Matrix- and tensor-based recommender systems for the discovery of currently unknown inorganic compounds

NASA Astrophysics Data System (ADS)

Seko, Atsuto; Hayashi, Hiroyuki; Kashima, Hisashi; Tanaka, Isao

2018-01-01

Chemically relevant compositions (CRCs) and atomic arrangements of inorganic compounds have been collected as inorganic crystal structure databases. Machine learning is a unique approach to search for currently unknown CRCs from vast candidates. Herein we propose matrix- and tensor-based recommender system approaches to predict currently unknown CRCs from database entries of CRCs. Firstly, the performance of the recommender system approaches to discover currently unknown CRCs is examined. A Tucker decomposition recommender system shows the best discovery rate of CRCs as the majority of the top 100 recommended ternary and quaternary compositions correspond to CRCs. Secondly, systematic density functional theory (DFT) calculations are performed to investigate the phase stability of the recommended compositions. The phase stability of the 27 compositions reveals that 23 currently unknown compounds are newly found to be stable. These results indicate that the recommender system has great potential to accelerate the discovery of new compounds.

Personalized Therapy: Tumor Antigen Discovery for Adoptive Cellular Therapy.

PubMed

Yee, Cassian; Lizee, Gregory A

Adoptive cell therapy using endogenous T cells involves the ex vivo isolation and expansion of antigen-specific T cells from the peripheral blood and is uniquely suited for validating and translating antigen discovery. Endogenous T-cell therapy does not require accessible tumor as a source of infiltrating T cells and is free of regulatory and logistical constraints associated with engineering T cells. Candidate epitope peptides identified through antigen discovery may be rapidly implemented as targets in clinical trials of endogenous T-cell therapy and even incorporated as an "ad hoc" approach to personalized treatment when autologous tumor is available. Several first-in-human studies using a uniform population of antigen-specific T cells defined by phenotype and specificity have provided a means to confirm candidate antigens as potential tumor rejection antigens and to evaluate the reasons for success or failure using as a "transferrable cellular biomarker" the adoptively transferred T cells.

The Terebridae and teretoxins: Combining phylogeny and anatomy for concerted discovery of bioactive compounds.

PubMed

Puillandre, Nicolas; Holford, Mandë

2010-09-17

The Conoidea superfamily, comprised of cone snails, terebrids, and turrids, is an exceptionally promising group for the discovery of natural peptide toxins. The potential of conoidean toxins has been realized with the distribution of the first Conus (cone snail) drug, Prialt (ziconotide), an analgesic used to alleviate chronic pain in HIV and cancer patients. Cone snail toxins (conotoxins) are highly variable, a consequence of a high mutation rate associated to duplication events and positive selection. As Conus and terebrids diverged in the early Paleocene, the toxins from terebrids (teretoxins) may demonstrate highly divergent and unique functionalities. Recent analyses of the Terebridae, a largely distributed family with more than 300 described species, indicate they have evolutionary and pharmacological potential. Based on a three gene (COI, 12S and 16S) molecular phylogeny, including ~50 species from the West-Pacific, five main terebrid lineages were discriminated: two of these lineages independently lost their venom apparatus, and one venomous lineage was previously unknown. Knowing the phylogenetic relationships within the Terebridae aids in effectively targeting divergent lineages with novel peptide toxins. Preliminary results indicate that teretoxins are similar in structure and composition to conotoxins, suggesting teretoxins are an attractive line of research to discover and develop new therapeutics that target ion channels and receptors. Using conotoxins as a guideline, and innovative natural products discovery strategies, such as the Concerted Discovery Strategy, the potential of the Terebridae and their toxins are explored as a pioneering pharmacological resource.

Viral Causes of Lymphoma: The History of Epstein-Barr Virus and Human T-Lymphotropic Virus 1.

PubMed

Esau, Daniel

2017-01-01

In 1964, Epstein, Barr, and Achong published a report outlining their discovery of viral particles in lymphoblasts isolated from a patient with Burkitt lymphoma. The Epstein-Barr virus (EBV) was the first human cancer virus to be described, and its discovery paved the way for further investigations into the oncogenic potential of viruses. In the decades following the discovery of EBV, multinational research efforts led to the discovery of further viral causes of various human cancers. Lymphomas are perhaps the cancer type that is most closely associated with oncogenic viruses: infection with EBV, human T-lymphotropic virus 1 (HTLV-1), human immunodeficiency virus (HIV), Kaposi sarcoma-associated herpesvirus/human herpesvirus 8, and hepatitis C virus have all been associated with lymphomagenesis. Lymphomas have also played an important role in the history of oncoviruses, as both the first human oncovirus (EBV) and the first human retrovirus (HTLV-1) were discovered through isolates taken from patients with unique lymphoma syndromes. The history of the discovery of these 2 key oncoviruses is presented here, and their impact on further medical research, using the specific example of HIV research, is briefly discussed.

Common characteristics of open source software development and applicability for drug discovery: a systematic review.

