Africa in 1938 of a fish believed to be extinct for over 70 million years. The case was developed for use in an introductory freshman biology course. In this setting, it could be used as a…
Building New Bridges between In Vitro and In Vivo in Early Drug Discovery: Where Molecular Modeling Meets Systems Biology.

PubMed

Pearlstein, Robert A; McKay, Daniel J J; Hornak, Viktor; Dickson, Callum; Golosov, Andrei; Harrison, Tyler; Velez-Vega, Camilo; Duca, José

2017-01-01

Cellular drug targets exist within networked function-generating systems whose constituent molecular species undergo dynamic interdependent non-equilibrium state transitions in response to specific perturbations (i.e.. inputs). Cellular phenotypic behaviors are manifested through the integrated behaviors of such networks. However, in vitro data are frequently measured and/or interpreted with empirical equilibrium or steady state models (e.g. Hill, Michaelis-Menten, Briggs-Haldane) relevant to isolated target populations. We propose that cells act as analog computers, "solving" sets of coupled "molecular differential equations" (i.e. represented by populations of interacting species)via "integration" of the dynamic state probability distributions among those populations. Disconnects between biochemical and functional/phenotypic assays (cellular/in vivo) may arise with targetcontaining systems that operate far from equilibrium, and/or when coupled contributions (including target-cognate partner binding and drug pharmacokinetics) are neglected in the analysis of biochemical results. The transformation of drug discovery from a trial-and-error endeavor to one based on reliable design criteria depends on improved understanding of the dynamic mechanisms powering cellular function/dysfunction at the systems level. Here, we address the general mechanisms of molecular and cellular function and pharmacological modulation thereof. We outline a first principles theory on the mechanisms by which free energy is stored and transduced into biological function, and by which biological function is modulated by drug-target binding. We propose that cellular function depends on dynamic counter-balanced molecular systems necessitated by the exponential behavior of molecular state transitions under non-equilibrium conditions, including positive versus negative mass action kinetics and solute-induced perturbations to the hydrogen bonds of solvating water versus kT. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
High-Throughput Screening of Na(V)1.7 Modulators Using a Giga-Seal Automated Patch Clamp Instrument.

PubMed

Chambers, Chris; Witton, Ian; Adams, Cathryn; Marrington, Luke; Kammonen, Juha

2016-03-01

Voltage-gated sodium (Na(V)) channels have an essential role in the initiation and propagation of action potentials in excitable cells, such as neurons. Of these channels, Na(V)1.7 has been indicated as a key channel for pain sensation. While extensive efforts have gone into discovering novel Na(V)1.7 modulating compounds for the treatment of pain, none has reached the market yet. In the last two years, new compound screening technologies have been introduced, which may speed up the discovery of such compounds. The Sophion Qube(®) is a next-generation 384-well giga-seal automated patch clamp (APC) screening instrument, capable of testing thousands of compounds per day. By combining high-throughput screening and follow-up compound testing on the same APC platform, it should be possible to accelerate the hit-to-lead stage of ion channel drug discovery and help identify the most interesting compounds faster. Following a period of instrument beta-testing, a Na(V)1.7 high-throughput screen was run with two Pfizer plate-based compound subsets. In total, data were generated for 158,000 compounds at a median success rate of 83%, which can be considered high in APC screening. In parallel, IC50 assay validation and protocol optimization was completed with a set of reference compounds to understand how the IC50 potencies generated on the Qube correlate with data generated on the more established Sophion QPatch(®) APC platform. In summary, the results presented here demonstrate that the Qube provides a comparable but much faster approach to study Na(V)1.7 in a robust and reliable APC assay for compound screening.
Constructing a Graph Database for Semantic Literature-Based Discovery.

PubMed

Hristovski, Dimitar; Kastrin, Andrej; Dinevski, Dejan; Rindflesch, Thomas C

2015-01-01

Literature-based discovery (LBD) generates discoveries, or hypotheses, by combining what is already known in the literature. Potential discoveries have the form of relations between biomedical concepts; for example, a drug may be determined to treat a disease other than the one for which it was intended. LBD views the knowledge in a domain as a network; a set of concepts along with the relations between them. As a starting point, we used SemMedDB, a database of semantic relations between biomedical concepts extracted with SemRep from Medline. SemMedDB is distributed as a MySQL relational database, which has some problems when dealing with network data. We transformed and uploaded SemMedDB into the Neo4j graph database, and implemented the basic LBD discovery algorithms with the Cypher query language. We conclude that storing the data needed for semantic LBD is more natural in a graph database. Also, implementing LBD discovery algorithms is conceptually simpler with a graph query language when compared with standard SQL.
Discovery and study of novel protein tyrosine phosphatase 1B inhibitors

NASA Astrophysics Data System (ADS)

Zhang, Qian; Chen, Xi; Feng, Changgen

2017-10-01

Protein tyrosine phosphatase 1B (PTP1B) is considered to be a target for therapy of type II diabetes and obesity. So it is of great significance to take advantage of a computer aided drug design protocol involving the structured-based virtual screening with docking simulations for fast searching small molecule PTP1B inhibitors. Based on optimized complex structure of PTP1B bound with specific inhibitor of IX1, structured-based virtual screening against a library of natural products containing 35308 molecules, which was constructed based on Traditional Chinese Medicine database@ Taiwan (TCM database@ Taiwan), was conducted to determine the occurrence of PTP1B inhibitors using the Lubbock module and CDOCKER module from Discovery Studio 3.1 software package. The results were further filtered by predictive ADME simulation and predictive toxic simulation. As a result, 2 good drug-like molecules, namely para-benzoquinone compound 1 and Clavepictine analogue 2 were identified ultimately with the dock score of original inhibitor (IX1) and the receptor as a threshold. Binding model analyses revealed that these two candidate compounds have good interactions with PTP1B. The PTP1B inhibitory activity of compound 2 hasn't been reported before. The optimized compound 2 has higher scores and deserves further study.
Complement in Action: An Analysis of Patent Trends from 1976 Through 2011.

PubMed

Yang, Kun; Deangelis, Robert A; Reed, Janet E; Ricklin, Daniel; Lambris, John D

2013-01-01

Complement is an essential part of the innate immune response. It interacts with diverse endogenous pathways and contributes to the maintenance of homeostasis, the modulation of adaptive immune responses, and the development of various pathologies. The potential usefulness, in both research and clinical settings, of compounds that detect or modulate complement activity has resulted in thousands of publications on complement-related innovations in fields such as drug discovery, disease diagnosis and treatment, and immunoassays, among others. This study highlights the distribution and publication trends of patents related to the complement system that were granted by the United States Patent and Trademark Office from 1976 to the present day. A comparison to complement-related documents published by the World Intellectual Property Organization is also included. Statistical analyses revealed increasing diversity in complement-related research interests over time. More than half of the patents were found to focus on the discovery of inhibitors; interest in various inhibitor classes exhibited a remarkable transformation from chemical compounds early on to proteins and antibodies in more recent years. Among clinical applications, complement proteins and their modulators have been extensively patented for the diagnosis and treatment of eye diseases (especially age-related macular degeneration), graft rejection, cancer, sepsis, and a variety of other inflammatory and immune diseases. All of the patents discussed in this chapter, as well as those from other databases, are available from our newly constructed complement patent database: www.innateimmunity.us/patent .
Complement in action: an analysis of patent trends from 1976 through 2011.

PubMed

Yang, Kun; DeAngelis, Robert A; Reed, Janet E; Ricklin, Daniel; Lambris, John D

2013-01-01

Complement is an essential part of the innate immune response. It interacts with diverse endogenous pathways and contributes to the maintenance of homeostasis, the modulation of adaptive immune responses, and the development of various pathologies. The potential usefulness, in both research and clinical settings, of compounds that detect or modulate complement activity has resulted in thousands of publications on complement-related innovations in fields such as drug discovery, disease diagnosis and treatment, and immunoassays, among others. This study highlights the distribution and publication trends of patents related to the complement system that were granted by the United States Patent and Trademark Office from 1976 to the present day. A comparison to complement-related documents published by the World Intellectual Property Organization is also included. Statistical analyses revealed increasing diversity in complement-related research interests over time. More than half of the patents were found to focus on the discovery of inhibitors; interest in various inhibitor classes exhibited a remarkable transformation from chemical compounds early on to proteins and antibodies in more recent years. Among clinical applications, complement proteins and their modulators have been extensively patented for the diagnosis and treatment of eye diseases (especially age-related macular degeneration), graft rejection, cancer, sepsis, and a variety of other inflammatory and immune diseases. All of the patents discussed in this chapter, as well as those from other databases, are available from our newly constructed complement patent database: www.innateimmunity.us/patent.
Student-Centered Modules to Support Active Learning in Hydrology: Development Experiences and Users' Perspectives

NASA Astrophysics Data System (ADS)

Tarboton, D. G.; Habib, E. H.; Deshotel, M.; Merck, M. F.; Lall, U.; Farnham, D. J.

2016-12-01

Traditional approaches to undergraduate hydrology and water resource education are textbook based, adopt unit processes and rely on idealized examples of specific applications, rather than examining the contextual relations in the processes and the dynamics connecting climate and ecosystems. The overarching goal of this project is to address the needed paradigm shift in undergraduate education of engineering hydrology and water resources education to reflect parallel advances in hydrologic research and technology, mainly in the areas of new observational settings, data and modeling resources and web-based technologies. This study presents efforts to develop a set of learning modules that are case-based, data and simulation driven and delivered via a web user interface. The modules are based on real-world case studies from three regional hydrologic settings: Coastal Louisiana, Utah Rocky Mountains and Florida Everglades. These three systems provide unique learning opportunities on topics such as: regional-scale budget analysis, hydrologic effects of human and natural changes, flashflood protection, climate-hydrology teleconnections and water resource management scenarios. The technical design and contents of the modules aim to support students' ability for transforming their learning outcomes and skills to hydrologic systems other than those used by the specific activity. To promote active learning, the modules take students through a set of highly engaging learning activities that are based on analysis of hydrologic data and model simulations. The modules include user support in the form of feedback and self-assessment mechanisms that are integrated within the online modules. Module effectiveness is assessed through an improvement-focused evaluation model using a mixed-method research approach guiding collection and analysis of evaluation data. Both qualitative and quantitative data are collected through student learning data, product analysis, and staff interviews. The presentation shares with the audience lessons learned from the development and implementation of the modules, students' feedback, guidelines on design and content attributes that support active learning in hydrology, and challenges encountered during the class implementation and evaluation of the modules.
KSC-07pd2593

NASA Image and Video Library

2007-09-27

KENNEDY SPACE CENTER, FLA. -- The payload canister containing the Italian-built U.S. Node 2 module, called Harmony, begins taking its cargo to Launch Pad 39A. At the pad, the canister will be lifted to the payload changeout room and the module transferred inside. The payload will be installed in space shuttle Discovery's payload bay after the vehicle rolls out to the pad. Discovery is targeted for launch to the International Space Station for mission STS-120 on Oct. 23. The pressurized module will act as an internal connecting port and passageway to additional international science labs and cargo spacecraft. Photo credit: NASA/George Shelton
KSC-07pd2594

NASA Image and Video Library

2007-09-27

KENNEDY SPACE CENTER, FLA. -- The payload canister containing the Italian-built U.S. Node 2 module, called Harmony, arrives on Launch Pad 39A. The canister will be lifted to the payload changeout room, seen at the top center, and the module transferred inside. The payload will be installed in space shuttle Discovery's payload bay after the vehicle rolls out to the pad. Discovery is targeted for launch to the International Space Station for mission STS-120 on Oct. 23. The pressurized module will act as an internal connecting port and passageway to additional international science labs and cargo spacecraft. Photo credit: NASA/George Shelton
Modulation of visual physiology by behavioral state in monkeys, mice, and flies.

PubMed

Maimon, Gaby

2011-08-01

When a monkey attends to a visual stimulus, neurons in visual cortex respond differently to that stimulus than when the monkey attends elsewhere. In the 25 years since the initial discovery, the study of attention in primates has been central to understanding flexible visual processing. Recent experiments demonstrate that visual neurons in mice and fruit flies are modulated by locomotor behaviors, like running and flying, in a manner that resembles attention-based modulations in primates. The similar findings across species argue for a more generalized view of state-dependent sensory processing and for a renewed dialogue among vertebrate and invertebrate research communities. Copyright © 2011 Elsevier Ltd. All rights reserved.
A Preliminary Research on the Development of the Hard X-Ray Imaging Telescope

NASA Astrophysics Data System (ADS)

Zheng, C. X.; Cai, M. S.; Hu, Y. M.; Huang, Y. Y.; Gong, Y. Z.

2014-03-01

Since the 1860s, astronomers have explored a new field with the discovery of X-ray. Instead of the conventional imaging technique by using mirrors or lens, which can not work in the high-energy bands, direct imaging, coded aperture, and Fourier transform are used for the high-energy imaging. It can be implemented in various hardware configurations, among which the spatial modulation collimator are widely used. We adopt the grating collimator based on Fourier transform that is discussed in detail. This paper makes an investigation on the fabrication process of grating. The key components of the hard X-ray telescope based on the spatial modulation are developed, which contains 8 CsI-detector modules, 8-channel shaping amplifiers, and data acquisition system. The preliminary test results of readout electronics system are obtained.

The crew of Space Shuttle mission STS-114 gathered in front of the shuttle Discovery following landing at Edwards Air Force Base, California, August 9, 2005

NASA Image and Video Library

2005-08-09

The crew of Space Shuttle mission STS-114 gathered in front of the shuttle Discovery following landing at Edwards Air Force Base, California, August 9, 2005. From left to right: Mission Specialist Stephen Robinson, Commander Eileen Collins, Mission Specialists Andrew Thomas, Wendy Lawrence, Soichi Noguchi and Charles Camarda, and Pilot James Kelly. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT this morning, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.
A graph-based approach to construct target-focused libraries for virtual screening.

PubMed

Naderi, Misagh; Alvin, Chris; Ding, Yun; Mukhopadhyay, Supratik; Brylinski, Michal

2016-01-01

Due to exorbitant costs of high-throughput screening, many drug discovery projects commonly employ inexpensive virtual screening to support experimental efforts. However, the vast majority of compounds in widely used screening libraries, such as the ZINC database, will have a very low probability to exhibit the desired bioactivity for a given protein. Although combinatorial chemistry methods can be used to augment existing compound libraries with novel drug-like compounds, the broad chemical space is often too large to be explored. Consequently, the trend in library design has shifted to produce screening collections specifically tailored to modulate the function of a particular target or a protein family. Assuming that organic compounds are composed of sets of rigid fragments connected by flexible linkers, a molecule can be decomposed into its building blocks tracking their atomic connectivity. On this account, we developed eSynth, an exhaustive graph-based search algorithm to computationally synthesize new compounds by reconnecting these building blocks following their connectivity patterns. We conducted a series of benchmarking calculations against the Directory of Useful Decoys, Enhanced database. First, in a self-benchmarking test, the correctness of the algorithm is validated with the objective to recover a molecule from its building blocks. Encouragingly, eSynth can efficiently rebuild more than 80 % of active molecules from their fragment components. Next, the capability to discover novel scaffolds is assessed in a cross-benchmarking test, where eSynth successfully reconstructed 40 % of the target molecules using fragments extracted from chemically distinct compounds. Despite an enormous chemical space to be explored, eSynth is computationally efficient; half of the molecules are rebuilt in less than a second, whereas 90 % take only about a minute to be generated. eSynth can successfully reconstruct chemically feasible molecules from molecular fragments. Furthermore, in a procedure mimicking the real application, where one expects to discover novel compounds based on a small set of already developed bioactives, eSynth is capable of generating diverse collections of molecules with the desired activity profiles. Thus, we are very optimistic that our effort will contribute to targeted drug discovery. eSynth is freely available to the academic community at www.brylinski.org/content/molecular-synthesis.Graphical abstractAssuming that organic compounds are composed of sets of rigid fragments connected by flexible linkers, a molecule can be decomposed into its building blocks tracking their atomic connectivity. Here, we developed eSynth, an automated method to synthesize new compounds by reconnecting these building blocks following the connectivity patterns via an exhaustive graph-based search algorithm. eSynth opens up a possibility to rapidly construct virtual screening libraries for targeted drug discovery.
Expression, Purification, and Characterization of a Carbohydrate-Active Enzyme: A Research-Inspired Methods Optimization Experiment for the Biochemistry Laboratory

ERIC Educational Resources Information Center

Willbur, Jaime F.; Vail, Justin D.; Mitchell, Lindsey N.; Jakeman, David L.; Timmons, Shannon C.

2016-01-01

The development and implementation of research-inspired, discovery-based experiences into science laboratory curricula is a proven strategy for increasing student engagement and ownership of experiments. In the novel laboratory module described herein, students learn to express, purify, and characterize a carbohydrate-active enzyme using modern…
Occupational Home Economics Education Series. Securing Employment. Competency Based Teaching Module.

ERIC Educational Resources Information Center

Lowe, Phyllis; And Others

This module, one of ten competency based modules developed for vocational teachers, focuses on securing employment in home economics. It is designed for a variety of levels of learners (secondary, postsecondary, adult) in both school and nonschool educational settings. Five competencies to be developed with this module deal with the meaning of…
KSC-08pd1144

NASA Image and Video Library

2008-05-05

CAPE CANAVERAL, Fla. -- Inside space shuttle Discovery's payload bay can be seen the red rain gutters, which prevent leaks into the bay from rain while the shuttle is on the pad. The STS-124 mission payload, the Japanese Experiment Module - Pressurized Module and the Japanese Remote Manipulator System (below the gutters), is being transferred from the Payload Changeout Room into the payload bay. Launch of Discovery is targeted for May 31. Photo credit: NASA/Jim Grossmann
KSC-07pd2681

NASA Image and Video Library

2007-10-05

KENNEDY SPACE CENTER, FLA. -- On Launch Pad 39A, workers remove the rain gutters from space shuttle Discovery's payload bay. The gutters prevent leaks into the bay from rain while the shuttle is on the pad. Beneath is the orbital docking system. Mission STS-120 will bring the Harmony module that will provide attachment points for European and Japanese laboratory modules to the International Space Station. Launch of Discovery is targeted for Oct. 23. Photo credit: NASA/George Shelton
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Occupational Strand: Textiles and Clothing. Module II-D-3: Merchandising Textiles and Ready-to-Wear.

ERIC Educational Resources Information Center

Gylling, Margaret

This competency-based preservice home economics teacher education module on merchandising textiles and ready-to-wear is the third in a set of three modules on occupational aspects of textiles and clothing. (This set is part of a larger series of sixty-seven modules on the Management Approach to Teaching Consumer and Homemaking Education…
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Consumer Approach Strand: Management. Module I-F-3: Environmental Issues and the Consumer.

ERIC Educational Resources Information Center

Movey, Jan

This competency-based preservice home economics teacher education module on environmental issues and the consumer is the third in a set of seven modules on consumer education related to management. (This set is part of a larger series of sixty-seven modules on the Management Approach to Teaching Consumer and Homemaking Education [MATCHE]--see CE…
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Consumer Approach Strand: Human Development. Module I-E-4: Individuals and Families in Crisis.

ERIC Educational Resources Information Center

California State Univ., Fresno. Dept. of Home Economics.

This competency-based preservice home economics teacher education module on individuals and families in crisis is the fourth in a set of five modules on consumer education related to human development. (This set is part of a larger series of sixty-seven modules on the Management Approach to Teaching Consumer and Homemaking Education [MATCHE]--see…
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Consumer Approach Strand: Core. Module I-A-4: Incorporating the Consumer Approach in Homemaking Classes.

ERIC Educational Resources Information Center

California State Univ., Fresno. Dept. of Home Economics.

This competency-based preservice home economics teacher education module on incorporating the consumer approach in homemaking classes is the fourth in a set of four core curriculum modules on consumer approach to homemaking education. (This set is part of a larger series of sixty-seven modules on the Management Approach to Teaching Consumer and…
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Occupational Strand: Textiles and Clothing. Module II-D-2: Assembly Line Garment Construction.

ERIC Educational Resources Information Center

Henry, Nina

This competency-based preservice home economics teacher education module on assembly line garment construction is the second in a set of three modules on occupational aspects of textiles and clothing. (This set is part of a larger series of sixty-seven modules on the Management Approach to Teaching Consumer and Homemaking Education [MATCHE]--see…
Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach.

PubMed

Innocenti, Paolo; Woodward, Hannah L; Solanki, Savade; Naud, Sébastien; Westwood, Isaac M; Cronin, Nora; Hayes, Angela; Roberts, Jennie; Henley, Alan T; Baker, Ross; Faisal, Amir; Mak, Grace Wing-Yan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; O'Fee, Lisa; Saville, Harry; Schmitt, Jessica; Matijssen, Berry; Burke, Rosemary; van Montfort, Rob L M; Raynaud, Florence I; Eccles, Suzanne A; Linardopoulos, Spiros; Blagg, Julian; Hoelder, Swen

2016-04-28

Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model.
Discovery of 2-methylpyridine-based biaryl amides as γ-secretase modulators for the treatment of Alzheimer's disease.

PubMed

Chen, Jian Jeffrey; Qian, Wenyuan; Biswas, Kaustav; Yuan, Chester; Amegadzie, Albert; Liu, Qingyian; Nixey, Thomas; Zhu, Joe; Ncube, Mqhele; Rzasa, Robert M; Chavez, Frank; Chen, Ning; DeMorin, Frenel; Rumfelt, Shannon; Tegley, Christopher M; Allen, Jennifer R; Hitchcock, Stephen; Hungate, Randy; Bartberger, Michael D; Zalameda, Leeanne; Liu, Yichin; McCarter, John D; Zhang, Jianhua; Zhu, Li; Babu-Khan, Safura; Luo, Yi; Bradley, Jodi; Wen, Paul H; Reid, Darren L; Koegler, Frank; Dean, Charles; Hickman, Dean; Correll, Tiffany L; Williamson, Toni; Wood, Stephen

2013-12-01

γ-Secretase modulators (GSMs) are potentially disease-modifying treatments for Alzheimer's disease. They selectively lower pathogenic Aβ42 levels by shifting the enzyme cleavage sites without inhibiting γ-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a GSM lead. Lead optimization studies identified compound 25 with improved cell potency, PKDM properties, and it lowered Aβ42 levels in the cerebrospinal fluid (CSF) of Sprague-Dawley rats following oral administration. Further optimization of 25 to improve cellular potency is described. Copyright © 2013 Elsevier Ltd. All rights reserved.
System-level multi-target drug discovery from natural products with applications to cardiovascular diseases.

PubMed

Zheng, Chunli; Wang, Jinan; Liu, Jianling; Pei, Mengjie; Huang, Chao; Wang, Yonghua

2014-08-01

The term systems pharmacology describes a field of study that uses computational and experimental approaches to broaden the view of drug actions rooted in molecular interactions and advance the process of drug discovery. The aim of this work is to stick out the role that the systems pharmacology plays across the multi-target drug discovery from natural products for cardiovascular diseases (CVDs). Firstly, based on network pharmacology methods, we reconstructed the drug-target and target-target networks to determine the putative protein target set of multi-target drugs for CVDs treatment. Secondly, we reintegrated a compound dataset of natural products and then obtained a multi-target compounds subset by virtual-screening process. Thirdly, a drug-likeness evaluation was applied to find the ADME-favorable compounds in this subset. Finally, we conducted in vitro experiments to evaluate the reliability of the selected chemicals and targets. We found that four of the five randomly selected natural molecules can effectively act on the target set for CVDs, indicating the reasonability of our systems-based method. This strategy may serve as a new model for multi-target drug discovery of complex diseases.
Identification of cancer cytotoxic modulators of PDE3A by predictive chemogenomics

PubMed Central

de Waal, Luc; Lewis, Timothy A.; Rees, Matthew G.; Tsherniak, Aviad; Wu, Xiaoyun; Choi, Peter S.; Gechijian, Lara; Hartigan, Christina; Faloon, Patrick W.; Hickey, Mark J.; Tolliday, Nicola; Carr, Steven A.; Clemons, Paul A.; Munoz, Benito; Wagner, Bridget K.; Shamji, Alykhan F.; Koehler, Angela N.; Schenone, Monica; Burgin, Alex B.; Schreiber, Stuart L.; Greulich, Heidi; Meyerson, Matthew

2015-01-01

High cancer death rates indicate the need for new anti-cancer therapeutic agents. Approaches to discover new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds by phenotypic compound library screening and target deconvolution by predictive chemogenomics. We found that sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, across 766 cancer cell lines correlates with expression of the phosphodiesterase 3A gene, PDE3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells while others do not. Furthermore, PDE3A depletion leads to DNMDP resistance. We demonstrated that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), suggesting a neomorphic activity. Co-expression of SLFN12 with PDE3A correlates with DNMDP sensitivity, while depletion of SLFN12 results in decreased DNMDP sensitivity. Our results implicate PDE3A modulators as candidate cancer therapeutic agents and demonstrate the power of predictive chemogenomics in small-molecule discovery. PMID:26656089
A prediction model of drug-induced ototoxicity developed by an optimal support vector machine (SVM) method.

PubMed

Zhou, Shu; Li, Guo-Bo; Huang, Lu-Yi; Xie, Huan-Zhang; Zhao, Ying-Lan; Chen, Yu-Zong; Li, Lin-Li; Yang, Sheng-Yong

2014-08-01

Drug-induced ototoxicity, as a toxic side effect, is an important issue needed to be considered in drug discovery. Nevertheless, current experimental methods used to evaluate drug-induced ototoxicity are often time-consuming and expensive, indicating that they are not suitable for a large-scale evaluation of drug-induced ototoxicity in the early stage of drug discovery. We thus, in this investigation, established an effective computational prediction model of drug-induced ototoxicity using an optimal support vector machine (SVM) method, GA-CG-SVM. Three GA-CG-SVM models were developed based on three training sets containing agents bearing different risk levels of drug-induced ototoxicity. For comparison, models based on naïve Bayesian (NB) and recursive partitioning (RP) methods were also used on the same training sets. Among all the prediction models, the GA-CG-SVM model II showed the best performance, which offered prediction accuracies of 85.33% and 83.05% for two independent test sets, respectively. Overall, the good performance of the GA-CG-SVM model II indicates that it could be used for the prediction of drug-induced ototoxicity in the early stage of drug discovery. Copyright © 2014 Elsevier Ltd. All rights reserved.
Pipe inspection and repair system

NASA Technical Reports Server (NTRS)

Schempf, Hagen (Inventor); Mutschler, Edward (Inventor); Chemel, Brian (Inventor); Boehmke, Scott (Inventor); Crowley, William (Inventor)

2004-01-01

A multi-module pipe inspection and repair device. The device includes a base module, a camera module, a sensor module, an MFL module, a brush module, a patch set/test module, and a marker module. Each of the modules may be interconnected to construct one of an inspection device, a preparation device, a marking device, and a repair device.
"Discoveries in Planetary Sciences": Slide Sets Highlighting New Advances for Astronomy Educators

NASA Astrophysics Data System (ADS)

Brain, D. A.; Schneider, N. M.; Beyer, R. A.

2010-12-01

Planetary science is a field that evolves rapidly, motivated by spacecraft mission results. Exciting new mission results are generally communicated rather quickly to the public in the form of press releases and news stories, but it can take several years for new advances to work their way into college textbooks. Yet it is important for students to have exposure to these new advances for a number of reasons. In some cases, new work renders older textbook knowledge incorrect or incomplete. In some cases, new discoveries make it possible to emphasize older textbook knowledge in a new way. In all cases, new advances provide exciting and accessible examples of the scientific process in action. To bridge the gap between textbooks and new advances in planetary sciences we have developed content on new discoveries for use by undergraduate instructors. Called 'Discoveries in Planetary Sciences', each new discovery is summarized in a 3-slide PowerPoint presentation. The first slide describes the discovery, the second slide discusses the underlying planetary science concepts, and the third presents the big picture implications of the discovery. A fourth slide includes links to associated press releases, images, and primary sources. This effort is generously sponsored by the Division for Planetary Sciences of the American Astronomical Society, and the slide sets are available at http://dps.aas.org/education/dpsdisc/. Sixteen slide sets have been released so far covering topics spanning all sub-disciplines of planetary science. Results from the following spacecraft missions have been highlighted: MESSENGER, the Spirit and Opportunity rovers, Cassini, LCROSS, EPOXI, Chandrayan, Mars Reconnaissance Orbiter, Mars Express, and Venus Express. Additionally, new results from Earth-orbiting and ground-based observing platforms and programs such as Hubble, Keck, IRTF, the Catalina Sky Survey, HARPS, MEarth, Spitzer, and amateur astronomers have been highlighted. 4-5 new slide sets are scheduled for release before December 2010. In this presentation we will discuss our motivation for this project, our implementation approach (from choosing topics to creating the slide sets, to getting them reviewed and released), and give examples of slide sets. We will present information in the form of web statistics on how many educators are using the slide sets, and which topics are most popular. We will also present feedback from educators who have used them in the classroom, and possible new directions for our activity.
Earth System Science Education Centered on Natural Climate Variability

NASA Astrophysics Data System (ADS)

Ramirez, P. C.; Ladochy, S.; Patzert, W. C.; Willis, J. K.

2009-12-01

Several new courses and many educational activities related to climate change are available to teachers and students of all grade levels. However, not all new discoveries in climate research have reached the science education community. In particular, effective learning tools explaining natural climate change are scarce. For example, the Pacific Decadal Oscillation (PDO) is a main cause of natural climate variability spanning decades. While most educators are familiar with the shorter-temporal events impacting climate, El Niño and La Niña, very little has trickled into the climate change curriculum on the PDO. We have developed two online educational modules, using an Earth system science approach, on the PDO and its role in climate change and variability. The first concentrates on the discovery of the PDO through records of salmon catch in the Pacific Northwest and Alaska. We present the connection between salmon abundance in the North Pacific to changing sea surface temperature patterns associated with the PDO. The connection between sea surface temperatures and salmon abundance led to the discovery of the PDO. Our activity also lets students explore the role of salmon in the economy and culture of the Pacific Northwest and Alaska and the environmental requirements for salmon survival. The second module is based on the climate of southern California and how changes in the Pacific Ocean , such as the PDO and ENSO (El Niño-Southern Oscillation), influence regional climate variability. PDO and ENSO signals are evident in the long-term temperature and precipitation record of southern California. Students are guided in the module to discover the relationships between Pacific Ocean conditions and southern California climate variability. The module also provides information establishing the relationship between climate change and variability and the state's water, energy, agriculture, wildfires and forestry, air quality and health issues. Both modules will be reviewed for inclusion on the ESSEA (Earth Systems Science Education Alliance) course module list. ESSEA is a NSF-funded organization dedicated to K-12 online Earth system science education.
Brewing for Students: An Inquiry-Based Microbiology Lab †

PubMed Central

Sato, Brian K.; Alam, Usman; Dacanay, Samantha J.; Lee, Amanda K.; Shaffer, Justin F.

2015-01-01

In an effort to improve and assess student learning, there has been a push to increase the incorporation of discovery-driven modules and those that contain real-world relevance into laboratory curricula. To further this effort, we have developed, implemented, and assessed an undergraduate microbiology laboratory experiment that requires students to use the scientific method while brewing beer. The experiment allows students to brew their own beer and characterize it based on taste, alcohol content, calorie content, pH, and standard reference method. In addition, we assessed whether students were capable of achieving the module learning objectives through a pre-/posttest, student self-evaluation, exam-embedded questions, and an associated worksheet. These objectives included describing the role of the brewing ingredients and predicting how altering the ingredients would affect the characteristics of the beer, amongst others. By completing this experimental module, students accomplished the module objectives, had greater interest in brewing, and were more likely to view beer in scientific terms. Journal of Microbiology & Biology Education PMID:26753030

Brewing for Students: An Inquiry-Based Microbiology Lab.

PubMed

Sato, Brian K; Alam, Usman; Dacanay, Samantha J; Lee, Amanda K; Shaffer, Justin F

2015-12-01

In an effort to improve and assess student learning, there has been a push to increase the incorporation of discovery-driven modules and those that contain real-world relevance into laboratory curricula. To further this effort, we have developed, implemented, and assessed an undergraduate microbiology laboratory experiment that requires students to use the scientific method while brewing beer. The experiment allows students to brew their own beer and characterize it based on taste, alcohol content, calorie content, pH, and standard reference method. In addition, we assessed whether students were capable of achieving the module learning objectives through a pre-/posttest, student self-evaluation, exam-embedded questions, and an associated worksheet. These objectives included describing the role of the brewing ingredients and predicting how altering the ingredients would affect the characteristics of the beer, amongst others. By completing this experimental module, students accomplished the module objectives, had greater interest in brewing, and were more likely to view beer in scientific terms. Journal of Microbiology & Biology Education.
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Consumer Approach Strand: Textiles and Clothing. Module I-D-1: Consumer Approach to Textiles and Clothing.

ERIC Educational Resources Information Center

California State Univ., Fresno. Dept. of Home Economics.

This competency-based preservice home economics teacher education module on consumer approach to textiles and clothing is the first in a set of four modules on consumer education related to textiles and clothing. (This set is part of a larger series of sixty-seven modules on the Management Approach to Teaching Consumer and Homemaking Education…
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Occupational Strand: Foods and Nutrition. Module II-C-2: Operations and Activities of a Food Service Operation.

ERIC Educational Resources Information Center

Waskey, Frank

This competency-based preservice home economics teacher education module on operations and activities of a food service operation is the second in a set of three modules on occupational education relating to foods and nutrition. (This set is part of a larger series of sixty-seven modules on the Management Approach to Teaching Consumer and…
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Consumer Approach Strand: Foods and Nutrition. Module I-C-1: Technological, Sociological, Ecological, and Environmental Factors Related to Food.

ERIC Educational Resources Information Center

Newsome, Ratana

This competency-based preservice home economics teacher education module on technological, sociological, ecological, and environmental factors related to food is the first in a set of five modules on consumer education related to foods and nutrition. (This set is part of a larger series of sixty-seven modules on the Management Approach to Teaching…
Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics.

PubMed

Penrod, Nadia M; Moore, Jason H

2014-02-05

The demand for novel molecularly targeted drugs will continue to rise as we move forward toward the goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. We use this approach to prioritize genes as drug target candidates in a set of ER⁺ breast tumor samples collected during the course of neoadjuvant treatment with the aromatase inhibitor letrozole. We show that influential genes, those with high influence scores, tend to be essential and include a higher proportion of essential genes than those prioritized based on their position (i.e. hubs or bottlenecks) within the same network. Additionally, we show that influential genes represent novel biologically relevant drug targets for the treatment of ER⁺ breast cancers. Moreover, we demonstrate that gene influence differs between untreated tumors and residual tumors that have adapted to drug treatment. In this way, influence scores capture the context-dependent functions of genes and present the opportunity to design combination treatment strategies that take advantage of the tumor adaptation process. Influence networks efficiently find essential genes as promising drug targets and combinations of targets to inform the development of molecularly targeted drugs and their use.
Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics

PubMed Central

2014-01-01

Background The demand for novel molecularly targeted drugs will continue to rise as we move forward toward the goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. Results We use this approach to prioritize genes as drug target candidates in a set of ER + breast tumor samples collected during the course of neoadjuvant treatment with the aromatase inhibitor letrozole. We show that influential genes, those with high influence scores, tend to be essential and include a higher proportion of essential genes than those prioritized based on their position (i.e. hubs or bottlenecks) within the same network. Additionally, we show that influential genes represent novel biologically relevant drug targets for the treatment of ER + breast cancers. Moreover, we demonstrate that gene influence differs between untreated tumors and residual tumors that have adapted to drug treatment. In this way, influence scores capture the context-dependent functions of genes and present the opportunity to design combination treatment strategies that take advantage of the tumor adaptation process. Conclusions Influence networks efficiently find essential genes as promising drug targets and combinations of targets to inform the development of molecularly targeted drugs and their use. PMID:24495353
Discovery and therapeutic promise of selective androgen receptor modulators.

PubMed

Chen, Jiyun; Kim, Juhyun; Dalton, James T

2005-06-01

Androgens are essential for male development and the maintenance of male secondary characteristics, such as bone mass, muscle mass, body composition, and spermatogenesis. The main disadvantages of steroidal androgens are their undesirable physicochemical and pharmacokinetic properties. The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies with advantages including oral bioavailability, flexibility of structural modification, androgen receptor specificity, tissue selectivity, and the lack of steroid-related side effects.
Discovery AND Therapeutic Promise OF Selective Androgen Receptor Modulators

PubMed Central

Chen, Jiyun; Kim, Juhyun; Dalton, James T.

2007-01-01

Androgens are essential for male development and the maintenance of male secondary characteristics, such as bone mass, muscle mass, body composition, and spermatogenesis. The main disadvantages of steroidal androgens are their undesirable physicochemical and pharmacokinetic properties. The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies with advantages including oral bioavailability, flexibility of structural modification, androgen receptor specificity, tissue selectivity, and the lack of steroid-related side effects. PMID:15994457
KSC-07pd2680

NASA Image and Video Library

2007-10-05

KENNEDY SPACE CENTER, FLA. -- On Launch Pad 39A, workers are removing the rain gutters from space shuttle Discovery's payload bay. The gutters prevent leaks into the bay from rain while the shuttle is on the pad. Beneath is the orbital docking system. Mission STS-120 will bring the Harmony module that will provide attachment points for European and Japanese laboratory modules to the International Space Station. Launch of Discovery is targeted for Oct. 23. Photo credit: NASA/George Shelton
KSC-07pd2678

NASA Image and Video Library

2007-10-05

KENNEDY SPACE CENTER, FLA. -- From the payload changeout room on Launch Pad 39A, the payloads for mission STS-120 have been transferred into space shuttle Discovery's payload bay. Seen at the lower end is the Italian-built U.S. Node 2 module, named Harmony. At the top is the orbital docking system. The red ring at top comprises rain gutters to prevent leaks into the bay from rain while the shuttle is on the pad. Mission STS-120 will bring the Harmony module that will provide attachment points for European and Japanese laboratory modules to the International Space Station. Launch of Discovery is targeted for Oct. 23. Photo credit: NASA/George Shelton
KSC-07pd2599

NASA Image and Video Library

2007-09-27

KENNEDY SPACE CENTER, FLA. -- In full light of day, the payload canister containing the Italian-built U.S. Node 2 module, called Harmony, is in place next to the payload changeout room on Launch Pad 39A. The canister will be opened and the module transferred inside. The payload will be installed in space shuttle Discovery's payload bay after the vehicle rolls out to the pad. Discovery is targeted for launch to the International Space Station for mission STS-120 on Oct. 23. The pressurized module will act as an internal connecting port and passageway to additional international science labs and cargo spacecraft. Photo credit: NASA/George Shelton
KSC-07pd2596

NASA Image and Video Library

2007-09-27

KENNEDY SPACE CENTER, FLA. -- With umbilical lines still attached, the payload canister containing the Italian-built U.S. Node 2 module, called Harmony, is lifted up toward the payload changeout room on Launch Pad 39A. The canister will be lifted to the payload changeout room and the module transferred inside. The payload will be installed in space shuttle Discovery's payload bay after the vehicle rolls out to the pad. Discovery is targeted for launch to the International Space Station for mission STS-120 on Oct. 23. The pressurized module will act as an internal connecting port and passageway to additional international science labs and cargo spacecraft. Photo credit: NASA/George Shelton
Integrative Analysis of GWASs, Human Protein Interaction, and Gene Expression Identified Gene Modules Associated With BMDs

PubMed Central

He, Hao; Zhang, Lei; Li, Jian; Wang, Yu-Ping; Zhang, Ji-Gang; Shen, Jie; Guo, Yan-Fang

2014-01-01

Context: To date, few systems genetics studies in the bone field have been performed. We designed our study from a systems-level perspective by integrating genome-wide association studies (GWASs), human protein-protein interaction (PPI) network, and gene expression to identify gene modules contributing to osteoporosis risk. Methods: First we searched for modules significantly enriched with bone mineral density (BMD)-associated genes in human PPI network by using 2 large meta-analysis GWAS datasets through a dense module search algorithm. One included 7 individual GWAS samples (Meta7). The other was from the Genetic Factors for Osteoporosis Consortium (GEFOS2). One was assigned as a discovery dataset and the other as an evaluation dataset, and vice versa. Results: In total, 42 modules and 129 modules were identified significantly in both Meta7 and GEFOS2 datasets for femoral neck and spine BMD, respectively. There were 3340 modules identified for hip BMD only in Meta7. As candidate modules, they were assessed for the biological relevance to BMD by gene set enrichment analysis in 2 expression profiles generated from circulating monocytes in subjects with low versus high BMD values. Interestingly, there were 2 modules significantly enriched in monocytes from the low BMD group in both gene expression datasets (nominal P value <.05). Two modules had 16 nonredundant genes. Functional enrichment analysis revealed that both modules were enriched for genes involved in Wnt receptor signaling and osteoblast differentiation. Conclusion: We highlighted 2 modules and novel genes playing important roles in the regulation of bone mass, providing important clues for therapeutic approaches for osteoporosis. PMID:25119315
Using HeLa Cell Stress Response to Introduce First Year Students to the Scientific Method, Laboratory Techniques, Primary Literature, and Scientific Writing

ERIC Educational Resources Information Center

Resendes, Karen K.