PubMed

Ardal, Christine; Alstadsæter, Annette; Røttingen, John-Arne

2011-09-28

Innovation through an open source model has proven to be successful for software development. This success has led many to speculate if open source can be applied to other industries with similar success. We attempt to provide an understanding of open source software development characteristics for researchers, business leaders and government officials who may be interested in utilizing open source innovation in other contexts and with an emphasis on drug discovery. A systematic review was performed by searching relevant, multidisciplinary databases to extract empirical research regarding the common characteristics and barriers of initiating and maintaining an open source software development project. Common characteristics to open source software development pertinent to open source drug discovery were extracted. The characteristics were then grouped into the areas of participant attraction, management of volunteers, control mechanisms, legal framework and physical constraints. Lastly, their applicability to drug discovery was examined. We believe that the open source model is viable for drug discovery, although it is unlikely that it will exactly follow the form used in software development. Hybrids will likely develop that suit the unique characteristics of drug discovery. We suggest potential motivations for organizations to join an open source drug discovery project. We also examine specific differences between software and medicines, specifically how the need for laboratories and physical goods will impact the model as well as the effect of patents.

Renaissance of the ~1 TeV Fixed-Target Program

NASA Astrophysics Data System (ADS)

Adams, T.; Appel, J. A.; Arms, K. E.; Balantekin, A. B.; Conrad, J. M.; Cooper, P. S.; Djurcic, Z.; Dunwoodie, W.; Engelfried, J.; Fisher, P. H.; Gottschalk, E.; de Gouvea, A.; Heller, K.; Ignarra, C. M.; Karagiorgi, G.; Kwan, S.; Loinaz, W. A.; Meadows, B.; Moore, R.; Morfín, J. G.; Naples, D.; Nienaber, P.; Pate, S. F.; Papavassiliou, V.; Petrov, A. A.; Purohit, M. V.; Ray, H.; Russ, J.; Schwartz, A. J.; Seligman, W. G.; Shaevitz, M. H.; Schellman, H.; Spitz, J.; Syphers, M. J.; Tait, T. M. P.; Vannucci, F.

This document describes the physics potential of a new fixed-target program based on a ~1 TeV proton source. Two proton sources are potentially available in the future: the existing Tevatron at Fermilab, which can provide 800 GeV protons for fixed-target physics, and a possible upgrade to the SPS at CERN, called SPS+, which would produce 1 TeV protons on target. In this paper we use an example Tevatron fixed-target program to illustrate the high discovery potential possible in the charm and neutrino sectors. We highlight examples which are either unique to the program or difficult to accomplish at other venues.

Renaissance of the ~ 1-TeV Fixed-Target Program

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

Adams, T.; /Florida State U.; Appel, J.A.

2011-12-02

This document describes the physics potential of a new fixed-target program based on a {approx}1 TeV proton source. Two proton sources are potentially available in the future: the existing Tevatron at Fermilab, which can provide 800 GeV protons for fixed-target physics, and a possible upgrade to the SPS at CERN, called SPS+, which would produce 1 TeV protons on target. In this paper we use an example Tevatron fixed-target program to illustrate the high discovery potential possible in the charm and neutrino sectors. We highlight examples which are either unique to the program or difficult to accomplish at other venues.

Determining conserved metabolic biomarkers from a million database queries.

PubMed

Kurczy, Michael E; Ivanisevic, Julijana; Johnson, Caroline H; Uritboonthai, Winnie; Hoang, Linh; Fang, Mingliang; Hicks, Matthew; Aldebot, Anthony; Rinehart, Duane; Mellander, Lisa J; Tautenhahn, Ralf; Patti, Gary J; Spilker, Mary E; Benton, H Paul; Siuzdak, Gary

2015-12-01

Metabolite databases provide a unique window into metabolome research allowing the most commonly searched biomarkers to be catalogued. Omic scale metabolite profiling, or metabolomics, is finding increased utility in biomarker discovery largely driven by improvements in analytical technologies and the concurrent developments in bioinformatics. However, the successful translation of biomarkers into clinical or biologically relevant indicators is limited. With the aim of improving the discovery of translatable metabolite biomarkers, we present search analytics for over one million METLIN metabolite database queries. The most common metabolites found in METLIN were cross-correlated against XCMS Online, the widely used cloud-based data processing and pathway analysis platform. Analysis of the METLIN and XCMS common metabolite data has two primary implications: these metabolites, might indicate a conserved metabolic response to stressors and, this data may be used to gauge the relative uniqueness of potential biomarkers. METLIN can be accessed by logging on to: https://metlin.scripps.edu siuzdak@scripps.edu Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Proceedings of a Workshop on Antarctic Meteorite Stranding Surfaces

NASA Technical Reports Server (NTRS)

Cassidy, W. A. (Editor); Whillans, I. M. (Editor)

1990-01-01

The discovery of large numbers of meteorites on the Antarctic Ice Sheet is one of the most exciting developments in polar science in recent years. The meteorites are found on areas of ice called stranding surfaces. Because of the sudden availability of hundreds, and then thousands, of new meteorite specimens at these sites, the significance of the discovery of meteorite stranding surfaces in Antarctica had an immediate and profound impact on planetary science, but there is also in this discovery an enormous, largely unrealized potential to glaciology for records of climatic and ice sheet changes. The glaciological interest derives from the antiquity of the ice in meteorite stranding surfaces. This exposed ice covers a range of ages, probably between zero and more than 500,000 years. The Workshop on Antarctic Meteorite Stranding Surfaces was convened to explore this potential and to devise a course of action that could be recommended to granting agencies. The workshop recognized three prime functions of meteorite stranding surfaces. They provide: (1) A proxy record of climatic change (i.e., a long record of climatic change is probably preserved in the exposed ice stratigraphy); (2) A proxy record of ice volume change; and (3) A source of unique nonterrestrial material.