2015-01-01

Incorporating scientific literacy into inquiry driven research is one of the most effective mechanisms for developing an undergraduate student's strength in writing. Additionally, discovery-based laboratories help develop students who approach science as critical thinkers. Thus, a three-week laboratory module for an introductory cell and molecular…
Occupational Home Economics Education Series. Consumer Services. Competency Based Teaching Module.

ERIC Educational Resources Information Center

Lowe, Phyllis; And Others

This module, one of ten competency based modules developed for vocational home economics teachers, is based on a job cluster in consumer services. It is designed for a variety of levels (secondary, post-secondary, adult) in both school and non-school settings. Focusing on the specific job title of consumer advisor, eight competencies are listed…
Occupational Home Economics Education Series. Catering Services. Competency Based Teaching Module.

ERIC Educational Resources Information Center

Lowe, Phyllis; And Others

This module, one of ten competency based modules developed for vocational home economics teachers, is based on a job cluster in the catering industry. It is designed for use with a variety of levels of learners (secondary, postsecondary, adult) in both school and non-school educational settings. Focusing on two levels of employment, food caterer…
A conserved BDNF, glutamate- and GABA-enriched gene module related to human depression identified by coexpression meta-analysis and DNA variant genome-wide association studies.

PubMed

Chang, Lun-Ching; Jamain, Stephane; Lin, Chien-Wei; Rujescu, Dan; Tseng, George C; Sibille, Etienne

2014-01-01

Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases. In support of the superior discriminative power of this novel approach, we observed no significant enrichment for GWAS-related genes in coexpression modules extracted from single studies or in meta-modules using gene expression data from non-psychiatric control subjects. Genes in the identified module encode proteins implicated in neuronal signaling and structure, including glutamate metabotropic receptors (GRM1, GRM7), GABA receptors (GABRA2, GABRA4), and neurotrophic and development-related proteins [BDNF, reelin (RELN), Ephrin receptors (EPHA3, EPHA5)]. These results are consistent with the current understanding of molecular mechanisms of MDD and provide a set of putative interacting molecular partners, potentially reflecting components of a functional module across cells and biological pathways that are synchronously recruited in MDD, other brain disorders and MDD-related illnesses. Collectively, this study demonstrates the importance of integrating transcriptome data, gene coexpression modules and GWAS results for providing novel and complementary approaches to investigate the molecular pathology of MDD and other complex brain disorders.
An integrative model for in-silico clinical-genomics discovery science.

PubMed

Lussier, Yves A; Sarkar, Indra Nell; Cantor, Michael

2002-01-01

Human Genome discovery research has set the pace for Post-Genomic Discovery Research. While post-genomic fields focused at the molecular level are intensively pursued, little effort is being deployed in the later stages of molecular medicine discovery research, such as clinical-genomics. The objective of this study is to demonstrate the relevance and significance of integrating mainstream clinical informatics decision support systems to current bioinformatics genomic discovery science. This paper is a feasibility study of an original model enabling novel "in-silico" clinical-genomic discovery science and that demonstrates its feasibility. This model is designed to mediate queries among clinical and genomic knowledge bases with relevant bioinformatic analytic tools (e.g. gene clustering). Briefly, trait-disease-gene relationships were successfully illustrated using QMR, OMIM, SNOMED-RT, GeneCluster and TreeView. The analyses were visualized as two-dimensional dendrograms of clinical observations clustered around genes. To our knowledge, this is the first study using knowledge bases of clinical decision support systems for genomic discovery. Although this study is a proof of principle, it provides a framework for the development of clinical decision-support-system driven, high-throughput clinical-genomic technologies which could potentially unveil significant high-level functions of genes.
Recent Progress in the Design and Discovery of RXR Modulators Targeting Alternate Binding Sites of the Receptor.

PubMed

Su, Ying; Zeng, Zhiping; Chen, Ziwen; Xu, Dan; Zhang, Weidong; Zhang, Xiao-Kun

2017-01-01

Retinoid X receptors (RXRs) occupy a central position within the nuclear receptor superfamily. They not only function as important transcriptional factors but also exhibit diverse nongenomic biological activities. The pleiotropic actions of RXRs under both physiological and pathophysiological conditions confer RXRs important drug targets for the treatment of cancer, and metabolic and neurodegenerative diseases. RXR modulators have been studied for the purpose of developing both drug molecules and chemical tools for biological investigation of RXR. Development of RXR modulators has focused on small molecules targeting the canonical ligand-binding pocket. However, accumulating results have demonstrated that there are other binding mechanisms by which small molecules interact with RXR to act as RXR modulators. This review discusses the recent development in the design and discovery of RXR modulators with a focus on those targeting novel binding sites on RXR.
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Consumer Approach Strand: Textiles and Clothing. Module I-D-4: Applications and Implications of New Technology in Textiles and Clothing.

ERIC Educational Resources Information Center

Joseph, Marjory

This competency-based preservice home economics teacher education module on applications and implications of new technology in textiles and clothing is the fourth in a set of four modules on consumer education related to textiles and clothing. (This set is part of a larger series of sixty-seven modules on the Management Approach to Teaching…

Identifying interactions between chemical entities in biomedical text.

PubMed

Lamurias, Andre; Ferreira, João D; Couto, Francisco M

2014-10-23

Interactions between chemical compounds described in biomedical text can be of great importance to drug discovery and design, as well as pharmacovigilance. We developed a novel system, \\"Identifying Interactions between Chemical Entities\\" (IICE), to identify chemical interactions described in text. Kernel-based Support Vector Machines first identify the interactions and then an ensemble classifier validates and classifies the type of each interaction. This relation extraction module was evaluated with the corpus released for the DDI Extraction task of SemEval 2013, obtaining results comparable to state-of-the-art methods for this type of task. We integrated this module with our chemical named entity recognition module and made the whole system available as a web tool at www.lasige.di.fc.ul.pt/webtools/iice.
Identifying interactions between chemical entities in biomedical text.

PubMed

Lamurias, Andre; Ferreira, João D; Couto, Francisco M

2014-12-01

Interactions between chemical compounds described in biomedical text can be of great importance to drug discovery and design, as well as pharmacovigilance. We developed a novel system, "Identifying Interactions between Chemical Entities" (IICE), to identify chemical interactions described in text. Kernel-based Support Vector Machines first identify the interactions and then an ensemble classifier validates and classifies the type of each interaction. This relation extraction module was evaluated with the corpus released for the DDI Extraction task of SemEval 2013, obtaining results comparable to stateof- the-art methods for this type of task. We integrated this module with our chemical named entity recognition module and made the whole system available as a web tool at www.lasige.di.fc.ul.pt/webtools/iice.
Identifying prognostic signature in ovarian cancer using DirGenerank

PubMed Central

Wang, Jian-Yong; Chen, Ling-Ling; Zhou, Xiong-Hui

2017-01-01

Identifying the prognostic genes in cancer is essential not only for the treatment of cancer patients, but also for drug discovery. However, it's still a big challenge to select the prognostic genes that can distinguish the risk of cancer patients across various data sets because of tumor heterogeneity. In this situation, the selected genes whose expression levels are statistically related to prognostic risks may be passengers. In this paper, based on gene expression data and prognostic data of ovarian cancer patients, we used conditional mutual information to construct gene dependency network in which the nodes (genes) with more out-degrees have more chances to be the modulators of cancer prognosis. After that, we proposed DirGenerank (Generank in direct netowrk) algorithm, which concerns both the gene dependency network and genes’ correlations to prognostic risks, to identify the gene signature that can predict the prognostic risks of ovarian cancer patients. Using ovarian cancer data set from TCGA (The Cancer Genome Atlas) as training data set, 40 genes with the highest importance were selected as prognostic signature. Survival analysis of these patients divided by the prognostic signature in testing data set and four independent data sets showed the signature can distinguish the prognostic risks of cancer patients significantly. Enrichment analysis of the signature with curated cancer genes and the drugs selected by CMAP showed the genes in the signature may be drug targets for therapy. In summary, we have proposed a useful pipeline to identify prognostic genes of cancer patients. PMID:28615526
Write Proposals. Module CG B-2 of Category B--Supporting. Competency-Based Career Guidance Modules.

ERIC Educational Resources Information Center

Gustafson, Richard A.

This module is intended to help guidance personnel in a variety of educational and agency settings plan and develop successful proposals to assist in financing the improvement of existing or future career guidance programs. The module is one of a series of competency-based guidance program training packages focusing upon specific professional and…
From Saccharomyces cerevisiae to human: The important gene co-expression modules.

PubMed

Liu, Wei; Li, Li; Ye, Hua; Chen, Haiwei; Shen, Weibiao; Zhong, Yuexian; Tian, Tian; He, Huaqin

2017-08-01

Network-based systems biology has become an important method for analyzing high-throughput gene expression data and gene function mining. Yeast has long been a popular model organism for biomedical research. In the current study, a weighted gene co-expression network analysis algorithm was applied to construct a gene co-expression network in Saccharomyces cerevisiae . Seventeen stable gene co-expression modules were detected from 2,814 S. cerevisiae microarray data. Further characterization of these modules with the Database for Annotation, Visualization and Integrated Discovery tool indicated that these modules were associated with certain biological processes, such as heat response, cell cycle, translational regulation, mitochondrion oxidative phosphorylation, amino acid metabolism and autophagy. Hub genes were also screened by intra-modular connectivity. Finally, the module conservation was evaluated in a human disease microarray dataset. Functional modules were identified in budding yeast, some of which are associated with patient survival. The current study provided a paradigm for single cell microorganisms and potentially other organisms.
Structural Analysis of Chemokine Receptor–Ligand Interactions

PubMed Central

2017-01-01

This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors with small-molecule ligands, peptide ligands, and large antibodies and chemokines. These studies demonstrate how the integration of new structural information on chemokine receptors with extensive structure–activity relationship and site-directed mutagenesis data facilitates the prediction of the structure of chemokine receptor–ligand complexes that have not been crystallized. Finally, a review of structure-based ligand discovery and design studies based on chemokine receptor crystal structures and homology models illustrates the possibilities and challenges to find novel ligands for chemokine receptors. PMID:28165741
Introduction to fragment-based drug discovery.

PubMed

Erlanson, Daniel A

2012-01-01

Fragment-based drug discovery (FBDD) has emerged in the past decade as a powerful tool for discovering drug leads. The approach first identifies starting points: very small molecules (fragments) that are about half the size of typical drugs. These fragments are then expanded or linked together to generate drug leads. Although the origins of the technique date back some 30 years, it was only in the mid-1990s that experimental techniques became sufficiently sensitive and rapid for the concept to be become practical. Since that time, the field has exploded: FBDD has played a role in discovery of at least 18 drugs that have entered the clinic, and practitioners of FBDD can be found throughout the world in both academia and industry. Literally dozens of reviews have been published on various aspects of FBDD or on the field as a whole, as have three books (Jahnke and Erlanson, Fragment-based approaches in drug discovery, 2006; Zartler and Shapiro, Fragment-based drug discovery: a practical approach, 2008; Kuo, Fragment based drug design: tools, practical approaches, and examples, 2011). However, this chapter will assume that the reader is approaching the field with little prior knowledge. It will introduce some of the key concepts, set the stage for the chapters to follow, and demonstrate how X-ray crystallography plays a central role in fragment identification and advancement.
The center for causal discovery of biomedical knowledge from big data

PubMed Central

Bahar, Ivet; Becich, Michael J; Benos, Panayiotis V; Berg, Jeremy; Espino, Jeremy U; Glymour, Clark; Jacobson, Rebecca Crowley; Kienholz, Michelle; Lee, Adrian V; Lu, Xinghua; Scheines, Richard

2015-01-01

The Big Data to Knowledge (BD2K) Center for Causal Discovery is developing and disseminating an integrated set of open source tools that support causal modeling and discovery of biomedical knowledge from large and complex biomedical datasets. The Center integrates teams of biomedical and data scientists focused on the refinement of existing and the development of new constraint-based and Bayesian algorithms based on causal Bayesian networks, the optimization of software for efficient operation in a supercomputing environment, and the testing of algorithms and software developed using real data from 3 representative driving biomedical projects: cancer driver mutations, lung disease, and the functional connectome of the human brain. Associated training activities provide both biomedical and data scientists with the knowledge and skills needed to apply and extend these tools. Collaborative activities with the BD2K Consortium further advance causal discovery tools and integrate tools and resources developed by other centers. PMID:26138794
Interpreting linear support vector machine models with heat map molecule coloring

PubMed Central

2011-01-01

Background Model-based virtual screening plays an important role in the early drug discovery stage. The outcomes of high-throughput screenings are a valuable source for machine learning algorithms to infer such models. Besides a strong performance, the interpretability of a machine learning model is a desired property to guide the optimization of a compound in later drug discovery stages. Linear support vector machines showed to have a convincing performance on large-scale data sets. The goal of this study is to present a heat map molecule coloring technique to interpret linear support vector machine models. Based on the weights of a linear model, the visualization approach colors each atom and bond of a compound according to its importance for activity. Results We evaluated our approach on a toxicity data set, a chromosome aberration data set, and the maximum unbiased validation data sets. The experiments show that our method sensibly visualizes structure-property and structure-activity relationships of a linear support vector machine model. The coloring of ligands in the binding pocket of several crystal structures of a maximum unbiased validation data set target indicates that our approach assists to determine the correct ligand orientation in the binding pocket. Additionally, the heat map coloring enables the identification of substructures important for the binding of an inhibitor. Conclusions In combination with heat map coloring, linear support vector machine models can help to guide the modification of a compound in later stages of drug discovery. Particularly substructures identified as important by our method might be a starting point for optimization of a lead compound. The heat map coloring should be considered as complementary to structure based modeling approaches. As such, it helps to get a better understanding of the binding mode of an inhibitor. PMID:21439031
Discovery and Validation of Novel Expression Signature for Postcystectomy Recurrence in High-Risk Bladder Cancer

PubMed Central

Lam, Lucia L.; Ghadessi, Mercedeh; Erho, Nicholas; Vergara, Ismael A.; Alshalalfa, Mohammed; Buerki, Christine; Haddad, Zaid; Sierocinski, Thomas; Triche, Timothy J.; Skinner, Eila C.; Davicioni, Elai; Daneshmand, Siamak; Black, Peter C.

2014-01-01

Background Nearly half of muscle-invasive bladder cancer patients succumb to their disease following cystectomy. Selecting candidates for adjuvant therapy is currently based on clinical parameters with limited predictive power. This study aimed to develop and validate genomic-based signatures that can better identify patients at risk for recurrence than clinical models alone. Methods Transcriptome-wide expression profiles were generated using 1.4 million feature-arrays on archival tumors from 225 patients who underwent radical cystectomy and had muscle-invasive and/or node-positive bladder cancer. Genomic (GC) and clinical (CC) classifiers for predicting recurrence were developed on a discovery set (n = 133). Performances of GC, CC, an independent clinical nomogram (IBCNC), and genomic-clinicopathologic classifiers (G-CC, G-IBCNC) were assessed in the discovery and independent validation (n = 66) sets. GC was further validated on four external datasets (n = 341). Discrimination and prognostic abilities of classifiers were compared using area under receiver-operating characteristic curves (AUCs). All statistical tests were two-sided. Results A 15-feature GC was developed on the discovery set with area under curve (AUC) of 0.77 in the validation set. This was higher than individual clinical variables, IBCNC (AUC = 0.73), and comparable to CC (AUC = 0.78). Performance was improved upon combining GC with clinical nomograms (G-IBCNC, AUC = 0.82; G-CC, AUC = 0.86). G-CC high-risk patients had elevated recurrence probabilities (P < .001), with GC being the best predictor by multivariable analysis (P = .005). Genomic-clinicopathologic classifiers outperformed clinical nomograms by decision curve and reclassification analyses. GC performed the best in validation compared with seven prior signatures. GC markers remained prognostic across four independent datasets. Conclusions The validated genomic-based classifiers outperform clinical models for predicting postcystectomy bladder cancer recurrence. This may be used to better identify patients who need more aggressive management. PMID:25344601
[MATCHE: Management Approach to Teaching Consumer and Homemaking Education.] Consumer Approach Strand: Core. Module I-A-3: Consumer Rights and Responsibilities.

ERIC Educational Resources Information Center

Smith, Sharman

This competency-based preservice home economics teacher education module on consumer rights and responsibilities is the third in a set of four core curriculum modules on consumer approach to homemaking education. (This set is part of a larger series of sixty-seven on the Management Approach to Teaching Consumer and Homemaking Education…
Occupational Home Economics Education Series. Housing Management Services. Competency Based Teaching Module.

ERIC Educational Resources Information Center

Lowe, Phyllis; And Others

This module, one of ten competency based modules developed for vocational home economics teachers, is based on a job cluster in the housing management field. It is designed for a variety of levels of learners (secondary, postsecondary, adult) in both school and non-school settings. Focusing on the specific job title of housing management aide,…
Development of allosteric modulators of GPCRs for treatment of CNS disorders.

PubMed

Nickols, Hilary Highfield; Conn, P Jeffrey

2014-01-01

The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as "bitopic" ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction. © 2013.
KSC-08pd1108

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At Launch Pad 39A at NASA's Kennedy Space Center, the payload for the STS-124 mission, secured in the payload changeout room on the rotating service structure, at left, awaits installation into the payload bay of space shuttle Discovery. Discovery's 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder
RCRA, Superfund and EPCRA hotline training module. Introduction to: the Superfund response program (updated February 1998); Directive

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

NONE

1998-06-01

This module includes the following: Regulatory Summary (Definitions; National Contingency Plan; Notification or Discovery; Response Process; Removal Process; Remedial Process; Community Involvement; State Role; Natural Resource Damage Assessments; Federal Facility Response; and Contractor Support); and Module Summary.
Multipurpose Logistics Module, Leonardo, Rests in Discovery's Payload Bay

NASA Technical Reports Server (NTRS)

2001-01-01

This in-orbit close up shows the Italian Space Agency-built multipurpose Logistics Module (MPLM), Leonardo, the primary cargo of the STS-102 mission, resting in the payload bay of the Space Shuttle Orbiter Discovery. The Leonardo MPLM is the first of three such pressurized modules that will serve as the International Space Station's (ISS') moving vans, carrying laboratory racks filled with equipment, experiments, and supplies to and from the Station aboard the Space Shuttle. The cylindrical module is approximately 21-feet long and 15- feet in diameter, weighing almost 4.5 tons. It can carry up to 10 tons of cargo in 16 standard Space Station equipment racks. Of the 16 racks the module can carry, 5 can be furnished with power, data, and fluid to support refrigerators or freezers. In order to function as an attached station module as well as a cargo transport, the logistics module also includes components that provide life support, fire detection and suppression, electrical distribution, and computer functions. The eighth station assembly flight and NASA's 103rd overall flight, STS-102 launched March 8, 2001 for an almost 13 day mission.
Harvest: a web-based biomedical data discovery and reporting application development platform.

PubMed

Italia, Michael J; Pennington, Jeffrey W; Ruth, Byron; Wrazien, Stacey; Loutrel, Jennifer G; Crenshaw, E Bryan; Miller, Jeffrey; White, Peter S

2013-01-01

Biomedical researchers share a common challenge of making complex data understandable and accessible. This need is increasingly acute as investigators seek opportunities for discovery amidst an exponential growth in the volume and complexity of laboratory and clinical data. To address this need, we developed Harvest, an open source framework that provides a set of modular components to aid the rapid development and deployment of custom data discovery software applications. Harvest incorporates visual representations of multidimensional data types in an intuitive, web-based interface that promotes a real-time, iterative approach to exploring complex clinical and experimental data. The Harvest architecture capitalizes on standards-based, open source technologies to address multiple functional needs critical to a research and development environment, including domain-specific data modeling, abstraction of complex data models, and a customizable web client.
Estimating the domain of applicability for machine learning QSAR models: a study on aqueous solubility of drug discovery molecules.

PubMed

Schroeter, Timon Sebastian; Schwaighofer, Anton; Mika, Sebastian; Ter Laak, Antonius; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-12-01

We investigate the use of different Machine Learning methods to construct models for aqueous solubility. Models are based on about 4000 compounds, including an in-house set of 632 drug discovery molecules of Bayer Schering Pharma. For each method, we also consider an appropriate method to obtain error bars, in order to estimate the domain of applicability (DOA) for each model. Here, we investigate error bars from a Bayesian model (Gaussian Process (GP)), an ensemble based approach (Random Forest), and approaches based on the Mahalanobis distance to training data (for Support Vector Machine and Ridge Regression models). We evaluate all approaches in terms of their prediction accuracy (in cross-validation, and on an external validation set of 536 molecules) and in how far the individual error bars can faithfully represent the actual prediction error.
Estimating the domain of applicability for machine learning QSAR models: a study on aqueous solubility of drug discovery molecules.

PubMed

Schroeter, Timon Sebastian; Schwaighofer, Anton; Mika, Sebastian; Ter Laak, Antonius; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-09-01

We investigate the use of different Machine Learning methods to construct models for aqueous solubility. Models are based on about 4000 compounds, including an in-house set of 632 drug discovery molecules of Bayer Schering Pharma. For each method, we also consider an appropriate method to obtain error bars, in order to estimate the domain of applicability (DOA) for each model. Here, we investigate error bars from a Bayesian model (Gaussian Process (GP)), an ensemble based approach (Random Forest), and approaches based on the Mahalanobis distance to training data (for Support Vector Machine and Ridge Regression models). We evaluate all approaches in terms of their prediction accuracy (in cross-validation, and on an external validation set of 536 molecules) and in how far the individual error bars can faithfully represent the actual prediction error.
Estimating the domain of applicability for machine learning QSAR models: a study on aqueous solubility of drug discovery molecules

NASA Astrophysics Data System (ADS)

Schroeter, Timon Sebastian; Schwaighofer, Anton; Mika, Sebastian; Ter Laak, Antonius; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-12-01

We investigate the use of different Machine Learning methods to construct models for aqueous solubility. Models are based on about 4000 compounds, including an in-house set of 632 drug discovery molecules of Bayer Schering Pharma. For each method, we also consider an appropriate method to obtain error bars, in order to estimate the domain of applicability (DOA) for each model. Here, we investigate error bars from a Bayesian model (Gaussian Process (GP)), an ensemble based approach (Random Forest), and approaches based on the Mahalanobis distance to training data (for Support Vector Machine and Ridge Regression models). We evaluate all approaches in terms of their prediction accuracy (in cross-validation, and on an external validation set of 536 molecules) and in how far the individual error bars can faithfully represent the actual prediction error.

Estimating the domain of applicability for machine learning QSAR models: a study on aqueous solubility of drug discovery molecules

NASA Astrophysics Data System (ADS)

Schroeter, Timon Sebastian; Schwaighofer, Anton; Mika, Sebastian; Ter Laak, Antonius; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-09-01

We investigate the use of different Machine Learning methods to construct models for aqueous solubility. Models are based on about 4000 compounds, including an in-house set of 632 drug discovery molecules of Bayer Schering Pharma. For each method, we also consider an appropriate method to obtain error bars, in order to estimate the domain of applicability (DOA) for each model. Here, we investigate error bars from a Bayesian model (Gaussian Process (GP)), an ensemble based approach (Random Forest), and approaches based on the Mahalanobis distance to training data (for Support Vector Machine and Ridge Regression models). We evaluate all approaches in terms of their prediction accuracy (in cross-validation, and on an external validation set of 536 molecules) and in how far the individual error bars can faithfully represent the actual prediction error.
Microarray and network-based identification of functional modules and pathways of active tuberculosis.

PubMed

Bian, Zhong-Rui; Yin, Juan; Sun, Wen; Lin, Dian-Jie

2017-04-01

Diagnose of active tuberculosis (TB) is challenging and treatment response is also difficult to efficiently monitor. The aim of this study was to use an integrated analysis of microarray and network-based method to the samples from publically available datasets to obtain a diagnostic module set and pathways in active TB. Towards this goal, background protein-protein interactions (PPI) network was generated based on global PPI information and gene expression data, following by identification of differential expression network (DEN) from the background PPI network. Then, ego genes were extracted according to the degree features in DEN. Next, module collection was conducted by ego gene expansion based on EgoNet algorithm. After that, differential expression of modules between active TB and controls was evaluated using random permutation test. Finally, biological significance of differential modules was detected by pathways enrichment analysis based on Reactome database, and Fisher's exact test was implemented to extract differential pathways for active TB. Totally, 47 ego genes and 47 candidate modules were identified from the DEN. By setting the cutoff-criteria of gene size >5 and classification accuracy ≥0.9, 7 ego modules (Module 4, Module 7, Module 9, Module 19, Module 25, Module 38 and Module 43) were extracted, and all of them had the statistical significance between active TB and controls. Then, Fisher's exact test was conducted to capture differential pathways for active TB. Interestingly, genes in Module 4, Module 25, Module 38, and Module 43 were enriched in the same pathway, formation of a pool of free 40S subunits. Significant pathway for Module 7 and Module 9 was eukaryotic translation termination, and for Module 19 was nonsense mediated decay enhanced by the exon junction complex (EJC). Accordingly, differential modules and pathways might be potential biomarkers for treating active TB, and provide valuable clues for better understanding of molecular mechanism of active TB. Copyright © 2017 Elsevier Ltd. All rights reserved.
Relay discovery and selection for large-scale P2P streaming

PubMed Central

Zhang, Chengwei; Wang, Angela Yunxian

2017-01-01

In peer-to-peer networks, application relays have been commonly used to provide various networking services. The service performance often improves significantly if a relay is selected appropriately based on its network location. In this paper, we studied the location-aware relay discovery and selection problem for large-scale P2P streaming networks. In these large-scale and dynamic overlays, it incurs significant communication and computation cost to discover a sufficiently large relay candidate set and further to select one relay with good performance. The network location can be measured directly or indirectly with the tradeoffs between timeliness, overhead and accuracy. Based on a measurement study and the associated error analysis, we demonstrate that indirect measurements, such as King and Internet Coordinate Systems (ICS), can only achieve a coarse estimation of peers’ network location and those methods based on pure indirect measurements cannot lead to a good relay selection. We also demonstrate that there exists significant error amplification of the commonly used “best-out-of-K” selection methodology using three RTT data sets publicly available. We propose a two-phase approach to achieve efficient relay discovery and accurate relay selection. Indirect measurements are used to narrow down a small number of high-quality relay candidates and the final relay selection is refined based on direct probing. This two-phase approach enjoys an efficient implementation using the Distributed-Hash-Table (DHT). When the DHT is constructed, the node keys carry the location information and they are generated scalably using indirect measurements, such as the ICS coordinates. The relay discovery is achieved efficiently utilizing the DHT-based search. We evaluated various aspects of this DHT-based approach, including the DHT indexing procedure, key generation under peer churn and message costs. PMID:28410384
Relay discovery and selection for large-scale P2P streaming.

PubMed

Zhang, Chengwei; Wang, Angela Yunxian; Hei, Xiaojun

2017-01-01

In peer-to-peer networks, application relays have been commonly used to provide various networking services. The service performance often improves significantly if a relay is selected appropriately based on its network location. In this paper, we studied the location-aware relay discovery and selection problem for large-scale P2P streaming networks. In these large-scale and dynamic overlays, it incurs significant communication and computation cost to discover a sufficiently large relay candidate set and further to select one relay with good performance. The network location can be measured directly or indirectly with the tradeoffs between timeliness, overhead and accuracy. Based on a measurement study and the associated error analysis, we demonstrate that indirect measurements, such as King and Internet Coordinate Systems (ICS), can only achieve a coarse estimation of peers' network location and those methods based on pure indirect measurements cannot lead to a good relay selection. We also demonstrate that there exists significant error amplification of the commonly used "best-out-of-K" selection methodology using three RTT data sets publicly available. We propose a two-phase approach to achieve efficient relay discovery and accurate relay selection. Indirect measurements are used to narrow down a small number of high-quality relay candidates and the final relay selection is refined based on direct probing. This two-phase approach enjoys an efficient implementation using the Distributed-Hash-Table (DHT). When the DHT is constructed, the node keys carry the location information and they are generated scalably using indirect measurements, such as the ICS coordinates. The relay discovery is achieved efficiently utilizing the DHT-based search. We evaluated various aspects of this DHT-based approach, including the DHT indexing procedure, key generation under peer churn and message costs.
The pump, the exchanger, and the holy spirit: origins and 40-year evolution of ideas about the ouabain-Na+ pump endocrine system.

PubMed

Blaustein, Mordecai P

2018-01-01

Two prescient 1953 publications set the stage for the elucidation of a novel endocrine system: Schatzmann's report that cardiotonic steroids (CTSs) are all Na + pump inhibitors, and Szent-Gyorgi's suggestion that there is an endogenous "missing screw" in heart failure that CTSs like digoxin may replace. In 1977 I postulated that an endogenous Na + pump inhibitor acts as a natriuretic hormone and simultaneously elevates blood pressure (BP) in salt-dependent hypertension. This hypothesis was based on the idea that excess renal salt retention promoted the secretion of a CTS-like hormone that inhibits renal Na + pumps and salt reabsorption. The hormone also inhibits arterial Na + pumps, elevates myocyte Na + and promotes Na/Ca exchanger-mediated Ca 2+ gain. This enhances vasoconstriction and arterial tone-the hallmark of hypertension. Here I describe how those ideas led to the discovery that the CTS-like hormone is endogenous ouabain (EO), a key factor in the pathogenesis of hypertension and heart failure. Seminal observations that underlie the still-emerging picture of the EO-Na + pump endocrine system in the physiology and pathophysiology of multiple organ systems are summarized. Milestones include: 1) cloning the Na + pump isoforms and physiological studies of mutated pumps in mice; 2) discovery that Na + pumps are also EO-triggered signaling molecules; 3) demonstration that ouabain, but not digoxin, is hypertensinogenic; 4) elucidation of EO's roles in kidney development and cardiovascular and renal physiology and pathophysiology; 5) discovery of "brain ouabain", a component of a novel hypothalamic neuromodulatory pathway; and 6) finding that EO and its brain receptors modulate behavior and learning.
Collins in Service Module

NASA Image and Video Library

2005-08-05

S114-E-7138 (5 August 2005) --- Astronaut Eileen M. Collins, STS-114 commander, waves while floating in the Zvezda Service Module of the international space station while Space Shuttle Discovery was docked to the station.
NASA's 747 Shuttle Carrier Aircraft with the Space Shuttle Discovery on top lifts off to begin its ferry flight back to the Kennedy Space Center in Florida

NASA Image and Video Library

2005-08-19

NASA's modified Boeing 747 Shuttle Carrier Aircraft with the Space Shuttle Discovery on top lifts off from Edwards Air Force Base to begin its ferry flight back to the Kennedy Space Center in Florida. The cross-country journey will take two days, with stops at several intermediate points for refueling. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.
Module for phosphorus separation and recycling from liquid manures

USDA-ARS?s Scientific Manuscript database

A method has been developed to extract and concentrate soluble phosphates from livestock wastewater. The research was conducted over a 10-year period and went from initial bench studies and discovery, to pilot module development, to full-scale demonstrations of the phosphorus (P) module in swine fa...
Overview Article: Identifying transcriptional cis-regulatory modules in animal genomes

PubMed Central

Suryamohan, Kushal; Halfon, Marc S.

2014-01-01

Gene expression is regulated through the activity of transcription factors and chromatin modifying proteins acting on specific DNA sequences, referred to as cis-regulatory elements. These include promoters, located at the transcription initiation sites of genes, and a variety of distal cis-regulatory modules (CRMs), the most common of which are transcriptional enhancers. Because regulated gene expression is fundamental to cell differentiation and acquisition of new cell fates, identifying, characterizing, and understanding the mechanisms of action of CRMs is critical for understanding development. CRM discovery has historically been challenging, as CRMs can be located far from the genes they regulate, have few readily-identifiable sequence characteristics, and for many years were not amenable to high-throughput discovery methods. However, the recent availability of complete genome sequences and the development of next-generation sequencing methods has led to an explosion of both computational and empirical methods for CRM discovery in model and non-model organisms alike. Experimentally, CRMs can be identified through chromatin immunoprecipitation directed against transcription factors or histone post-translational modifications, identification of nucleosome-depleted “open” chromatin regions, or sequencing-based high-throughput functional screening. Computational methods include comparative genomics, clustering of known or predicted transcription factor binding sites, and supervised machine-learning approaches trained on known CRMs. All of these methods have proven effective for CRM discovery, but each has its own considerations and limitations, and each is subject to a greater or lesser number of false-positive identifications. Experimental confirmation of predictions is essential, although shortcomings in current methods suggest that additional means of validation need to be developed. PMID:25704908
Identification of potential transcriptomic markers in developing pediatric sepsis: a weighted gene co-expression network analysis and a case-control validation study.

PubMed

Li, Yiping; Li, Yanhong; Bai, Zhenjiang; Pan, Jian; Wang, Jian; Fang, Fang

2017-12-13

Sepsis represents a complex disease with the dysregulated inflammatory response and high mortality rate. The goal of this study was to identify potential transcriptomic markers in developing pediatric sepsis by a co-expression module analysis of the transcriptomic dataset. Using the R software and Bioconductor packages, we performed a weighted gene co-expression network analysis to identify co-expression modules significantly associated with pediatric sepsis. Functional interpretation (gene ontology and pathway analysis) and enrichment analysis with known transcription factors and microRNAs of the identified candidate modules were then performed. In modules significantly associated with sepsis, the intramodular analysis was further performed and "hub genes" were identified and validated by quantitative real-time PCR (qPCR) in this study. 15 co-expression modules in total were detected, and four modules ("midnight blue", "cyan", "brown", and "tan") were most significantly associated with pediatric sepsis and suggested as potential sepsis-associated modules. Gene ontology analysis and pathway analysis revealed that these four modules strongly associated with immune response. Three of the four sepsis-associated modules were also enriched with known transcription factors (false discovery rate-adjusted P < 0.05). Hub genes were identified in each of the four modules. Four of the identified hub genes (MYB proto-oncogene like 1, killer cell lectin like receptor G1, stomatin, and membrane spanning 4-domains A4A) were further validated to be differentially expressed between septic children and controls by qPCR. Four pediatric sepsis-associated co-expression modules were identified in this study. qPCR results suggest that hub genes in these modules are potential transcriptomic markers for pediatric sepsis diagnosis. These results provide novel insights into the pathogenesis of pediatric sepsis and promote the generation of diagnostic gene sets.
Space Shuttle Discovery (STS-124) Landing

NASA Image and Video Library

2008-06-14

The space shuttle Discovery touches down at 11:15 a.m. EDT, Saturday, June 14, 2008, at the Kennedy Space Center in Florida. During the 13-day mission, Discovery and the crew of STS-124 delivered new components of the Japanese Experiment Module, or Kibo, to the International Space Station and the Canadian-built Special Purpose Dextrous Manipulator to the International Space Station. Photo Credit: (NASA/Bill Ingalls)
ACFIS: a web server for fragment-based drug discovery

PubMed Central

Hao, Ge-Fei; Jiang, Wen; Ye, Yuan-Nong; Wu, Feng-Xu; Zhu, Xiao-Lei; Guo, Feng-Biao; Yang, Guang-Fu

2016-01-01

In order to foster innovation and improve the effectiveness of drug discovery, there is a considerable interest in exploring unknown ‘chemical space’ to identify new bioactive compounds with novel and diverse scaffolds. Hence, fragment-based drug discovery (FBDD) was developed rapidly due to its advanced expansive search for ‘chemical space’, which can lead to a higher hit rate and ligand efficiency (LE). However, computational screening of fragments is always hampered by the promiscuous binding model. In this study, we developed a new web server Auto Core Fragment in silico Screening (ACFIS). It includes three computational modules, PARA_GEN, CORE_GEN and CAND_GEN. ACFIS can generate core fragment structure from the active molecule using fragment deconstruction analysis and perform in silico screening by growing fragments to the junction of core fragment structure. An integrated energy calculation rapidly identifies which fragments fit the binding site of a protein. We constructed a simple interface to enable users to view top-ranking molecules in 2D and the binding mode in 3D for further experimental exploration. This makes the ACFIS a highly valuable tool for drug discovery. The ACFIS web server is free and open to all users at http://chemyang.ccnu.edu.cn/ccb/server/ACFIS/. PMID:27150808
ACFIS: a web server for fragment-based drug discovery.

PubMed

Hao, Ge-Fei; Jiang, Wen; Ye, Yuan-Nong; Wu, Feng-Xu; Zhu, Xiao-Lei; Guo, Feng-Biao; Yang, Guang-Fu

2016-07-08

In order to foster innovation and improve the effectiveness of drug discovery, there is a considerable interest in exploring unknown 'chemical space' to identify new bioactive compounds with novel and diverse scaffolds. Hence, fragment-based drug discovery (FBDD) was developed rapidly due to its advanced expansive search for 'chemical space', which can lead to a higher hit rate and ligand efficiency (LE). However, computational screening of fragments is always hampered by the promiscuous binding model. In this study, we developed a new web server Auto Core Fragment in silico Screening (ACFIS). It includes three computational modules, PARA_GEN, CORE_GEN and CAND_GEN. ACFIS can generate core fragment structure from the active molecule using fragment deconstruction analysis and perform in silico screening by growing fragments to the junction of core fragment structure. An integrated energy calculation rapidly identifies which fragments fit the binding site of a protein. We constructed a simple interface to enable users to view top-ranking molecules in 2D and the binding mode in 3D for further experimental exploration. This makes the ACFIS a highly valuable tool for drug discovery. The ACFIS web server is free and open to all users at http://chemyang.ccnu.edu.cn/ccb/server/ACFIS/. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.
Hybrid coexpression link similarity graph clustering for mining biological modules from multiple gene expression datasets.

PubMed

Salem, Saeed; Ozcaglar, Cagri

2014-01-01

Advances in genomic technologies have enabled the accumulation of vast amount of genomic data, including gene expression data for multiple species under various biological and environmental conditions. Integration of these gene expression datasets is a promising strategy to alleviate the challenges of protein functional annotation and biological module discovery based on a single gene expression data, which suffers from spurious coexpression. We propose a joint mining algorithm that constructs a weighted hybrid similarity graph whose nodes are the coexpression links. The weight of an edge between two coexpression links in this hybrid graph is a linear combination of the topological similarities and co-appearance similarities of the corresponding two coexpression links. Clustering the weighted hybrid similarity graph yields recurrent coexpression link clusters (modules). Experimental results on Human gene expression datasets show that the reported modules are functionally homogeneous as evident by their enrichment with biological process GO terms and KEGG pathways.
Reactivity-based drug discovery using vitamin B(6)-derived pharmacophores.