Common characteristics of open source software development and applicability for drug discovery: a systematic review

PubMed Central

2011-01-01

Background Innovation through an open source model has proven to be successful for software development. This success has led many to speculate if open source can be applied to other industries with similar success. We attempt to provide an understanding of open source software development characteristics for researchers, business leaders and government officials who may be interested in utilizing open source innovation in other contexts and with an emphasis on drug discovery. Methods A systematic review was performed by searching relevant, multidisciplinary databases to extract empirical research regarding the common characteristics and barriers of initiating and maintaining an open source software development project. Results Common characteristics to open source software development pertinent to open source drug discovery were extracted. The characteristics were then grouped into the areas of participant attraction, management of volunteers, control mechanisms, legal framework and physical constraints. Lastly, their applicability to drug discovery was examined. Conclusions We believe that the open source model is viable for drug discovery, although it is unlikely that it will exactly follow the form used in software development. Hybrids will likely develop that suit the unique characteristics of drug discovery. We suggest potential motivations for organizations to join an open source drug discovery project. We also examine specific differences between software and medicines, specifically how the need for laboratories and physical goods will impact the model as well as the effect of patents. PMID:21955914

Emerging concepts promising new horizons for marine biodiscovery and synthetic biology.

PubMed

Reen, F Jerry; Gutiérrez-Barranquero, José A; Dobson, Alan D W; Adams, Claire; O'Gara, Fergal

2015-05-13

The vast oceans of the world, which comprise a huge variety of unique ecosystems, are emerging as a rich and relatively untapped source of novel bioactive compounds with invaluable biotechnological and pharmaceutical potential. Evidence accumulated over the last decade has revealed that the diversity of marine microorganisms is enormous with many thousands of bacterial species detected that were previously unknown. Associated with this diversity is the production of diverse repertoires of bioactive compounds ranging from peptides and enzymes to more complex secondary metabolites that have significant bioactivity and thus the potential to be exploited for innovative biotechnology. Here we review the discovery and functional potential of marine bioactive peptides such as lantibiotics, nanoantibiotics and peptidomimetics, which have received particular attention in recent years in light of their broad spectrum of bioactivity. The significance of marine peptides in cell-to-cell communication and how this may be exploited in the discovery of novel bioactivity is also explored. Finally, with the recent advances in bioinformatics and synthetic biology, it is becoming clear that the integration of these disciplines with genetic and biochemical characterization of the novel marine peptides, offers the most potential in the development of the next generation of societal solutions.

Emerging Concepts Promising New Horizons for Marine Biodiscovery and Synthetic Biology

PubMed Central

Reen, F. Jerry; Gutiérrez-Barranquero, José A.; Dobson, Alan D. W.; Adams, Claire; O’Gara, Fergal

2015-01-01

The vast oceans of the world, which comprise a huge variety of unique ecosystems, are emerging as a rich and relatively untapped source of novel bioactive compounds with invaluable biotechnological and pharmaceutical potential. Evidence accumulated over the last decade has revealed that the diversity of marine microorganisms is enormous with many thousands of bacterial species detected that were previously unknown. Associated with this diversity is the production of diverse repertoires of bioactive compounds ranging from peptides and enzymes to more complex secondary metabolites that have significant bioactivity and thus the potential to be exploited for innovative biotechnology. Here we review the discovery and functional potential of marine bioactive peptides such as lantibiotics, nanoantibiotics and peptidomimetics, which have received particular attention in recent years in light of their broad spectrum of bioactivity. The significance of marine peptides in cell-to-cell communication and how this may be exploited in the discovery of novel bioactivity is also explored. Finally, with the recent advances in bioinformatics and synthetic biology, it is becoming clear that the integration of these disciplines with genetic and biochemical characterization of the novel marine peptides, offers the most potential in the development of the next generation of societal solutions. PMID:25984990

A Novel mRNA Level Subtraction Method for Quick Identification of Target-Orientated Uniquely Expressed Genes Between Peanut Immature Pod and Leaf

PubMed Central

2010-01-01

Subtraction technique has been broadly applied for target gene discovery. However, most current protocols apply relative differential subtraction and result in great amount clone mixtures of unique and differentially expressed genes. This makes it more difficult to identify unique or target-orientated expressed genes. In this study, we developed a novel method for subtraction at mRNA level by integrating magnetic particle technology into driver preparation and tester–driver hybridization to facilitate uniquely expressed gene discovery between peanut immature pod and leaf through a single round subtraction. The resulting target clones were further validated through polymerase chain reaction screening using peanut immature pod and leaf cDNA libraries as templates. This study has resulted in identifying several genes expressed uniquely in immature peanut pod. These target genes can be used for future peanut functional genome and genetic engineering research. PMID:21406066

AGN in the Swift/BAT and INTEGRAL Hard X-ray Surveys

NASA Technical Reports Server (NTRS)

Beckmann, Volker; Tueller, Jack; Baumgartner, Wayne; Markwardt, Craig; Mushotzky, Richard; Skinner, Gerry

2008-01-01

Two hard X-ray surveys are in progress at this time. They provide a unique new window on compact objects and black holes. I will discuss how these two surveys complement each other and the potential for improved coordination that could yield significant near term results in both sensitivity and time coverage. I will pay particular attention to the discovery of faint sources including new results from the 36 month survey from Swift/Burst Alert Telescope (BAT).