PubMed

Wondrak, Georg T

2008-05-01

Endogenous reactive intermediates including photoexcited states of tissue chromophores, reactive oxygen species (ROS), reactive carbonyl species (RCS), transition metal ions, and Schiff bases have been implicated in the initiation and progression of diverse human pathologies including tumorigenesis, atherosclerosis, diabetes, and neurodegenerative disease. In contrast to structure-based approaches that target macromolecules by selective ligands, reactivity-based drug discovery uses chemical reagents as therapeutics that target reactive chemical species involved in human pathology. Reactivity-based design of prototype agents that effectively antagonize, modulate, and potentially even reverse the chemistry underlying tissue damage from oxidative and carbonyl stress therefore holds great promise in delivering significant therapeutic benefit. Apart from its established role as an essential cofactor for numerous enzymes, a large body of evidence suggests that B(6)-vitamers contain reactive pharmacophores that mediate therapeutically useful non-vitamin drug actions as potent antioxidants, metal chelators, carbonyl scavengers, Schiff base forming agents, and photosensitizers. Based on the fascinating chemical versatility of B(6)-derived pharmacophores, B(6)-vitamers are therefore promising lead compounds for reactivity-based drug design.
Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non–Small-Cell Lung Cancer

PubMed Central

Le Teuff, Gwénaël; Marguet, Sophie; Lantuejoul, Sylvie; Dunant, Ariane; Graziano, Stephen; Pirker, Robert; Douillard, Jean-Yves; Le Chevalier, Thierry; Filipits, Martin; Rosell, Rafael; Kratzke, Robert; Popper, Helmut; Soria, Jean-Charles; Shepherd, Frances A.; Seymour, Lesley; Tsao, Ming Sound

2016-01-01

Purpose Tumor lymphocytic infiltration (TLI) has differing prognostic value among various cancers. The objective of this study was to assess the effect of TLI in lung cancer. Patients and Methods A discovery set (one trial, n = 824) and a validation set (three trials, n = 984) that evaluated the benefit of platinum-based adjuvant chemotherapy in non–small-cell lung cancer were used as part of the LACE-Bio (Lung Adjuvant Cisplatin Evaluation Biomarker) study. TLI was defined as intense versus nonintense. The main end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs associated with TLI were estimated through a multivariable Cox model in both sets. TLI-histology and TLI-treatment interactions were explored in the combined set. Results Discovery and validation sets with complete data included 783 (409 deaths) and 763 (344 deaths) patients, respectively. Median follow-up was 4.8 and 6 years, respectively. TLI was intense in 11% of patients in the discovery set compared with 6% in the validation set (P < .001). The prognostic value of TLI in the discovery set (OS: HR, 0.56; 95% CI, 0.38 to 0.81; P = .002; DFS: HR, 0.59; 95% CI, 0.42 to 0.83; P = .002; SDFS: HR, 0.56; 95% CI, 0.38 to 0.82; P = .003) was confirmed in the validation set (OS: HR, 0.45; 95% CI, 0.23 to 0.85; P = .01; DFS: HR, 0.44; 95% CI, 0.24 to 0.78; P = .005; SDFS: HR, 0.42; 95% CI, 0.22 to 0.80; P = .008) with no heterogeneity across trials (P ≥ .38 for all end points). No significant predictive effect was observed for TLI (P ≥ .78 for all end points). Conclusion Intense lymphocytic infiltration, found in a minority of tumors, was validated as a favorable prognostic marker for survival in resected non–small-cell lung cancer. PMID:26834066
MZmine 2: Modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data

PubMed Central

2010-01-01

Background Mass spectrometry (MS) coupled with online separation methods is commonly applied for differential and quantitative profiling of biological samples in metabolomic as well as proteomic research. Such approaches are used for systems biology, functional genomics, and biomarker discovery, among others. An ongoing challenge of these molecular profiling approaches, however, is the development of better data processing methods. Here we introduce a new generation of a popular open-source data processing toolbox, MZmine 2. Results A key concept of the MZmine 2 software design is the strict separation of core functionality and data processing modules, with emphasis on easy usability and support for high-resolution spectra processing. Data processing modules take advantage of embedded visualization tools, allowing for immediate previews of parameter settings. Newly introduced functionality includes the identification of peaks using online databases, MSn data support, improved isotope pattern support, scatter plot visualization, and a new method for peak list alignment based on the random sample consensus (RANSAC) algorithm. The performance of the RANSAC alignment was evaluated using synthetic datasets as well as actual experimental data, and the results were compared to those obtained using other alignment algorithms. Conclusions MZmine 2 is freely available under a GNU GPL license and can be obtained from the project website at: http://mzmine.sourceforge.net/. The current version of MZmine 2 is suitable for processing large batches of data and has been applied to both targeted and non-targeted metabolomic analyses. PMID:20650010
Metavisitor, a Suite of Galaxy Tools for Simple and Rapid Detection and Discovery of Viruses in Deep Sequence Data

PubMed Central

Vernick, Kenneth D.

2017-01-01

Metavisitor is a software package that allows biologists and clinicians without specialized bioinformatics expertise to detect and assemble viral genomes from deep sequence datasets. The package is composed of a set of modular bioinformatic tools and workflows that are implemented in the Galaxy framework. Using the graphical Galaxy workflow editor, users with minimal computational skills can use existing Metavisitor workflows or adapt them to suit specific needs by adding or modifying analysis modules. Metavisitor works with DNA, RNA or small RNA sequencing data over a range of read lengths and can use a combination of de novo and guided approaches to assemble genomes from sequencing reads. We show that the software has the potential for quick diagnosis as well as discovery of viruses from a vast array of organisms. Importantly, we provide here executable Metavisitor use cases, which increase the accessibility and transparency of the software, ultimately enabling biologists or clinicians to focus on biological or medical questions. PMID:28045932
Computer-assisted initial diagnosis of rare diseases

PubMed Central

Piñol, Marc; Vilaplana, Jordi; Teixidó, Ivan; Cruz, Joaquim; Comas, Jorge; Vilaprinyo, Ester; Sorribas, Albert

2016-01-01

Introduction. Most documented rare diseases have genetic origin. Because of their low individual frequency, an initial diagnosis based on phenotypic symptoms is not always easy, as practitioners might never have been exposed to patients suffering from the relevant disease. It is thus important to develop tools that facilitate symptom-based initial diagnosis of rare diseases by clinicians. In this work we aimed at developing a computational approach to aid in that initial diagnosis. We also aimed at implementing this approach in a user friendly web prototype. We call this tool Rare Disease Discovery. Finally, we also aimed at testing the performance of the prototype. Methods. Rare Disease Discovery uses the publicly available ORPHANET data set of association between rare diseases and their symptoms to automatically predict the most likely rare diseases based on a patient’s symptoms. We apply the method to retrospectively diagnose a cohort of 187 rare disease patients with confirmed diagnosis. Subsequently we test the precision, sensitivity, and global performance of the system under different scenarios by running large scale Monte Carlo simulations. All settings account for situations where absent and/or unrelated symptoms are considered in the diagnosis. Results. We find that this expert system has high diagnostic precision (≥80%) and sensitivity (≥99%), and is robust to both absent and unrelated symptoms. Discussion. The Rare Disease Discovery prediction engine appears to provide a fast and robust method for initial assisted differential diagnosis of rare diseases. We coupled this engine with a user-friendly web interface and it can be freely accessed at http://disease-discovery.udl.cat/. The code and most current database for the whole project can be downloaded from https://github.com/Wrrzag/DiseaseDiscovery/tree/no_classifiers. PMID:27547534
Network Discovery Pipeline Elucidates Conserved Time-of-Day–Specific cis-Regulatory Modules

PubMed Central

McEntee, Connor; Byer, Amanda; Trout, Jonathan D; Hazen, Samuel P; Shen, Rongkun; Priest, Henry D; Sullivan, Christopher M; Givan, Scott A; Yanovsky, Marcelo; Hong, Fangxin; Kay, Steve A; Chory, Joanne

2008-01-01

Correct daily phasing of transcription confers an adaptive advantage to almost all organisms, including higher plants. In this study, we describe a hypothesis-driven network discovery pipeline that identifies biologically relevant patterns in genome-scale data. To demonstrate its utility, we analyzed a comprehensive matrix of time courses interrogating the nuclear transcriptome of Arabidopsis thaliana plants grown under different thermocycles, photocycles, and circadian conditions. We show that 89% of Arabidopsis transcripts cycle in at least one condition and that most genes have peak expression at a particular time of day, which shifts depending on the environment. Thermocycles alone can drive at least half of all transcripts critical for synchronizing internal processes such as cell cycle and protein synthesis. We identified at least three distinct transcription modules controlling phase-specific expression, including a new midnight specific module, PBX/TBX/SBX. We validated the network discovery pipeline, as well as the midnight specific module, by demonstrating that the PBX element was sufficient to drive diurnal and circadian condition-dependent expression. Moreover, we show that the three transcription modules are conserved across Arabidopsis, poplar, and rice. These results confirm the complex interplay between thermocycles, photocycles, and the circadian clock on the daily transcription program, and provide a comprehensive view of the conserved genomic targets for a transcriptional network key to successful adaptation. PMID:18248097

PG-Metrics: A chemometric-based approach for classifying bacterial peptidoglycan data sets and uncovering their subjacent chemical variability

PubMed Central

Kumar, Keshav; Espaillat, Akbar; Cava, Felipe

2017-01-01

Bacteria cells are protected from osmotic and environmental stresses by an exoskeleton-like polymeric structure called peptidoglycan (PG) or murein sacculus. This structure is fundamental for bacteria’s viability and thus, the mechanisms underlying cell wall assembly and how it is modulated serve as targets for many of our most successful antibiotics. Therefore, it is now more important than ever to understand the genetics and structural chemistry of the bacterial cell walls in order to find new and effective methods of blocking it for the treatment of disease. In the last decades, liquid chromatography and mass spectrometry have been demonstrated to provide the required resolution and sensitivity to characterize the fine chemical structure of PG. However, the large volume of data sets that can be produced by these instruments today are difficult to handle without a proper data analysis workflow. Here, we present PG-metrics, a chemometric based pipeline that allows fast and easy classification of bacteria according to their muropeptide chromatographic profiles and identification of the subjacent PG chemical variability between e.g. bacterial species, growth conditions and, mutant libraries. The pipeline is successfully validated here using PG samples from different bacterial species and mutants in cell wall proteins. The obtained results clearly demonstrated that PG-metrics pipeline is a valuable bioanalytical tool that can lead us to cell wall classification and biomarker discovery. PMID:29040278
Molecular Basis for Modulation of Metabotropic Glutamate Receptors and Their Drug Actions by Extracellular Ca2+

PubMed Central

Zou, Juan; Jiang, Jason Y.; Yang, Jenny J.

2017-01-01

Metabotropic glutamate receptors (mGluRs) associated with the slow phase of the glutamatergic signaling pathway in neurons of the central nervous system have gained importance as drug targets for chronic neurodegenerative diseases. While extracellular Ca2+ was reported to exhibit direct activation and modulation via an allosteric site, the identification of those binding sites was challenged by weak binding. Herein, we review the discovery of extracellular Ca2+ in regulation of mGluRs, summarize the recent developments in probing Ca2+ binding and its co-regulation of the receptor based on structural and biochemical analysis, and discuss the molecular basis for Ca2+ to regulate various classes of drug action as well as its importance as an allosteric modulator in mGluRs. PMID:28335551
Enhanced STEM Learning with the GeoMapApp Data Exploration Tool

NASA Astrophysics Data System (ADS)

Goodwillie, A. M.

2014-12-01

GeoMapApp (http://www.geomapapp.org), is a free, map-based data discovery and visualisation tool developed with NSF funding at Lamont-Doherty Earth Observatory. GeoMapApp provides casual and specialist users alike with access to hundreds of built-in geoscience data sets covering geology, geophysics, geochemistry, oceanography, climatology, cryospherics, and the environment. Users can also import their own data tables, spreadsheets, shapefiles, grids and images. Simple manipulation and analysis tools combined with layering capabilities and engaging visualisations provide a powerful platform with which to explore and interrogate geoscience data in its proper geospatial context thus helping users to more easily gain insight into the meaning of the data. A global elevation base map covering the oceans as well as continents forms the backbone of GeoMapApp. The multi-resolution base map is updated regularly and includes data sources ranging from Space Shuttle elevation data for land areas to ultra-high-resolution surveys of coral reefs and seafloor hydrothermal vent fields. Examples of built-in data sets that can be layered over the elevation model include interactive earthquake and volcano data, plate tectonic velocities, hurricane tracks, land and ocean temperature, water column properties, age of the ocean floor, and deep submersible bottom photos. A versatile profiling tool provides instant access to data cross-sections. Contouring and 3-D views are also offered - the attached image shows a 3-D view of East Africa's Ngorongoro Crater as an example. Tabular data - both imported and built-in - can be displayed in a variety of ways and a lasso tool enables users to quickly select data points directly from the map. A range of STEM-based education material based upon GeoMapApp is already available, including a number of self-contained modules for school- and college-level students (http://www.geomapapp.org/education/contributed_material.html). More learning modules are planned, such as one on the effects of sea-level rise. GeoMapApp users include students, teachers, researchers, curriculum developers and outreach specialists.
KSC01padig074

NASA Image and Video Library

2001-02-12

KENNEDY SPACE CENTER, Fla. -- This closeup shows Space Shuttle Discovery as it travels to Launch Pad 39B. Underneath Discovery is the Mobile Launcher Platform, a two-story movable launch base. Part of the MPLM is the tail service mast, seen here at the bottom of the wind and next to the Shuttle’s main engines. The tail service mast is 31 feet high, 15 feet long and 9 feet wide. A second TSM is on the other side. They support the fluid, gas and electrical requirements of the orbiter’s liquid oxygen and liquid hydrogen aft T-0 umbilicals. Discovery will be flying on mission STS-102 to the International Space Station. Its payload is the Multi-Purpose Logistics Module Leonardo, a “moving van,” to carry laboratory racks filled with equipment, experiments and supplies to and from the Space Station aboard the Space Shuttle. The flight will also carry the Expedition Two crew up to the Space Station, replacing Expedition One, who will return to Earth on Discovery. Launch is scheduled for March 8 at 6:45 a.m. EST
Comparison of Deep Learning With Multiple Machine Learning Methods and Metrics Using Diverse Drug Discovery Data Sets.

PubMed

Korotcov, Alexandru; Tkachenko, Valery; Russo, Daniel P; Ekins, Sean

2017-12-04

Machine learning methods have been applied to many data sets in pharmaceutical research for several decades. The relative ease and availability of fingerprint type molecular descriptors paired with Bayesian methods resulted in the widespread use of this approach for a diverse array of end points relevant to drug discovery. Deep learning is the latest machine learning algorithm attracting attention for many of pharmaceutical applications from docking to virtual screening. Deep learning is based on an artificial neural network with multiple hidden layers and has found considerable traction for many artificial intelligence applications. We have previously suggested the need for a comparison of different machine learning methods with deep learning across an array of varying data sets that is applicable to pharmaceutical research. End points relevant to pharmaceutical research include absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) properties, as well as activity against pathogens and drug discovery data sets. In this study, we have used data sets for solubility, probe-likeness, hERG, KCNQ1, bubonic plague, Chagas, tuberculosis, and malaria to compare different machine learning methods using FCFP6 fingerprints. These data sets represent whole cell screens, individual proteins, physicochemical properties as well as a data set with a complex end point. Our aim was to assess whether deep learning offered any improvement in testing when assessed using an array of metrics including AUC, F1 score, Cohen's kappa, Matthews correlation coefficient and others. Based on ranked normalized scores for the metrics or data sets Deep Neural Networks (DNN) ranked higher than SVM, which in turn was ranked higher than all the other machine learning methods. Visualizing these properties for training and test sets using radar type plots indicates when models are inferior or perhaps over trained. These results also suggest the need for assessing deep learning further using multiple metrics with much larger scale comparisons, prospective testing as well as assessment of different fingerprints and DNN architectures beyond those used.
Perceptual learning modules in mathematics: enhancing students' pattern recognition, structure extraction, and fluency.

PubMed

Kellman, Philip J; Massey, Christine M; Son, Ji Y

2010-04-01

Learning in educational settings emphasizes declarative and procedural knowledge. Studies of expertise, however, point to other crucial components of learning, especially improvements produced by experience in the extraction of information: perceptual learning (PL). We suggest that such improvements characterize both simple sensory and complex cognitive, even symbolic, tasks through common processes of discovery and selection. We apply these ideas in the form of perceptual learning modules (PLMs) to mathematics learning. We tested three PLMs, each emphasizing different aspects of complex task performance, in middle and high school mathematics. In the MultiRep PLM, practice in matching function information across multiple representations improved students' abilities to generate correct graphs and equations from word problems. In the Algebraic Transformations PLM, practice in seeing equation structure across transformations (but not solving equations) led to dramatic improvements in the speed of equation solving. In the Linear Measurement PLM, interactive trials involving extraction of information about units and lengths produced successful transfer to novel measurement problems and fraction problem solving. Taken together, these results suggest (a) that PL techniques have the potential to address crucial, neglected dimensions of learning, including discovery and fluent processing of relations; (b) PL effects apply even to complex tasks that involve symbolic processing; and (c) appropriately designed PL technology can produce rapid and enduring advances in learning. Copyright © 2009 Cognitive Science Society, Inc.
The CUAHSI Water Data Center: Enabling Data Publication, Discovery and Re-use

NASA Astrophysics Data System (ADS)

Seul, M.; Pollak, J.

2014-12-01

The CUAHSI Water Data Center (WDC) supports a standards-based, services-oriented architecture for time-series data and provides a separate service to publish spatial data layers as shape files. Two new services that the WDC offers are a cloud-based server (Cloud HydroServer) for publishing data and a web-based client for data discovery. The Cloud HydroServer greatly simplifies data publication by eliminating the need for scientists to set up an SQL-server data base, a requirement that has proven to be a significant barrier, and ensures greater reliability and continuity of service. Uploaders have been developed to simplify the metadata documentation process. The web-based data client eliminates the need for installing a program to be used as a client and works across all computer operating systems. The services provided by the WDC is a foundation for big data use, re-use, and meta-analyses. Using data transmission standards enables far more effective data sharing and discovery; standards used by the WDC are part of a global set of standards that should enable scientists to access unprecedented amount of data to address larger-scale research questions than was previously possible. A central mission of the WDC is to ensure these services meet the needs of the water science community and are effective at advancing water science.
Haplotag: Software for Haplotype-Based Genotyping-by-Sequencing Analysis

PubMed Central

Tinker, Nicholas A.; Bekele, Wubishet A.; Hattori, Jiro

2016-01-01

Genotyping-by-sequencing (GBS), and related methods, are based on high-throughput short-read sequencing of genomic complexity reductions followed by discovery of single nucleotide polymorphisms (SNPs) within sequence tags. This provides a powerful and economical approach to whole-genome genotyping, facilitating applications in genomics, diversity analysis, and molecular breeding. However, due to the complexity of analyzing large data sets, applications of GBS may require substantial time, expertise, and computational resources. Haplotag, the novel GBS software described here, is freely available, and operates with minimal user-investment on widely available computer platforms. Haplotag is unique in fulfilling the following set of criteria: (1) operates without a reference genome; (2) can be used in a polyploid species; (3) provides a discovery mode, and a production mode; (4) discovers polymorphisms based on a model of tag-level haplotypes within sequenced tags; (5) reports SNPs as well as haplotype-based genotypes; and (6) provides an intuitive visual “passport” for each inferred locus. Haplotag is optimized for use in a self-pollinating plant species. PMID:26818073
Application for managing model-based material properties for simulation-based engineering

DOEpatents

Hoffman, Edward L [Alameda, CA

2009-03-03

An application for generating a property set associated with a constitutive model of a material includes a first program module adapted to receive test data associated with the material and to extract loading conditions from the test data. A material model driver is adapted to receive the loading conditions and a property set and operable in response to the loading conditions and the property set to generate a model response for the material. A numerical optimization module is adapted to receive the test data and the model response and operable in response to the test data and the model response to generate the property set.
Human Movement Detection and Idengification Using Pyroelectric Infrared Sensors

PubMed Central

Yun, Jaeseok; Lee, Sang-Shin

2014-01-01

Pyroelectric infrared (PIR) sensors are widely used as a presence trigger, but the analog output of PIR sensors depends on several other aspects, including the distance of the body from the PIR sensor, the direction and speed of movement, the body shape and gait. In this paper, we present an empirical study of human movement detection and idengification using a set of PIR sensors. We have developed a data collection module having two pairs of PIR sensors orthogonally aligned and modified Fresnel lenses. We have placed three PIR-based modules in a hallway for monitoring people; one module on the ceiling; two modules on opposite walls facing each other. We have collected a data set from eight subjects when walking in three different conditions: two directions (back and forth), three distance intervals (close to one wall sensor, in the middle, close to the other wall sensor) and three speed levels (slow, moderate, fast). We have used two types of feature sets: a raw data set and a reduced feature set composed of amplitude and time to peaks; and passage duration extracted from each PIR sensor. We have performed classification analysis with well-known machine learning algorithms, including instance-based learning and support vector machine. Our findings show that with the raw data set captured from a single PIR sensor of each of the three modules, we could achieve more than 92% accuracy in classifying the direction and speed of movement, the distance interval and idengifying subjects. We could also achieve more than 94% accuracy in classifying the direction, speed and distance and idengifying subjects using the reduced feature set extracted from two pairs of PIR sensors of each of the three modules. PMID:24803195
KSC-06pd0924

NASA Image and Video Library

2006-05-23

KENNEDY SPACE CENTER, FLA. -- From inside the payload changeout room on the rotating service structure on Launch Pad 39B, the multi-purpose logistics module Leonardo is being moved into Space Shuttle Discovery's payload bay. The payload ground-handling mechanism (PGHM) is used to transfer the module into the payload bay. Leonardo is a reusable logistics carrier. It is the primary delivery system used to resupply and return station cargo requiring a pressurized environment. Leonardo is part of the payload on mission STS-121. Other payloads include the integrated cargo carrier with the mobile transporter reel assembly and a spare pump module, and the lightweight multi-purpose experiment support structure carrier. Discovery is scheduled to launch in a window extending from July 1 through July 19. Photo credit: NASA/Jack Pfaller
KSC-06pd0927

NASA Image and Video Library

2006-05-23

KENNEDY SPACE CENTER, FLA. -- From inside the payload changeout room on the rotating service structure on Launch Pad 39B, the multi-purpose logistics module Leonardo is lowered into Space Shuttle Discovery's payload bay. The payload ground-handling mechanism (PGHM) is used to transfer the module into the payload bay. Leonardo is a reusable logistics carrier. It is the primary delivery system used to resupply and return station cargo requiring a pressurized environment. Leonardo is part of the payload on mission STS-121. Other payloads include the integrated cargo carrier with the mobile transporter reel assembly and a spare pump module, and the lightweight multi-purpose experiment support structure carrier. Discovery is scheduled to launch in a window extending from July 1 through July 19. Photo credit: NASA/Jack Pfaller
Development of allosteric modulators of GPCRs for treatment of CNS disorders

PubMed Central

Nickols, Hilary Highfield; Conn, P. Jeffrey

2013-01-01

The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than do orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as “bitopic” ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction. PMID:24076101
A multi-model approach to nucleic acid-based drug development.

PubMed

Gautherot, Isabelle; Sodoyer, Regís

2004-01-01

With the advent of functional genomics and the shift of interest towards sequence-based therapeutics, the past decades have witnessed intense research efforts on nucleic acid-mediated gene regulation technologies. Today, RNA interference is emerging as a groundbreaking discovery, holding promise for development of genetic modulators of unprecedented potency. Twenty-five years after the discovery of antisense RNA and ribozymes, gene control therapeutics are still facing developmental difficulties, with only one US FDA-approved antisense drug currently available in the clinic. Limited predictability of target site selection models is recognized as one major stumbling block that is shared by all of the so-called complementary technologies, slowing the progress towards a commercial product. Currently employed in vitro systems for target site selection include RNAse H-based mapping, antisense oligonucleotide microarrays, and functional screening approaches using libraries of catalysts with randomized target-binding arms to identify optimal ribozyme/DNAzyme cleavage sites. Individually, each strategy has its drawbacks from a drug development perspective. Utilization of message-modulating sequences as therapeutic agents requires that their action on a given target transcript meets criteria of potency and selectivity in the natural physiological environment. In addition to sequence-dependent characteristics, other factors will influence annealing reactions and duplex stability, as well as nucleic acid-mediated catalysis. Parallel consideration of physiological selection systems thus appears essential for screening for nucleic acid compounds proposed for therapeutic applications. Cellular message-targeting studies face issues relating to efficient nucleic acid delivery and appropriate analysis of response. For reliability and simplicity, prokaryotic systems can provide a rapid and cost-effective means of studying message targeting under pseudo-cellular conditions, but such approaches also have limitations. To streamline nucleic acid drug discovery, we propose a multi-model strategy integrating high-throughput-adapted bacterial screening, followed by reporter-based and/or natural cellular models and potentially also in vitro assays for characterization of the most promising candidate sequences, before final in vivo testing.
Multiple reaction monitoring (MRM)-profiling for biomarker discovery applied to human polycystic ovarian syndrome.

PubMed

Cordeiro, Fernanda B; Ferreira, Christina R; Sobreira, Tiago Jose P; Yannell, Karen E; Jarmusch, Alan K; Cedenho, Agnaldo P; Lo Turco, Edson G; Cooks, R Graham

2017-09-15

We describe multiple reaction monitoring (MRM)-profiling, which provides accelerated discovery of discriminating molecular features, and its application to human polycystic ovary syndrome (PCOS) diagnosis. The discovery phase of the MRM-profiling seeks molecular features based on some prior knowledge of the chemical functional groups likely to be present in the sample. It does this through use of a limited number of pre-chosen and chemically specific neutral loss and/or precursor ion MS/MS scans. The output of the discovery phase is a set of precursor/product transitions. In the screening phase these MRM transitions are used to interrogate multiple samples (hence the name MRM-profiling). MRM-profiling was applied to follicular fluid samples of 22 controls and 29 clinically diagnosed PCOS patients. Representative samples were delivered by flow injection to a triple quadrupole mass spectrometer set to perform a number of pre-chosen and chemically specific neutral loss and/or precursor ion MS/MS scans. The output of this discovery phase was a set of 1012 precursor/product transitions. In the screening phase each individual sample was interrogated for these MRM transitions. Principal component analysis (PCA) and receiver operating characteristic (ROC) curves were used for statistical analysis. To evaluate the method's performance, half the samples were used to build a classification model (testing set) and half were blinded (validation set). Twenty transitions were used for the classification of the blind samples, most of them (N = 19) showed lower abundances in the PCOS group and corresponded to phosphatidylethanolamine (PE) and phosphatidylserine (PS) lipids. Agreement of 73% with clinical diagnosis was found when classifying the 26 blind samples. MRM-profiling is a supervised method characterized by its simplicity, speed and the absence of chromatographic separation. It can be used to rapidly isolate discriminating molecules in healthy/disease conditions by tailored screening of signals associated with hundreds of molecules in complex samples. Copyright © 2017 John Wiley & Sons, Ltd.
High-order UWB pulses scheme to generate multilevel modulation formats based on incoherent optical sources.

PubMed

Bolea, Mario; Mora, José; Ortega, Beatriz; Capmany, José

2013-11-18

We present a high-order UWB pulses generator based on a microwave photonic filter which provides a set of positive and negative samples by using the slicing of an incoherent optical source and the phase inversion in a Mach-Zehnder modulator. The simple scalability and high reconfigurability of the system permit a better accomplishment of the FCC requirements. Moreover, the proposed scheme permits an easy adaptation to pulse amplitude modulation, bi phase modulation, pulse shape modulation and pulse position modulation. The flexibility of the scheme for being adaptable to multilevel modulation formats permits to increase the transmission bit rate by using hybrid modulation formats.
STS-102 MPLM Leonardo is transferred from the PCR into Discovery's payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. - The Multi-Purpose Logistics Module Leonardo is moved into Space Shuttle Discovery'''s payload bay. The primary delivery system used to resupply and return Station cargo requiring a pressurized environment, Leonardo will deliver up to 10 tons of laboratory racks filled with equipment, experiments and supplies for outfitting the newly installed U.S. Laboratory Destiny. Discovery is scheduled to launch March 8 at 6:42 a.m. EST on mission STS-102, the eighth construction flight to the International Space Station.
In the Context of Multiple Intelligences Theory, Intelligent Data Analysis of Learning Styles Was Based on Rough Set Theory

ERIC Educational Resources Information Center

Narli, Serkan; Ozgen, Kemal; Alkan, Huseyin

2011-01-01

The present study aims to identify the relationship between individuals' multiple intelligence areas and their learning styles with mathematical clarity using the concept of rough sets which is used in areas such as artificial intelligence, data reduction, discovery of dependencies, prediction of data significance, and generating decision…
STS-41 Ulysses Launch (10/06/90), Ulysses Deploy (10/06/90), Landing (10/10/90)

NASA Technical Reports Server (NTRS)

1990-01-01

Live footage shows the crewmembers of STS-41, Commander Richard N. Richards, Pilot Robert D. Cabana, Mission Specialists William M. Shepherd, Bruce E. Melnick, and Thomas D. Akers, participating in the traditional activities the day of their flight. The crew are seen eating breakfast, suiting-up, walking out to the Astronaut-Van, putting on life vests in the 'White Room' area, and entering the crew module of the Discovery Orbiter. Footage also includes the deployment of the Ulysses satellite. The Discovery spacecraft is seen as it approaches and lands at Edwards Air Force Base. Also shown are several scenes from different cameras of both launching and landing of the STS-41 spacecraft.
The space shuttle Discovery atop NASA's modified 747 is captured over the Mojave Desert while being ferried from NASA Dryden to the Kennedy Space Center

NASA Image and Video Library

2005-08-19

The space shuttle Discovery atop NASA's modified 747 is captured over the Mojave Desert while being ferried from NASA Dryden to the Kennedy Space Center. NASA's modified Boeing 747 Shuttle Carrier Aircraft with the Space Shuttle Discovery on top lifts off from Edwards Air Force Base to begin its ferry flight back to the Kennedy Space Center in Florida. The cross-country journey will take two days, with stops at several intermediate points for refueling. Space shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.

Biochemical mechanisms of cisplatin cytotoxicity.

PubMed

Cepeda, Victoria; Fuertes, Miguel A; Castilla, Josefina; Alonso, Carlos; Quevedo, Celia; Pérez, Jose M

2007-01-01

Since the discovery by Rosenberg and collaborators of the antitumor activity of cisplatin 35 years ago, three platinum antitumor drugs (cisplatin, carboplatin and oxaliplatin) have enjoyed a huge clinical and commercial hit. Ever since the initial discovery of the anticancer activity of cisplatin, major efforts have been devoted to elucidate the biochemical mechanisms of antitumor activity of cisplatin in order to be able to rationally design novel platinum based drugs with superior pharmacological profiles. In this report we attempt to provide a current picture of the known facts pertaining to the mechanism of action of the drug, including those involved in drug uptake, DNA damage signals transduction, and cell death through apoptosis or necrosis. A deep knowledge of the biochemical mechanisms, which are triggered in the tumor cell in response to cisplatin injury not only may lead to the design of more efficient platinum antitumor drugs but also may provide new therapeutic strategies based on the biochemical modulation of cisplatin activity.
Construction of multi-functional open modulized Matlab simulation toolbox for imaging ladar system

NASA Astrophysics Data System (ADS)

Wu, Long; Zhao, Yuan; Tang, Meng; He, Jiang; Zhang, Yong

2011-06-01

Ladar system simulation is to simulate the ladar models using computer simulation technology in order to predict the performance of the ladar system. This paper presents the developments of laser imaging radar simulation for domestic and overseas studies and the studies of computer simulation on ladar system with different application requests. The LadarSim and FOI-LadarSIM simulation facilities of Utah State University and Swedish Defence Research Agency are introduced in details. This paper presents the low level of simulation scale, un-unified design and applications of domestic researches in imaging ladar system simulation, which are mostly to achieve simple function simulation based on ranging equations for ladar systems. Design of laser imaging radar simulation with open and modularized structure is proposed to design unified modules for ladar system, laser emitter, atmosphere models, target models, signal receiver, parameters setting and system controller. Unified Matlab toolbox and standard control modules have been built with regulated input and output of the functions, and the communication protocols between hardware modules. A simulation based on ICCD gain-modulated imaging ladar system for a space shuttle is made based on the toolbox. The simulation result shows that the models and parameter settings of the Matlab toolbox are able to simulate the actual detection process precisely. The unified control module and pre-defined parameter settings simplify the simulation of imaging ladar detection. Its open structures enable the toolbox to be modified for specialized requests. The modulization gives simulations flexibility.
Design and development of data acquisition system based on WeChat hardware

NASA Astrophysics Data System (ADS)

Wang, Zhitao; Ding, Lei

2018-06-01

Data acquisition system based on WeChat hardware provides methods for popularization and practicality of data acquisition. The whole system is based on WeChat hardware platform, where the hardware part is developed on DA14580 development board and the software part is based on Alibaba Cloud. We designed service module, logic processing module, data processing module and database module. The communication between hardware and software uses AirSync Protocal. We tested this system by collecting temperature and humidity data, and the result shows that the system can aquisite the temperature and humidity in real time according to settings.
The relative vertex clustering value - a new criterion for the fast discovery of functional modules in protein interaction networks

PubMed Central

2015-01-01

Background Cellular processes are known to be modular and are realized by groups of proteins implicated in common biological functions. Such groups of proteins are called functional modules, and many community detection methods have been devised for their discovery from protein interaction networks (PINs) data. In current agglomerative clustering approaches, vertices with just a very few neighbors are often classified as separate clusters, which does not make sense biologically. Also, a major limitation of agglomerative techniques is that their computational efficiency do not scale well to large PINs. Finally, PIN data obtained from large scale experiments generally contain many false positives, and this makes it hard for agglomerative clustering methods to find the correct clusters, since they are known to be sensitive to noisy data. Results We propose a local similarity premetric, the relative vertex clustering value, as a new criterion allowing to decide when a node can be added to a given node's cluster and which addresses the above three issues. Based on this criterion, we introduce a novel and very fast agglomerative clustering technique, FAC-PIN, for discovering functional modules and protein complexes from a PIN data. Conclusions Our proposed FAC-PIN algorithm is applied to nine PIN data from eight different species including the yeast PIN, and the identified functional modules are validated using Gene Ontology (GO) annotations from DAVID Bioinformatics Resources. Identified protein complexes are also validated using experimentally verified complexes. Computational results show that FAC-PIN can discover functional modules or protein complexes from PINs more accurately and more efficiently than HC-PIN and CNM, the current state-of-the-art approaches for clustering PINs in an agglomerative manner. PMID:25734691
Space Shuttle Discovery (STS-124) Lands

NASA Image and Video Library

2008-06-14

NASA Associate Administrator for Space Operations Bill Gerstenmaier watches the space shuttle Discovery touch down at 11:15 a.m. EDT, Saturday, June 14, 2008, at the Kennedy Space Center in Florida. During the 13-day mission, Discovery and the crew of STS-124 delivered new components of the Japanese Experiment Module, or Kibo, to the International Space Station and the Canadian-built Special Purpose Dextrous Manipulator to the International Space Station. Photo Credit: (NASA/Bill Ingalls)
Space Shuttle Discovery is Prepared for Launch

NASA Image and Video Library

2011-02-23

The space shuttle Discovery is seen shortly after the Rotating Service Structure was rolled back at launch pad 39A, at the Kennedy Space Center in Cape Canaveral, Florida, on Wednesday, Feb. 23, 2011. Discovery, on its 39th and final flight, will carry the Italian-built Permanent Multipurpose Module (PMM), Express Logistics Carrier 4 (ELC4) and Robonaut 2, the first humanoid robot in space to the International Space Station. Photo Credit: (NASA/Bill Ingalls)
Three education modules using EnviroAtlas-Exploration and Discovery Through Maps: Teaching Science with Technology

EPA Science Inventory

Session #1: Exploration and Discovery through Maps: Teaching Science with Technology (elementary school) - EnviroAtlas is a tool developed by the U.S. Environmental Protection Agency and its partners that empowers anyone with the internet to be a highly informed local decision-ma...
Discovery with MPLM

NASA Image and Video Library

2010-04-16

S131-E-010463 (16 April 2010) --- The docked space shuttle Discovery is featured in this image photographed by an STS-131 crew member on the International Space Station. The Leonardo Multi-Purpose Logistics Module is visible in Discovery’s payload bay. Earth’s horizon and the blackness of space provide the backdrop for the scene.
STS-102 crew members check out Discovery's payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

Members of the STS-102 crew check out Discovery's payload bay in the Orbiter Processing Facility bay 1. Dressed in green, they are Mission Specialist Paul W. Richards (left) and Pilot James W. Kelly. The crew is at KSC for Crew Equipment Interface Test activities. Above their heads on the left side are two of the experiments being carried on the flight. STS-102 is the 8th construction flight to the International Space Station and will carry the Multi-Purpose Logistics Module Leonardo. STS-102 is scheduled for launch March 1, 2001. On that flight, Leonardo will be filled with equipment and supplies to outfit the U.S. laboratory module Destiny. The mission will also be carrying the Expedition Two crew to the Space Station, replacing the Expedition One crew who will return on Shuttle Discovery.
STS-42 crewmembers work in the IML-1 module located in OV-103's payload bay

NASA Image and Video Library

1992-01-30

STS042-201-009 (22-30 Jan 1992) --- Canadian Roberta L. Bondar, payload specialist representing the Canadian Space Agency (CSA), works at the International Microgravity Laboratory's (IML-1) biorack while astronaut Stephen S. Oswald, pilot, changes a film magazine on the IMAX camera. The two were joined by five fellow crew members for eight-days of scientific research aboard the Space Shuttle Discovery in Earth-orbit. Most of their on-duty time was spent in this IML-1 Science Module, positioned in the cargo bay and attached via a tunnel to Discovery's airlock.
KSC-08pd1455

NASA Image and Video Library

2008-05-28

CAPE CANAVERAL, Fla. -- After their arrival on the Shuttle Landing Facility at NASA's Kennedy Space Center, the crew members of space shuttle Discovery's STS-124 mission pose for a group photo. From left are Mission Specialists Gregory Chamitoff and Akihiko Hoshide, Pilot Ken Ham, Mission Specialists Karen Nyberg and Mike Fossum, Commander Mark Kelly and Mission Specialist Ron Garan. Launch of Discovery is scheduled for 5:02 p.m. May 31. On the STS-124 mission, the crew of seven will deliver and install the Japanese Experiment Module – Pressurized Module and Japanese Remote Manipulator System. Photo credit: NASA/Kim Shiflett
Switch in Site of Inhibition: A Strategy for Structure-Based Discovery of Human Topoisomerase IIα Catalytic Inhibitors

PubMed Central

2015-01-01

A study of structure-based modulation of known ligands of hTopoIIα, an important enzyme involved in DNA processes, coupled with synthesis and in vitro assays led to the establishment of a strategy of rational switch in mode of inhibition of the enzyme’s catalytic cycle. 6-Arylated derivatives of known imidazopyridine ligands were found to be selective inhibitors of hTopoIIα, while not showing TopoI inhibition and DNA binding. Interestingly, while the parent imidazopyridines acted as ATP-competitive inhibitors, arylated derivatives inhibited DNA cleavage similar to merbarone, indicating a switch in mode of inhibition from ATP-hydrolysis to the DNA-cleavage stage of catalytic cycle of the enzyme. The 6-aryl-imidazopyridines were relatively more cytotoxic than etoposide in cancer cells and less toxic to normal cells. Such unprecedented strategy will encourage research on “choice-based change” in target-specific mode of action for rapid drug discovery. PMID:25941559
An Interactive Medical Knowledge Assistant

NASA Astrophysics Data System (ADS)

Czejdo, Bogdan D.; Baszun, Mikolaj

This paper describes an interactive medical knowledge assistant that can help a doctor or a patient in making important health related decisions. The system is Web based and consists of several modules, including a medical knowledge base, a doctor interface module, patient interface module and a the main module of the medical knowledge assistant. The medical assistant is designed to help interpret the fuzzy data using rough sets approach. The patient interface includes sub-system for real time monitoring of patients' health parameters and sending them to the main module of the medical knowledge assistant.
KSC-06pd0926

NASA Image and Video Library

2006-05-23

KENNEDY SPACE CENTER, FLA. -- From inside the payload changeout room on the rotating service structure on Launch Pad 39B, workers maneuver the multi-purpose logistics module Leonardo into Space Shuttle Discovery's payload bay (at left). The payload ground-handling mechanism (PGHM) is used to transfer the module into the payload bay. Leonardo is a reusable logistics carrier. It is the primary delivery system used to resupply and return station cargo requiring a pressurized environment. Leonardo is part of the payload on mission STS-121. Other payloads include the integrated cargo carrier with the mobile transporter reel assembly and a spare pump module, and the lightweight multi-purpose experiment support structure carrier. Discovery is scheduled to launch in a window extending from July 1 through July 19. Photo credit: NASA/Jack Pfaller
KSC-06pd0925

NASA Image and Video Library

2006-05-23

KENNEDY SPACE CENTER, FLA. -- From inside the payload changeout room on the rotating service structure on Launch Pad 39B, the multi-purpose logistics module Leonardo is being moved into Space Shuttle Discovery's payload bay (at left). The payload ground-handling mechanism (PGHM) is used to transfer the module into the payload bay. Leonardo is a reusable logistics carrier. It is the primary delivery system used to resupply and return station cargo requiring a pressurized environment. Leonardo is part of the payload on mission STS-121. Other payloads include the integrated cargo carrier with the mobile transporter reel assembly and a spare pump module, and the lightweight multi-purpose experiment support structure carrier. Discovery is scheduled to launch in a window extending from July 1 through July 19. Photo credit: NASA/Jack Pfaller
STS-42 MS/PLC Norman E. Thagard adjusts Rack 10 FES equipment in IML-1 module

NASA Image and Video Library

1992-01-30

STS042-05-006 (22-30 Jan 1992) --- Astronaut Norman E. Thagard, payload commander, performs the Fluids Experiment System (FES) in the International Microgravity Laboratory (IML-1) science module. The FES is a NASA-developed facility that produces optical images of fluid flows during the processing of materials in space. The system's sophisticated optics consist of a laser to make holograms of samples and a video camera to record images of flows in and around samples. Thagard was joined by six fellow crewmembers for eight days of scientific research aboard Discovery in Earth-orbit. Most of their on-duty time was spent in this IML-1 science module, positioned in the cargo bay and attached via a tunnel to Discovery's airlock.
Human Development Student Modules.

ERIC Educational Resources Information Center

South Carolina State Dept. of Education, Columbia. Office of Vocational Education.

This set of 61 student learning modules deals with various topics pertaining to human development. The modules, which are designed for use in performance-based vocational education programs, each contain the following components: an introduction for the student, a performance objective, a variety of learning activities, content information, a…
Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery

PubMed Central

Park, Soo-Jin; Im, Dong-Soon

2017-01-01

Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, S1P1–5. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors. Another unexpected finding that fingolimod (FTY720) modulates S1P receptors accelerated drug discovery in this field. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials. In addition, more selective S1P receptor modulators with better pharmacokinetic profiles and fewer side effects are under development. Some of them are being clinically tested in the contexts of multiple sclerosis and other autoimmune and inflammatory disorders, such as, psoriasis, Crohn’s disease, ulcerative colitis, polymyositis, dermatomyositis, liver failure, renal failure, acute stroke, and transplant rejection. In this review, the authors discuss the state of the art regarding the status of drug discovery efforts targeting S1P receptors and place emphasis on potential clinical applications. PMID:28035084
Targeting legume loci: A comparison of three methods for target enrichment bait design in Leguminosae phylogenomics.

PubMed

Vatanparast, Mohammad; Powell, Adrian; Doyle, Jeff J; Egan, Ashley N

2018-03-01

The development of pipelines for locus discovery has spurred the use of target enrichment for plant phylogenomics. However, few studies have compared pipelines from locus discovery and bait design, through validation, to tree inference. We compared three methods within Leguminosae (Fabaceae) and present a workflow for future efforts. Using 30 transcriptomes, we compared Hyb-Seq, MarkerMiner, and the Yang and Smith (Y&S) pipelines for locus discovery, validated 7501 baits targeting 507 loci across 25 genera via Illumina sequencing, and inferred gene and species trees via concatenation- and coalescent-based methods. Hyb-Seq discovered loci with the longest mean length. MarkerMiner discovered the most conserved loci with the least flagged as paralogous. Y&S offered the most parsimony-informative sites and putative orthologs. Target recovery averaged 93% across taxa. We optimized our targeted locus set based on a workflow designed to minimize paralog/ortholog conflation and thus present 423 loci for legume phylogenomics. Methods differed across criteria important for phylogenetic marker development. We recommend Hyb-Seq as a method that may be useful for most phylogenomic projects. Our targeted locus set is a resource for future, community-driven efforts to reconstruct the legume tree of life.
miRegulome: a knowledge-base of miRNA regulomics and analysis.

PubMed

Barh, Debmalya; Kamapantula, Bhanu; Jain, Neha; Nalluri, Joseph; Bhattacharya, Antaripa; Juneja, Lucky; Barve, Neha; Tiwari, Sandeep; Miyoshi, Anderson; Azevedo, Vasco; Blum, Kenneth; Kumar, Anil; Silva, Artur; Ghosh, Preetam

2015-08-05

miRNAs regulate post transcriptional gene expression by targeting multiple mRNAs and hence can modulate multiple signalling pathways, biological processes, and patho-physiologies. Therefore, understanding of miRNA regulatory networks is essential in order to modulate the functions of a miRNA. The focus of several existing databases is to provide information on specific aspects of miRNA regulation. However, an integrated resource on the miRNA regulome is currently not available to facilitate the exploration and understanding of miRNA regulomics. miRegulome attempts to bridge this gap. The current version of miRegulome v1.0 provides details on the entire regulatory modules of miRNAs altered in response to chemical treatments and transcription factors, based on validated data manually curated from published literature. Modules of miRegulome (upstream regulators, downstream targets, miRNA regulated pathways, functions, diseases, etc) are hyperlinked to an appropriate external resource and are displayed visually to provide a comprehensive understanding. Four analysis tools are incorporated to identify relationships among different modules based on user specified datasets. miRegulome and its tools are helpful in understanding the biology of miRNAs and will also facilitate the discovery of biomarkers and therapeutics. With added features in upcoming releases, miRegulome will be an essential resource to the scientific community. http://bnet.egr.vcu.edu/miRegulome.

Assessing differential expression in two-color microarrays: a resampling-based empirical Bayes approach.

PubMed

Li, Dongmei; Le Pape, Marc A; Parikh, Nisha I; Chen, Will X; Dye, Timothy D

2013-01-01

Microarrays are widely used for examining differential gene expression, identifying single nucleotide polymorphisms, and detecting methylation loci. Multiple testing methods in microarray data analysis aim at controlling both Type I and Type II error rates; however, real microarray data do not always fit their distribution assumptions. Smyth's ubiquitous parametric method, for example, inadequately accommodates violations of normality assumptions, resulting in inflated Type I error rates. The Significance Analysis of Microarrays, another widely used microarray data analysis method, is based on a permutation test and is robust to non-normally distributed data; however, the Significance Analysis of Microarrays method fold change criteria are problematic, and can critically alter the conclusion of a study, as a result of compositional changes of the control data set in the analysis. We propose a novel approach, combining resampling with empirical Bayes methods: the Resampling-based empirical Bayes Methods. This approach not only reduces false discovery rates for non-normally distributed microarray data, but it is also impervious to fold change threshold since no control data set selection is needed. Through simulation studies, sensitivities, specificities, total rejections, and false discovery rates are compared across the Smyth's parametric method, the Significance Analysis of Microarrays, and the Resampling-based empirical Bayes Methods. Differences in false discovery rates controls between each approach are illustrated through a preterm delivery methylation study. The results show that the Resampling-based empirical Bayes Methods offer significantly higher specificity and lower false discovery rates compared to Smyth's parametric method when data are not normally distributed. The Resampling-based empirical Bayes Methods also offers higher statistical power than the Significance Analysis of Microarrays method when the proportion of significantly differentially expressed genes is large for both normally and non-normally distributed data. Finally, the Resampling-based empirical Bayes Methods are generalizable to next generation sequencing RNA-seq data analysis.
Global integrated drought monitoring and prediction system

PubMed Central

Hao, Zengchao; AghaKouchak, Amir; Nakhjiri, Navid; Farahmand, Alireza

2014-01-01

Drought is by far the most costly natural disaster that can lead to widespread impacts, including water and food crises. Here we present data sets available from the Global Integrated Drought Monitoring and Prediction System (GIDMaPS), which provides drought information based on multiple drought indicators. The system provides meteorological and agricultural drought information based on multiple satellite-, and model-based precipitation and soil moisture data sets. GIDMaPS includes a near real-time monitoring component and a seasonal probabilistic prediction module. The data sets include historical drought severity data from the monitoring component, and probabilistic seasonal forecasts from the prediction module. The probabilistic forecasts provide essential information for early warning, taking preventive measures, and planning mitigation strategies. GIDMaPS data sets are a significant extension to current capabilities and data sets for global drought assessment and early warning. The presented data sets would be instrumental in reducing drought impacts especially in developing countries. Our results indicate that GIDMaPS data sets reliably captured several major droughts from across the globe. PMID:25977759
Global integrated drought monitoring and prediction system.

PubMed

Hao, Zengchao; AghaKouchak, Amir; Nakhjiri, Navid; Farahmand, Alireza

2014-01-01

Drought is by far the most costly natural disaster that can lead to widespread impacts, including water and food crises. Here we present data sets available from the Global Integrated Drought Monitoring and Prediction System (GIDMaPS), which provides drought information based on multiple drought indicators. The system provides meteorological and agricultural drought information based on multiple satellite-, and model-based precipitation and soil moisture data sets. GIDMaPS includes a near real-time monitoring component and a seasonal probabilistic prediction module. The data sets include historical drought severity data from the monitoring component, and probabilistic seasonal forecasts from the prediction module. The probabilistic forecasts provide essential information for early warning, taking preventive measures, and planning mitigation strategies. GIDMaPS data sets are a significant extension to current capabilities and data sets for global drought assessment and early warning. The presented data sets would be instrumental in reducing drought impacts especially in developing countries. Our results indicate that GIDMaPS data sets reliably captured several major droughts from across the globe.
4 CFR 28.43 - Compelling discovery.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 4 Accounts 1 2011-01-01 2011-01-01 false Compelling discovery. 28.43 Section 28.43 Accounts... Procedures Discovery § 28.43 Compelling discovery. (a) Motion for an order compelling discovery. Motions for orders compelling discovery shall be submitted to the administrative judge as set forth at § 28.42(c)(2...
Rational selection of structurally diverse natural product scaffolds with favorable ADME properties for drug discovery.

PubMed

Samiulla, D S; Vaidyanathan, V V; Arun, P C; Balan, G; Blaze, M; Bondre, S; Chandrasekhar, G; Gadakh, A; Kumar, R; Kharvi, G; Kim, H O; Kumar, S; Malikayil, J A; Moger, M; Mone, M K; Nagarjuna, P; Ogbu, C; Pendhalkar, D; Rao, A V S Raja; Rao, G Venkateshwar; Sarma, V K; Shaik, S; Sharma, G V R; Singh, S; Sreedhar, C; Sonawane, R; Timmanna, U; Hardy, L W

2005-01-01

Natural product analogs are significant sources for therapeutic agents. To capitalize efficiently on the effective features of naturally occurring substances, a natural product-based library production platform has been devised at Aurigene for drug lead discovery. This approach combines the attractive biological and physicochemical properties of natural product scaffolds, provided by eons of natural selection, with the chemical diversity available from parallel synthetic methods. Virtual property analysis, using computational methods described here, guides the selection of a set of natural product scaffolds that are both structurally diverse and likely to have favorable pharmacokinetic properties. The experimental characterization of several in vitro ADME properties of twenty of these scaffolds, and of a small set of designed congeners based upon one scaffold, is also described. These data confirm that most of the scaffolds and the designed library members have properties favorable to their utilization for creating libraries of lead-like molecules.
Chronicles in drug discovery.

PubMed

Davies, Shelley L; Ferrer, Elisa; Moral, Maria Angels

2006-06-01

Chronicles in Drug Discovery features special interest reports on advances in drug discovery. This month we highlight new options to prevent oral mucositis, a treatment-limiting adverse effect of chemotherapy. Studies are currently focusing on mechanism-based therapies to prevent or repair DNA damage to epithelial and submucosal cells and the cascade or events that follow to cause tissue damage or analgesics to ease the associated oral cavity pain. Therapeutic limitations also exist for the use of the highly effective antibiotic gentamicin, as it evokes acute renal failure. Mechanistic investigations have shed some light on potential targets: the kallikreins, peroxynitrite-related pathways, superoxide production and the accumulation of aminoglycosides. New antibiotic strategies for trachoma, the leading cause of preventable blindness, are also explored along with studies to aid the development of vaccine candidates. Finally, we discuss the utility of allosteric-potentiating ligands to modulate nicotinic acetylcholine receptors, mimicking the reward/addictive effects of nicotine, as potential strategies for smoking cessation. (c) 2006 Prous Science. All rights reserved.
Worming our way to novel drug discovery with the Caenorhabditis elegans proteostasis network, stress response and insulin-signaling pathways.

PubMed

O'Reilly, Linda P; Benson, Joshua A; Cummings, Erin E; Perlmutter, David H; Silverman, Gary A; Pak, Stephen C

2014-09-01

Many human diseases result from a failure of a single protein to achieve the correct folding and tertiary conformation. These so-called 'conformational diseases' involve diverse proteins and distinctive cellular pathologies. They all engage the proteostasis network (PN), to varying degrees in an attempt to mange cellular stress and restore protein homeostasis. The insulin/insulin-like growth factor signaling (IIS) pathway is a master regulator of cellular stress response, which is implicated in regulating components of the PN. This review focuses on novel approaches to target conformational diseases. The authors discuss the evidence supporting the involvement of the IIS pathway in modulating the PN and regulating proteostasis in Caenorhabditis elegans. Furthermore, they review previous PN and IIS drug screens and explore the possibility of using C. elegans for whole organism-based drug discovery for modulators of IIS-proteostasis pathways. An alternative approach to develop individualized therapy for each conformational disease is to modulate the global PN. The involvement of the IIS pathway in regulating longevity and response to a variety of stresses is well documented. Increasing data now provide evidence for the close association between the IIS and the PN pathways. The authors believe that high-throughput screening campaigns, which target the C. elegans IIS pathway, may identify drugs that are efficacious in treating numerous conformational diseases.
Discovery and Annotation of Plant Endogenous Target Mimicry Sequences from Public Transcriptome Libraries: A Case Study of Prunus persica.

PubMed

Karakülah, Gökhan

2017-06-28

Novel transcript discovery through RNA sequencing has substantially improved our understanding of the transcriptome dynamics of biological systems. Endogenous target mimicry (eTM) transcripts, a novel class of regulatory molecules, bind to their target microRNAs (miRNAs) by base pairing and block their biological activity. The objective of this study was to provide a computational analysis framework for the prediction of putative eTM sequences in plants, and as an example, to discover previously un-annotated eTMs in Prunus persica (peach) transcriptome. Therefore, two public peach transcriptome libraries downloaded from Sequence Read Archive (SRA) and a previously published set of long non-coding RNAs (lncRNAs) were investigated with multi-step analysis pipeline, and 44 putative eTMs were found. Additionally, an eTM-miRNA-mRNA regulatory network module associated with peach fruit organ development was built via integration of the miRNA target information and predicted eTM-miRNA interactions. My findings suggest that one of the most widely expressed miRNA families among diverse plant species, miR156, might be potentially sponged by seven putative eTMs. Besides, the study indicates eTMs potentially play roles in the regulation of development processes in peach fruit via targeting specific miRNAs. In conclusion, by following the step-by step instructions provided in this study, novel eTMs can be identified and annotated effectively in public plant transcriptome libraries.
Assessing Robustness Properties in Dynamic Discovery of Ad Hoc Network Services (Briefing Charts)

DTIC Science & Technology

2001-10-04

JINI entities in directed -- discovery mode. It is part of the SCM_Discovery -- Module. Sends Unicast messages to SCMs on list of -- SCMS to be...discovered until all SCMS are found. -- Receives updates from SCM DB of discovered SCMs and -- removes SCMs accordingly -- NOTE: Failure and...For All (SM, SD, SCM ): (SM, SD) IsElementOf SCM registered-services (CC1) implies SCM IsElementOf SM discovered- SCMs For All
Hoshide in sleeping bag in JEM module

NASA Image and Video Library

2008-06-09

S124-E-007983 (9 June 2008) --- Japan Aerospace Exploration Agency astronaut Akihiko Hoshide, STS-124 mission specialist, is pictured in his sleeping bag in Kibo Japanese Pressurized Module of the International Space Station while Space Shuttle Discovery is docked with the station.
Project COLD.

ERIC Educational Resources Information Center

Kazanjian, Wendy C.

1982-01-01

Describes Project COLD (Climate, Ocean, Land, Discovery) a scientific study of the Polar Regions, a collection of 35 modules used within the framework of existing subjects: oceanography, biology, geology, meterology, geography, social science. Includes a partial list of topics and one activity (geodesic dome) from a module. (Author/SK)
Evidence-Based Diagnostic Algorithm for Glioma: Analysis of the Results of Pathology Panel Review and Molecular Parameters of EORTC 26951 and 26882 Trials.

PubMed

Kros, Johan M; Huizer, Karin; Hernández-Laín, Aurelio; Marucci, Gianluca; Michotte, Alex; Pollo, Bianca; Rushing, Elisabeth J; Ribalta, Teresa; French, Pim; Jaminé, David; Bekka, Nawal; Lacombe, Denis; van den Bent, Martin J; Gorlia, Thierry

2015-06-10

With the rapid discovery of prognostic and predictive molecular parameters for glioma, the status of histopathology in the diagnostic process should be scrutinized. Our project aimed to construct a diagnostic algorithm for gliomas based on molecular and histologic parameters with independent prognostic values. The pathology slides of 636 patients with gliomas who had been included in EORTC 26951 and 26882 trials were reviewed using virtual microscopy by a panel of six neuropathologists who independently scored 18 histologic features and provided an overall diagnosis. The molecular data for IDH1, 1p/19q loss, EGFR amplification, loss of chromosome 10 and chromosome arm 10q, gain of chromosome 7, and hypermethylation of the promoter of MGMT were available for some of the cases. The slides were divided in discovery (n = 426) and validation sets (n = 210). The diagnostic algorithm resulting from analysis of the discovery set was validated in the latter. In 66% of cases, consensus of overall diagnosis was present. A diagnostic algorithm consisting of two molecular markers and one consensus histologic feature was created by conditional inference tree analysis. The order of prognostic significance was: 1p/19q loss, EGFR amplification, and astrocytic morphology, which resulted in the identification of four diagnostic nodes. Validation of the nodes in the validation set confirmed the prognostic value (P < .001). We succeeded in the creation of a timely diagnostic algorithm for anaplastic glioma based on multivariable analysis of consensus histopathology and molecular parameters. © 2015 by American Society of Clinical Oncology.
STS-102 MPLM Leonardo is transferred from the PCR into Discovery's payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. - In the Payload Changeout Room, Launch Pad 39B, the Multi-Purpose Logistics Module Leonardo is ready to be transferred into Space Shuttle Discovery'''s payload bay. Discovery is scheduled to launch March 8 at 6:42 a.m. EST on mission STS-102, the eighth construction flight to the International Space Station. The primary delivery system used to resupply and return Station cargo requiring a pressurized environment, Leonardo will deliver up to 10 tons of laboratory racks filled with equipment, experiments and supplies for outfitting the newly installed U.S. Laboratory Destiny.
Computational modeling-based discovery of novel classes of anti-inflammatory drugs that target lanthionine synthetase C-like protein 2.

PubMed

Lu, Pinyi; Hontecillas, Raquel; Horne, William T; Carbo, Adria; Viladomiu, Monica; Pedragosa, Mireia; Bevan, David R; Lewis, Stephanie N; Bassaganya-Riera, Josep

2012-01-01

Lanthionine synthetase component C-like protein 2 (LANCL2) is a member of the eukaryotic lanthionine synthetase component C-Like protein family involved in signal transduction and insulin sensitization. Recently, LANCL2 is a target for the binding and signaling of abscisic acid (ABA), a plant hormone with anti-diabetic and anti-inflammatory effects. The goal of this study was to determine the role of LANCL2 as a potential therapeutic target for developing novel drugs and nutraceuticals against inflammatory diseases. Previously, we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of lanthionine synthetase component C-like protein 1 (LANCL1) as a template. Using this model, structure-based virtual screening was performed using compounds from NCI (National Cancer Institute) Diversity Set II, ChemBridge, ZINC natural products, and FDA-approved drugs databases. Several potential ligands were identified using molecular docking. In order to validate the anti-inflammatory efficacy of the top ranked compound (NSC61610) in the NCI Diversity Set II, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Our findings showed that the lead compound, NSC61610, activated peroxisome proliferator-activated receptor gamma in a LANCL2- and adenylate cyclase/cAMP dependent manner in vitro and ameliorated experimental colitis by down-modulating colonic inflammatory gene expression and favoring regulatory T cell responses. LANCL2 is a novel therapeutic target for inflammatory diseases. High-throughput, structure-based virtual screening is an effective computational-based drug design method for discovering anti-inflammatory LANCL2-based drug candidates.
Computational Modeling-Based Discovery of Novel Classes of Anti-Inflammatory Drugs That Target Lanthionine Synthetase C-Like Protein 2

PubMed Central

Lu, Pinyi; Hontecillas, Raquel; Horne, William T.; Carbo, Adria; Viladomiu, Monica; Pedragosa, Mireia; Bevan, David R.; Lewis, Stephanie N.; Bassaganya-Riera, Josep

2012-01-01

Background Lanthionine synthetase component C-like protein 2 (LANCL2) is a member of the eukaryotic lanthionine synthetase component C-Like protein family involved in signal transduction and insulin sensitization. Recently, LANCL2 is a target for the binding and signaling of abscisic acid (ABA), a plant hormone with anti-diabetic and anti-inflammatory effects. Methodology/Principal Findings The goal of this study was to determine the role of LANCL2 as a potential therapeutic target for developing novel drugs and nutraceuticals against inflammatory diseases. Previously, we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of lanthionine synthetase component C-like protein 1 (LANCL1) as a template. Using this model, structure-based virtual screening was performed using compounds from NCI (National Cancer Institute) Diversity Set II, ChemBridge, ZINC natural products, and FDA-approved drugs databases. Several potential ligands were identified using molecular docking. In order to validate the anti-inflammatory efficacy of the top ranked compound (NSC61610) in the NCI Diversity Set II, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Our findings showed that the lead compound, NSC61610, activated peroxisome proliferator-activated receptor gamma in a LANCL2- and adenylate cyclase/cAMP dependent manner in vitro and ameliorated experimental colitis by down-modulating colonic inflammatory gene expression and favoring regulatory T cell responses. Conclusions/Significance LANCL2 is a novel therapeutic target for inflammatory diseases. High-throughput, structure-based virtual screening is an effective computational-based drug design method for discovering anti-inflammatory LANCL2-based drug candidates. PMID:22509338
Myocardial Injury Is Distinguished from Stable Angina by a Set of Candidate Plasma Biomarkers Identified Using iTRAQ/MRM-Based Approach.

PubMed

Cheow, Esther Sok Hwee; Cheng, Woo Chin; Yap, Terence; Dutta, Bamaprasad; Lee, Chuen Neng; Kleijn, Dominique P V de; Sorokin, Vitaly; Sze, Siu Kwan

2018-01-05

The lack of precise biomarkers that identify patients at risk for myocardial injury and stable angina delays administration of optimal therapy. Hence, the search for noninvasive biomarkers that could accurately stratify patients with impending heart attack, from patients with stable coronary artery disease (CAD), is urgently needed in the clinic. Herein, we performed comparative quantitative proteomics on whole plasma sampled from patients with stable angina (NMI), acute myocardial infarction (MI), and healthy control subjects (Ctrl). We detected a total of 371 proteins with high confidence (FDR < 1%, p < 0.05) including 53 preliminary biomarkers that displayed ≥2-fold modulated expression in patients with CAD (27 associated with atherosclerotic stable angina, 26 with myocardial injury). In the verification phase, we used label-free LC-MRM-MS-based targeted method to verify the preliminary biomarkers in pooled plasma, excluded peptides that were poorly distinguished from background, and performed further validation of the remaining candidates in 49 individual plasma samples. Using this approach, we identified a final panel of eight novel candidate biomarkers that were significantly modulated in CAD (p < 0.05) including proteins associated with atherosclerotic stable angina that were implicated in endothelial dysfunction (F10 and MST1), proteins associated with myocardial injury reportedly involved in plaque destabilization (SERPINA3, CPN2, LUM), and in tissue protection/repair mechanisms (ORM2, ACTG1, NAGLU). Taken together, our data showed that candidate biomarkers with potential diagnostic values can be successfully detected in nondepleted human plasma using an iTRAQ/MRM-based discovery-validation approach and demonstrated the plausible clinical utility of the proposed panel in discriminating atherosclerotic stable angina from myocardial injury in the studied cohort.
Natural science modules with SETS approach to improve students’ critical thinking ability

NASA Astrophysics Data System (ADS)

Budi, A. P. S.; Sunarno, W.; Sugiyarto

2018-05-01

SETS (Science, Environment, Technology and Society) approach for learning is important to be developed for middle school, since it can improve students’ critical thinking ability. This research aimed to determine feasibility and the effectiveness of Natural Science Module with SETS approach to increase their critical thinking ability. The module development was done by invitation, exploration, explanation, concept fortifying, and assessment. Questionnaire and test performed including pretest and posttest with control group design were used as data collection technique in this research. Two classes were selected randomly as samples and consisted of 32 students in each group. Descriptive data analysis was used to analyze the module feasibility and t-test was used to analyze their critical thinking ability. The results showed that the feasibility of the module development has a very good results based on assessment of the experts, practitioners and peers. Based on the t-test results, there was significant difference between control class and experiment class (0.004), with n-gain score of control and the experiment class respectively 0.270 (low) and 0.470 (medium). It showed that the module was more effective than the textbook. It was able to improve students’ critical thinking ability and appropriate to be used in learning process.
Counting of oligomers in sequences generated by markov chains for DNA motif discovery.

PubMed

Shan, Gao; Zheng, Wei-Mou

2009-02-01

By means of the technique of the imbedded Markov chain, an efficient algorithm is proposed to exactly calculate first, second moments of word counts and the probability for a word to occur at least once in random texts generated by a Markov chain. A generating function is introduced directly from the imbedded Markov chain to derive asymptotic approximations for the problem. Two Z-scores, one based on the number of sequences with hits and the other on the total number of word hits in a set of sequences, are examined for discovery of motifs on a set of promoter sequences extracted from A. thaliana genome. Source code is available at http://www.itp.ac.cn/zheng/oligo.c.
Pharmacokinetic de-risking tools for selection of monoclonal antibody lead candidates

PubMed Central

Dostalek, Miroslav; Prueksaritanont, Thomayant; Kelley, Robert F.

2017-01-01

ABSTRACT Pharmacokinetic studies play an important role in all stages of drug discovery and development. Recent advancements in the tools for discovery and optimization of therapeutic proteins have created an abundance of candidates that may fulfill target product profile criteria. Implementing a set of in silico, small scale in vitro and in vivo tools can help to identify a clinical lead molecule with promising properties at the early stages of drug discovery, thus reducing the labor and cost in advancing multiple candidates toward clinical development. In this review, we describe tools that should be considered during drug discovery, and discuss approaches that could be included in the pharmacokinetic screening part of the lead candidate generation process to de-risk unexpected pharmacokinetic behaviors of Fc-based therapeutic proteins, with an emphasis on monoclonal antibodies. PMID:28463063
Knowledge discovery with classification rules in a cardiovascular dataset.

PubMed

Podgorelec, Vili; Kokol, Peter; Stiglic, Milojka Molan; Hericko, Marjan; Rozman, Ivan

2005-12-01

In this paper we study an evolutionary machine learning approach to data mining and knowledge discovery based on the induction of classification rules. A method for automatic rules induction called AREX using evolutionary induction of decision trees and automatic programming is introduced. The proposed algorithm is applied to a cardiovascular dataset consisting of different groups of attributes which should possibly reveal the presence of some specific cardiovascular problems in young patients. A case study is presented that shows the use of AREX for the classification of patients and for discovering possible new medical knowledge from the dataset. The defined knowledge discovery loop comprises a medical expert's assessment of induced rules to drive the evolution of rule sets towards more appropriate solutions. The final result is the discovery of a possible new medical knowledge in the field of pediatric cardiology.

Sordaria, a model system to uncover links between meiotic pairing and recombination

PubMed Central

Zickler, Denise; Espagne, Eric

2017-01-01

The mycelial fungus Sordaria macrospora was first used as experimental system for meiotic recombination. This review shows that it provides also a powerful cytological system for dissecting chromosome dynamics in wild-type and mutant meioses. Fundamental cytogenetic findings include: (1) The identification of presynaptic alignment as a key step in pairing of homologous chromosomes. (2) The discovery that biochemical complexes that mediate recombination at the DNA level concomitantly mediate pairing of homologs. (3) This pairing process involves not only resolution but also avoidance of chromosomal entanglements and the resolution system includes dissolution of constraining DNA recombination interactions, achieved by a unique role of Mlh1. (4) Discovery that the central components of the synaptonemal complex directly mediate the re-localization of the recombination proteins from on-axis to in-between homologue axis positions. (5) Identification of putative STUbL protein Hei10 as a structure-based signal transduction molecule that coordinates progression and differentiation of recombinational interactions at multiple stages. (6) Discovery that a single interference process mediates both nucleation of the SC and designation of crossover sites, thereby ensuring even spacing of both features. (7) Discovery of local modulation of sister-chromatid cohesion at sites of crossover recombination. PMID:26877138
Boosting standard order sets utilization through clinical decision support.

PubMed

Li, Haomin; Zhang, Yinsheng; Cheng, Haixia; Lu, Xudong; Duan, Huilong

2013-01-01

Well-designed standard order sets have the potential to integrate and coordinate care by communicating best practices through multiple disciplines, levels of care, and services. However, there are several challenges which certainly affected the benefits expected from standard order sets. To boost standard order sets utilization, a problem-oriented knowledge delivery solution was proposed in this study to facilitate access of standard order sets and evaluation of its treatment effect. In this solution, standard order sets were created along with diagnostic rule sets which can trigger a CDS-based reminder to help clinician quickly discovery hidden clinical problems and corresponding standard order sets during ordering. Those rule set also provide indicators for targeted evaluation of standard order sets during treatment. A prototype system was developed based on this solution and will be presented at Medinfo 2013.
RNA 3D Modules in Genome-Wide Predictions of RNA 2D Structure

PubMed Central

Theis, Corinna; Zirbel, Craig L.; zu Siederdissen, Christian Höner; Anthon, Christian; Hofacker, Ivo L.; Nielsen, Henrik; Gorodkin, Jan

2015-01-01

Recent experimental and computational progress has revealed a large potential for RNA structure in the genome. This has been driven by computational strategies that exploit multiple genomes of related organisms to identify common sequences and secondary structures. However, these computational approaches have two main challenges: they are computationally expensive and they have a relatively high false discovery rate (FDR). Simultaneously, RNA 3D structure analysis has revealed modules composed of non-canonical base pairs which occur in non-homologous positions, apparently by independent evolution. These modules can, for example, occur inside structural elements which in RNA 2D predictions appear as internal loops. Hence one question is if the use of such RNA 3D information can improve the prediction accuracy of RNA secondary structure at a genome-wide level. Here, we use RNAz in combination with 3D module prediction tools and apply them on a 13-way vertebrate sequence-based alignment. We find that RNA 3D modules predicted by metaRNAmodules and JAR3D are significantly enriched in the screened windows compared to their shuffled counterparts. The initially estimated FDR of 47.0% is lowered to below 25% when certain 3D module predictions are present in the window of the 2D prediction. We discuss the implications and prospects for further development of computational strategies for detection of RNA 2D structure in genomic sequence. PMID:26509713
Hybrid coexpression link similarity graph clustering for mining biological modules from multiple gene expression datasets

PubMed Central

2014-01-01

Background Advances in genomic technologies have enabled the accumulation of vast amount of genomic data, including gene expression data for multiple species under various biological and environmental conditions. Integration of these gene expression datasets is a promising strategy to alleviate the challenges of protein functional annotation and biological module discovery based on a single gene expression data, which suffers from spurious coexpression. Results We propose a joint mining algorithm that constructs a weighted hybrid similarity graph whose nodes are the coexpression links. The weight of an edge between two coexpression links in this hybrid graph is a linear combination of the topological similarities and co-appearance similarities of the corresponding two coexpression links. Clustering the weighted hybrid similarity graph yields recurrent coexpression link clusters (modules). Experimental results on Human gene expression datasets show that the reported modules are functionally homogeneous as evident by their enrichment with biological process GO terms and KEGG pathways. PMID:25221624
Integration of Chinese medicine with Western medicine could lead to future medicine: molecular module medicine.

PubMed

Zhang, Chi; Zhang, Ge; Chen, Ke-ji; Lu, Ai-ping

2016-04-01

The development of an effective classification method for human health conditions is essential for precise diagnosis and delivery of tailored therapy to individuals. Contemporary classification of disease systems has properties that limit its information content and usability. Chinese medicine pattern classification has been incorporated with disease classification, and this integrated classification method became more precise because of the increased understanding of the molecular mechanisms. However, we are still facing the complexity of diseases and patterns in the classification of health conditions. With continuing advances in omics methodologies and instrumentation, we are proposing a new classification approach: molecular module classification, which is applying molecular modules to classifying human health status. The initiative would be precisely defining the health status, providing accurate diagnoses, optimizing the therapeutics and improving new drug discovery strategy. Therefore, there would be no current disease diagnosis, no disease pattern classification, and in the future, a new medicine based on this classification, molecular module medicine, could redefine health statuses and reshape the clinical practice.
Technology for the Organic Chemist: Three Exploratory Modules

ERIC Educational Resources Information Center

Esteb, John J.; McNulty, LuAnne M.; Magers, John; Morgan, Paul; Wilson, Anne M.

2010-01-01

The ability to use computer-based technology is an essential skill set for students majoring in chemistry. This exercise details the introduction of appropriate uses for this technology in the organic chemistry series. The incorporation of chemically appropriate online resources (module 1), scientific databases (module 2), and the use of a…
Mathematics for Drafting.

ERIC Educational Resources Information Center

Clary, Joseph R.; Nery, Karen P.

This set of three modules was designed for use primarily to help teach and reinforce the basic mathematics skills in drafting classes. The modules are based on the needs of drafting students in beginning courses as determined by a survey of teachers across North Carolina. Each module consists of basic information and examples and problem sheets…
Mathematics for Electronics.

ERIC Educational Resources Information Center

Clary, Joseph R.; Nery, Karen P.

This set of 20 modules was designed for use primarily to help teach and reinforce the basic mathematics skills in electronics classes. The modules are based on electronics competencies that require mathematics skills, as determined by a panel of high school electronics and mathematics teachers. Each module consists of one or two pages of basic…
Interferometric phase locking of two electronic oscillators with a cascade electro-optic modulator

NASA Astrophysics Data System (ADS)

Chao, C. H.; Chien, P. Y.; Chang, L. W.; Juang, F. Y.; Hsia, C. H.; Chang, C. C.

1993-01-01

An optical-type electrical phase-locked-loop system based on a cascade electro-optic modulator has been demonstrated. By using this technique, a set of optical-type phase detectors, operating at any harmonic frequencies of two applied phase-modulation signals, has been implemented.
Southeast Asian Career Exploration Program.

ERIC Educational Resources Information Center

Podolske, Mel

This set of competency-based learning modules consists of four career exploration modules and three science modules for use with adults with limited English proficiency. The four career exploration models contain activities designed to introduce students to career opportunities and basic job skills and safety procedures in the following fields:…
STS-96 FD Highlights and Crew Activities Report: Flight Day 06

NASA Technical Reports Server (NTRS)

1999-01-01

On this sixth day of the STS-96 Discovery mission, the flight crew, Commander Kent V. Rominger, Pilot Rick D. Husband, and Mission Specialists Ellen Ochoa, Tamara E. Jernigan, Daniel T. Barry, Julie Payette, and Valery Ivanovich Tokarev are seen performing logistics transfer activities within the Discovery/International Space Station orbiting complex. Ochoa, Jernigan, Husband and Barry devote a significant part of their day to the transfer of bags of different sizes and shapes from the SPACEHAB module in Discovery's cargo bay to resting places inside the International Space Station. Payette and Tokarev complete the maintenance on the storage batteries. Barry and Tokarev complete installation of the remaining sound mufflers over the fans in Zarya. Barry then measures the sound levels at different positions inside the module. Rominger and Tokarev conduct a news conference with Russian reporters from the Mission Control Center in Moscow.
Early Probe and Drug Discovery in Academia: A Minireview.

PubMed

Roy, Anuradha

2018-02-09

Drug discovery encompasses processes ranging from target selection and validation to the selection of a development candidate. While comprehensive drug discovery work flows are implemented predominantly in the big pharma domain, early discovery focus in academia serves to identify probe molecules that can serve as tools to study targets or pathways. Despite differences in the ultimate goals of the private and academic sectors, the same basic principles define the best practices in early discovery research. A successful early discovery program is built on strong target definition and validation using a diverse set of biochemical and cell-based assays with functional relevance to the biological system being studied. The chemicals identified as hits undergo extensive scaffold optimization and are characterized for their target specificity and off-target effects in in vitro and in animal models. While the active compounds from screening campaigns pass through highly stringent chemical and Absorption, Distribution, Metabolism, and Excretion (ADME) filters for lead identification, the probe discovery involves limited medicinal chemistry optimization. The goal of probe discovery is identification of a compound with sub-µM activity and reasonable selectivity in the context of the target being studied. The compounds identified from probe discovery can also serve as starting scaffolds for lead optimization studies.
Bandwidth tunable microwave photonic filter based on digital and analog modulation

NASA Astrophysics Data System (ADS)

Zhang, Qi; Zhang, Jie; Li, Qiang; Wang, Yubing; Sun, Xian; Dong, Wei; Zhang, Xindong

2018-05-01

A bandwidth tunable microwave photonic filter based on digital and analog modulation is proposed and experimentally demonstrated. The digital modulation is used to broaden the effective gain spectrum and the analog modulation is to get optical lines. By changing the symbol rate of data pattern, the bandwidth is tunable from 50 MHz to 700 MHz. The interval of optical lines is set according to the bandwidth of gain spectrum which is related to the symbol rate. Several times of bandwidth increase are achieved compared to a single analog modulation and the selectivity of the response is increased by 3.7 dB compared to a single digital modulation.
Emerging concepts in smooth muscle contributions to airway structure and function: implications for health and disease

PubMed Central

2016-01-01

Airway structure and function are key aspects of normal lung development, growth, and aging, as well as of lung responses to the environment and the pathophysiology of important diseases such as asthma, chronic obstructive pulmonary disease, and fibrosis. In this regard, the contributions of airway smooth muscle (ASM) are both functional, in the context of airway contractility and relaxation, as well as synthetic, involving production and modulation of extracellular components, modulation of the local immune environment, cellular contribution to airway structure, and, finally, interactions with other airway cell types such as epithelium, fibroblasts, and nerves. These ASM contributions are now found to be critical in airway hyperresponsiveness and remodeling that occur in lung diseases. This review emphasizes established and recent discoveries that underline the central role of ASM and sets the stage for future research toward understanding how ASM plays a central role by being both upstream and downstream in the many interactive processes that determine airway structure and function in health and disease. PMID:27742732
Evaluation method for the potential functionome harbored in the genome and metagenome.