Human HDAC isoform selectivity achieved via exploitation of the acetate release channel with structurally unique small molecule inhibitors

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

Whitehead, Lewis; Dobler, Markus R.; Radetich, Branko

2013-11-20

Herein we report the discovery of a family of novel yet simple, amino-acid derived class I HDAC inhibitors that demonstrate isoform selectivity via access to the internal acetate release channel. Isoform selectivity criteria is discussed on the basis of X-ray crystallography and molecular modeling of these novel inhibitors bound to HDAC8, potentially revealing insights into the mechanism of enzymatic function through novel structural features revealed at the atomic level.

HSQC-TOCSY Fingerprinting for Prioritization of Polyketide- and Peptide-Producing Microbial Isolates.

PubMed

Buedenbender, Larissa; Habener, Leesa J; Grkovic, Tanja; Kurtböke, D İpek; Duffy, Sandra; Avery, Vicky M; Carroll, Anthony R

2018-04-27

Microbial products are a promising source for drug leads as a result of their unique structural diversity. However, reisolation of already known natural products significantly hampers the discovery process, and it is therefore important to incorporate effective microbial isolate selection and dereplication protocols early in microbial natural product studies. We have developed a systematic approach for prioritization of microbial isolates for natural product discovery based on heteronuclear single-quantum correlation-total correlation spectroscopy (HSQC-TOCSY) nuclear magnetic resonance profiles in combination with antiplasmodial activity of extracts. The HSQC-TOCSY experiments allowed for unfractionated microbial extracts containing polyketide and peptidic natural products to be rapidly identified. Here, we highlight how this approach was used to prioritize extracts derived from a library of 119 ascidian-associated actinomycetes that possess a higher potential to produce bioactive polyketides and peptides.

Integrated (Meta) Genomic and Synthetic Biology Approaches to Develop New Biocatalysts

PubMed Central

Parages, María L.; Gutiérrez-Barranquero, José A.; Reen, F. Jerry; Dobson, Alan D.W.; O’Gara, Fergal

2016-01-01

In recent years, the marine environment has been the subject of increasing attention from biotechnological and pharmaceutical industries as a valuable and promising source of novel bioactive compounds. Marine biodiscovery programmes have begun to reveal the extent of novel compounds encoded within the enormous bacterial richness and diversity of the marine ecosystem. A combination of unique physicochemical properties and spatial niche-specific substrates, in wide-ranging and extreme habitats, underscores the potential of the marine environment to deliver on functionally novel biocatalytic activities. With the growing need for green alternatives to industrial processes, and the unique transformations which nature is capable of performing, marine biocatalysts have the potential to markedly improve current industrial pipelines. Furthermore, biocatalysts are known to possess chiral selectivity and specificity, a key focus of pharmaceutical drug design. In this review, we discuss how the explosion in genomics based sequence analysis, allied with parallel developments in synthetic and molecular biology, have the potential to fast-track the discovery and subsequent improvement of a new generation of marine biocatalysts. PMID:27007381

Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT).

PubMed

Yang, Hongfang; Medeiros, Patricia F; Raha, Kaushik; Elkins, Patricia; Lind, Kenneth E; Lehr, Ruth; Adams, Nicholas D; Burgess, Joelle L; Schmidt, Stanley J; Knight, Steven D; Auger, Kurt R; Schaber, Michael D; Franklin, G Joseph; Ding, Yun; DeLorey, Jennifer L; Centrella, Paolo A; Mataruse, Sibongile; Skinner, Steven R; Clark, Matthew A; Cuozzo, John W; Evindar, Ghotas

2015-05-14

In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein.

Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT)

PubMed Central

2015-01-01

In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein. PMID:26005528

Drugs from the Oceans: Marine Natural Products as Leads for Drug Discovery.

PubMed

Altmann, Karl-Heinz

2017-10-25

The marine environment harbors a vast number of species that are the source of a wide array of structurally diverse bioactive secondary metabolites. At this point in time, roughly 27'000 marine natural products are known, of which eight are (were) at the origin of seven marketed drugs, mostly for the treatment of cancer. The majority of these drugs and also of drug candidates currently undergoing clinical evaluation (excluding antibody-drug conjugates) are unmodified natural products, but synthetic chemistry has played a central role in the discovery and/or development of all but one of the approved marine-derived drugs. More than 1000 new marine natural products have been isolated per year over the last decade, but the pool of new and unique structures is far from exhausted. To fully leverage the potential offered by the structural diversity of marine-produced secondary metabolites for drug discovery will require their broad assessment for different bioactivities and the productive interplay between new fermentation technologies, synthetic organic chemistry, and medicinal chemistry, in order to secure compound supply and enable lead optimization.

Role of Open Source Tools and Resources in Virtual Screening for Drug Discovery.