PubMed

Takami, Hideto; Taniguchi, Takeaki; Moriya, Yuki; Kuwahara, Tomomi; Kanehisa, Minoru; Goto, Susumu

2012-12-12

One of the main goals of genomic analysis is to elucidate the comprehensive functions (functionome) in individual organisms or a whole community in various environments. However, a standard evaluation method for discerning the functional potentials harbored within the genome or metagenome has not yet been established. We have developed a new evaluation method for the potential functionome, based on the completion ratio of Kyoto Encyclopedia of Genes and Genomes (KEGG) functional modules. Distribution of the completion ratio of the KEGG functional modules in 768 prokaryotic species varied greatly with the kind of module, and all modules primarily fell into 4 patterns (universal, restricted, diversified and non-prokaryotic modules), indicating the universal and unique nature of each module, and also the versatility of the KEGG Orthology (KO) identifiers mapped to each one. The module completion ratio in 8 phenotypically different bacilli revealed that some modules were shared only in phenotypically similar species. Metagenomes of human gut microbiomes from 13 healthy individuals previously determined by the Sanger method were analyzed based on the module completion ratio. Results led to new discoveries in the nutritional preferences of gut microbes, believed to be one of the mutualistic representations of gut microbiomes to avoid nutritional competition with the host. The method developed in this study could characterize the functionome harbored in genomes and metagenomes. As this method also provided taxonomical information from KEGG modules as well as the gene hosts constructing the modules, interpretation of completion profiles was simplified and we could identify the complementarity between biochemical functions in human hosts and the nutritional preferences in human gut microbiomes. Thus, our method has the potential to be a powerful tool for comparative functional analysis in genomics and metagenomics, able to target unknown environments containing various uncultivable microbes within unidentified phyla.
Increasing the space-time product of super-resolution structured illumination microscopy by means of two-pattern illumination

NASA Astrophysics Data System (ADS)

Inochkin, F. M.; Pozzi, P.; Bezzubik, V. V.; Belashenkov, N. R.

2017-06-01

Superresolution image reconstruction method based on the structured illumination microscopy (SIM) principle with reduced and simplified pattern set is presented. The method described needs only 2 sinusoidal patterns shifted by half a period for each spatial direction of reconstruction, instead of the minimum of 3 for the previously known methods. The method is based on estimating redundant frequency components in the acquired set of modulated images. Digital processing is based on linear operations. When applied to several spatial orientations, the image set can be further reduced to a single pattern for each spatial orientation, complemented by a single non-modulated image for all the orientations. By utilizing this method for the case of two spatial orientations, the total input image set is reduced up to 3 images, providing up to 2-fold improvement in data acquisition time compared to the conventional 3-pattern SIM method. Using the simplified pattern design, the field of view can be doubled with the same number of spatial light modulator raster elements, resulting in a total 4-fold increase in the space-time product. The method requires precise knowledge of the optical transfer function (OTF). The key limitation is the thickness of object layer that scatters or emits light, which requires to be sufficiently small relatively to the lens depth of field. Numerical simulations and experimental results are presented. Experimental results are obtained on the SIM setup with the spatial light modulator based on the 1920x1080 digital micromirror device.
Differential network analysis reveals the genome-wide landscape of estrogen receptor modulation in hormonal cancers

PubMed Central

Hsiao, Tzu-Hung; Chiu, Yu-Chiao; Hsu, Pei-Yin; Lu, Tzu-Pin; Lai, Liang-Chuan; Tsai, Mong-Hsun; Huang, Tim H.-M.; Chuang, Eric Y.; Chen, Yidong

2016-01-01

Several mutual information (MI)-based algorithms have been developed to identify dynamic gene-gene and function-function interactions governed by key modulators (genes, proteins, etc.). Due to intensive computation, however, these methods rely heavily on prior knowledge and are limited in genome-wide analysis. We present the modulated gene/gene set interaction (MAGIC) analysis to systematically identify genome-wide modulation of interaction networks. Based on a novel statistical test employing conjugate Fisher transformations of correlation coefficients, MAGIC features fast computation and adaption to variations of clinical cohorts. In simulated datasets MAGIC achieved greatly improved computation efficiency and overall superior performance than the MI-based method. We applied MAGIC to construct the estrogen receptor (ER) modulated gene and gene set (representing biological function) interaction networks in breast cancer. Several novel interaction hubs and functional interactions were discovered. ER+ dependent interaction between TGFβ and NFκB was further shown to be associated with patient survival. The findings were verified in independent datasets. Using MAGIC, we also assessed the essential roles of ER modulation in another hormonal cancer, ovarian cancer. Overall, MAGIC is a systematic framework for comprehensively identifying and constructing the modulated interaction networks in a whole-genome landscape. MATLAB implementation of MAGIC is available for academic uses at https://github.com/chiuyc/MAGIC. PMID:26972162
Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides.

PubMed

Tarr, James C; Wood, Michael R; Noetzel, Meredith J; Bertron, Jeanette L; Weiner, Rebecca L; Rodriguez, Alice L; Lamsal, Atin; Byers, Frank W; Chang, Sichen; Cho, Hyekyung P; Jones, Carrie K; Niswender, Colleen M; Wood, Michael W; Brandon, Nicholas J; Duggan, Mark E; Conn, P Jeffrey; Bridges, Thomas M; Lindsley, Craig W

2017-07-01

This letter details the continued chemical optimization of a novel series of M 4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M 4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3mg/kg. Copyright © 2017 Elsevier Ltd. All rights reserved.
Modulation of the Endocannabinoid System: Vulnerability Factor and New Treatment Target for Stimulant Addiction

PubMed Central

Olière, Stéphanie; Jolette-Riopel, Antoine; Potvin, Stéphane; Jutras-Aswad, Didier

2013-01-01

Cannabis is one of the most widely used illicit substance among users of stimulants such as cocaine and amphetamines. Interestingly, increasing recent evidence points toward the involvement of the endocannabinoid system (ECBS) in the neurobiological processes related to stimulant addiction. This article presents an up-to-date review with deep insights into the pivotal role of the ECBS in the neurobiology of stimulant addiction and the effects of its modulation on addictive behaviors. This article aims to: (1) review the role of cannabis use and ECBS modulation in the neurobiological substrates of psychostimulant addiction and (2) evaluate the potential of cannabinoid-based pharmacological strategies to treat stimulant addiction. A growing number of studies support a critical role of the ECBS and its modulation by synthetic or natural cannabinoids in various neurobiological and behavioral aspects of stimulants addiction. Thus, cannabinoids modulate brain reward systems closely involved in stimulants addiction, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for treating addiction across different classes of stimulants. PMID:24069004
Allosteric Modulation of protein oligomerization: an emerging approach to drug design

NASA Astrophysics Data System (ADS)

Gabizon, Ronen; Friedler, Assaf

2014-03-01

Many disease-related proteins are in equilibrium between different oligomeric forms. The regulation of this equilibrium plays a central role in maintaining the activity of these proteins in vitro and in vivo. Modulation of the oligomerization equilibrium of proteins by molecules that bind preferentially to a specific oligomeric state is emerging as a potential therapeutic strategy that can be applied to many biological systems such as cancer and viral infections. The target proteins for such compounds are diverse in structure and sequence, and may require different approaches for shifting their oligomerization equilibrium. The discovery of such oligomerization-modulating compounds is thus achieved based on existing structural knowledge about the specific target proteins, as well as on their interactions with partner proteins or with ligands. In silico design and combinatorial tools such as peptide arrays and phage display are also used for discovering compounds that modulate protein oligomerization. The current review highlights some of the recent developments in the design of compounds aimed at modulating the oligomerization equilibrium of proteins, including the "shiftides" approach developed in our lab.

KSC-08pd1462

NASA Image and Video Library

2008-05-29

CAPE CANAVERAL, Fla. -- At Launch Pad 39A at Kennedy Space Center, replacement parts for the Zvezda service module toilet on the International Space Station are loaded aboard space shuttle Discovery. The toilet malfunctioned last week and was initially repaired by replacing a microprocessor valve. After the station crew members experienced additional difficulties with the toilet, they were directed to use Soyuz toilet facilities at first and are using the main toilet again after rigging a urine bypass. The spare toilet parts have been added to Discovery’s manifest for delivery to the station on the STS-124 mission. On the 14-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is scheduled for 5:02 p.m. EDT May 31. Photo credit: NASA/Dimitri Gerondidakis
KSC-08pd1464

NASA Image and Video Library

2008-05-29

CAPE CANAVERAL, Fla. -- At Launch Pad 39A at Kennedy Space Center, technicians load replacement parts for the Zvezda service module toilet on the International Space Station aboard space shuttle Discovery. The toilet malfunctioned last week and was initially repaired by replacing a microprocessor valve. After the station crew members experienced additional difficulties with the toilet, they were directed to use Soyuz toilet facilities at first and are using the main toilet again after rigging a urine bypass. The spare toilet parts have been added to Discovery’s manifest for delivery to the station on the STS-124 mission. On the 14-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is scheduled for 5:02 p.m. EDT May 31. Photo credit: NASA/Dimitri Gerondidakis
KSC-08pd1463

NASA Image and Video Library

2008-05-29

CAPE CANAVERAL, Fla. -- At Launch Pad 39A at Kennedy Space Center, technicians load replacement parts for the Zvezda service module toilet on the International Space Station aboard space shuttle Discovery. The toilet malfunctioned last week and was initially repaired by replacing a microprocessor valve. After the station crew members experienced additional difficulties with the toilet, they were directed to use Soyuz toilet facilities at first and are using the main toilet again after rigging a urine bypass. The spare toilet parts have been added to Discovery’s manifest for delivery to the station on the STS-124 mission. On the 14-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is scheduled for 5:02 p.m. EDT May 31. Photo credit: NASA/Dimitri Gerondidakis
KSC-08pd1465

NASA Image and Video Library

2008-05-29

CAPE CANAVERAL, Fla. -- At Launch Pad 39A at Kennedy Space Center, a technician loads replacement parts for the Zvezda service module toilet on the International Space Station aboard space shuttle Discovery. The toilet malfunctioned last week and was initially repaired by replacing a microprocessor valve. After the station crew members experienced additional difficulties with the toilet, they were directed to use Soyuz toilet facilities at first and are using the main toilet again after rigging a urine bypass. The spare toilet parts have been added to Discovery’s manifest for delivery to the station on the STS-124 mission. On the 14-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is scheduled for 5:02 p.m. EDT May 31. Photo credit: NASA/Dimitri Gerondidakis
KSC-01padig090

NASA Image and Video Library

2001-02-15

STS-102 Mission Specialist James Voss occupies seat 5 in orbiter Discovery, getting ready for a simulated countdown. At left is Eugenia Tucker, Space Gateway Support Fire Safety. Voss is part of the Expedition Two crew who will be going to the International Space Station for their four-month rotation. Expedition One will return to Earth with Discovery. STS-102 is the eighth construction flight to the Space Station, with Space Shuttle Discovery carrying the Multi-Purpose Logistics Module Leonardo. Launch on mission STS-102 is scheduled for March 8
Applying ADLs to Assess Emerging Industry Specifications for Dynamic Discovery of Ad Hoc Network Services

DTIC Science & Technology

2001-01-31

function of Jini, UPnP, SLP, Bluetooth , and HAVi • Projected specific UML models for Jini, UPnP, and SLP • Developed a Rapide Model of Jini...is used by all JINI entities in directed -- discovery mode. It is part of the SCM_Discovery -- Module. Sends Unicast messages to SCMs on list of... SCMS to be discovered until all SCMS are found. -- Receives updates from SCM DB of discovered SCMs and -- removes SCMs accordingly -- NOTE
Oblique view of the Orbiter Discovery from ground level in ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Oblique view of the Orbiter Discovery from ground level in the Vehicle Assembly Building at NASA's Kennedy Space Center. Note that the Forward Reaction Control System Module has been removed from the forward section. The void left behind by the removal of the reaction control system has been sealed with a clear flexible barrier and kept under positive pressure to reduce the contaminant infiltration potential. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX
Connecting the virtual world of computers to the real world of medicinal chemistry.

PubMed

Glen, Robert C

2011-03-01

Drug discovery involves the simultaneous optimization of chemical and biological properties, usually in a single small molecule, which modulates one of nature's most complex systems: the balance between human health and disease. The increased use of computer-aided methods is having a significant impact on all aspects of the drug-discovery and development process and with improved methods and ever faster computers, computer-aided molecular design will be ever more central to the discovery process.
Discovery touches down after successful mission STS-95

NASA Technical Reports Server (NTRS)

1998-01-01

Orbiter Discovery smokes its tires as it touches down on runway 33 at the Shuttle Landing Facility. Discovery returns to Earth with its crew of seven after a successful mission STS-95 lasting nearly nine days and 3.6 million miles. The mission included research payloads such as the Spartan solar-observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process.
Discovery touches down after successful mission STS-95

NASA Technical Reports Server (NTRS)

1998-01-01

Orbiter Discovery startles a great white egret next to runway 33 as it touches down at the Shuttle Landing Facility. Discovery returns to Earth with its crew of seven after a successful mission STS-95 lasting nearly nine days and 3.6 million miles. The mission included research payloads such as the Spartan solar- observing deployable spacecraft, the Hubble Space Telescope Orbital Systems Test Platform, the International Extreme Ultraviolet Hitchhiker, as well as the SPACEHAB single module with experiments on space flight and the aging process.
Therapeutic modulators of STAT signalling for human diseases

PubMed Central

Miklossy, Gabriella; Hilliard, Tyvette S.; Turkson, James

2014-01-01

The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials. PMID:23903221
QSARpy: A new flexible algorithm to generate QSAR models based on dissimilarities. The log Kow case study.

PubMed

Ferrari, Thomas; Lombardo, Anna; Benfenati, Emilio

2018-05-14

Several methods exist to develop QSAR models automatically. Some are based on indices of the presence of atoms, other on the most similar compounds, other on molecular descriptors. Here we introduce QSARpy v1.0, a new QSAR modeling tool based on a different approach: the dissimilarity. This tool fragments the molecules of the training set to extract fragments that can be associated to a difference in the property/activity value, called modulators. If the target molecule share part of the structure with a molecule of the training set and differences can be explained with one or more modulators, the property/activity value of the molecule of the training set is adjusted using the value associated to the modulator(s). This tool is tested here on the n-octanol/water partition coefficient (Kow, usually expressed in logarithmic units as log Kow). It is a key parameter in risk assessment since it is a measure of hydrophobicity. Its wide spread use makes these estimation methods very useful to reduce testing costs. Using QSARpy v1.0, we obtained a new model to predict log Kow with accurate performance (RMSE 0.43 and R 2 0.94 for the external test set), comparing favorably with other programs. QSARpy is freely available on request. Copyright © 2018 Elsevier B.V. All rights reserved.
NASA's Space Shuttle Discovery is raised to allow ample clearance for the modified 747 Shuttle Carrier Aircraft to position underneath for attachment

NASA Image and Video Library

2005-08-18

NASA's specially modified 747 Shuttle Carrier Aircraft, or SCA, is positioned under the Space Shuttle Discovery to be attached for their ferry flight to the Kennedy Space Center in Florida. After its post-flight servicing and preparation at NASA Dryden in California, Discovery's return flight to Kennedy aboard the 747 will take approximately 2 days, with stops at several intermediate points for refueling. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.
NASA's modified 747 Shuttle Carrier Aircraft is positioned under the Space Shuttle Discovery to be attached for their ferry flight to the Kennedy Space Center

NASA Image and Video Library

2005-08-18

NASA's specially modified 747 Shuttle Carrier Aircraft, or SCA, is positioned under the Space Shuttle Discovery to be attached for their ferry flight to the Kennedy Space Center in Florida. After its post-flight servicing and preparation at NASA Dryden in California, Discovery's return flight to Kennedy aboard the 747 will take approximately 2 days, with stops at several intermediate points for refueling. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.
The Space Shuttle Discovery hitched a ride on a special 747 carrier aircraft for the flight from California to the Kennedy Space Center, FL, on August 19, 2005

NASA Image and Video Library

2005-08-19

The Space Shuttle Discovery hitched a ride on NASA's modified Boeing 747 Shuttle Carrier Aircraft for the flight from the Dryden Flight Research Center in California, to Kennedy Space Center, Florida, on August 19, 2005. The cross-country ferry flight to return Discovery to Florida after it's landing in California will take two days, with stops at several intermediate points for refueling. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.
49 CFR 1121.2 - Discovery.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 49 Transportation 8 2014-10-01 2014-10-01 false Discovery. 1121.2 Section 1121.2 Transportation... TRANSPORTATION RULES OF PRACTICE RAIL EXEMPTION PROCEDURES § 1121.2 Discovery. Discovery shall follow the procedures set forth at 49 CFR part 1114, subpart B. Discovery may begin upon the filing of the petition for...
49 CFR 1121.2 - Discovery.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 49 Transportation 8 2013-10-01 2013-10-01 false Discovery. 1121.2 Section 1121.2 Transportation... TRANSPORTATION RULES OF PRACTICE RAIL EXEMPTION PROCEDURES § 1121.2 Discovery. Discovery shall follow the procedures set forth at 49 CFR part 1114, subpart B. Discovery may begin upon the filing of the petition for...
49 CFR 1121.2 - Discovery.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 49 Transportation 8 2012-10-01 2012-10-01 false Discovery. 1121.2 Section 1121.2 Transportation... TRANSPORTATION RULES OF PRACTICE RAIL EXEMPTION PROCEDURES § 1121.2 Discovery. Discovery shall follow the procedures set forth at 49 CFR part 1114, subpart B. Discovery may begin upon the filing of the petition for...
49 CFR 1121.2 - Discovery.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 8 2011-10-01 2011-10-01 false Discovery. 1121.2 Section 1121.2 Transportation... TRANSPORTATION RULES OF PRACTICE RAIL EXEMPTION PROCEDURES § 1121.2 Discovery. Discovery shall follow the procedures set forth at 49 CFR part 1114, subpart B. Discovery may begin upon the filing of the petition for...
49 CFR 1121.2 - Discovery.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 8 2010-10-01 2010-10-01 false Discovery. 1121.2 Section 1121.2 Transportation... TRANSPORTATION RULES OF PRACTICE RAIL EXEMPTION PROCEDURES § 1121.2 Discovery. Discovery shall follow the procedures set forth at 49 CFR part 1114, subpart B. Discovery may begin upon the filing of the petition for...

The neural correlates of gist-based true and false recognition

PubMed Central

Gutchess, Angela H.; Schacter, Daniel L.

2012-01-01

When information is thematically related to previously studied information, gist-based processes contribute to false recognition. Using functional MRI, we examined the neural correlates of gist-based recognition as a function of increasing numbers of studied exemplars. Sixteen participants incidentally encoded small, medium, and large sets of pictures, and we compared the neural response at recognition using parametric modulation analyses. For hits, regions in middle occipital, middle temporal, and posterior parietal cortex linearly modulated their activity according to the number of related encoded items. For false alarms, visual, parietal, and hippocampal regions were modulated as a function of the encoded set size. The present results are consistent with prior work in that the neural regions supporting veridical memory also contribute to false memory for related information. The results also reveal that these regions respond to the degree of relatedness among similar items, and implicate perceptual and constructive processes in gist-based false memory. PMID:22155331
Combining NMR and X-ray crystallography in fragment-based drug discovery: discovery of highly potent and selective BACE-1 inhibitors.

PubMed

Wyss, Daniel F; Wang, Yu-Sen; Eaton, Hugh L; Strickland, Corey; Voigt, Johannes H; Zhu, Zhaoning; Stamford, Andrew W

2012-01-01

Fragment-based drug discovery (FBDD) has become increasingly popular over the last decade. We review here how we have used highly structure-driven fragment-based approaches to complement more traditional lead discovery to tackle high priority targets and those struggling for leads. Combining biomolecular nuclear magnetic resonance (NMR), X-ray crystallography, and molecular modeling with structure-assisted chemistry and innovative biology as an integrated approach for FBDD can solve very difficult problems, as illustrated in this chapter. Here, a successful FBDD campaign is described that has allowed the development of a clinical candidate for BACE-1, a challenging CNS drug target. Crucial to this achievement were the initial identification of a ligand-efficient isothiourea fragment through target-based NMR screening and the determination of its X-ray crystal structure in complex with BACE-1, which revealed an extensive H-bond network with the two active site aspartate residues. This detailed 3D structural information then enabled the design and validation of novel, chemically stable and accessible heterocyclic acylguanidines as aspartic acid protease inhibitor cores. Structure-assisted fragment hit-to-lead optimization yielded iminoheterocyclic BACE-1 inhibitors that possess desirable molecular properties as potential therapeutic agents to test the amyloid hypothesis of Alzheimer's disease in a clinical setting.
Limitations and potentials of current motif discovery algorithms

PubMed Central

Hu, Jianjun; Li, Bin; Kihara, Daisuke

2005-01-01

Computational methods for de novo identification of gene regulation elements, such as transcription factor binding sites, have proved to be useful for deciphering genetic regulatory networks. However, despite the availability of a large number of algorithms, their strengths and weaknesses are not sufficiently understood. Here, we designed a comprehensive set of performance measures and benchmarked five modern sequence-based motif discovery algorithms using large datasets generated from Escherichia coli RegulonDB. Factors that affect the prediction accuracy, scalability and reliability are characterized. It is revealed that the nucleotide and the binding site level accuracy are very low, while the motif level accuracy is relatively high, which indicates that the algorithms can usually capture at least one correct motif in an input sequence. To exploit diverse predictions from multiple runs of one or more algorithms, a consensus ensemble algorithm has been developed, which achieved 6–45% improvement over the base algorithms by increasing both the sensitivity and specificity. Our study illustrates limitations and potentials of existing sequence-based motif discovery algorithms. Taking advantage of the revealed potentials, several promising directions for further improvements are discussed. Since the sequence-based algorithms are the baseline of most of the modern motif discovery algorithms, this paper suggests substantial improvements would be possible for them. PMID:16284194
Discovery of highly potent, selective, covalent inhibitors of JAK3

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

Kempson, James; Ovalle, Damaso; Guo, Junqing

A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.
A community initiative for developing data and modeling driven curriculum modules for hydrology education

NASA Astrophysics Data System (ADS)

Ruddell, B. L.; Merwade, V.

2010-12-01

Hydrology and geoscience education at the undergraduate and graduate levels may benefit greatly from a structured approach to pedagogy that utilizes modeling, authentic data, and simulation exercises to engage students in practice-like activities. Extensive evidence in the educational literature suggests that students retain more of their instruction, and attain higher levels of mastery over content, when interactive and practice-like activities are used to contextualize traditional lecture-based and theory-based instruction. However, it is also important that these activities carefully link the use of data and modeling to abstract theory, to promote transfer of knowledge to other contexts. While this type of data-based activity has been practiced in the hydrology classroom for decades, the hydrology community still lacks a set of standards and a mechanism for community-based development, publication, and review of this type of curriculum material. A community-based initiative is underway to develop a set curriculum materials to teach hydrology in the engineering and geoscience university classroom using outcomes-based, pedagogically rigorous modules that use authentic data and modeling experiences to complement traditional lecture-based instruction. A preliminary design for a community cyberinfrastructure for shared module development and publication, and for module topics and outcomes and ametadata and module interoperability standards, will be presented, along with the results of a series of community surveys and workshops informing this design.
Microbial Source Module (MSM): Documenting the Science and Software for Discovery, Evaluation, and Integration

EPA Science Inventory

The Microbial Source Module (MSM) estimates microbial loading rates to land surfaces from non-point sources, and to streams from point sources for each subwatershed within a watershed. A subwatershed, the smallest modeling unit, represents the common basis for information consume...
"Discoveries in Planetary Sciences": Slide Sets Highlighting New Advances for Astronomy Educators

NASA Astrophysics Data System (ADS)

Brain, David; Schneider, N.; Molaverdikhani, K.; Afsharahmadi, F.

2012-10-01

We present two new features of an ongoing effort to bring recent newsworthy advances in planetary science to undergraduate lecture halls. The effort, called 'Discoveries in Planetary Sciences', summarizes selected recently announced discoveries that are 'too new for textbooks' in the form of 3-slide PowerPoint presentations. The first slide describes the discovery, the second slide discusses the underlying planetary science concepts at a level appropriate for students of 'Astronomy 101', and the third presents the big picture implications of the discovery. A fourth slide includes links to associated press releases, images, and primary sources. This effort is generously sponsored by the Division for Planetary Sciences of the American Astronomical Society, and the slide sets are available at http://dps.aas.org/education/dpsdisc/ for download by undergraduate instructors or any interested party. Several new slide sets have just been released, and we summarize the topics covered. The slide sets are also being translated into languages other than English (including Spanish and Farsi), and we will provide an overview of the translation strategy and process. Finally, we will present web statistics on how many people are using the slide sets, as well as individual feedback from educators.
BEER ANALYSIS OF KEPLER AND CoRoT LIGHT CURVES. I. DISCOVERY OF KEPLER-76b: A HOT JUPITER WITH EVIDENCE FOR SUPERROTATION

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

Faigler, S.; Tal-Or, L.; Mazeh, T.

We present the first case in which the BEER algorithm identified a hot Jupiter in the Kepler light curve, and its reality was confirmed by orbital solutions based on follow-up spectroscopy. The companion Kepler-76b was identified by the BEER algorithm, which detected the BEaming (sometimes called Doppler boosting) effect together with the Ellipsoidal and Reflection/emission modulations (BEER), at an orbital period of 1.54 days, suggesting a planetary companion orbiting the 13.3 mag F star. Further investigation revealed that this star appeared in the Kepler eclipsing binary catalog with estimated primary and secondary eclipse depths of 5 Multiplication-Sign 10{sup -3} andmore » 1 Multiplication-Sign 10{sup -4}, respectively. Spectroscopic radial velocity follow-up observations with Tillinghast Reflector Echelle Spectrograph and SOPHIE confirmed Kepler-76b as a transiting 2.0 {+-} 0.26 M{sub Jup} hot Jupiter. The mass of a transiting planet can be estimated from either the beaming or the ellipsoidal amplitude. The ellipsoidal-based mass estimate of Kepler-76b is consistent with the spectroscopically measured mass while the beaming-based estimate is significantly inflated. We explain this apparent discrepancy as evidence for the superrotation phenomenon, which involves eastward displacement of the hottest atmospheric spot of a tidally locked planet by an equatorial superrotating jet stream. This phenomenon was previously observed only for HD 189733b in the infrared. We show that a phase shift of 10. Degree-Sign 3 {+-} 2. Degree-Sign 0 of the planet reflection/emission modulation, due to superrotation, explains the apparently inflated beaming modulation, resolving the ellipsoidal/beaming amplitude discrepancy. Kepler-76b is one of very few confirmed planets in the Kepler light curves that show BEER modulations and the first to show superrotation evidence in the Kepler band. Its discovery illustrates for the first time the ability of the BEER algorithm to detect short-period planets and brown dwarfs.« less
Harvest: an open platform for developing web-based biomedical data discovery and reporting applications.

PubMed

Pennington, Jeffrey W; Ruth, Byron; Italia, Michael J; Miller, Jeffrey; Wrazien, Stacey; Loutrel, Jennifer G; Crenshaw, E Bryan; White, Peter S

2014-01-01

Biomedical researchers share a common challenge of making complex data understandable and accessible as they seek inherent relationships between attributes in disparate data types. Data discovery in this context is limited by a lack of query systems that efficiently show relationships between individual variables, but without the need to navigate underlying data models. We have addressed this need by developing Harvest, an open-source framework of modular components, and using it for the rapid development and deployment of custom data discovery software applications. Harvest incorporates visualizations of highly dimensional data in a web-based interface that promotes rapid exploration and export of any type of biomedical information, without exposing researchers to underlying data models. We evaluated Harvest with two cases: clinical data from pediatric cardiology and demonstration data from the OpenMRS project. Harvest's architecture and public open-source code offer a set of rapid application development tools to build data discovery applications for domain-specific biomedical data repositories. All resources, including the OpenMRS demonstration, can be found at http://harvest.research.chop.edu.
The center for causal discovery of biomedical knowledge from big data.

PubMed

Cooper, Gregory F; Bahar, Ivet; Becich, Michael J; Benos, Panayiotis V; Berg, Jeremy; Espino, Jeremy U; Glymour, Clark; Jacobson, Rebecca Crowley; Kienholz, Michelle; Lee, Adrian V; Lu, Xinghua; Scheines, Richard

2015-11-01

The Big Data to Knowledge (BD2K) Center for Causal Discovery is developing and disseminating an integrated set of open source tools that support causal modeling and discovery of biomedical knowledge from large and complex biomedical datasets. The Center integrates teams of biomedical and data scientists focused on the refinement of existing and the development of new constraint-based and Bayesian algorithms based on causal Bayesian networks, the optimization of software for efficient operation in a supercomputing environment, and the testing of algorithms and software developed using real data from 3 representative driving biomedical projects: cancer driver mutations, lung disease, and the functional connectome of the human brain. Associated training activities provide both biomedical and data scientists with the knowledge and skills needed to apply and extend these tools. Collaborative activities with the BD2K Consortium further advance causal discovery tools and integrate tools and resources developed by other centers. © 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.
Harvest: an open platform for developing web-based biomedical data discovery and reporting applications

PubMed Central

Pennington, Jeffrey W; Ruth, Byron; Italia, Michael J; Miller, Jeffrey; Wrazien, Stacey; Loutrel, Jennifer G; Crenshaw, E Bryan; White, Peter S

2014-01-01

Biomedical researchers share a common challenge of making complex data understandable and accessible as they seek inherent relationships between attributes in disparate data types. Data discovery in this context is limited by a lack of query systems that efficiently show relationships between individual variables, but without the need to navigate underlying data models. We have addressed this need by developing Harvest, an open-source framework of modular components, and using it for the rapid development and deployment of custom data discovery software applications. Harvest incorporates visualizations of highly dimensional data in a web-based interface that promotes rapid exploration and export of any type of biomedical information, without exposing researchers to underlying data models. We evaluated Harvest with two cases: clinical data from pediatric cardiology and demonstration data from the OpenMRS project. Harvest's architecture and public open-source code offer a set of rapid application development tools to build data discovery applications for domain-specific biomedical data repositories. All resources, including the OpenMRS demonstration, can be found at http://harvest.research.chop.edu PMID:24131510
How does non-formal marine education affect student attitude and knowledge? A case study using SCDNR's Discovery program

NASA Astrophysics Data System (ADS)

McGovern, Mary Francis

Non-formal environmental education provides students the opportunity to learn in ways that would not be possible in a traditional classroom setting. Outdoor learning allows students to make connections to their environment and helps to foster an appreciation for nature. This type of education can be interdisciplinary---students not only develop skills in science, but also in mathematics, social studies, technology, and critical thinking. This case study focuses on a non-formal marine education program, the South Carolina Department of Natural Resources' (SCDNR) Discovery vessel based program. The Discovery curriculum was evaluated to determine impact on student knowledge about and attitude toward the estuary. Students from two South Carolina coastal counties who attended the boat program during fall 2014 were asked to complete a brief survey before, immediately after, and two weeks following the program. The results of this study indicate that both student knowledge about and attitude significantly improved after completion of the Discovery vessel based program. Knowledge and attitude scores demonstrated a positive correlation.
STS-114 Discovery's approach for docking

NASA Image and Video Library

2005-07-28

ISS011-E-11233 (28 July 2005) --- One of a series of photographs showing the Space Shuttle Discovery as taken from aboard the International Space Station during rendezvous and docking operations. The Italian-built Raffaello Multi-Purpose Logistics Module (MPLM) is in the Shuttle;s cargo bay. Earth, dotted with popcorn-like clouds, provides the backdrop for this image.
Thinking Processes Associated with Undergraduate Chemistry Students' Success at Applying a Molecular-Level Model in a New Context

ERIC Educational Resources Information Center

Teichert, Melonie A.; Tien, Lydia T.; Dysleski, Lisa; Rickey, Dawn

2017-01-01

This study investigated relationships between the thinking processes that 28 undergraduate chemistry students engaged in during guided discovery and their subsequent success at reasoning through a transfer problem during an end-of-semester interview. During a guided-discovery laboratory module, students were prompted to use words, pictures, and…
Multi-level bandwidth efficient block modulation codes

NASA Technical Reports Server (NTRS)

Lin, Shu

1989-01-01

The multilevel technique is investigated for combining block coding and modulation. There are four parts. In the first part, a formulation is presented for signal sets on which modulation codes are to be constructed. Distance measures on a signal set are defined and their properties are developed. In the second part, a general formulation is presented for multilevel modulation codes in terms of component codes with appropriate Euclidean distances. The distance properties, Euclidean weight distribution and linear structure of multilevel modulation codes are investigated. In the third part, several specific methods for constructing multilevel block modulation codes with interdependency among component codes are proposed. Given a multilevel block modulation code C with no interdependency among the binary component codes, the proposed methods give a multilevel block modulation code C which has the same rate as C, a minimum squared Euclidean distance not less than that of code C, a trellis diagram with the same number of states as that of C and a smaller number of nearest neighbor codewords than that of C. In the last part, error performance of block modulation codes is analyzed for an AWGN channel based on soft-decision maximum likelihood decoding. Error probabilities of some specific codes are evaluated based on their Euclidean weight distributions and simulation results.
ISO 19115 Experiences in NASA's Earth Observing System (EOS) ClearingHOuse (ECHO)

NASA Astrophysics Data System (ADS)

Cechini, M. F.; Mitchell, A.

2011-12-01

Metadata is an important entity in the process of cataloging, discovering, and describing earth science data. As science research and the gathered data increases in complexity, so does the complexity and importance of descriptive metadata. To meet these growing needs, the metadata models required utilize richer and more mature metadata attributes. Categorizing, standardizing, and promulgating these metadata models to a politically, geographically, and scientifically diverse community is a difficult process. An integral component of metadata management within NASA's Earth Observing System Data and Information System (EOSDIS) is the Earth Observing System (EOS) ClearingHOuse (ECHO). ECHO is the core metadata repository for the EOSDIS data centers providing a centralized mechanism for metadata and data discovery and retrieval. ECHO has undertaken an internal restructuring to meet the changing needs of scientists, the consistent advancement in technology, and the advent of new standards such as ISO 19115. These improvements were based on the following tenets for data discovery and retrieval: + There exists a set of 'core' metadata fields recommended for data discovery. + There exists a set of users who will require the entire metadata record for advanced analysis. + There exists a set of users who will require a 'core' set metadata fields for discovery only. + There will never be a cessation of new formats or a total retirement of all old formats. + Users should be presented metadata in a consistent format of their choosing. In order to address the previously listed items, ECHO's new metadata processing paradigm utilizes the following approach: + Identify a cross-format set of 'core' metadata fields necessary for discovery. + Implement format-specific indexers to extract the 'core' metadata fields into an optimized query capability. + Archive the original metadata in its entirety for presentation to users requiring the full record. + Provide on-demand translation of 'core' metadata to any supported result format. Lessons learned by the ECHO team while implementing its new metadata approach to support usage of the ISO 19115 standard will be presented. These lessons learned highlight some discovered strengths and weaknesses in the ISO 19115 standard as it is introduced to an existing metadata processing system.
Drug discovery in an academic setting: playing to the strengths.

PubMed

Huryn, Donna M

2013-03-14

Drug discovery and medicinal chemistry initiatives in academia provide an opportunity to create a unique environment that is distinct from the traditional industrial model. Two characteristics of a university setting that are not usually associated with pharma are the ability to pursue high-risk projects and a depth of expertise, infrastructure, and capabilities in focused areas. Encouraging, supporting, and fostering drug discovery efforts that take advantage of these and other distinguishing characteristics of an academic setting can lead to novel and innovative therapies that might not be discovered otherwise.
Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch

PubMed Central

Gallagher, Ciara M; Garri, Carolina; Cain, Erica L; Ang, Kenny Kean-Hooi; Wilson, Christopher G; Chen, Steven; Hearn, Brian R; Jaishankar, Priyadarshini; Aranda-Diaz, Andres; Arkin, Michelle R; Renslo, Adam R; Walter, Peter

2016-01-01

The membrane-bound transcription factor ATF6α plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of ATF6α promotes cell survival in cancer models. We used cell-based screens to discover and develop Ceapins, a class of pyrazole amides, that block ATF6α signaling in response to ER stress. Ceapins sensitize cells to ER stress without impacting viability of unstressed cells. Ceapins are highly specific inhibitors of ATF6α signaling, not affecting signaling through the other branches of the UPR, or proteolytic processing of its close homolog ATF6β or SREBP (a cholesterol-regulated transcription factor), both activated by the same proteases. Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6α and its role in pathological settings. The discovery of Ceapins now enables pharmacological modulation all three UPR branches either singly or in combination. DOI: http://dx.doi.org/10.7554/eLife.11878.001 PMID:27435960
12 CFR 1081.210 - Expert discovery.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 12 Banks and Banking 8 2012-01-01 2012-01-01 false Expert discovery. 1081.210 Section 1081.210... Initiation of Proceedings and Prehearing Rules § 1081.210 Expert discovery. (a) At a date set by the hearing... discovery in appropriate cases. ...
Quantum chemical approaches in structure-based virtual screening and lead optimization

NASA Astrophysics Data System (ADS)

Cavasotto, Claudio N.; Adler, Natalia S.; Aucar, Maria G.

2018-05-01

Today computational chemistry is a consolidated tool in drug lead discovery endeavors. Due to methodological developments and to the enormous advance in computer hardware, methods based on quantum mechanics (QM) have gained great attention in the last 10 years, and calculations on biomacromolecules are becoming increasingly explored, aiming to provide better accuracy in the description of protein-ligand interactions and the prediction of binding affinities. In principle, the QM formulation includes all contributions to the energy, accounting for terms usually missing in molecular mechanics force-fields, such as electronic polarization effects, metal coordination, and covalent binding; moreover, QM methods are systematically improvable, and provide a greater degree of transferability. In this mini-review we present recent applications of explicit QM-based methods in small-molecule docking and scoring, and in the calculation of binding free-energy in protein-ligand systems. Although the routine use of QM-based approaches in an industrial drug lead discovery setting remains a formidable challenging task, it is likely they will increasingly become active players within the drug discovery pipeline.

Design of Mobile Health Tools to Promote Goal Achievement in Self-Management Tasks

PubMed Central

Henderson, Geoffrey; Parmanto, Bambang

2017-01-01

Background Goal-setting within rehabilitation is a common practice ultimately geared toward helping patients make functional progress. Objective The purposes of this study were to (1) qualitatively analyze data from a wellness program for patients with spina bifida (SB) and spinal cord injury (SCI) in order to generate software requirements for a goal-setting module to support their complex goal-setting routines, (2) design a prototype of a goal-setting module within an existing mobile health (mHealth) system, and (3) identify what educational content might be necessary to integrate into the system. Methods A total of 750 goals were analyzed from patients with SB and SCI enrolled in a wellness program. These goals were qualitatively analyzed in order to operationalize a set of software requirements for an mHealth goal-setting module and identify important educational content. Results Those of male sex (P=.02) and with SCI diagnosis (P<.001) were more likely to achieve goals than females or those with SB. Temporality (P<.001) and type (P<.001) of goal were associated with likelihood that the goal would be achieved. Nearly all (210/213; 98.6%) of the fact-finding goals were achieved. There was no significant difference in achievement based on goal theme. Checklists, data tracking, and fact-finding tools were identified as three functionalities that could support goal-setting and achievement in an mHealth system. Based on the qualitative analysis, a list of software requirements for a goal-setting module was generated, and a prototype was developed. Targets for educational content were also generated. Conclusions Innovative mHealth tools can be developed to support commonly set goals by individuals with disabilities. PMID:28739558
Computational approaches for drug discovery.

PubMed

Hung, Che-Lun; Chen, Chi-Chun

2014-09-01

Cellular proteins are the mediators of multiple organism functions being involved in physiological mechanisms and disease. By discovering lead compounds that affect the function of target proteins, the target diseases or physiological mechanisms can be modulated. Based on knowledge of the ligand-receptor interaction, the chemical structures of leads can be modified to improve efficacy, selectivity and reduce side effects. One rational drug design technology, which enables drug discovery based on knowledge of target structures, functional properties and mechanisms, is computer-aided drug design (CADD). The application of CADD can be cost-effective using experiments to compare predicted and actual drug activity, the results from which can used iteratively to improve compound properties. The two major CADD-based approaches are structure-based drug design, where protein structures are required, and ligand-based drug design, where ligand and ligand activities can be used to design compounds interacting with the protein structure. Approaches in structure-based drug design include docking, de novo design, fragment-based drug discovery and structure-based pharmacophore modeling. Approaches in ligand-based drug design include quantitative structure-affinity relationship and pharmacophore modeling based on ligand properties. Based on whether the structure of the receptor and its interaction with the ligand are known, different design strategies can be seed. After lead compounds are generated, the rule of five can be used to assess whether these have drug-like properties. Several quality validation methods, such as cost function analysis, Fisher's cross-validation analysis and goodness of hit test, can be used to estimate the metrics of different drug design strategies. To further improve CADD performance, multi-computers and graphics processing units may be applied to reduce costs. © 2014 Wiley Periodicals, Inc.
A Low-Cost, Hands-on Module to Characterize Antimicrobial Compounds Using an Interdisciplinary, Biophysical Approach

PubMed Central

Kaushik, Karishma S.; Kessel, Ashley; Ratnayeke, Nalin; Gordon, Vernita D.

2015-01-01

We have developed a hands-on experimental module that combines biology experiments with a physics-based analytical model in order to characterize antimicrobial compounds. To understand antibiotic resistance, participants perform a disc diffusion assay to test the antimicrobial activity of different compounds and then apply a diffusion-based analytical model to gain insights into the behavior of the active antimicrobial component. In our experience, this module was robust, reproducible, and cost-effective, suggesting that it could be implemented in diverse settings such as undergraduate research, STEM (science, technology, engineering, and math) camps, school programs, and laboratory training workshops. By providing valuable interdisciplinary research experience in science outreach and education initiatives, this module addresses the paucity of structured training or education programs that integrate diverse scientific fields. Its low-cost requirements make it especially suitable for use in resource-limited settings. PMID:25602254
12 CFR 509.24 - Scope of document discovery.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Scope of document discovery. 509.24 Section 509... discovery. (a) Limits on discovery. (1) Subject to the limitations set out in paragraphs (b), (c), and (d) of this section, a party to a proceeding under this subpart may obtain document discovery by serving...
Collins in Service Module

NASA Image and Video Library

2005-08-05

S114-E-7139 (5 August 2005) --- Astronaut Eileen M. Collins, STS-114 commander, floats in the Zvezda Service Module of the International Space Station while Space Shuttle Discovery was docked to the Station. Astronaut John L. Phillips, Expedition 11 NASA Space Station science officer and flight engineer, is visible at bottom right.
A Model-Based Analysis of Semi-Automated Data Discovery and Entry Using Automated Content Extraction

DTIC Science & Technology

2011-02-01

Accomplish Goal) to (a) visually search the contents of a file folder until the icon corresponding to the desired file is located (Choose...Item_from_set), and (b) move the mouse to that icon and double click to open it (Double_select Object). Note that Choose Item_from_set and Double_select...argument, which Open File fills with <found_item>, a working memory pointer to the file icon that Choose_item_from Set finds. Look_at, Point_to
Key aspects of the Novartis compound collection enhancement project for the compilation of a comprehensive chemogenomics drug discovery screening collection.

PubMed

Jacoby, Edgar; Schuffenhauer, Ansgar; Popov, Maxim; Azzaoui, Kamal; Havill, Benjamin; Schopfer, Ulrich; Engeloch, Caroline; Stanek, Jaroslav; Acklin, Pierre; Rigollier, Pascal; Stoll, Friederike; Koch, Guido; Meier, Peter; Orain, David; Giger, Rudolph; Hinrichs, Jürgen; Malagu, Karine; Zimmermann, Jürg; Roth, Hans-Joerg

2005-01-01

The NIBR (Novartis Institutes for BioMedical Research) compound collection enrichment and enhancement project integrates corporate internal combinatorial compound synthesis and external compound acquisition activities in order to build up a comprehensive screening collection for a modern drug discovery organization. The main purpose of the screening collection is to supply the Novartis drug discovery pipeline with hit-to-lead compounds for today's and the future's portfolio of drug discovery programs, and to provide tool compounds for the chemogenomics investigation of novel biological pathways and circuits. As such, it integrates designed focused and diversity-based compound sets from the synthetic and natural paradigms able to cope with druggable and currently deemed undruggable targets and molecular interaction modes. Herein, we will summarize together with new trends published in the literature, scientific challenges faced and key approaches taken at NIBR to match the chemical and biological spaces.
Connecting rules from paired miRNA and mRNA expression data sets of HCV patients to detect both inverse and positive regulatory relationships

PubMed Central

2015-01-01

Background Intensive research based on the inverse expression relationship has been undertaken to discover the miRNA-mRNA regulatory modules involved in the infection of Hepatitis C virus (HCV), the leading cause of chronic liver diseases. However, biological studies in other fields have found that inverse expression relationship is not the only regulatory relationship between miRNAs and their targets, and some miRNAs can positively regulate a mRNA by binding at the 5' UTR of the mRNA. Results This work focuses on the detection of both inverse and positive regulatory relationships from a paired miRNA and mRNA expression data set of HCV patients through a 'change-to-change' method which can derive connected discriminatory rules. Our study uncovered many novel miRNA-mRNA regulatory modules. In particular, it was revealed that GFRA2 is positively regulated by miR-557, miR-765 and miR-17-3p that probably bind at different locations of the 5' UTR of this mRNA. The expression relationship between GFRA2 and any of these three miRNAs has not been studied before, although separate research for this gene and these miRNAs have all drawn conclusions linked to hepatocellular carcinoma. This suggests that the binding of mRNA GFRA2 with miR-557, miR-765, or miR-17-3p, or their combinations, is worthy of further investigation by experimentation. We also report another mRNA QKI which has a strong inverse expression relationship with miR-129 and miR-493-3p which may bind at the 3' UTR of QKI with a perfect sequence match. Furthermore, the interaction between hsa-miR-129-5p (previous ID: hsa-miR-129) and QKI is supported with CLIP-Seq data from starBase. Our method can be easily extended for the expression data analysis of other diseases. Conclusion Our rule discovery method is useful for integrating binding information and expression profile for identifying HCV miRNA-mRNA regulatory modules and can be applied to the study of the expression profiles of other complex human diseases. PMID:25707620
Statistics and Discoveries at the LHC (1/4)

ScienceCinema

Cowan, Glen

2018-02-09

The lectures will give an introduction to statistics as applied in particle physics and will provide all the necessary basics for data analysis at the LHC. Special emphasis will be placed on the the problems and questions that arise when searching for new phenomena, including p-values, discovery significance, limit setting procedures, treatment of small signals in the presence of large backgrounds. Specific issues that will be addressed include the advantages and drawbacks of different statistical test procedures (cut-based, likelihood-ratio, etc.), the look-elsewhere effect and treatment of systematic uncertainties.
Statistics and Discoveries at the LHC (3/4)

ScienceCinema

Cowan, Glen

2018-02-19

The lectures will give an introduction to statistics as applied in particle physics and will provide all the necessary basics for data analysis at the LHC. Special emphasis will be placed on the the problems and questions that arise when searching for new phenomena, including p-values, discovery significance, limit setting procedures, treatment of small signals in the presence of large backgrounds. Specific issues that will be addressed include the advantages and drawbacks of different statistical test procedures (cut-based, likelihood-ratio, etc.), the look-elsewhere effect and treatment of systematic uncertainties.
Statistics and Discoveries at the LHC (4/4)

ScienceCinema

Cowan, Glen

2018-05-22

The lectures will give an introduction to statistics as applied in particle physics and will provide all the necessary basics for data analysis at the LHC. Special emphasis will be placed on the the problems and questions that arise when searching for new phenomena, including p-values, discovery significance, limit setting procedures, treatment of small signals in the presence of large backgrounds. Specific issues that will be addressed include the advantages and drawbacks of different statistical test procedures (cut-based, likelihood-ratio, etc.), the look-elsewhere effect and treatment of systematic uncertainties.
Statistics and Discoveries at the LHC (2/4)

ScienceCinema

Cowan, Glen

2018-04-26

The lectures will give an introduction to statistics as applied in particle physics and will provide all the necessary basics for data analysis at the LHC. Special emphasis will be placed on the the problems and questions that arise when searching for new phenomena, including p-values, discovery significance, limit setting procedures, treatment of small signals in the presence of large backgrounds. Specific issues that will be addressed include the advantages and drawbacks of different statistical test procedures (cut-based, likelihood-ratio, etc.), the look-elsewhere effect and treatment of systematic uncertainties.
Microfluidics platform for single-shot dose-response analysis of chloride channel-modulating compounds.

PubMed

Jin, Byung-Ju; Ko, Eun-A; Namkung, Wan; Verkman, A S

2013-10-07

We previously developed cell-based kinetics assays of chloride channel modulators utilizing genetically encoded yellow fluorescent proteins. Fluorescence platereader-based high-throughput screens yielded small-molecule activators and inhibitors of the cAMP-activated chloride channel CFTR and calcium-activated chloride channels, including TMEM16A. Here, we report a microfluidics platform for single-shot determination of concentration-activity relations in which a 1.5 × 1.5 mm square area of adherent cultured cells is exposed for 5-10 min to a pseudo-logarithmic gradient of test compound generated by iterative, two-component channel mixing. Cell fluorescence is imaged following perfusion with an iodide-containing solution to give iodide influx rate at each location in the image field, thus quantifying modulator effects over a wide range of concentrations in a single measurement. IC50 determined for CFTR and TMEM16A activators and inhibitors by single-shot microfluidics were in agreement with conventional plate reader measurements. The microfluidics approach developed here may accelerate the discovery and characterization of chloride channel-targeted drugs.
Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

PubMed

Heightman, Tom D; Berdini, Valerio; Braithwaite, Hannah; Buck, Ildiko M; Cassidy, Megan; Castro, Juan; Courtin, Aurélie; Day, James E H; East, Charlotte; Fazal, Lynsey; Graham, Brent; Griffiths-Jones, Charlotte M; Lyons, John F; Martins, Vanessa; Muench, Sandra; Munck, Joanne M; Norton, David; O'Reilly, Marc; Palmer, Nick; Pathuri, Puja; Reader, Michael; Rees, David C; Rich, Sharna J; Richardson, Caroline; Saini, Harpreet; Thompson, Neil T; Wallis, Nicola G; Walton, Hugh; Wilsher, Nicola E; Woolford, Alison J-A; Cooke, Michael; Cousin, David; Onions, Stuart; Shannon, Jonathan; Watts, John; Murray, Christopher W

2018-05-31

Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors.
Tackling the conformational sampling of larger flexible compounds and macrocycles in pharmacology and drug discovery.

PubMed

Chen, I-Jen; Foloppe, Nicolas

2013-12-15

Computational conformational sampling underpins much of molecular modeling and design in pharmaceutical work. The sampling of smaller drug-like compounds has been an active area of research. However, few studies have tested in details the sampling of larger more flexible compounds, which are also relevant to drug discovery, including therapeutic peptides, macrocycles, and inhibitors of protein-protein interactions. Here, we investigate extensively mainstream conformational sampling methods on three carefully curated compound sets, namely the 'Drug-like', larger 'Flexible', and 'Macrocycle' compounds. These test molecules are chemically diverse with reliable X-ray protein-bound bioactive structures. The compared sampling methods include Stochastic Search and the recent LowModeMD from MOE, all the low-mode based approaches from MacroModel, and MD/LLMOD recently developed for macrocycles. In addition to default settings, key parameters of the sampling protocols were explored. The performance of the computational protocols was assessed via (i) the reproduction of the X-ray bioactive structures, (ii) the size, coverage and diversity of the output conformational ensembles, (iii) the compactness/extendedness of the conformers, and (iv) the ability to locate the global energy minimum. The influence of the stochastic nature of the searches on the results was also examined. Much better results were obtained by adopting search parameters enhanced over the default settings, while maintaining computational tractability. In MOE, the recent LowModeMD emerged as the method of choice. Mixed torsional/low-mode from MacroModel performed as well as LowModeMD, and MD/LLMOD performed well for macrocycles. The low-mode based approaches yielded very encouraging results with the flexible and macrocycle sets. Thus, one can productively tackle the computational conformational search of larger flexible compounds for drug discovery, including macrocycles. Copyright © 2013 Elsevier Ltd. All rights reserved.
KSC-05PD-1449

NASA Technical Reports Server (NTRS)

2005-01-01

KENNEDY SPACE CENTER, FLA. At Launch Pad 39B, the Orbiter Boom Sensor System (OBSS) sensor package is viewed before the orbiter's payload bay doors are closed for launch. Payload bay door closure is a significant milestone in the preparations of Discovery for the first Return to Flight mission, STS-114. This sensor package will provide surface area and depth defect inspection for all the surfaces of the orbiter. It includes an intensified television camera (ITVC) and a laser dynamic range imager, which are mounted on a pan and tilt unit, and a laser camera system (LCS) mounted on a stationary bracket. The package is part of the new safety measures added for all future Space Shuttle missions. During its 12-day mission, Discoverys seven- person crew will test new hardware and techniques to improve Shuttle safety, as well as deliver supplies to the International Space Station. Discoverys payloads include the Multi-Purpose Logistics Module Raffaello, the Lightweight Multi-Purpose Experiment Support Structure Carrier (LMC), and the External Stowage Platform-2 (ESP-2). Raffaello will deliver supplies to the International Space Station including food, clothing and research equipment. The LMC supports a replacement Control Moment Gyroscope and a tile repair sample box. The ESP-2 is outfitted with replacement parts. Launch of mission STS-114 was set for July 13 at the conclusion of the Flight Readiness Review yesterday.
12 CFR 1081.210 - Expert discovery.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 12 Banks and Banking 8 2013-01-01 2013-01-01 false Expert discovery. 1081.210 Section 1081.210... Initiation of Proceedings and Prehearing Rules § 1081.210 Expert discovery. (a) At a date set by the hearing... requirement of expert discovery in appropriate cases. ...
The Influence of Metabolic Syndrome and Sex on the DNA Methylome in Schizophrenia

PubMed Central

Lines, Brittany N.

2018-01-01

Introduction The mechanism by which metabolic syndrome occurs in schizophrenia is not completely known; however, previous work suggests that changes in DNA methylation may be involved which is further influenced by sex. Within this study, the DNA methylome was profiled to identify altered methylation associated with metabolic syndrome in a schizophrenia population on atypical antipsychotics. Methods Peripheral blood from schizophrenia subjects was utilized for DNA methylation analyses. Discovery analyses (n = 96) were performed using an epigenome-wide analysis on the Illumina HumanMethylation450K BeadChip based on metabolic syndrome diagnosis. A secondary discovery analysis was conducted based on sex. The top hits from the discovery analyses were assessed in an additional validation set (n = 166) using site-specific methylation pyrosequencing. Results A significant increase in CDH22 gene methylation in subjects with metabolic syndrome was identified in the overall sample. Additionally, differential methylation was found within the MAP3K13 gene in females and the CCDC8 gene within males. Significant differences in methylation were again observed for the CDH22 and MAP3K13 genes, but not CCDC8, in the validation sample set. Conclusions This study provides preliminary evidence that DNA methylation may be associated with metabolic syndrome and sex in schizophrenia. PMID:29850476
Calibration-free absolute frequency response measurement of directly modulated lasers based on additional modulation.

PubMed

Zhang, Shangjian; Zou, Xinhai; Wang, Heng; Zhang, Yali; Lu, Rongguo; Liu, Yong

2015-10-15

A calibration-free electrical method is proposed for measuring the absolute frequency response of directly modulated semiconductor lasers based on additional modulation. The method achieves the electrical domain measurement of the modulation index of directly modulated lasers without the need for correcting the responsivity fluctuation in the photodetection. Moreover, it doubles measuring frequency range by setting a specific frequency relationship between the direct and additional modulation. Both the absolute and relative frequency response of semiconductor lasers are experimentally measured from the electrical spectrum of the twice-modulated optical signal, and the measured results are compared to those obtained with conventional methods to check the consistency. The proposed method provides calibration-free and accurate measurement for high-speed semiconductor lasers with high-resolution electrical spectrum analysis.
Design of a fragment library that maximally represents available chemical space.

PubMed

Schulz, M N; Landström, J; Bright, K; Hubbard, R E

2011-07-01

Cheminformatics protocols have been developed and assessed that identify a small set of fragments which can represent the compounds in a chemical library for use in fragment-based ligand discovery. Six different methods have been implemented and tested on Input Libraries of compounds from three suppliers. The resulting Fragment Sets have been characterised on the basis of computed physico-chemical properties and their similarity to the Input Libraries. A method that iteratively identifies fragments with the maximum number of similar compounds in the Input Library (Nearest Neighbours) produces the most diverse library. This approach could increase the success of experimental ligand discovery projects, by providing fragments that can be progressed rapidly to larger compounds through access to available similar compounds (known as SAR by Catalog).

Modeling Single-Event Transient Propagation in a SiGe BiCMOS Direct-Conversion Receiver

NASA Astrophysics Data System (ADS)

Ildefonso, Adrian; Song, Ickhyun; Tzintzarov, George N.; Fleetwood, Zachary E.; Lourenco, Nelson E.; Wachter, Mason T.; Cressler, John D.

2017-08-01

The propagation of single-event transient (SET) signals in a silicon-germanium direct-conversion receiver carrying modulated data is explored. A theoretical analysis of transient propagation, verified by simulation, is presented. A new methodology to characterize and quantify the impact of SETs in communication systems carrying modulated data is proposed. The proposed methodology uses a pulsed radiation source to induce distortions in the signal constellation. The error vector magnitude due to SETs can then be calculated to quantify errors. Two different modulation schemes were simulated: QPSK and 16-QAM. The distortions in the constellation diagram agree with the presented circuit theory. Furthermore, the proposed methodology was applied to evaluate the improvements in the SET response due to a known radiation-hardening-by-design (RHBD) technique, where the common-base device of the low-noise amplifier was operated in inverse mode. The proposed methodology can be a valid technique to determine the most sensitive parts of a system carrying modulated data.
Reflective photovoltaics

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

Lentine, Anthony L.; Nielson, Gregory N.; Cruz-Campa, Jose Luis

A photovoltaic module includes colorized reflective photovoltaic cells that act as pixels. The colorized reflective photovoltaic cells are arranged so that reflections from the photovoltaic cells or pixels visually combine into an image on the photovoltaic module. The colorized photovoltaic cell or pixel is composed of a set of 100 to 256 base color sub-pixel reflective segments or sub-pixels. The color of each pixel is determined by the combination of base color sub-pixels forming the pixel. As a result, each pixel can have a wide variety of colors using a set of base colors, which are created, from sub-pixel reflectivemore » segments having standard film thicknesses.« less
KSC-2010-1134

NASA Image and Video Library

2010-01-08

CAPE CANAVERAL, Fla. - In Orbiter Processing Facility 3 at NASA's Kennedy Space Center in Florida, members of space shuttle Discovery's STS-131 crew participate in training activities during the Crew Equipment Interface Test, or CEIT, for their mission. Here, Pilot James P. Dutton Jr. experiences the feel of the cockpit from inside the crew module. The CEIT provides the crew with hands-on training and observation of shuttle and flight hardware. The seven-member crew will deliver the multi-purpose logistics module Leonardo, filled with resupply stowage platforms and racks to be transferred to locations around the International Space Station. Three spacewalks will include work to attach a spare ammonia tank assembly to the station's exterior and return a European experiment from outside the station's Columbus module. Discovery's launch is targeted for March 18. For information on the STS-131 mission and crew, visit http://www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts131/index.html. Photo credit: NASA/Kim Shiflett
A critique of the molecular target-based drug discovery paradigm based on principles of metabolic control: advantages of pathway-based discovery.

PubMed

Hellerstein, Marc K

2008-01-01

Contemporary drug discovery and development (DDD) is dominated by a molecular target-based paradigm. Molecular targets that are potentially important in disease are physically characterized; chemical entities that interact with these targets are identified by ex vivo high-throughput screening assays, and optimized lead compounds enter testing as drugs. Contrary to highly publicized claims, the ascendance of this approach has in fact resulted in the lowest rate of new drug approvals in a generation. The primary explanation for low rates of new drugs is attrition, or the failure of candidates identified by molecular target-based methods to advance successfully through the DDD process. In this essay, I advance the thesis that this failure was predictable, based on modern principles of metabolic control that have emerged and been applied most forcefully in the field of metabolic engineering. These principles, such as the robustness of flux distributions, address connectivity relationships in complex metabolic networks and make it unlikely a priori that modulating most molecular targets will have predictable, beneficial functional outcomes. These same principles also suggest, however, that unexpected therapeutic actions will be common for agents that have any effect (i.e., that complexity can be exploited therapeutically). A potential operational solution (pathway-based DDD), based on observability rather than predictability, is described, focusing on emergent properties of key metabolic pathways in vivo. Recent examples of pathway-based DDD are described. In summary, the molecular target-based DDD paradigm is built on a naïve and misleading model of biologic control and is not heuristically adequate for advancing the mission of modern therapeutics. New approaches that take account of and are built on principles described by metabolic engineers are needed for the next generation of DDD.
Brain penetrant liver X receptor (LXR) modulators based on a 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole core.

PubMed

Tice, Colin M; Noto, Paul B; Fan, Kristi Yi; Zhao, Wei; Lotesta, Stephen D; Dong, Chengguo; Marcus, Andrew P; Zheng, Ya-Jun; Chen, Guozhou; Wu, Zhongren; Van Orden, Rebecca; Zhou, Jing; Bukhtiyarov, Yuri; Zhao, Yi; Lipinski, Kerri; Howard, Lamont; Guo, Joan; Kandpal, Geeta; Meng, Shi; Hardy, Andrew; Krosky, Paula; Gregg, Richard E; Leftheris, Katerina; McKeever, Brian M; Singh, Suresh B; Lala, Deepak; McGeehan, Gerard M; Zhuang, Linghang; Claremon, David A

2016-10-15

Liver X receptor (LXR) agonists have been reported to lower brain amyloid beta (Aβ) and thus to have potential for the treatment of Alzheimer's disease. Structure and property based design led to the discovery of a series of orally bioavailable, brain penetrant LXR agonists. Oral administration of compound 18 to rats resulted in significant upregulation of the expression of the LXR target gene ABCA1 in brain tissue, but no significant effect on Aβ levels was detected. Copyright © 2016 Elsevier Ltd. All rights reserved.
Mirror neuron system based therapy for emotional disorders.

PubMed

Yuan, Ti-Fei; Hoff, Robert

2008-11-01

Mirror neuron system (MNS) represents one of the most important discoveries in the area of neuropsychology of past decades. More than 500 papers have been published in this area (PubMed), and the major functions of MNS include action understanding, imitation, empathy, all of which are critical for an individual to be social. Recent studies suggested that MNS can modulate emotion states possibly through the empathy mechanism. Here we propose that MNS-based therapies provide a non-invasive approach in treatments to emotional disorders that were observed in autism patients, post-stroke patients with depression as well as other mood dysregulation conditions.
Prior knowledge based mining functional modules from Yeast PPI networks with gene ontology

PubMed Central

2010-01-01

Background In the literature, there are fruitful algorithmic approaches for identification functional modules in protein-protein interactions (PPI) networks. Because of accumulation of large-scale interaction data on multiple organisms and non-recording interaction data in the existing PPI database, it is still emergent to design novel computational techniques that can be able to correctly and scalably analyze interaction data sets. Indeed there are a number of large scale biological data sets providing indirect evidence for protein-protein interaction relationships. Results The main aim of this paper is to present a prior knowledge based mining strategy to identify functional modules from PPI networks with the aid of Gene Ontology. Higher similarity value in Gene Ontology means that two gene products are more functionally related to each other, so it is better to group such gene products into one functional module. We study (i) to encode the functional pairs into the existing PPI networks; and (ii) to use these functional pairs as pairwise constraints to supervise the existing functional module identification algorithms. Topology-based modularity metric and complex annotation in MIPs will be used to evaluate the identified functional modules by these two approaches. Conclusions The experimental results on Yeast PPI networks and GO have shown that the prior knowledge based learning methods perform better than the existing algorithms. PMID:21172053
An assessment of envelope-based demodulation in case of proximity of carrier and modulation frequencies

NASA Astrophysics Data System (ADS)

Shahriar, Md Rifat; Borghesani, Pietro; Randall, R. B.; Tan, Andy C. C.

2017-11-01

Demodulation is a necessary step in the field of diagnostics to reveal faults whose signatures appear as an amplitude and/or frequency modulation. The Hilbert transform has conventionally been used for the calculation of the analytic signal required in the demodulation process. However, the carrier and modulation frequencies must meet the conditions set by the Bedrosian identity for the Hilbert transform to be applicable for demodulation. This condition, basically requiring the carrier frequency to be sufficiently higher than the frequency of the modulation harmonics, is usually satisfied in many traditional diagnostic applications (e.g. vibration analysis of gear and bearing faults) due to the order-of-magnitude ratio between the carrier and modulation frequency. However, the diversification of the diagnostic approaches and applications shows cases (e.g. electrical signature analysis-based diagnostics) where the carrier frequency is in close proximity to the modulation frequency, thus challenging the applicability of the Bedrosian theorem. This work presents an analytic study to quantify the error introduced by the Hilbert transform-based demodulation when the Bedrosian identity is not satisfied and proposes a mitigation strategy to combat the error. An experimental study is also carried out to verify the analytical results. The outcome of the error analysis sets a confidence limit on the estimated modulation (both shape and magnitude) achieved through the Hilbert transform-based demodulation in case of violated Bedrosian theorem. However, the proposed mitigation strategy is found effective in combating the demodulation error aroused in this scenario, thus extending applicability of the Hilbert transform-based demodulation.
Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development

PubMed Central

Sharma, Charu; Sadek, Bassem; Goyal, Sameer N.; Sinha, Satyesh; Ojha, Shreesh

2015-01-01

The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB1 and CB2) which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ9-tetrahydrocannabinol mediates its action through CB1/CB2 receptors. However, these synthetic based Cannabis derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than Cannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics. PMID:26664449
Evidence for Deep Regulatory Similarities in Early Developmental Programs across Highly Diverged Insects

PubMed Central

Zhang, Yinan; Samee, Md. Abul Hassan; Halfon, Marc S.; Sinha, Saurabh

2014-01-01

Many genes familiar from Drosophila development, such as the so-called gap, pair-rule, and segment polarity genes, play important roles in the development of other insects and in many cases appear to be deployed in a similar fashion, despite the fact that Drosophila-like “long germband” development is highly derived and confined to a subset of insect families. Whether or not these similarities extend to the regulatory level is unknown. Identification of regulatory regions beyond the well-studied Drosophila has been challenging as even within the Diptera (flies, including mosquitoes) regulatory sequences have diverged past the point of recognition by standard alignment methods. Here, we demonstrate that methods we previously developed for computational cis-regulatory module (CRM) discovery in Drosophila can be used effectively in highly diverged (250–350 Myr) insect species including Anopheles gambiae, Tribolium castaneum, Apis mellifera, and Nasonia vitripennis. In Drosophila, we have successfully used small sets of known CRMs as “training data” to guide the search for other CRMs with related function. We show here that although species-specific CRM training data do not exist, training sets from Drosophila can facilitate CRM discovery in diverged insects. We validate in vivo over a dozen new CRMs, roughly doubling the number of known CRMs in the four non-Drosophila species. Given the growing wealth of Drosophila CRM annotation, these results suggest that extensive regulatory sequence annotation will be possible in newly sequenced insects without recourse to costly and labor-intensive genome-scale experiments. We develop a new method, Regulus, which computes a probabilistic score of similarity based on binding site composition (despite the absence of nucleotide-level sequence alignment), and demonstrate similarity between functionally related CRMs from orthologous loci. Our work represents an important step toward being able to trace the evolutionary history of gene regulatory networks and defining the mechanisms underlying insect evolution. PMID:25173756
Evidence for deep regulatory similarities in early developmental programs across highly diverged insects.

PubMed

Kazemian, Majid; Suryamohan, Kushal; Chen, Jia-Yu; Zhang, Yinan; Samee, Md Abul Hassan; Halfon, Marc S; Sinha, Saurabh

2014-09-01

Many genes familiar from Drosophila development, such as the so-called gap, pair-rule, and segment polarity genes, play important roles in the development of other insects and in many cases appear to be deployed in a similar fashion, despite the fact that Drosophila-like "long germband" development is highly derived and confined to a subset of insect families. Whether or not these similarities extend to the regulatory level is unknown. Identification of regulatory regions beyond the well-studied Drosophila has been challenging as even within the Diptera (flies, including mosquitoes) regulatory sequences have diverged past the point of recognition by standard alignment methods. Here, we demonstrate that methods we previously developed for computational cis-regulatory module (CRM) discovery in Drosophila can be used effectively in highly diverged (250-350 Myr) insect species including Anopheles gambiae, Tribolium castaneum, Apis mellifera, and Nasonia vitripennis. In Drosophila, we have successfully used small sets of known CRMs as "training data" to guide the search for other CRMs with related function. We show here that although species-specific CRM training data do not exist, training sets from Drosophila can facilitate CRM discovery in diverged insects. We validate in vivo over a dozen new CRMs, roughly doubling the number of known CRMs in the four non-Drosophila species. Given the growing wealth of Drosophila CRM annotation, these results suggest that extensive regulatory sequence annotation will be possible in newly sequenced insects without recourse to costly and labor-intensive genome-scale experiments. We develop a new method, Regulus, which computes a probabilistic score of similarity based on binding site composition (despite the absence of nucleotide-level sequence alignment), and demonstrate similarity between functionally related CRMs from orthologous loci. Our work represents an important step toward being able to trace the evolutionary history of gene regulatory networks and defining the mechanisms underlying insect evolution. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
Cancer genomics: technology, discovery, and translation.

PubMed

Tran, Ben; Dancey, Janet E; Kamel-Reid, Suzanne; McPherson, John D; Bedard, Philippe L; Brown, Andrew M K; Zhang, Tong; Shaw, Patricia; Onetto, Nicole; Stein, Lincoln; Hudson, Thomas J; Neel, Benjamin G; Siu, Lillian L

2012-02-20

In recent years, the increasing awareness that somatic mutations and other genetic aberrations drive human malignancies has led us within reach of personalized cancer medicine (PCM). The implementation of PCM is based on the following premises: genetic aberrations exist in human malignancies; a subset of these aberrations drive oncogenesis and tumor biology; these aberrations are actionable (defined as having the potential to affect management recommendations based on diagnostic, prognostic, and/or predictive implications); and there are highly specific anticancer agents available that effectively modulate these targets. This article highlights the technology underlying cancer genomics and examines the early results of genome sequencing and the challenges met in the discovery of new genetic aberrations. Finally, drawing from experiences gained in a feasibility study of somatic mutation genotyping and targeted exome sequencing led by Princess Margaret Hospital-University Health Network and the Ontario Institute for Cancer Research, the processes, challenges, and issues involved in the translation of cancer genomics to the clinic are discussed.
Implications of gamma band activity in the pedunculopontine nucleus

PubMed Central

Garcia-Rill, E.; Luster, B.; D’Onofrio, S.; Mahaffey, S.; Bisagno, V.; Urbano, F. J.

2015-01-01

The fact that the pedunculopontine nucleus (PPN) is part of the reticular activating system places it in a unique position to modulate sensory input and fight-or-flight responses. Arousing stimuli simultaneously activate ascending projections of the PPN to the intralaminar thalamus to trigger cortical high frequency activity and arousal, as well as descending projections to reticulospinal systems to alter posture and locomotion. As such, the PPN has become a target for deep brain stimulation (DBS) for the treatment of Parkinson’s disease (PD), modulating gait, posture, and higher functions. This article describes the latest discoveries on PPN physiology and the role of the PPN in a number of disorders. It has now been determined that high frequency activity during waking and REM sleep is controlled by two different intracellular pathways and two calcium channels in PPN cells. Moreover, there are three different PPN cell types that have one or both calcium channels and may be active during waking only, REM sleep only, or both. Based on the new discoveries, novel mechanisms are proposed for insomnia as a waking disorder. In addition, neuronal calcium sensor protein-1 (NCS-1), which is over expressed in schizophrenia and bipolar disorder, may be responsible for the dysregulation in gamma band activity in at least some patients with these diseases. Recent results suggest that NCS-1 modulates PPN gamma band activity and that lithium acts to reduce the effects of over expressed NCS-1, accounting for its effectiveness in bipolar disorder. PMID:26597124
Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias

PubMed Central

Sengmany, K

2015-01-01

The metabotropic glutamate receptor subtype 5 (mGlu5) is a family C GPCR that has been implicated in various neuronal processes and, consequently, in several CNS disorders. Over the past few decades, GPCR‐based drug discovery, including that for mGlu5 receptors, has turned considerable attention to targeting allosteric binding sites. Modulation of endogenous agonists by allosteric ligands offers the advantages of spatial and temporal fine‐tuning of receptor activity, increased selectivity and reduced adverse effects with the potential to elicit improved clinical outcomes. Further, with greater appreciation of the multifaceted nature of the transduction of mGlu5 receptor signalling, it is increasingly apparent that drug discovery must take into consideration unique receptor conformations and the potential for stimulus‐bias. This novel paradigm proposes that different ligands may differentially modulate distinct signalling pathways arising from the same receptor. We review our current understanding of the complexities of mGlu5 receptor signalling and regulation, and how these relate to allosteric ligands. Ultimately, a deeper appreciation of these relationships will provide the foundation for targeted drug design of compounds with increased selectivity, not only for the desired receptor but also for the desired signalling outcome from the receptor. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein‐Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc PMID:26276909
An integrated micromechanical large particle in flow sorter (MILPIS)

NASA Astrophysics Data System (ADS)

Fuad, Nurul M.; Skommer, Joanna; Friedrich, Timo; Kaslin, Jan; Wlodkowic, Donald

2015-06-01

At present, the major hurdle to widespread deployment of zebrafish embryo and larvae in large-scale drug development projects is lack of enabling high-throughput analytical platforms. In order to spearhead drug discovery with the use of zebrafish as a model, platforms need to integrate automated pre-test sorting of organisms (to ensure quality control and standardization) and their in-test positioning (suitable for high-content imaging) with modules for flexible drug delivery. The major obstacle hampering sorting of millimetre sized particles such as zebrafish embryos on chip-based devices is their substantial diameter (above one millimetre), mass (above one milligram), which both lead to rapid gravitational-induced sedimentation and high inertial forces. Manual procedures associated with sorting hundreds of embryos are very monotonous and as such prone to significant analytical errors due to operator's fatigue. In this work, we present an innovative design of a micromechanical large particle in-flow sorter (MILPIS) capable of analysing, sorting and dispensing living zebrafish embryos for drug discovery applications. The system consisted of a microfluidic network, revolving micromechanical receptacle actuated by robotic servomotor and opto-electronic sensing module. The prototypes were fabricated in poly(methyl methacrylate) (PMMA) transparent thermoplastic using infrared laser micromachining. Elements of MILPIS were also fabricated in an optically transparent VisiJet resin using 3D stereolithography (SLA) processes (ProJet 7000HD, 3D Systems). The device operation was based on a rapidly revolving miniaturized mechanical receptacle. The latter function was to hold and position individual fish embryos for (i) interrogation, (ii) sorting decision-making and (iii) physical sorting..The system was designed to separate between fertilized (LIVE) and non-fertilized (DEAD) eggs, based on optical transparency using infrared (IR) emitters and receivers embedded in the system. Digital oscilloscope were used to distinguish the diffraction signals from IR sensors when both LIVE and DEAD embryos were flow through in the chip. Image process analysis were also used as detection module to track DEAD embryos as it flowed in the channel.
Flow Cytometry: Impact on Early Drug Discovery.

PubMed

Edwards, Bruce S; Sklar, Larry A

2015-07-01

Modern flow cytometers can make optical measurements of 10 or more parameters per cell at tens of thousands of cells per second and more than five orders of magnitude dynamic range. Although flow cytometry is used in most drug discovery stages, "sip-and-spit" sampling technology has restricted it to low-sample-throughput applications. The advent of HyperCyt sampling technology has recently made possible primary screening applications in which tens of thousands of compounds are analyzed per day. Target-multiplexing methodologies in combination with extended multiparameter analyses enable profiling of lead candidates early in the discovery process, when the greatest numbers of candidates are available for evaluation. The ability to sample small volumes with negligible waste reduces reagent costs, compound usage, and consumption of cells. Improved compound library formatting strategies can further extend primary screening opportunities when samples are scarce. Dozens of targets have been screened in 384- and 1536-well assay formats, predominantly in academic screening lab settings. In concert with commercial platform evolution and trending drug discovery strategies, HyperCyt-based systems are now finding their way into mainstream screening labs. Recent advances in flow-based imaging, mass spectrometry, and parallel sample processing promise dramatically expanded single-cell profiling capabilities to bolster systems-level approaches to drug discovery. © 2015 Society for Laboratory Automation and Screening.
Flow Cytometry: Impact On Early Drug Discovery

PubMed Central

Edwards, Bruce S.; Sklar, Larry A.

2015-01-01

Summary Modern flow cytometers can make optical measurements of 10 or more parameters per cell at tens-of-thousands of cells per second and over five orders of magnitude dynamic range. Although flow cytometry is used in most drug discovery stages, “sip-and-spit” sampling technology has restricted it to low sample throughput applications. The advent of HyperCyt sampling technology has recently made possible primary screening applications in which tens-of-thousands of compounds are analyzed per day. Target-multiplexing methodologies in combination with extended multi-parameter analyses enable profiling of lead candidates early in the discovery process, when the greatest numbers of candidates are available for evaluation. The ability to sample small volumes with negligible waste reduces reagent costs, compound usage and consumption of cells. Improved compound library formatting strategies can further extend primary screening opportunities when samples are scarce. Dozens of targets have been screened in 384- and 1536-well assay formats, predominantly in academic screening lab settings. In concert with commercial platform evolution and trending drug discovery strategies, HyperCyt-based systems are now finding their way into mainstream screening labs. Recent advances in flow-based imaging, mass spectrometry and parallel sample processing promise dramatically expanded single cell profiling capabilities to bolster systems level approaches to drug discovery. PMID:25805180
Cloud Atlas: Discovery of Rotational Spectral Modulations in a Low-mass, L-type Brown Dwarf Companion to a Star

NASA Astrophysics Data System (ADS)

Manjavacas, Elena; Apai, Dániel; Zhou, Yifan; Karalidi, Theodora; Lew, Ben W. P.; Schneider, Glenn; Cowan, Nicolas; Metchev, Stan; Miles-Páez, Paulo A.; Burgasser, Adam J.; Radigan, Jacqueline; Bedin, Luigi R.; Lowrance, Patrick J.; Marley, Mark S.