PubMed

Karthikeyan, Muthukumarasamy; Vyas, Renu

2015-01-01

Advancement in chemoinformatics research in parallel with availability of high performance computing platform has made handling of large scale multi-dimensional scientific data for high throughput drug discovery easier. In this study we have explored publicly available molecular databases with the help of open-source based integrated in-house molecular informatics tools for virtual screening. The virtual screening literature for past decade has been extensively investigated and thoroughly analyzed to reveal interesting patterns with respect to the drug, target, scaffold and disease space. The review also focuses on the integrated chemoinformatics tools that are capable of harvesting chemical data from textual literature information and transform them into truly computable chemical structures, identification of unique fragments and scaffolds from a class of compounds, automatic generation of focused virtual libraries, computation of molecular descriptors for structure-activity relationship studies, application of conventional filters used in lead discovery along with in-house developed exhaustive PTC (Pharmacophore, Toxicophores and Chemophores) filters and machine learning tools for the design of potential disease specific inhibitors. A case study on kinase inhibitors is provided as an example.

Biomarker discovery and transcriptomic responses in Daphnia magna exposed to munitions constituents.

PubMed

Garcia-Reyero, Natalia; Poynton, Helen C; Kennedy, Alan J; Guan, Xin; Escalon, B Lynn; Chang, Bonnie; Varshavsky, Julia; Loguinov, Alex V; Vulpe, Chris D; Perkins, Edward J

2009-06-01

Ecotoxicogenomic approaches are emerging as alternative methods in environmental monitoring because they allow insight into pollutant modes of action and help assess the causal agents and potential toxicity beyond the traditional end points of death, growth, and reproduction. Gene expression analysis has shown particular promise for identifying gene expression biomarkers of chemical exposure that can be further used to monitor specific chemical exposures in the environment. We focused on the development of gene expression markers to detect and discriminate between chemical exposures. Using a custom cDNA microarray for Daphnia magna, we identified distinct expression fingerprints in response to exposure at sublethal concentrations of Cu, Zn, Pb, and munitions constituents. Using the results obtained from microarray analysis, we chose a suite of potential biomarkers for each of the specific exposures. The selected potential biomarkers were tested in independent chemical exposures for specificity using quantitative reverse transcription polymerase chain reaction. Six genes were confirmed as differentially regulated bythe selected chemical exposures. Furthermore, each exposure was identified by response of a unique combination (suite) of individual gene expression biomarkers. These results demonstrate the potential for discovery and validation of novel biomarkers of chemical exposures using gene expression analysis, which could have broad applicability in environmental monitoring.

Exploring the Potential of Direct-To-Consumer Genomic Test Data for Predicting Adverse Drug Events.

PubMed

Zhang, Patrick M; Sarkar, Indra Neil

2018-01-01

Recent technological advancements in genetic testing and the growing accessibility of public genomic data provide researchers with a unique avenue to approach personalized medicine. This feasibility study examined the potential of direct-to-consumer (DTC) genomic tests (focusing on 23andMe) in research and clinical applications. In particular, we combined population genetics information from the Personal Genome Project with adverse event reports from AEOLUS and pharmacogenetic information from PharmGKB. Primarily, associations between drugs based on co-occurring genetic variations and associations between variants and adverse events were used to assess the potential for leveraging single nucleotide polymorphism information from 23andMe. The results of this study suggest potential clinical uses of DTC tests in light of potential drug interactions. Furthermore, the results suggest great potential for analyzing associations at a population level to facilitate knowledge discovery in the realm of predicting adverse drug events.

K2 Citizen Science Discovery of a Four-Planet System in a Chain of 3:2 Resonances

NASA Astrophysics Data System (ADS)

Barentsen, Geert; Christiansen, Jessie; Crossfield, Ian; Barclay, Thomas; Lintott, Chris; Cox, Brian; Zemiro, Julia; Simmons, Brooke; Miller, Grant; NASA K2, Zooniverse, BBC, ABC

2017-06-01

We report on the discovery of a compact system of four transiting super-Earth-sized planets around a moderately bright K-type star (V=12) using data from Campaign 12 of NASA's K2 mission. Uniquely, the periods of the planets are 3.6d, 5.4d, 8.3d, and 12.8d, forming an unbroken chain of near 3:2 resonances. It is the first discovery made by citizen scientists participating in the Exoplanet Explorers project on the Zooniverse platform, and was discovered with the help of 15,000 volunteers recruited via the "Stargazing Live" show on Australia's ABC TV channel. K2's open data policy, combined with the unique format of a BBC TV production that does not shy away from including advanced scientific content, enabled the process of a genuine scientific discovery to be executed and witnessed live on air by nearly a million viewers.

The future of quantum dots in drug discovery.

PubMed

Lin, Guimiao; Yin, Feng; Yong, Ken-Tye

2014-09-01

The rapid development of drug discovery today is inseparable from the interaction of advanced particle technologies and new drug synthesis protocols. Quantum dots (QDs) are regarded as a unique class of fluorescent labels, with unique optical properties such as high brightness and long-term colloidal and optical stability; these are suitable for optical imaging, drug delivery and optical tracking, fluorescence immunoassay and other medicinal applications. More importantly, QD possesses a rich surface chemistry property that is useful for incorporating various drug molecules, targeting ligands, and additional contrast agents (e.g., MRI, PET, etc.) onto the nanoparticle surface for achieving targeted and traceable drug delivery therapy at both cellular and systemic levels. In recent times, the advancement of QD technology has promoted the use of functionalized nanocrystals for in vivo applications. Such research is paving the way for drug discovery using various bioconjugated QD formulations. In this editorial, the authors highlight the current research progress and future applications of QDs in drug discovery.

Discovery of a Highly Selective NAMPT Inhibitor That Demonstrates Robust Efficacy and Improved Retinal Toxicity with Nicotinic Acid Coadministration.

PubMed

Zhao, Genshi; Green, Colin F; Hui, Yu-Hua; Prieto, Lourdes; Shepard, Robert; Dong, Sucai; Wang, Tao; Tan, Bo; Gong, Xueqian; Kays, Lisa; Johnson, Robert L; Wu, Wenjuan; Bhattachar, Shobha; Del Prado, Miriam; Gillig, James R; Fernandez, Maria-Carmen; Roth, Ken D; Buchanan, Sean; Kuo, Ming-Shang; Geeganage, Sandaruwan; Burkholder, Timothy P

2017-12-01

NAMPT, an enzyme essential for NAD + biosynthesis, has been extensively studied as an anticancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective and has a potent and broad spectrum of anticancer activity. Its inhibitory activity can be rescued with nicotinic acid (NA) against the cell lines proficient, but not those deficient in NAPRT1, essential for converting NA to NAD + LSN3154567 also exhibits robust efficacy in multiple tumor models deficient in NAPRT1. Importantly, this molecule when coadministered with NA does not cause observable retinal and hematological toxicities in the rodents, yet still retains robust efficacy. Thus, LSN3154567 has the potential to be further developed clinically into a novel cancer therapeutic. Mol Cancer Ther; 16(12); 2677-88. ©2017 AACR . ©2017 American Association for Cancer Research.

Trends in GPCR drug discovery: new agents, targets and indications.

PubMed

Hauser, Alexander S; Attwood, Misty M; Rask-Andersen, Mathias; Schiöth, Helgi B; Gloriam, David E

2017-12-01

G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.

LSST Survey Data: Models for EPO Interaction

NASA Astrophysics Data System (ADS)

Olsen, J. K.; Borne, K. D.

2007-12-01

The potential for education and public outreach with the Large Synoptic Survey Telescope is as far reaching as the telescope itself. LSST data will be available to the public, giving anyone with a web browser a movie-like window on the Universe. The LSST project is unique in designing its data management and data access systems with the public and community users in mind. The enormous volume of data to be generated by LSST is staggering: 30 Terabytes per night, 10 Petabytes per year. The final database of extracted science parameters from the images will also be enormous -- 50-100 Petabytes -- a rich gold mine for data mining and scientific discovery potential. LSST will also generate 100,000 astronomical alerts per night, for 10 years. The LSST EPO team is examining models for EPO interaction with the survey data, particularly in how the community (amateurs, teachers, students, and general public) can participate in the discovery process. We will outline some of our models of community interaction for inquiry-based science using the LSST survey data, and we invite discussion on these topics.

Probing the String Landscape

ScienceCinema

Dienes, Keith

2018-01-10

We are currently in the throes of a potentially huge paradigm shift in physics. Motivated by recent developments in string theory and the discovery of the so-called "string landscape", physicists are beginning to question the uniqueness of fundamental theories of physics and the methods by which such theories might be understood and investigated. In this colloquium, I will give a non-technical introduction to the nature of this paradigm shift and how it developed. I will also discuss some of the questions to which it has led, and the nature of the controversies it has spawned.

[Advances in the study of anti-MRSA natural products].

PubMed

Song, Hao; Qin, Yong

2016-05-01

Methicillin-resistant Staphylococcus aureus (MRSA) is a multi-drug resistant pathogenic bacteria, which has seriously threatened human health for a long time. Discovery of novel anti-MRSA lead compounds with high efficiency and low toxicity represents an important research focus in the realm of antibiotic studies. Owing to their structural diversity and complexity, natural products have exhibited unique advantages and great potential in the development of anti-MRSA new drugs.This review summarizes the studies of anti-MRSA natural products and their relevant medicinal chemistry reported since 2010.

Revealing Nature’s Synthetic Potential Through the Study of Ribosomal Natural Product Biosynthesis

PubMed Central

Dunbar, Kyle L.; Mitchell, Douglas A.

2013-01-01

Ribosomally synthesized posttranslationally modified peptides (RiPPs) are a rapidly growing class of natural products with diverse structures and activities. In recent years, a great deal of progress has been made in elucidating the biosynthesis of various RiPP family members. As with the study of nonribosomal peptide and polyketide biosynthetic enzymes, these investigations have led to the discovery of entirely new biological chemistry. With each unique enzyme investigated, a more complex picture of Nature’s synthetic potential is revealed. This review focuses on recent reports (since 2008) that have changed the way that we think about ribosomal natural product biosynthesis and the enzymology of complex bond-forming reactions. PMID:23286465

Nature Bank and the Queensland Compound Library: unique international resources at the Eskitis Institute for Drug Discovery.