2018-01-01

Observations of rotational modulations of brown dwarfs and giant exoplanets allow the characterization of condensate cloud properties. As of now, rotational spectral modulations have only been seen in three L-type brown dwarfs. We report here the discovery of rotational spectral modulations in LP261-75B, an L6-type intermediate surface gravity companion to an M4.5 star. As a part of the Cloud Atlas Treasury program, we acquired time-resolved Wide Field Camera 3 grism spectroscopy (1.1–1.69 μm) of LP261-75B. We find gray spectral variations with the relative amplitude displaying only a weak wavelength dependence and no evidence for lower-amplitude modulations in the 1.4 μm water band than in the adjacent continuum. The likely rotational modulation period is 4.78 ± 0.95 hr, although the rotational phase is not well sampled. The minimum relative amplitude in the white light curve measured over the whole wavelength range is 2.41% ± 0.14%. We report an unusual light curve, which seems to have three peaks approximately evenly distributed in rotational phase. The spectral modulations suggests that the upper atmosphere cloud properties in LP261-75B are similar to two other mid-L dwarfs of typical infrared colors, but differ from that of the extremely red L-dwarf WISE0047.
Validation of Skeletal Muscle cis-Regulatory Module Predictions Reveals Nucleotide Composition Bias in Functional Enhancers

PubMed Central

Kwon, Andrew T.; Chou, Alice Yi; Arenillas, David J.; Wasserman, Wyeth W.

2011-01-01

We performed a genome-wide scan for muscle-specific cis-regulatory modules (CRMs) using three computational prediction programs. Based on the predictions, 339 candidate CRMs were tested in cell culture with NIH3T3 fibroblasts and C2C12 myoblasts for capacity to direct selective reporter gene expression to differentiated C2C12 myotubes. A subset of 19 CRMs validated as functional in the assay. The rate of predictive success reveals striking limitations of computational regulatory sequence analysis methods for CRM discovery. Motif-based methods performed no better than predictions based only on sequence conservation. Analysis of the properties of the functional sequences relative to inactive sequences identifies nucleotide sequence composition can be an important characteristic to incorporate in future methods for improved predictive specificity. Muscle-related TFBSs predicted within the functional sequences display greater sequence conservation than non-TFBS flanking regions. Comparison with recent MyoD and histone modification ChIP-Seq data supports the validity of the functional regions. PMID:22144875
Charting, navigating, and populating natural product chemical space for drug discovery.

PubMed

Lachance, Hugo; Wetzel, Stefan; Kumar, Kamal; Waldmann, Herbert

2012-07-12

Natural products are a heterogeneous group of compounds with diverse, yet particular molecular properties compared to synthetic compounds and drugs. All relevant analyses show that natural products indeed occupy parts of chemical space not explored by available screening collections while at the same time largely adhering to the rule-of-five. This renders them a valuable, unique, and necessary component of screening libraries used in drug discovery. With ChemGPS-NP on the Web and Scaffold Hunter two tools are available to the scientific community to guide exploration of biologically relevant NP chemical space in a focused and targeted fashion with a view to guide novel synthesis approaches. Several of the examples given illustrate the possibility of bridging the gap between computational methods and compound library synthesis and the possibility of integrating cheminformatics and chemical space analyses with synthetic chemistry and biochemistry to successfully explore chemical space for the identification of novel small molecule modulators of protein function.The examples also illustrate the synergistic potential of the chemical space concept and modern chemical synthesis for biomedical research and drug discovery. Chemical space analysis can map under explored biologically relevant parts of chemical space and identify the structure types occupying these parts. Modern synthetic methodology can then be applied to efficiently fill this “virtual space” with real compounds.From a cheminformatics perspective, there is a clear demand for open-source and easy to use tools that can be readily applied by educated nonspecialist chemists and biologists in their daily research. This will include further development of Scaffold Hunter, ChemGPS-NP, and related approaches on the Web. Such a “cheminformatics toolbox” would enable chemists and biologists to mine their own data in an intuitive and highly interactive process and without the need for specialized computer science and cheminformatics expertise. We anticipate that it may be a viable, if not necessary, step for research initiatives based on large high-throughput screening campaigns,in particular in the pharmaceutical industry, to make the most out of the recent advances in computational tools in order to leverage and take full advantage of the large data sets generated and available in house. There are “holes” in these data sets that can and should be identified and explored by chemistry and biology.

KSC-06pd0840

NASA Image and Video Library

2006-05-17

KENNEDY SPACE CENTER, FLA. -- The payload canister passes NASA's Vehicle Assembly Building and Launch Control Center on its way to Launch Pad 39B. Inside are the payloads for mission STS-121: the multi-purpose logistics module Leonardo, with supplies and equipment for the International Space Station; the lightweight multi-purpose experiment support structure carrier; and the integrated cargo carrier, with the mobile transporter reel assembly and a spare pump module. The payload will be transferred from the canister to Space Shuttle Discovery's payload bay at the pad. Discovery is scheduled to launch on mission STS-121 from Launch Pad 39B in a window that opens July 1 and extends to July 19. Photo credit: NASA/Kim Shiflett
KSC-06pd0845

NASA Image and Video Library

2006-05-17

KENNEDY SPACE CENTER, FLA. -- The payload canister passes NASA's Vehicle Assembly Building and Launch Control Center on its way to Launch Pad 39B. Inside are the payloads for mission STS-121: the multi-purpose logistics module Leonardo, with supplies and equipment for the International Space Station; the lightweight multi-purpose experiment support structure carrier; and the integrated cargo carrier, with the mobile transporter reel assembly and a spare pump module. The payload will be transferred from the canister to Space Shuttle Discovery's payload bay at the pad. Discovery is scheduled to launch on mission STS-121 from Launch Pad 39B in a window that opens July 1 and extends to July 19. Photo credit: NASA/Troy Cryder
KSC-06pd0841

NASA Image and Video Library

2006-05-17

KENNEDY SPACE CENTER, FLA. -- The payload canister passes NASA's Vehicle Assembly Building and Launch Control Center on its way to Launch Pad 39B. Inside are the payloads for mission STS-121: the multi-purpose logistics module Leonardo, with supplies and equipment for the International Space Station; the lightweight multi-purpose experiment support structure carrier; and the integrated cargo carrier, with the mobile transporter reel assembly and a spare pump module. The payload will be transferred from the canister to Space Shuttle Discovery's payload bay at the pad. Discovery is scheduled to launch on mission STS-121 from Launch Pad 39B in a window that opens July 1 and extends to July 19. Photo credit: NASA/George Shelton
Raffaello Multi-Purpose Logistics Module (MPLM) in Discovery Cargo Bay

NASA Technical Reports Server (NTRS)

2005-01-01

Launched on July 26, 2005 from the Kennedy Space Center in Florida, STS-114 was classified as Logistics Flight 1. Among the Station-related activities of the mission were the delivery of new supplies and the replacement of one of the orbital outpost's Control Moment Gyroscopes (CMGs). STS-114 also carried the Raffaello Multi-Purpose Logistics Module (MPLM) and the External Stowage Platform-2. Back dropped by popcorn-like clouds, the MPLM can be seen in the cargo bay as Discovery undergoes rendezvous and docking operations. Cosmonaut Sergei K. Kriklev, Expedition 11 Commander, and John L. Phillips, NASA Space Station officer and flight engineer photographed the spacecraft from the International Space Station (ISS).
Raffaello Multi-Purpose Logistics Module (MPLM) in Discovery Cargo Bay

NASA Technical Reports Server (NTRS)

2005-01-01

Launched on July 26 2005 from the Kennedy Space Center in Florida, STS-114 was classified as Logistics Flight 1. Among the Station-related activities of the mission were the delivery of new supplies and the replacement of one of the orbital outpost's Control Moment Gyroscopes (CMGs). STS-114 also carried the Raffaello Multi-Purpose Logistics Module (MPLM) and the External Stowage Platform-2. Back dropped by popcorn-like clouds, the MPLM can be seen in the cargo bay as Discovery undergoes rendezvous and docking operations. Cosmonaut Sergei K. Kriklev, Expedition 11 Commander, and John L. Phillips, NASA Space Station officer and flight engineer photographed the spacecraft from the International Space Station (ISS).
KSC-08pd1109

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, dawn reveals the arrival of space shuttle Discovery, secured atop the mobile launch platform below, at Launch Pad 39A to begin prelaunch processing for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder
KSC-08pd1106

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, space shuttle Discovery, secured atop the mobile launch platform below, arrives at Launch Pad 39A to begin prelaunch processing for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder
KSC-08pd1105

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- This aerial view of NASA's Kennedy Space Center shows space shuttle Discovery, secured atop a mobile launch platform as it is moved into position at Launch Pad 39A to prepare for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder
KSC-08pd1110

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, the sun rises upon the arrival of space shuttle Discovery, secured atop the mobile launch platform below, at Launch Pad 39A to begin prelaunch processing for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder
Genome-wide association studies identify several new loci associated with pigmentation traits and skin cancer risk in European Americans

PubMed Central

Zhang, Mingfeng; Song, Fengju; Liang, Liming; Nan, Hongmei; Zhang, Jiangwen; Liu, Hongliang; Wang, Li-E.; Wei, Qingyi; Lee, Jeffrey E.; Amos, Christopher I.; Kraft, Peter; Qureshi, Abrar A.; Han, Jiali

2013-01-01

Aiming to identify novel genetic loci for pigmentation and skin cancer, we conducted a series of genome-wide association studies on hair color, eye color, number of sunburns, tanning ability and number of non-melanoma skin cancers (NMSCs) among 10 183 European Americans in the discovery stage and 4504 European Americans in the replication stage (for eye color, 3871 males in the discovery stage and 2496 males in the replication stage). We targeted novel chromosome regions besides the known ones for replication. As a result, we identified a new region downstream of the EDNRB gene on 13q22 associated with hair color and the strongest association was the single-nucleotide polymorphism (SNP) rs975739 (P = 2.4 × 10−14; P = 5.4 × 10−9 in the discovery set and P = 1.2 × 10−6 in the replication set). Using blue, intermediate (including green) and brown eye colors as co-dominant outcomes, we identified the SNP rs3002288 in VASH2 on 1q32.3 associated with brown eye (P = 7.0 × 10−8; P = 5.3 × 10−5 in the discovery set and P = 0.02 in the replication set). Additionally, we identified a significant interaction between the SNPs rs7173419 and rs12913832 in the OCA2 gene region on brown eye color (P-value for interaction = 3.8 × 10−3). As for the number of NMSCs, we identified two independent SNPs on chr6 and one SNP on chromosome 14: rs12203592 in IRF4 (P = 7.2 × 10−14; P = 1.8 × 10−8 in the discovery set and P = 6.7 × 10−7 in the replication set), rs12202284 between IRF4 and EXOC2 (P = 5.0 × 10−8; P = 6.6 × 10−7 in the discovery set and P = 3.0 × 10−3 in the replication set) and rs8015138 upstream of GNG2 (P = 6.6 × 10−8; P = 5.3 × 10−7 in the discovery set and P = 0.01 in the replication set). PMID:23548203
Training Scientific Thinking Skills: Evidence from an MCAT[superscript 2015]-Aligned Classroom Module

ERIC Educational Resources Information Center

Stevens, Courtney; Witkow, Melissa R.

2014-01-01

The present study reports on the development and evaluation of a classroom module to train scientific thinking skills. The module was implemented in two of four parallel sections of introductory psychology. To assess learning, a passage-based question set from the medical college admissions test (MCAT[superscript 2015]) preview guide was included…
Parenting Skills: A Trainer's Manual. A Performance Based Early Childhood-Special Education Teacher Preparation Program. Monograph 3.

ERIC Educational Resources Information Center

Abidin, Richard R.

This manual, developed as part of the performance-based Early Childhood-Special Education Teacher Preparation Program, is a trainer's manual for teaching parenting skills. Each module or set of modules presents effective skills for managing and changing behaviors of adults and children. Several profession strategies and theoretical orientations…
Air Quality uFIND: User-oriented Tool Set for Air Quality Data Discovery and Access

NASA Astrophysics Data System (ADS)

Hoijarvi, K.; Robinson, E. M.; Husar, R. B.; Falke, S. R.; Schultz, M. G.; Keating, T. J.

2012-12-01

Historically, there have been major impediments to seamless and effective data usage encountered by both data providers and users. Over the last five years, the international Air Quality (AQ) Community has worked through forums such as the Group on Earth Observations AQ Community of Practice, the ESIP AQ Working Group, and the Task Force on Hemispheric Transport of Air Pollution to converge on data format standards (e.g., netCDF), data access standards (e.g., Open Geospatial Consortium Web Coverage Services), metadata standards (e.g., ISO 19115), as well as other conventions (e.g., CF Naming Convention) in order to build an Air Quality Data Network. The centerpiece of the AQ Data Network is the web service-based tool set: user-oriented Filtering and Identification of Networked Data. The purpose of uFIND is to provide rich and powerful facilities for the user to: a) discover and choose a desired dataset by navigation through the multi-dimensional metadata space using faceted search, b) seamlessly access and browse datasets, and c) use uFINDs facilities as a web service for mashups with other AQ applications and portals. In a user-centric information system such as uFIND, the user experience is improved by metadata that includes the general fields for discovery as well as community-specific metadata to narrow the search beyond space, time and generic keyword searches. However, even with the community-specific additions, the ISO 19115 records were formed in compliance with the standard, so that other standards-based search interface could leverage this additional information. To identify the fields necessary for metadata discovery we started with the ISO 19115 Core Metadata fields and fields that were needed for a Catalog Service for the Web (CSW) Record. This fulfilled two goals - one to create valid ISO 19115 records and the other to be able to retrieve the records through a Catalog Service for the Web query. Beyond the required set of fields, the AQ Community added additional fields using a combination of keywords and ISO 19115 fields. These extensions allow discovery by measurement platform or observed phenomena. Beyond discovery metadata, the AQ records include service identification objects that allow standards-based clients, such as some brokers, to access the data found via OGC WCS or WMS data access protocols. uFIND, is one such smart client, this combination of discovery and access metadata allows the user to preview each registered dataset through spatial and temporal views; observe the data access and usage pattern and also find links to dataset-specific metadata directly in uFIND. The AQ data providers also benefit from this architecture since their data products are easier to find and re-use, enhancing the relevance and importance of their products. Finally, the earth science community at large benefits from the Service Oriented Architecture of uFIND, since it is a service itself and allows service-based interfacing with providers and users of the metadata, allowing uFIND facets to be further refined for a particular AQ application or completely repurposed for other Earth Science domains that use the same set of data access and metadata standards.
Cell-based assays in GPCR drug discovery.

PubMed

Siehler, Sandra

2008-04-01

G protein-coupled receptors (GPCRs) transmit extracellular signals into the intracellular space, and play key roles in the physiological regulation of virtually every cell and tissue. Characteristic for the GPCR superfamily of cell surface receptors are their seven transmembrane-spanning alpha-helices, an extracellular N terminus and intracellular C-terminal tail. Besides transmission of extracellular signals, their activity is modulated by cellular signals in an auto- or transregulatory fashion. The molecular complexity of GPCRs and their regulated signaling networks triggered the interest in academic research groups to explore them further, and their drugability and role in pathophysiology triggers pharmaceutical research towards small molecular weight ligands and therapeutic antibodies. About 30% of marketed drugs target GPCRs, which underlines the importance of this target class. This review describes current and emerging cellular assays for the ligand discovery of GPCRs.
Systematic assessment of survey scan and MS2-based abundance strategies for label-free quantitative proteomics using high-resolution MS data.

PubMed

Tu, Chengjian; Li, Jun; Sheng, Quanhu; Zhang, Ming; Qu, Jun

2014-04-04

Survey-scan-based label-free method have shown no compelling benefit over fragment ion (MS2)-based approaches when low-resolution mass spectrometry (MS) was used, the growing prevalence of high-resolution analyzers may have changed the game. This necessitates an updated, comparative investigation of these approaches for data acquired by high-resolution MS. Here, we compared survey scan-based (ion current, IC) and MS2-based abundance features including spectral-count (SpC) and MS2 total-ion-current (MS2-TIC), for quantitative analysis using various high-resolution LC/MS data sets. Key discoveries include: (i) study with seven different biological data sets revealed only IC achieved high reproducibility for lower-abundance proteins; (ii) evaluation with 5-replicate analyses of a yeast sample showed IC provided much higher quantitative precision and lower missing data; (iii) IC, SpC, and MS2-TIC all showed good quantitative linearity (R(2) > 0.99) over a >1000-fold concentration range; (iv) both MS2-TIC and IC showed good linear response to various protein loading amounts but not SpC; (v) quantification using a well-characterized CPTAC data set showed that IC exhibited markedly higher quantitative accuracy, higher sensitivity, and lower false-positives/false-negatives than both SpC and MS2-TIC. Therefore, IC achieved an overall superior performance than the MS2-based strategies in terms of reproducibility, missing data, quantitative dynamic range, quantitative accuracy, and biomarker discovery.
Systematic Assessment of Survey Scan and MS2-Based Abundance Strategies for Label-Free Quantitative Proteomics Using High-Resolution MS Data

PubMed Central

2015-01-01

Survey-scan-based label-free method have shown no compelling benefit over fragment ion (MS2)-based approaches when low-resolution mass spectrometry (MS) was used, the growing prevalence of high-resolution analyzers may have changed the game. This necessitates an updated, comparative investigation of these approaches for data acquired by high-resolution MS. Here, we compared survey scan-based (ion current, IC) and MS2-based abundance features including spectral-count (SpC) and MS2 total-ion-current (MS2-TIC), for quantitative analysis using various high-resolution LC/MS data sets. Key discoveries include: (i) study with seven different biological data sets revealed only IC achieved high reproducibility for lower-abundance proteins; (ii) evaluation with 5-replicate analyses of a yeast sample showed IC provided much higher quantitative precision and lower missing data; (iii) IC, SpC, and MS2-TIC all showed good quantitative linearity (R2 > 0.99) over a >1000-fold concentration range; (iv) both MS2-TIC and IC showed good linear response to various protein loading amounts but not SpC; (v) quantification using a well-characterized CPTAC data set showed that IC exhibited markedly higher quantitative accuracy, higher sensitivity, and lower false-positives/false-negatives than both SpC and MS2-TIC. Therefore, IC achieved an overall superior performance than the MS2-based strategies in terms of reproducibility, missing data, quantitative dynamic range, quantitative accuracy, and biomarker discovery. PMID:24635752
Assessing the State-of-the-Art in Dynamic Discovery of Ad Hoc Network Services

DTIC Science & Technology

2001-07-18

directed -- discovery mode. It is part of the SCM_Discovery -- Module. Sends Unicast messages to SCMs on list of -- SCMS to be discovered until all... SCMS are found. -- Receives updates from SCM DB of discovered SCMs and -- removes SCMs accordingly -- NOTE: Failure and recovery behavior are not...ALLFindService10 SM4 GROUP1GroupJoin10 SCM1 SM4LinkFail5 SM4NodeFail5 ParametersCommandTime TopologyScenario Execute with Rapide For All (SM, SD, SCM
Low-inductance switch and capacitor energy storage modules made of packages of industrial condensers IK50-3

NASA Astrophysics Data System (ADS)

Bykov, Yu A.; Krastelev, E. G.; Sedin, A. A.; Feduschak, V. F.

2017-05-01

A low-inductance module of a high-current capacitive energy storage with an operating voltage of 40 kV is developed. The design of the module is based on the application of capacitive sections of the industrial condenser IK50-3. The module includes two capacitors of 0.35 μF each, one common low-jitter triggered gas switch and 2 groups of output cables of 4 from each capacitor. A bus bars topology developed for the switch and cables connections provides a small total inductance of the discharge circuit, for the module with the output cables KVIM of 0.5 m long, it is lower than 40 nH. The set of 10 modules is now used for driving the 20 stages linear transformer for a fast charging of the pulse forming line of the high-current nanosecond accelerator. A design of the module and the results of tests of a single module and a set of 10 are presented.
Recent developments with boron as a platform for novel drug design.

PubMed

Leśnikowski, Zbigniew J

2016-06-01

After decades of development, the medicinal chemistry of compounds that contain a single boron atom has matured to the present status of having equal rights with other branches of drug discovery, although it remains a relative newcomer. In contrast, the medicinal chemistry of boron clusters is less advanced, but it is expanding and may soon become a productive area of drug discovery. The author reviews the current developments of medicinal chemistry of boron and its applications in drug design. First generation boron drugs that bear a single boron atom and second generation boron drugs that utilize boron clusters as pharmacophores or modulators of bioactive molecules are discussed. The advantages and gaps in our current understanding of boron medicinal chemistry, with a special focus on boron clusters, are highlighted. Boron is not a panacea for every drug discovery problem, but there is a good chance that it will become a useful addition to the medicinal chemistry tool box. The present status of boron resembles the medicinal chemistry status of fluorine three decades ago; indeed, currently, approximately 20% of pharmaceuticals on the market contain fluorine. The fact that novel boron compounds, especially those based on abiotic polyhedral boron hydrides, are currently unfamiliar could be advantageous because organisms may be less prone to developing resistance against boron cluster-based drugs.
Portable detection system of vegetable oils based on laser induced fluorescence

NASA Astrophysics Data System (ADS)

Zhu, Li; Zhang, Yinchao; Chen, Siying; Chen, He; Guo, Pan; Mu, Taotao

2015-11-01

Food safety, especially edible oils, has attracted more and more attention recently. Many methods and instruments have emerged to detect the edible oils, which include oils classification and adulteration. It is well known than the adulteration is based on classification. Then, in this paper, a portable detection system, based on laser induced fluorescence, is proposed and designed to classify the various edible oils, including (olive, rapeseed, walnut, peanut, linseed, sunflower, corn oils). 532 nm laser modules are used in this equipment. Then, all the components are assembled into a module (100*100*25mm). A total of 700 sets of fluorescence data (100 sets of each type oil) are collected. In order to classify different edible oils, principle components analysis and support vector machine have been employed in the data analysis. The training set consisted of 560 sets of data (80 sets of each oil) and the test set consisted of 140 sets of data (20 sets of each oil). The recognition rate is up to 99%, which demonstrates the reliability of this potable system. With nonintrusive and no sample preparation characteristic, the potable system can be effectively applied for food detection.

Simultaneously firing two cylinders of an even firing camless engine

DOEpatents

Brennan, Daniel G

2014-03-11

A valve control system includes an engine speed control module that determines an engine speed and a desired engine stop position. A piston position module determines a desired stopping position of a first piston based on the desired engine stop position. A valve control module receives the desired stopping position, commands a set of valves to close at the desired stopping position if the engine speed is less than a predetermined shutdown threshold, and commands the set of valves to reduce the engine speed if the engine speed is greater than the predetermined shutdown threshold.
37 CFR 42.51 - Discovery.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 37 Patents, Trademarks, and Copyrights 1 2014-07-01 2014-07-01 false Discovery. 42.51 Section 42... Production § 42.51 Discovery. (a) Mandatory initial disclosures. (1) With agreement. Parties may agree to mandatory discovery requiring the initial disclosures set forth in the Office Patent Trial Practice Guide...
37 CFR 42.51 - Discovery.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 37 Patents, Trademarks, and Copyrights 1 2013-07-01 2013-07-01 false Discovery. 42.51 Section 42... Production § 42.51 Discovery. (a) Mandatory initial disclosures. (1) With agreement. Parties may agree to mandatory discovery requiring the initial disclosures set forth in the Office Patent Trial Practice Guide...
Lightning strikes in the distance as the Space Shuttle Discovery receives post-flight processing in the Mate-Demate Device, following its landing at NASA DFRC

NASA Image and Video Library

2005-08-14

Lightning strikes in the distance as the Space Shuttle Discovery receives post-flight processing in the Mate-Demate Device (MDD), following its landing at NASA's Dryden Flight Research Center in California. The gantry-like MDD structure is used for servicing the shuttle orbiters in preparation for their ferry flight back to the Kennedy Space Center in Florida, including mounting the shuttle atop NASA's modified Boeing 747 Shuttle Carrier Aircraft. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.
A technician leaves the 'white room,' the access point for entering the Space Shuttle Discovery during post-flight processing at NASA DFRC in California

NASA Image and Video Library

2005-08-14

A technician leaves the 'white room', the access point for entering the Space Shuttle Discovery during post-flight processing in the Mate-Demate Device (MDD) at NASA's Dryden Flight Research Center in California. The gantry-like MDD structure is used for servicing the shuttle orbiters in preparation for their ferry flight back to the Kennedy Space Center in Florida, including mounting the shuttle atop NASA's modified Boeing 747 Shuttle Carrier Aircraft. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.
The Space Shuttle Discovery receives post-flight servicing in the Mate-Demate Device (MDD) at NASA's Dryden Flight Research Center, Edwards, California

NASA Image and Video Library

2005-08-11

The Space Shuttle Discovery receives post-flight servicing in the Mate-Demate Device (MDD), following its landing at NASA's Dryden Flight Research Center, Edwards, California, August 9, 2005. The gantry-like MDD structure is used for servicing the shuttle orbiters in preparation for their ferry flight back to the Kennedy Space Center in Florida, including mounting the shuttle atop NASA's modified Boeing 747 Shuttle Carrier Aircraft. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.
The Space Shuttle Discovery receives post-flight servicing in the Mate-Demate Device (MDD) at NASA's Dryden Flight Research Center, Edwards, California

NASA Image and Video Library

2005-08-11

The Space Shuttle Discovery receives post-flight servicing in the Mate-Demate Device (MDD), following its landing at NASA's Dryden Flight Research Center, Edwards, California, August 9, 2005. The gantry-like MDD structure is used for servicing the shuttle orbiters in preparation for their ferry flight back to the Kennedy Space Center in Florida, including mounting the shuttle atop NASA's modified Boeing 747 Shuttle Carrier Aircraft. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT this morning, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.
Data-driven Inquiry in Environmental Restoration Studies

NASA Astrophysics Data System (ADS)

Zalles, D. R.; Montgomery, D. R.

2008-12-01

Place-based field work has been recognized as an important component of geoscience education programs for engaging students. Field work helps students appreciate the spatial extent of data and the systems operating in a locale. Data collected in a place has a temporal aspect that can be explored through representations such as photographs and maps and also though numerical data sets that capture characteristics of place. Yet, experiencing authentic geoscience research in an educational setting requires going beyond fieldwork: students must develop data literacy skills that will enable them to connect abstract representations of spatio-temporal data with place. Educational researchers at SRI International led by Dr. Daniel Zalles, developer of inquiry-based geoscience curricula, and geoscientists at the University of Washington (UW) led by Dr. David Montgomery, Professor of Earth and Space Sciences, are building educational curriculum modules that help students make these connections. The modules concern the environmental history of the Puget Sound area in Washington State and its relevance for the American Indians living there. This collaborative project relies on environmental data collected in the Puget Sound Regional Synthesis Model (PRISM) and Puget Sound River History Project. The data sets are being applied to inquiry-based geoscience investigations at the undergraduate and high school level. The modules consist of problem-based units centered on the data sets, plus geographic and other data representations. The modules will rely on educational "design patterns" that characterize geoscientific inquiry tasks. Use of design patterns will enable other modules to be built that align to the modes of student thinking and practice articulated in the design patterns. The modules will be accompanied by performance assessments that measure student learning from their data investigations. The design principles that drive this project have already been used effectively in a prior SRI project reported about at AGU 2007 called Data Sets and Inquiry in Geoscience Education. The modules are being readied for pilot-testing with undergraduate students in a new environmental history course at the University of Washington and with students taking science courses in high schools serving American Indian students in the Puget Sound area. This NSF-funded project is contributing to our knowledge base about how students can become more engaged and more skilled in geoscience inquiry and data analysis and what variations in educational supports and expectations need to exist to build successful experiences for the students with the materials. It is also expanding our knowledge of how to better connect place-based education to inquiry tasks that expand students" quantitative reasoning skills. Lastly, it is providing a model of how scientists can work effectively with educational researchers to provide educational outlets for their research. We will report on the progress of the project so far, which is in its first year of funding.
Comparative Initial and Sustained Engagement in Web-based Training by Behavioral Healthcare Providers in New York State.

PubMed

Talley, Rachel; Chiang, I-Chin; Covell, Nancy H; Dixon, Lisa

2018-06-01

Improved dissemination is critical to implementation of evidence-based practice in community behavioral healthcare settings. Web-based training modalities are a promising strategy for dissemination of evidence-based practice in community behavioral health settings. Initial and sustained engagement of these modalities in large, multidisciplinary community provider samples is not well understood. This study evaluates comparative engagement and user preferences by provider type in a web-based training platform in a large, multidisciplinary community sample of behavioral health staff in New York State. Workforce make-up among platform registrants was compared to the general NYS behavioral health workforce. Training completion by functional job type was compared to characterize user engagement and preferences. Frequently completed modules were classified by credit and requirement incentives. High initial training engagement across professional role was demonstrated, with significant differences in initial and sustained engagement by professional role. The most frequently completed modules across functional job types contained credit or requirement incentives. The analysis demonstrated that high engagement of a web-based training in a multidisciplinary provider audience can be achieved without tailoring content to specific professional roles. Overlap between frequently completed modules and incentives suggests a role for incentives in promoting engagement of web-based training. These findings further the understanding of strategies to promote large-scale dissemination of evidence-based practice in community behavioral health settings.
DPS Discovery Slide Sets for the Introductory Astronomy Instructor

NASA Astrophysics Data System (ADS)

Meinke, Bonnie K.; Jackson, Brian; Buxner, Sanlyn; Horst, Sarah; Brain, David; Schneider, Nicholas M.

2016-10-01

The DPS actively supports the E/PO needs of the society's membership, including those at the front of the college classroom. The DPS Discovery Slide Sets are an opportunity for instructors to put the latest planetary science into their lectures and for scientists to get their exciting results to college students.In an effort to keep the astronomy classroom apprised of the fast moving field of planetary science, the Division for Planetary Sciences (DPS) has developed "DPS Discoveries", which are 3-slide presentations that can be incorporated into college lectures. The slide sets are targeted at the Introductory Astronomy undergraduate level. Each slide set consists of three slides which cover a description of the discovery, a discussion of the underlying science, and a presentation of the big picture implications of the discovery, with a fourth slide that includes links to associated press releases, images, and primary sources. Topics span all subdisciplines of planetary science, and 26 sets are available in Farsi and Spanish. We intend for these slide sets to help Astronomy 101 instructors include new developments (not yet in their textbooks) into the broader context of the course. If you need supplemental material for your classroom, please checkout the archived collection: http://dps.aas.org/education/dpsdiscMore slide sets are now in development and will be available soon! In the meantime, we seek input, feedback, and help from the DPS membership to add fresh slide sets to the series and to connect the college classroom to YOUR science. It's easy to get involved - we'll provide a content template, tips and tricks for a great slide set, and pedagogy reviews. Talk to a coauthor to find out how you can disseminate your science or get involved in E/PO with your contributions.
Modulation of PPAR-γ by Nutraceutics as Complementary Treatment for Obesity-Related Disorders and Inflammatory Diseases

PubMed Central

Ortuño Sahagún, D.; Márquez-Aguirre, A. L.; Quintero-Fabián, S.; López-Roa, R. I.; Rojas-Mayorquín, A. E.

2012-01-01

A direct correlation between adequate nutrition and health is a universally accepted truth. The Western lifestyle, with a high intake of simple sugars, saturated fat, and physical inactivity, promotes pathologic conditions. The main adverse consequences range from cardiovascular disease, type 2 diabetes, and metabolic syndrome to several cancers. Dietary components influence tissue homeostasis in multiple ways and many different functional foods have been associated with various health benefits when consumed. Natural products are an important and promising source for drug discovery. Many anti-inflammatory natural products activate peroxisome proliferator-activated receptors (PPAR); therefore, compounds that activate or modulate PPAR-gamma (PPAR-γ) may help to fight all of these pathological conditions. Consequently, the discovery and optimization of novel PPAR-γ agonists and modulators that would display reduced side effects is of great interest. In this paper, we present some of the main naturally derived products studied that exert an influence on metabolism through the activation or modulation of PPAR-γ, and we also present PPAR-γ-related diseases that can be complementarily treated with nutraceutics from functional foods. PMID:23251142
Methods for Discovery of Novel Cellulosomal Cellulases Using Genomics and Biochemical Tools.

PubMed

Ben-David, Yonit; Dassa, Bareket; Bensoussan, Lizi; Bayer, Edward A; Moraïs, Sarah

2018-01-01

Cell wall degradation by cellulases is extensively explored owing to its potential contribution to biofuel production. The cellulosome is an extracellular multienzyme complex that can degrade the plant cell wall very efficiently, and cellulosomal enzymes are therefore of great interest. The cellulosomal cellulases are defined as enzymes that contain a dockerin module, which can interact with a cohesin module contained in multiple copies in a noncatalytic protein, termed scaffoldin. The assembly of the cellulosomal cellulases into the cellulosomal complex occurs via specific protein-protein interactions. Cellulosome systems have been described initially only in several anaerobic cellulolytic bacteria. However, owing to ongoing genome sequencing and metagenomic projects, the discovery of novel cellulosome-producing bacteria and the description of their cellulosomal genes have dramatically increased in the recent years. In this chapter, methods for discovery of novel cellulosomal cellulases from a DNA sequence by bioinformatics and biochemical tools are described. Their biochemical characterization is also described, including both the enzymatic activity of the putative cellulases and their assembly into mature designer cellulosomes.
Sordaria, a model system to uncover links between meiotic pairing and recombination.

PubMed

Zickler, Denise; Espagne, Eric

2016-06-01

The mycelial fungus Sordaria macrospora was first used as experimental system for meiotic recombination. This review shows that it provides also a powerful cytological system for dissecting chromosome dynamics in wild-type and mutant meioses. Fundamental cytogenetic findings include: (1) the identification of presynaptic alignment as a key step in pairing of homologous chromosomes. (2) The discovery that biochemical complexes that mediate recombination at the DNA level concomitantly mediate pairing of homologs. (3) This pairing process involves not only resolution but also avoidance of chromosomal entanglements and the resolution system includes dissolution of constraining DNA recombination interactions, achieved by a unique role of Mlh1. (4) Discovery that the central components of the synaptonemal complex directly mediate the re-localization of the recombination proteins from on-axis to in-between homologue axis positions. (5) Identification of putative STUbL protein Hei10 as a structure-based signal transduction molecule that coordinates progression and differentiation of recombinational interactions at multiple stages. (6) Discovery that a single interference process mediates both nucleation of the SC and designation of crossover sites, thereby ensuring even spacing of both features. (7) Discovery of local modulation of sister-chromatid cohesion at sites of crossover recombination. Copyright © 2016 Elsevier Ltd. All rights reserved.
Daily life activity routine discovery in hemiparetic rehabilitation patients using topic models.

PubMed

Seiter, J; Derungs, A; Schuster-Amft, C; Amft, O; Tröster, G

2015-01-01

Monitoring natural behavior and activity routines of hemiparetic rehabilitation patients across the day can provide valuable progress information for therapists and patients and contribute to an optimized rehabilitation process. In particular, continuous patient monitoring could add type, frequency and duration of daily life activity routines and hence complement standard clinical scores that are assessed for particular tasks only. Machine learning methods have been applied to infer activity routines from sensor data. However, supervised methods require activity annotations to build recognition models and thus require extensive patient supervision. Discovery methods, including topic models could provide patient routine information and deal with variability in activity and movement performance across patients. Topic models have been used to discover characteristic activity routine patterns of healthy individuals using activity primitives recognized from supervised sensor data. Yet, the applicability of topic models for hemiparetic rehabilitation patients and techniques to derive activity primitives without supervision needs to be addressed. We investigate, 1) whether a topic model-based activity routine discovery framework can infer activity routines of rehabilitation patients from wearable motion sensor data. 2) We compare the performance of our topic model-based activity routine discovery using rule-based and clustering-based activity vocabulary. We analyze the activity routine discovery in a dataset recorded with 11 hemiparetic rehabilitation patients during up to ten full recording days per individual in an ambulatory daycare rehabilitation center using wearable motion sensors attached to both wrists and the non-affected thigh. We introduce and compare rule-based and clustering-based activity vocabulary to process statistical and frequency acceleration features to activity words. Activity words were used for activity routine pattern discovery using topic models based on Latent Dirichlet Allocation. Discovered activity routine patterns were then mapped to six categorized activity routines. Using the rule-based approach, activity routines could be discovered with an average accuracy of 76% across all patients. The rule-based approach outperformed clustering by 10% and showed less confusions for predicted activity routines. Topic models are suitable to discover daily life activity routines in hemiparetic rehabilitation patients without trained classifiers and activity annotations. Activity routines show characteristic patterns regarding activity primitives including body and extremity postures and movement. A patient-independent rule set can be derived. Including expert knowledge supports successful activity routine discovery over completely data-driven clustering.
Transfer of the MPLM Leonardo from the ISS to the Orbiter Discovery Payload Bay

NASA Image and Video Library

2006-07-14

ISS013-E-51269 (14 July 2006) --- Canadarm2 or the Space Station Remote Manipulator System (SSRMS) arm (out of frame) grasps the Italian-built Multi-Purpose Logistics Module Leonardo to place it back in Discovery's cargo bay. On the other end of the arm, inside the shirt sleeve environment of the Destiny laboratory on the International Space Station, astronauts Stephanie D. Wilson and Lisa M. Nowak, STS-121 mission specialists, were in control of the transfer. The MPLM was being moved from its temporary parking place on the station's Unity node to the payload bay of Discovery for the return trip to Earth. Discovery's vertical stabilizer is at left.
Benchmarking Ligand-Based Virtual High-Throughput Screening with the PubChem Database

PubMed Central

Butkiewicz, Mariusz; Lowe, Edward W.; Mueller, Ralf; Mendenhall, Jeffrey L.; Teixeira, Pedro L.; Weaver, C. David; Meiler, Jens

2013-01-01

With the rapidly increasing availability of High-Throughput Screening (HTS) data in the public domain, such as the PubChem database, methods for ligand-based computer-aided drug discovery (LB-CADD) have the potential to accelerate and reduce the cost of probe development and drug discovery efforts in academia. We assemble nine data sets from realistic HTS campaigns representing major families of drug target proteins for benchmarking LB-CADD methods. Each data set is public domain through PubChem and carefully collated through confirmation screens validating active compounds. These data sets provide the foundation for benchmarking a new cheminformatics framework BCL::ChemInfo, which is freely available for non-commercial use. Quantitative structure activity relationship (QSAR) models are built using Artificial Neural Networks (ANNs), Support Vector Machines (SVMs), Decision Trees (DTs), and Kohonen networks (KNs). Problem-specific descriptor optimization protocols are assessed including Sequential Feature Forward Selection (SFFS) and various information content measures. Measures of predictive power and confidence are evaluated through cross-validation, and a consensus prediction scheme is tested that combines orthogonal machine learning algorithms into a single predictor. Enrichments ranging from 15 to 101 for a TPR cutoff of 25% are observed. PMID:23299552
The Hands-On Optics Project: a demonstration of module 3-magnificent magnifications

NASA Astrophysics Data System (ADS)

Pompea, Stephen M.; Sparks, Robert T.; Walker, Constance E.