PubMed

Camp, David; Newman, Stuart; Pham, Ngoc B; Quinn, Ronald J

2014-03-01

The Eskitis Institute for Drug Discovery is home to two unique resources, Nature Bank and the Queensland Compound Library (QCL), that differentiate it from many other academic institutes pursuing chemical biology or early phase drug discovery. Nature Bank is a comprehensive collection of plants and marine invertebrates that have been subjected to a process which aligns downstream extracts and fractions with lead- and drug-like physicochemical properties. Considerable expertise in screening natural product extracts/fractions was developed at Eskitis over the last two decades. Importantly, biodiscovery activities have been conducted from the beginning in accordance with the UN Convention on Biological Diversity (CBD) to ensure compliance with all international and national legislative requirements. The QCL is a compound management and logistics facility that was established from public funds to augment previous investments in high throughput and phenotypic screening in the region. A unique intellectual property (IP) model has been developed in the case of the QCL to stimulate applied, basic and translational research in the chemical and life sciences by industry, non-profit, and academic organizations.

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…

Neonicotinoid insecticides: highlights of a symposium on strategic molecular designs.

PubMed

Tomizawa, Motohiro; Casida, John E

2011-04-13

Neonicotinoids are the newest of the five major classes of insecticides (the others are chlorinated hydrocarbons, organophosphorus compounds, methylcarbamates, and pyrethroids), and they make up approximately one-fourth of the world insecticide market. Nithiazine was the lead compound from Shell Development Co. in California later optimized by Shinzo Kagabu of Nihon Tokushu Noyaku Seizo to increase the potency and photostability, resulting in imidacloprid and thiacloprid. These discoveries are the basis for the International Award for Research in Agrochemicals of the American Chemical Society presented in 2010 to Professor Shinzo Kagabu. Five other neonicotinoids were added by others for the current set of seven commercial compounds. This symposium considers the progress in discovery and development of novel chemotype nicotinic insecticides with enhanced effectiveness, unique biological properties, and maximal safety. Chemorational approaches considered include physicochemical properties, metabolic activation and detoxification, and chemical and structural biology aspects potentially facilitating receptor structure-guided insecticide design.

Selection of phage-displayed accessible recombinant targeted antibodies (SPARTA): methodology and applications.

PubMed

D'Angelo, Sara; Staquicini, Fernanda I; Ferrara, Fortunato; Staquicini, Daniela I; Sharma, Geetanjali; Tarleton, Christy A; Nguyen, Huynh; Naranjo, Leslie A; Sidman, Richard L; Arap, Wadih; Bradbury, Andrew Rm; Pasqualini, Renata

2018-05-03

We developed a potentially novel and robust antibody discovery methodology, termed selection of phage-displayed accessible recombinant targeted antibodies (SPARTA). This combines an in vitro screening step of a naive human antibody library against known tumor targets, with in vivo selections based on tumor-homing capabilities of a preenriched antibody pool. This unique approach overcomes several rate-limiting challenges to generate human antibodies amenable to rapid translation into medical applications. As a proof of concept, we evaluated SPARTA on 2 well-established tumor cell surface targets, EphA5 and GRP78. We evaluated antibodies that showed tumor-targeting selectivity as a representative panel of antibody-drug conjugates (ADCs) and were highly efficacious. Our results validate a discovery platform to identify and validate monoclonal antibodies with favorable tumor-targeting attributes. This approach may also extend to other diseases with known cell surface targets and affected tissues easily isolated for in vivo selection.

Analytical Pipeline for Discovery and Verification of Glycoproteins from Plasma-Derived Extracellular Vesicles as Breast Cancer Biomarkers.

PubMed

Chen, I-Hsuan; Aguilar, Hillary Andaluz; Paez Paez, J Sebastian; Wu, Xiaofeng; Pan, Li; Wendt, Michael K; Iliuk, Anton B; Zhang, Ying; Tao, W Andy

2018-05-15

Glycoproteins comprise more than half of current FDA-approved protein cancer markers, but the development of new glycoproteins as disease biomarkers has been stagnant. Here we present a pipeline to develop glycoproteins from extracellular vesicles (EVs) through integrating quantitative glycoproteomics with a novel reverse phase glycoprotein array and then apply it to identify novel biomarkers for breast cancer. EV glycoproteomics show promise in circumventing the problems plaguing current serum/plasma glycoproteomics and allowed us to identify hundreds of glycoproteins that have not been identified in blood. We identified 1,453 unique glycopeptides representing 556 glycoproteins in EVs, among which 20 were verified significantly higher in individual breast cancer patients. We further applied a novel glyco-specific reverse phase protein array to quantify a subset of the candidates. Together, this study demonstrates the great potential of this integrated pipeline for biomarker discovery.

International Search for Life in Ocean Worlds

NASA Astrophysics Data System (ADS)

Sherwood, B.

2015-12-01

We now know that our solar system contains diverse "ocean worlds." One has abundant surface water and life; another had significant surface water in the distant past and has drawn significant exploration attention; several contain large amounts of water beneath ice shells; and several others evince unexpected, diverse transient or dynamic water-related processes. In this century, humanity will explore these worlds, searching for life beyond Earth and seeking thereby to understand the limits of habitability. Of our ocean worlds, Enceladus presents a unique combination of attributes: large reservoir of subsurface water already known to contain salts, organics, and silica nanoparticles originating from hydrothermal activity; and able to be sampled via a plume predictably expressed into space. These special circumstances immediately tag Enceladus as a key destination for potential missions to search for evidence of non-Earth life, and lead to a range of potential mission concepts: for orbital reconnaissance; in situ and returned-sample analysis of plume and surface-fallback material; and direct sulcus, vent, cavern, and ocean exploration. Each mission type can address a unique set of science questions, and would require a unique set of capabilities, most of which are not yet developed. Both the questions and the capability developments can be sequenced into a programmatic precedence network, the realization of which requires international cooperation. Three factors make this true: exploring remote oceans autonomously will cost a lot; the Outer Space Treaty governs planetary protection; and discovery of non-Earth life is an epochal human imperative. Results of current planning will be presented in AGU session 8599: how ocean-world science questions and capability requirements can be parsed into programmatically acceptable mission increments; how one mission proposed into the Discovery program in 2015 would take the next step on this path; the Decadal calendar of decision points and program options that will constrain ocean-world exploration through mid-century; and findings of the COSPAR Planetary Protection Panel colloquium for ocean-world exploration held in September 2015.