2014-07-01

The Hands-On Optics project offers an example of a set of instructional modules that foster active prolonged engagement. Developed by SPIE, OSA, and NOAO through funding from the U.S. National Science Foundation, the modules were originally designed for afterschool settings and museums. However, because they were based on national standards in mathematics, science, and technology, they were easily adapted for use in classrooms. The philosophy and implementation strategies of the six modules will be described as well as lessons learned in training educators. The modules were implementing with the help of optics industry professionals who served as expert volunteers to assist educators. A key element of the modules was that they were developed around an understanding of optics misconceptions and used culminating activities in each module as a form of authentic assessment. Thus student achievement could be measured by evaluating the actual product created by each student in applying key concepts, tools, and applications together at the end of each module. The program used a progression of disciplinary core concepts to build an integrated sequence and crosscutting ideas and practices to infuse the principles of the modern electro-optical field into the modules. Whenever possible, students were encouraged to experiment and to create, and to pursue inquiry-based approaches. The result was a program that had high appeal to regular as well as gifted students.
Identifying core gene modules in glioblastoma based on multilayer factor-mediated dysfunctional regulatory networks through integrating multi-dimensional genomic data

PubMed Central

Ping, Yanyan; Deng, Yulan; Wang, Li; Zhang, Hongyi; Zhang, Yong; Xu, Chaohan; Zhao, Hongying; Fan, Huihui; Yu, Fulong; Xiao, Yun; Li, Xia

2015-01-01

The driver genetic aberrations collectively regulate core cellular processes underlying cancer development. However, identifying the modules of driver genetic alterations and characterizing their functional mechanisms are still major challenges for cancer studies. Here, we developed an integrative multi-omics method CMDD to identify the driver modules and their affecting dysregulated genes through characterizing genetic alteration-induced dysregulated networks. Applied to glioblastoma (GBM), the CMDD identified a core gene module of 17 genes, including seven known GBM drivers, and their dysregulated genes. The module showed significant association with shorter survival of GBM. When classifying driver genes in the module into two gene sets according to their genetic alteration patterns, we found that one gene set directly participated in the glioma pathway, while the other indirectly regulated the glioma pathway, mostly, via their dysregulated genes. Both of the two gene sets were significant contributors to survival and helpful for classifying GBM subtypes, suggesting their critical roles in GBM pathogenesis. Also, by applying the CMDD to other six cancers, we identified some novel core modules associated with overall survival of patients. Together, these results demonstrate integrative multi-omics data can identify driver modules and uncover their dysregulated genes, which is useful for interpreting cancer genome. PMID:25653168
12 CFR 1780.26 - Discovery.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Discovery. 1780.26 Section 1780.26 Banks and... OF PRACTICE AND PROCEDURE RULES OF PRACTICE AND PROCEDURE Prehearing Proceedings § 1780.26 Discovery. (a) Limits on discovery. Subject to the limitations set out in paragraphs (b), (d), and (e) of this...
An Inquiry-Based Biochemistry Laboratory Structure Emphasizing Competency in the Scientific Process: A Guided Approach with an Electronic Notebook Format

ERIC Educational Resources Information Center

Hall, Mona L.; Vardar-Ulu, Didem

2014-01-01

The laboratory setting is an exciting and gratifying place to teach because you can actively engage the students in the learning process through hands-on activities; it is a dynamic environment amenable to collaborative work, critical thinking, problem-solving and discovery. The guided inquiry-based approach described here guides the students…

Learning in the Discovery Sciences: The History of a "Radical" Conceptual Change, or the Scientific Revolution That Was Not

ERIC Educational Resources Information Center

Roth, Wolff-Michael

2014-01-01

In this study, I provide a microgenetic-historical account of learning in an informal setting: the conceptual change that occurred while a university-based scientific research laboratory investigated the absorption of light in rod-based photoreceptors of coho salmon, which the "dogma" had suggested to be related to the migration between…
ksc-84pc-248

NASA Image and Video Library

2013-10-19

KSC-84PC-248 (For release Aug. 27, 1984) --- The Continuous Flow Electrophoresis System (CFES) is being installed in the middeck of the Orbiter Discovery in preparation for the flight of mission STS-41D in June. The CFES, originating from the McDonnell Douglas Astronautics Co. includes a fluid systems module, and experiment control and monitoring module, a sample storage module and a pump/accumulator package along with miscellaneous equipment stored in a middeck locker. Photo credit: NASA
Straightforward hit identification approach in fragment-based discovery of bromodomain-containing protein 4 (BRD4) inhibitors.

PubMed

Borysko, Petro; Moroz, Yurii S; Vasylchenko, Oleksandr V; Hurmach, Vasyl V; Starodubtseva, Anastasia; Stefanishena, Natalia; Nesteruk, Kateryna; Zozulya, Sergey; Kondratov, Ivan S; Grygorenko, Oleksandr O

2018-05-09

A combination approach of a fragment screening and "SAR by catalog" was used for the discovery of bromodomain-containing protein 4 (BRD4) inhibitors. Initial screening of 3695-fragment library against bromodomain 1 of BRD4 using thermal shift assay (TSA), followed by initial hit validation, resulted in 73 fragment hits, which were used to construct a follow-up library selected from available screening collection. Additionally, analogs of inactive fragments, as well as a set of randomly selected compounds were also prepared (3 × 3200 compounds in total). Screening of the resulting sets using TSA, followed by re-testing at several concentrations, counter-screen, and TR-FRET assay resulted in 18 confirmed hits. Compounds derived from the initial fragment set showed better hit rate as compared to the other two sets. Finally, building dose-response curves revealed three compounds with IC 50  = 1.9-7.4 μM. For these compounds, binding sites and conformations in the BRD4 (4UYD) have been determined by docking. Copyright © 2018 Elsevier Ltd. All rights reserved.
[Criteria for the classification as a "domestic-setting corpse"--a literature search and review to define the term].

PubMed

Merz, Marius; Birngruber, Christoph G; Heidorn, Frank; Ramsthaler, Frank; Risse, Manfred; Kreutz, Kerstin; Krähahn, Jonathan; Verhoff, Marcel A

2011-01-01

In German medical and media circles (daily routine, specialist literature, press, novels), the term "domestic-setting corpse" is frequently used, but the term is only vaguely defined. The authors thus decided to perform an in-depth study of the literature, including historic textbooks and all German- and English-language medicolegal journals, going as far back as their first issues, in an attempt to more clearly define the term. Inclusion criteria used in the search were a post-mortem interval of at least 24 hours prior to discovery and discovery of the corpse in a domestic setting. In the literature, 37 cases that complied with the above-mentioned inclusion criteria were found. These cases frequently described "advanced decomposition", often "unclear cause of death" and "problems in identification". These characteristics can thus be considered as being additional pointers in the definition. However, we suggest that the two general defining characteristics of a "domestic-setting corpse" are a post-mortem interval of more than 24 hours before discovery and the discovery of the corpse in a domestic setting.
Antimicrobial activity of organometallic isonicotinyl and pyrazinyl ferrocenyl-derived complexes

USDA-ARS?s Scientific Manuscript database

The discovery of new drugs against microbial diseases is imperative to human and animal health. In this study, we synthesized a novel set of iron-based compounds and tested them against three widespread microbial diseases –tuberculosis, malaria, and trichomoniasis. Our results identified several lea...
At the cross-roads of participatory research and biomarker discovery in autism: the need for empirical data.

PubMed

Yusuf, Afiqah; Elsabbagh, Mayada

2015-12-15

Identifying biomarkers for autism can improve outcomes for those affected by autism. Engaging the diverse stakeholders in the research process using community-based participatory research (CBPR) can accelerate biomarker discovery into clinical applications. However, there are limited examples of stakeholder involvement in autism research, possibly due to conceptual and practical concerns. We evaluate the applicability of CBPR principles to biomarker discovery in autism and critically review empirical studies adopting these principles. Using a scoping review methodology, we identified and evaluated seven studies using CBPR principles in biomarker discovery. The limited number of studies in biomarker discovery adopting CBPR principles coupled with their methodological limitations suggests that such applications are feasible but challenging. These studies illustrate three CBPR themes: community assessment, setting global priorities, and collaboration in research design. We propose that further research using participatory principles would be useful in accelerating the pace of discovery and the development of clinically meaningful biomarkers. For this goal to be successful we advocate for increased attention to previously identified conceptual and methodological challenges to participatory approaches in health research, including improving scientific rigor and developing long-term partnerships among stakeholders.
Knowledge-Based Topic Model for Unsupervised Object Discovery and Localization.

PubMed

Niu, Zhenxing; Hua, Gang; Wang, Le; Gao, Xinbo

Unsupervised object discovery and localization is to discover some dominant object classes and localize all of object instances from a given image collection without any supervision. Previous work has attempted to tackle this problem with vanilla topic models, such as latent Dirichlet allocation (LDA). However, in those methods no prior knowledge for the given image collection is exploited to facilitate object discovery. On the other hand, the topic models used in those methods suffer from the topic coherence issue-some inferred topics do not have clear meaning, which limits the final performance of object discovery. In this paper, prior knowledge in terms of the so-called must-links are exploited from Web images on the Internet. Furthermore, a novel knowledge-based topic model, called LDA with mixture of Dirichlet trees, is proposed to incorporate the must-links into topic modeling for object discovery. In particular, to better deal with the polysemy phenomenon of visual words, the must-link is re-defined as that one must-link only constrains one or some topic(s) instead of all topics, which leads to significantly improved topic coherence. Moreover, the must-links are built and grouped with respect to specific object classes, thus the must-links in our approach are semantic-specific , which allows to more efficiently exploit discriminative prior knowledge from Web images. Extensive experiments validated the efficiency of our proposed approach on several data sets. It is shown that our method significantly improves topic coherence and outperforms the unsupervised methods for object discovery and localization. In addition, compared with discriminative methods, the naturally existing object classes in the given image collection can be subtly discovered, which makes our approach well suited for realistic applications of unsupervised object discovery.Unsupervised object discovery and localization is to discover some dominant object classes and localize all of object instances from a given image collection without any supervision. Previous work has attempted to tackle this problem with vanilla topic models, such as latent Dirichlet allocation (LDA). However, in those methods no prior knowledge for the given image collection is exploited to facilitate object discovery. On the other hand, the topic models used in those methods suffer from the topic coherence issue-some inferred topics do not have clear meaning, which limits the final performance of object discovery. In this paper, prior knowledge in terms of the so-called must-links are exploited from Web images on the Internet. Furthermore, a novel knowledge-based topic model, called LDA with mixture of Dirichlet trees, is proposed to incorporate the must-links into topic modeling for object discovery. In particular, to better deal with the polysemy phenomenon of visual words, the must-link is re-defined as that one must-link only constrains one or some topic(s) instead of all topics, which leads to significantly improved topic coherence. Moreover, the must-links are built and grouped with respect to specific object classes, thus the must-links in our approach are semantic-specific , which allows to more efficiently exploit discriminative prior knowledge from Web images. Extensive experiments validated the efficiency of our proposed approach on several data sets. It is shown that our method significantly improves topic coherence and outperforms the unsupervised methods for object discovery and localization. In addition, compared with discriminative methods, the naturally existing object classes in the given image collection can be subtly discovered, which makes our approach well suited for realistic applications of unsupervised object discovery.
How iSamples (Internet of Samples in the Earth Sciences) Improves Sample and Data Stewardship in the Next Generation of Geoscientists

NASA Astrophysics Data System (ADS)

Hallett, B. W.; Dere, A. L. D.; Lehnert, K.; Carter, M.

2016-12-01

Vast numbers of physical samples are routinely collected by geoscientists to probe key scientific questions related to global climate change, biogeochemical cycles, magmatic processes, mantle dynamics, etc. Despite their value as irreplaceable records of nature the majority of these samples remain undiscoverable by the broader scientific community because they lack a digital presence or are not well-documented enough to facilitate their discovery and reuse for future scientific and educational use. The NSF EarthCube iSamples Research Coordination Network seeks to develop a unified approach across all Earth Science disciplines for the registration, description, identification, and citation of physical specimens in order to take advantage of the new opportunities that cyberinfrastructure offers. Even as consensus around best practices begins to emerge, such as the use of the International Geo Sample Number (IGSN), more work is needed to communicate these practices to investigators to encourage widespread adoption. Recognizing the importance of students and early career scientists in particular to transforming data and sample management practices, the iSamples Education and Training Working Group is developing training modules for sample collection, documentation, and management workflows. These training materials are made available to educators/research supervisors online at http://earthcube.org/group/isamples and can be modularized for supervisors to create a customized research workflow. This study details the design and development of several sample management tutorials, created by early career scientists and documented in collaboration with undergraduate research students in field and lab settings. Modules under development focus on rock outcrops, rock cores, soil cores, and coral samples, with an emphasis on sample management throughout the collection, analysis and archiving process. We invite others to share their sample management/registration workflows and to develop training modules. This educational approach, with evolving digital materials, can help prepare future scientists to perform research in a way that will contribute to EarthCube data integration and discovery.
Beyond adaptive-critic creative learning for intelligent mobile robots

NASA Astrophysics Data System (ADS)

Liao, Xiaoqun; Cao, Ming; Hall, Ernest L.

2001-10-01

Intelligent industrial and mobile robots may be considered proven technology in structured environments. Teach programming and supervised learning methods permit solutions to a variety of applications. However, we believe that to extend the operation of these machines to more unstructured environments requires a new learning method. Both unsupervised learning and reinforcement learning are potential candidates for these new tasks. The adaptive critic method has been shown to provide useful approximations or even optimal control policies to non-linear systems. The purpose of this paper is to explore the use of new learning methods that goes beyond the adaptive critic method for unstructured environments. The adaptive critic is a form of reinforcement learning. A critic element provides only high level grading corrections to a cognition module that controls the action module. In the proposed system the critic's grades are modeled and forecasted, so that an anticipated set of sub-grades are available to the cognition model. The forecasting grades are interpolated and are available on the time scale needed by the action model. The success of the system is highly dependent on the accuracy of the forecasted grades and adaptability of the action module. Examples from the guidance of a mobile robot are provided to illustrate the method for simple line following and for the more complex navigation and control in an unstructured environment. The theory presented that is beyond the adaptive critic may be called creative theory. Creative theory is a form of learning that models the highest level of human learning - imagination. The application of the creative theory appears to not only be to mobile robots but also to many other forms of human endeavor such as educational learning and business forecasting. Reinforcement learning such as the adaptive critic may be applied to known problems to aid in the discovery of their solutions. The significance of creative theory is that it permits the discovery of the unknown problems, ones that are not yet recognized but may be critical to survival or success.
Structure-Based Virtual Screening for Drug Discovery: Principles, Applications and Recent Advances

PubMed Central

Lionta, Evanthia; Spyrou, George; Vassilatis, Demetrios K.; Cournia, Zoe

2014-01-01

Structure-based drug discovery (SBDD) is becoming an essential tool in assisting fast and cost-efficient lead discovery and optimization. The application of rational, structure-based drug design is proven to be more efficient than the traditional way of drug discovery since it aims to understand the molecular basis of a disease and utilizes the knowledge of the three-dimensional structure of the biological target in the process. In this review, we focus on the principles and applications of Virtual Screening (VS) within the context of SBDD and examine different procedures ranging from the initial stages of the process that include receptor and library pre-processing, to docking, scoring and post-processing of topscoring hits. Recent improvements in structure-based virtual screening (SBVS) efficiency through ensemble docking, induced fit and consensus docking are also discussed. The review highlights advances in the field within the framework of several success studies that have led to nM inhibition directly from VS and provides recent trends in library design as well as discusses limitations of the method. Applications of SBVS in the design of substrates for engineered proteins that enable the discovery of new metabolic and signal transduction pathways and the design of inhibitors of multifunctional proteins are also reviewed. Finally, we contribute two promising VS protocols recently developed by us that aim to increase inhibitor selectivity. In the first protocol, we describe the discovery of micromolar inhibitors through SBVS designed to inhibit the mutant H1047R PI3Kα kinase. Second, we discuss a strategy for the identification of selective binders for the RXRα nuclear receptor. In this protocol, a set of target structures is constructed for ensemble docking based on binding site shape characterization and clustering, aiming to enhance the hit rate of selective inhibitors for the desired protein target through the SBVS process. PMID:25262799
Food Service Worker. A Competency Based Instructor's Guide Including Student Modules for Food Management, Production and Services.

ERIC Educational Resources Information Center

Tennessee State Dept. of Education, Nashville. Div. of Vocational-Technical Education.

This instructor's guide is designed to accompany a set of 52 competency-based modules dealing with food management, production, and service. It is part of an instructional package that is intended to be taught in secondary and postsecondary vocational programs in Tennessee. Following a brief outline of the development of the curriculum, the…
Electrically heated particulate filter diagnostic systems and methods

DOEpatents

Gonze, Eugene V [Pinckney, MI

2009-09-29

A system that diagnoses regeneration of an electrically heated particulate filter is provided. The system generally includes a grid module that diagnoses a fault of the grid based on at least one of a current signal and a voltage signal. A diagnostic module at least one of sets a fault status and generates a warning signal based on the fault of the grid.
Study of Tools for Network Discovery and Network Mapping

DTIC Science & Technology

2003-11-01

connected to the switch. iv. Accessibility of historical data and event data In general, network discovery tools keep a history of the collected...has the following software dependencies: - Java Virtual machine 76 - Perl modules - RRD Tool - TomCat - PostgreSQL STRENGTHS AND...systems - provide a simple view of the current network status - generate alarms on status change - generate history of status change VISUAL MAP
Adaptively loaded IM/DD optical OFDM based on set-partitioned QAM formats.

PubMed

Zhao, Jian; Chen, Lian-Kuan

2017-04-17

We investigate the constellation design and symbol error rate (SER) of set-partitioned (SP) quadrature amplitude modulation (QAM) formats. Based on the SER analysis, we derive the adaptive bit and power loading algorithm for SP QAM based intensity-modulation direct-detection (IM/DD) orthogonal frequency division multiplexing (OFDM). We experimentally show that the proposed system significantly outperforms the conventional adaptively-loaded IM/DD OFDM and can increase the data rate from 36 Gbit/s to 42 Gbit/s in the presence of severe dispersion-induced spectral nulls after 40-km single-mode fiber. It is also shown that the adaptive algorithm greatly enhances the tolerance to fiber nonlinearity and allows for more power budget.
Big Data, Small Data: Accessing and Manipulating Geoscience Data Ranging From Repositories to Student-Collected Data Sets Using GeoMapApp

NASA Astrophysics Data System (ADS)

Goodwillie, A. M.

2015-12-01

We often demand information and data to be accessible over the web at no cost, and no longer do we expect to spend time labouriously compiling data from myriad sources with frustratingly-different formats. Instead, we increasingly expect convenience and consolidation. Recent advances in web-enabled technologies and cyberinfrastructure are answering those calls by providing data tools and resources that can transform undergraduate education. By freeing up valuable classroom time, students can focus upon gaining deeper insights and understanding from real-world data. GeoMapApp (http://www.geomapapp.org) is a map-based data discovery and visualisation tool developed at Lamont-Doherty Earth Observatory. GeoMapApp promotes U-Learning by working across all major computer platforms and functioning anywhere with internet connectivity, by lowering socio-economic barriers (it is free), by seamlessly integrating thousands of built-in research-grade data sets under intuitive menus, and by being adaptable to a range of learning environments - from lab sessions, group projects, and homework assignments to in-class pop-ups. GeoMapApp caters to casual and specialist users alike. Contours, artificial illumination, 3-D displays, data point manipulations, cross-sectional profiles, and other display techniques help students better grasp the content and geospatial context of data. Layering capabilities allow easy data set comparisons. The core functionality also applies to imported data sets: Student-collected data can thus be imported and analysed using the same techniques. A new Save Session function allows educators to preserve a pre-loaded state of GeoMapApp. When shared with a class, the saved file allows every student to open GeoMapApp at exactly the same starting point from which to begin their data explorations. Examples of built-in data sets include seafloor crustal age, earthquake locations and focal mechanisms, analytical geochemistry, ocean water physical properties, US and international geological maps, and satellite imagery. Student-generated data sets can be imported in Excel, ASCII, shapefile, and gridded format. Base maps can be saved for posters and publications. A wide range of undergraduate enquiry-driven education modules for GeoMapApp is already available at SERC.
Efficient and accurate Greedy Search Methods for mining functional modules in protein interaction networks.

PubMed

He, Jieyue; Li, Chaojun; Ye, Baoliu; Zhong, Wei

2012-06-25

Most computational algorithms mainly focus on detecting highly connected subgraphs in PPI networks as protein complexes but ignore their inherent organization. Furthermore, many of these algorithms are computationally expensive. However, recent analysis indicates that experimentally detected protein complexes generally contain Core/attachment structures. In this paper, a Greedy Search Method based on Core-Attachment structure (GSM-CA) is proposed. The GSM-CA method detects densely connected regions in large protein-protein interaction networks based on the edge weight and two criteria for determining core nodes and attachment nodes. The GSM-CA method improves the prediction accuracy compared to other similar module detection approaches, however it is computationally expensive. Many module detection approaches are based on the traditional hierarchical methods, which is also computationally inefficient because the hierarchical tree structure produced by these approaches cannot provide adequate information to identify whether a network belongs to a module structure or not. In order to speed up the computational process, the Greedy Search Method based on Fast Clustering (GSM-FC) is proposed in this work. The edge weight based GSM-FC method uses a greedy procedure to traverse all edges just once to separate the network into the suitable set of modules. The proposed methods are applied to the protein interaction network of S. cerevisiae. Experimental results indicate that many significant functional modules are detected, most of which match the known complexes. Results also demonstrate that the GSM-FC algorithm is faster and more accurate as compared to other competing algorithms. Based on the new edge weight definition, the proposed algorithm takes advantages of the greedy search procedure to separate the network into the suitable set of modules. Experimental analysis shows that the identified modules are statistically significant. The algorithm can reduce the computational time significantly while keeping high prediction accuracy.
CREDO: a structural interactomics database for drug discovery

PubMed Central

Schreyer, Adrian M.; Blundell, Tom L.

2013-01-01

CREDO is a unique relational database storing all pairwise atomic interactions of inter- as well as intra-molecular contacts between small molecules and macromolecules found in experimentally determined structures from the Protein Data Bank. These interactions are integrated with further chemical and biological data. The database implements useful data structures and algorithms such as cheminformatics routines to create a comprehensive analysis platform for drug discovery. The database can be accessed through a web-based interface, downloads of data sets and web services at http://www-cryst.bioc.cam.ac.uk/credo. Database URL: http://www-cryst.bioc.cam.ac.uk/credo PMID:23868908
Functional Module Search in Protein Networks based on Semantic Similarity Improves the Analysis of Proteomics Data*

PubMed Central

Boyanova, Desislava; Nilla, Santosh; Klau, Gunnar W.; Dandekar, Thomas; Müller, Tobias; Dittrich, Marcus

2014-01-01

The continuously evolving field of proteomics produces increasing amounts of data while improving the quality of protein identifications. Albeit quantitative measurements are becoming more popular, many proteomic studies are still based on non-quantitative methods for protein identification. These studies result in potentially large sets of identified proteins, where the biological interpretation of proteins can be challenging. Systems biology develops innovative network-based methods, which allow an integrated analysis of these data. Here we present a novel approach, which combines prior knowledge of protein-protein interactions (PPI) with proteomics data using functional similarity measurements of interacting proteins. This integrated network analysis exactly identifies network modules with a maximal consistent functional similarity reflecting biological processes of the investigated cells. We validated our approach on small (H9N2 virus-infected gastric cells) and large (blood constituents) proteomic data sets. Using this novel algorithm, we identified characteristic functional modules in virus-infected cells, comprising key signaling proteins (e.g. the stress-related kinase RAF1) and demonstrate that this method allows a module-based functional characterization of cell types. Analysis of a large proteome data set of blood constituents resulted in clear separation of blood cells according to their developmental origin. A detailed investigation of the T-cell proteome further illustrates how the algorithm partitions large networks into functional subnetworks each representing specific cellular functions. These results demonstrate that the integrated network approach not only allows a detailed analysis of proteome networks but also yields a functional decomposition of complex proteomic data sets and thereby provides deeper insights into the underlying cellular processes of the investigated system. PMID:24807868
12 CFR 308.24 - Scope of document discovery.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Scope of document discovery. 308.24 Section 308... PRACTICE AND PROCEDURE Uniform Rules of Practice and Procedure § 308.24 Scope of document discovery. (a) Limits on discovery. (1) Subject to the limitations set out in paragraphs (b), (c), and (d) of this...
12 CFR 308.107 - Document discovery.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 12 Banks and Banking 5 2014-01-01 2014-01-01 false Document discovery. 308.107 Section 308.107... PRACTICE AND PROCEDURE General Rules of Procedure § 308.107 Document discovery. (a) Parties to proceedings set forth at § 308.01 of the Uniform Rules and as provided in the Local Rules may obtain discovery...

12 CFR 908.46 - Discovery.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 12 Banks and Banking 7 2011-01-01 2011-01-01 false Discovery. 908.46 Section 908.46 Banks and... PRACTICE AND PROCEDURE IN HEARINGS ON THE RECORD Pre-Hearing Proceedings § 908.46 Discovery. (a) Limits on discovery. Subject to the limitations set out in paragraphs (b), (d), and (e) of this section, any party to...
12 CFR 308.107 - Document discovery.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 12 Banks and Banking 4 2011-01-01 2011-01-01 false Document discovery. 308.107 Section 308.107... PRACTICE AND PROCEDURE General Rules of Procedure § 308.107 Document discovery. (a) Parties to proceedings set forth at § 308.01 of the Uniform Rules and as provided in the Local Rules may obtain discovery...
12 CFR 308.107 - Document discovery.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 12 Banks and Banking 5 2012-01-01 2012-01-01 false Document discovery. 308.107 Section 308.107... PRACTICE AND PROCEDURE General Rules of Procedure § 308.107 Document discovery. (a) Parties to proceedings set forth at § 308.01 of the Uniform Rules and as provided in the Local Rules may obtain discovery...
12 CFR 308.107 - Document discovery.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 12 Banks and Banking 5 2013-01-01 2013-01-01 false Document discovery. 308.107 Section 308.107... PRACTICE AND PROCEDURE General Rules of Procedure § 308.107 Document discovery. (a) Parties to proceedings set forth at § 308.01 of the Uniform Rules and as provided in the Local Rules may obtain discovery...
12 CFR 308.107 - Document discovery.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Document discovery. 308.107 Section 308.107... PRACTICE AND PROCEDURE General Rules of Procedure § 308.107 Document discovery. (a) Parties to proceedings set forth at § 308.01 of the Uniform Rules and as provided in the Local Rules may obtain discovery...
12 CFR 908.46 - Discovery.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Discovery. 908.46 Section 908.46 Banks and... PRACTICE AND PROCEDURE IN HEARINGS ON THE RECORD Pre-Hearing Proceedings § 908.46 Discovery. (a) Limits on discovery. Subject to the limitations set out in paragraphs (b), (d), and (e) of this section, any party to...
A Monte Carlo-based framework enhances the discovery and interpretation of regulatory sequence motifs

PubMed Central

2012-01-01

Background Discovery of functionally significant short, statistically overrepresented subsequence patterns (motifs) in a set of sequences is a challenging problem in bioinformatics. Oftentimes, not all sequences in the set contain a motif. These non-motif-containing sequences complicate the algorithmic discovery of motifs. Filtering the non-motif-containing sequences from the larger set of sequences while simultaneously determining the identity of the motif is, therefore, desirable and a non-trivial problem in motif discovery research. Results We describe MotifCatcher, a framework that extends the sensitivity of existing motif-finding tools by employing random sampling to effectively remove non-motif-containing sequences from the motif search. We developed two implementations of our algorithm; each built around a commonly used motif-finding tool, and applied our algorithm to three diverse chromatin immunoprecipitation (ChIP) data sets. In each case, the motif finder with the MotifCatcher extension demonstrated improved sensitivity over the motif finder alone. Our approach organizes candidate functionally significant discovered motifs into a tree, which allowed us to make additional insights. In all cases, we were able to support our findings with experimental work from the literature. Conclusions Our framework demonstrates that additional processing at the sequence entry level can significantly improve the performance of existing motif-finding tools. For each biological data set tested, we were able to propose novel biological hypotheses supported by experimental work from the literature. Specifically, in Escherichia coli, we suggested binding site motifs for 6 non-traditional LexA protein binding sites; in Saccharomyces cerevisiae, we hypothesize 2 disparate mechanisms for novel binding sites of the Cse4p protein; and in Halobacterium sp. NRC-1, we discoverd subtle differences in a general transcription factor (GTF) binding site motif across several data sets. We suggest that small differences in our discovered motif could confer specificity for one or more homologous GTF proteins. We offer a free implementation of the MotifCatcher software package at http://www.bme.ucdavis.edu/facciotti/resources_data/software/. PMID:23181585
Data Discretization for Novel Relationship Discovery in Information Retrieval.

ERIC Educational Resources Information Center

Benoit, G.

2002-01-01

Describes an information retrieval, visualization, and manipulation model which offers the user multiple ways to exploit the retrieval set, based on weighted query terms, via an interactive interface. Outlines the mathematical model and describes an information retrieval application built on the model to search structured and full-text files.…
KSC-08pd1113

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, the rotating service structure, at left, at Launch Pad 39A has been rolled back for the delivery of space shuttle Discovery, secured atop the mobile launch platform below, for final prelaunch processing for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder
KSC-08pd1101

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, a crawler transporter moves space shuttle Discovery, secured atop a mobile launch platform, along the crawlerway from the Vehicle Assembly Building to Launch Pad 39A to prepare for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder
KSC-08pd1111

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, access arms from the fixed service structure at Launch Pad 39A are in place against space shuttle Discovery, secured atop the mobile launch platform below, as final prelaunch processing for the STS-124 mission begins at the pad. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder
KSC-08pd1102

NASA Image and Video Library

2008-05-03

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center, space shuttle Discovery, secured atop a mobile launch platform, is reflected in water beside the crawlerway as it is moved from the Vehicle Assembly Building to Launch Pad 39A to prepare for the STS-124 mission. The 3.4-mile journey from the Vehicle Assembly Building began at 11:47 p.m. on May 2. The shuttle arrived at the launch pad at 4:25 a.m. EDT May 3 and was secured, or hard down, by 6:06 a.m. On the 13-day mission, Discovery and its crew will deliver the Japan Aerospace Exploration Agency's Japanese Experiment Module – Pressurized Module and the Japanese Remote Manipulator System. Launch is targeted for May 31. Photo credit: NASA/Troy Cryder
Evaluation method for the potential functionome harbored in the genome and metagenome

PubMed Central

2012-01-01

Background One of the main goals of genomic analysis is to elucidate the comprehensive functions (functionome) in individual organisms or a whole community in various environments. However, a standard evaluation method for discerning the functional potentials harbored within the genome or metagenome has not yet been established. We have developed a new evaluation method for the potential functionome, based on the completion ratio of Kyoto Encyclopedia of Genes and Genomes (KEGG) functional modules. Results Distribution of the completion ratio of the KEGG functional modules in 768 prokaryotic species varied greatly with the kind of module, and all modules primarily fell into 4 patterns (universal, restricted, diversified and non-prokaryotic modules), indicating the universal and unique nature of each module, and also the versatility of the KEGG Orthology (KO) identifiers mapped to each one. The module completion ratio in 8 phenotypically different bacilli revealed that some modules were shared only in phenotypically similar species. Metagenomes of human gut microbiomes from 13 healthy individuals previously determined by the Sanger method were analyzed based on the module completion ratio. Results led to new discoveries in the nutritional preferences of gut microbes, believed to be one of the mutualistic representations of gut microbiomes to avoid nutritional competition with the host. Conclusions The method developed in this study could characterize the functionome harbored in genomes and metagenomes. As this method also provided taxonomical information from KEGG modules as well as the gene hosts constructing the modules, interpretation of completion profiles was simplified and we could identify the complementarity between biochemical functions in human hosts and the nutritional preferences in human gut microbiomes. Thus, our method has the potential to be a powerful tool for comparative functional analysis in genomics and metagenomics, able to target unknown environments containing various uncultivable microbes within unidentified phyla. PMID:23234305
A two-step hierarchical hypothesis set testing framework, with applications to gene expression data on ordered categories

PubMed Central

2014-01-01

Background In complex large-scale experiments, in addition to simultaneously considering a large number of features, multiple hypotheses are often being tested for each feature. This leads to a problem of multi-dimensional multiple testing. For example, in gene expression studies over ordered categories (such as time-course or dose-response experiments), interest is often in testing differential expression across several categories for each gene. In this paper, we consider a framework for testing multiple sets of hypothesis, which can be applied to a wide range of problems. Results We adopt the concept of the overall false discovery rate (OFDR) for controlling false discoveries on the hypothesis set level. Based on an existing procedure for identifying differentially expressed gene sets, we discuss a general two-step hierarchical hypothesis set testing procedure, which controls the overall false discovery rate under independence across hypothesis sets. In addition, we discuss the concept of the mixed-directional false discovery rate (mdFDR), and extend the general procedure to enable directional decisions for two-sided alternatives. We applied the framework to the case of microarray time-course/dose-response experiments, and proposed three procedures for testing differential expression and making multiple directional decisions for each gene. Simulation studies confirm the control of the OFDR and mdFDR by the proposed procedures under independence and positive correlations across genes. Simulation results also show that two of our new procedures achieve higher power than previous methods. Finally, the proposed methodology is applied to a microarray dose-response study, to identify 17 β-estradiol sensitive genes in breast cancer cells that are induced at low concentrations. Conclusions The framework we discuss provides a platform for multiple testing procedures covering situations involving two (or potentially more) sources of multiplicity. The framework is easy to use and adaptable to various practical settings that frequently occur in large-scale experiments. Procedures generated from the framework are shown to maintain control of the OFDR and mdFDR, quantities that are especially relevant in the case of multiple hypothesis set testing. The procedures work well in both simulations and real datasets, and are shown to have better power than existing methods. PMID:24731138
Empirical predictions of hypervelocity impact damage to the space station

NASA Technical Reports Server (NTRS)

Rule, W. K.; Hayashida, K. B.

1991-01-01

A family of user-friendly, DOS PC based, Microsoft BASIC programs written to provide spacecraft designers with empirical predictions of space debris damage to orbiting spacecraft is described. The spacecraft wall configuration is assumed to consist of multilayer insulation (MLI) placed between a Whipple style bumper and the pressure wall. Predictions are based on data sets of experimental results obtained from simulating debris impacts on spacecraft using light gas guns on Earth. A module of the program facilitates the creation of the data base of experimental results that are used by the damage prediction modules of the code. The user has the choice of three different prediction modules to predict damage to the bumper, the MLI, and the pressure wall. One prediction module is based on fitting low order polynomials through subsets of the experimental data. Another prediction module fits functions based on nondimensional parameters through the data. The last prediction technique is a unique approach that is based on weighting the experimental data according to the distance from the design point.
Airlock Battery Charge module

NASA Image and Video Library

2008-06-06

S124-E-006865 (6 June 2008) --- One of a series of digital still images documenting the Japanese Experiment Module, or JEM, also called Kibo, in its new home on the International Space Station, this view features Kibo's exterior, Earth's horizon and a couple of "visiting" spacecraft. The Space Shuttle Discovery and a Russian Progress resupply craft are seen near foreground.
The teaching of drug development to medical students: collaboration between the pharmaceutical industry and medical school

PubMed Central

Stanley, A G; Jackson, D; Barnett, D B

2005-01-01

Collaboration between the medical school at Leicester and a local pharmaceutical company, AstraZeneca, led to the design and implementation of an optional third year special science skills module teaching medical students about drug discovery and development. The module includes didactic teaching about the complexities of the drug discovery process leading to development of candidate drugs for clinical investigation as well as practical experience of the processes involved in drug evaluation preclinically and clinically. It highlights the major ethical and regulatory issues concerned with the production and testing of novel therapies in industry and the NHS. In addition it helps to reinforce other areas of the medical school curriculum, particularly the understanding of clinical study design and critical appraisal. The module is assessed on the basis of a written dissertation and the critical appraisal of a drug advertisement. This paper describes the objectives of the module and its content. In addition we outline the results of an initial student evaluation of the module and an assessment of its impact on student knowledge and the opinion of the pharmaceutical industry partner. This module has proven to be popular with medical students, who acquire a greater understanding of the work required for drug development and therefore reflect more favourably on the role of pharmaceutical companies in the UK. PMID:15801942
EXTraS discovery of a 1.2-s X-ray pulsar in M31

NASA Astrophysics Data System (ADS)

Esposito, P.; Israel, G.; Belfiore, A.; Novara, G.; Sidoli, L.; Rodriguez Castillo, G.; De Luca, A.; Tiengo, A.; Haberl, F.; Salvaterra, R.

2017-10-01

A systematic search for periodic signals in the XMM-Newton's EPIC archive carried out within the EXTraS project resulted in the discovery of a 1.2-s flux modulation in 3XMM J004301.4+413017. It is the first accreting neutron star in M31 for which the spin period has been detected. Besides this distinction, 3XMM J0043 proved to be an interesting system. Doppler shifts of the spin modulation revealed an orbital motion with period of 1.27 d and the analysis of optical data shows that, while the source is likely associated to a globular cluster, a counterpart with V ˜ 22 outside the cluster cannot be excluded. The emission of the pulsar appears rather hard (most data are described by a power law with photon index <1) and, assuming the distance to M31, the 0.3-10 keV luminosity was variable, from ˜3×10^{37} to 2×10^{38} erg/s. Based on this, we discuss two main possible scenarios for 3X J0043: a peculiar low-mass X-ray binary, perhaps similar to 4U 1822-37 or 4U 1626-67, or an intermediate-mass X-ray binary akin Her X-1.
The T1R2/T1R3 sweet receptor and TRPM5 ion channel taste targets with therapeutic potential.

PubMed

Sprous, Dennis; Palmer, Kyle R

2010-01-01

Taste signaling is a critical determinant of ingestive behaviors and thereby linked to obesity and related metabolic dysfunctions. Recent evidence of taste signaling pathways in the gut suggests the link to be more direct, raising the possibility that taste receptor systems could be regarded as therapeutic targets. T1R2/T1R3, the G protein coupled receptor that mediates sweet taste, and the TRPM5 ion channel have been the focus of discovery programs seeking novel compounds that could be useful in modifying taste. We review in this chapter the hypothesis of gastrointestinal taste signaling and discuss the potential for T1R2/T1R3 and TRPM5 as targets of therapeutic intervention in obesity and diabetes. Critical to the development of a drug discovery program is the creation of libraries that enhance the likelihood of identifying novel compounds that modulate the target of interest. We advocate a computer-based chemoinformatic approach for assembling natural and synthetic compound libraries as well as for supporting optimization of structure activity relationships. Strategies for discovering modulators of T1R2/T1R3 and TRPM5 using methods of chemoinformatics are presented herein. Copyright 2010 Elsevier Inc. All rights reserved.
Targeting Cullin–RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation

PubMed Central

Bulatov, Emil; Ciulli, Alessio

2015-01-01

In the last decade, the ubiquitin–proteasome system has emerged as a valid target for the development of novel therapeutics. E3 ubiquitin ligases are particularly attractive targets because they confer substrate specificity on the ubiquitin system. CRLs [Cullin–RING (really interesting new gene) E3 ubiquitin ligases] draw particular attention, being the largest family of E3s. The CRLs assemble into functional multisubunit complexes using a repertoire of substrate receptors, adaptors, Cullin scaffolds and RING-box proteins. Drug discovery targeting CRLs is growing in importance due to mounting evidence pointing to significant roles of these enzymes in diverse biological processes and human diseases, including cancer, where CRLs and their substrates often function as tumour suppressors or oncogenes. In the present review, we provide an account of the assembly and structure of CRL complexes, and outline the current state of the field in terms of available knowledge of small-molecule inhibitors and modulators of CRL activity. A comprehensive overview of the reported crystal structures of CRL subunits, components and full-size complexes, alone or with bound small molecules and substrate peptides, is included. This information is providing increasing opportunities to aid the rational structure-based design of chemical probes and potential small-molecule therapeutics targeting CRLs. PMID:25886174

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