The Unique Scientific Assets of Multi-Wavelength Total Solar Eclipse Observations

NASA Astrophysics Data System (ADS)

Habbal, S. R.; Druckmuller, M.; Ding, A.

2017-12-01

Total solar eclipses continue to yield new discoveries regarding the dynamics and thermodynamics of the corona, due to the radial span of the field of view available during totality, starting from the solar surface out to several solar radii, and due to the diagnostic potential provided by coronal emission lines. Scientific highlights from past eclipse observations as well as from the 21 August 2017 eclipse, now spanning a solar cycle, will be presented. These include white light and spectral line imaging as well as imaging spectrometry. Emphasis will be placed on the unique insights into the origin of dynamic structures captured in eclipse images, and the temperature distribution in the corona derived from these eclipse observations. Implications of these results for the general problem of coronal heating, as well as for the next generation of space instrumentation will be discussed.

Unique Prokaryotic Consortia in Geochemically Distinct Sediments from Red Sea Atlantis II and Discovery Deep Brine Pools

PubMed Central

Siam, Rania; Mustafa, Ghada A.; Sharaf, Hazem; Moustafa, Ahmed; Ramadan, Adham R.; Antunes, Andre; Bajic, Vladimir B.; Stingl, Uli; Marsis, Nardine G. R.; Coolen, Marco J. L.; Sogin, Mitchell; Ferreira, Ari J. S.; Dorry, Hamza El

2012-01-01

The seafloor is a unique environment, which allows insights into how geochemical processes affect the diversity of biological life. Among its diverse ecosystems are deep-sea brine pools - water bodies characterized by a unique combination of extreme conditions. The ‘polyextremophiles’ that constitute the microbial assemblage of these deep hot brines have not been comprehensively studied. We report a comparative taxonomic analysis of the prokaryotic communities of the sediments directly below the Red Sea brine pools, namely, Atlantis II, Discovery, Chain Deep, and an adjacent brine-influenced site. Analyses of sediment samples and high-throughput pyrosequencing of PCR-amplified environmental 16S ribosomal RNA genes (16S rDNA) revealed that one sulfur (S)-rich Atlantis II and one nitrogen (N)-rich Discovery Deep section contained distinct microbial populations that differed from those found in the other sediment samples examined. Proteobacteria, Actinobacteria, Cyanobacteria, Deferribacteres, and Euryarchaeota were the most abundant bacterial and archaeal phyla in both the S- and N-rich sections. Relative abundance-based hierarchical clustering of the 16S rDNA pyrotags assigned to major taxonomic groups allowed us to categorize the archaeal and bacterial communities into three major and distinct groups; group I was unique to the S-rich Atlantis II section (ATII-1), group II was characteristic for the N-rich Discovery sample (DD-1), and group III reflected the composition of the remaining sediments. Many of the groups detected in the S-rich Atlantis II section are likely to play a dominant role in the cycling of methane and sulfur due to their phylogenetic affiliations with bacteria and archaea involved in anaerobic methane oxidation and sulfate reduction. PMID:22916172

Use of combinatorial chemistry to speed drug discovery.

PubMed

Rádl, S

1998-10-01

IBC's International Conference on Integrating Combinatorial Chemistry into the Discovery Pipeline was held September 14-15, 1998. The program started with a pre-conference workshop on High-Throughput Compound Characterization and Purification. The agenda of the main conference was divided into sessions of Synthesis, Automation and Unique Chemistries; Integrating Combinatorial Chemistry, Medicinal Chemistry and Screening; Combinatorial Chemistry Applications for Drug Discovery; and Information and Data Management. This meeting was an excellent opportunity to see how big pharma, biotech and service companies are addressing the current bottlenecks in combinatorial chemistry to speed drug discovery. (c) 1998 Prous Science. All rights reserved.

Authentic Astronomical Discovery in Planetariums: Bringing Data to Domes

NASA Astrophysics Data System (ADS)

Wyatt, Ryan Jason; Subbarao, Mark; Christensen, Lars; Emmons, Ben; Hurt, Robert

2018-01-01

Planetariums offer a unique opportunity to disseminate astronomical discoveries using data visualization at all levels of complexity: the technical infrastructure to display data and a sizeable cohort of enthusiastic educators to interpret results. “Data to Dome” is an initiative the International Planetarium Society to develop our community’s capacity to integrate data in fulldome planetarium systems—including via open source software platforms such as WorldWide Telescope and OpenSpace. We are cultivating a network of planetarium professionals who integrate data into their presentations and share their content with others. Furthermore, we propose to shorten the delay between discovery and dissemination in planetariums. Currently, the “latest science” is often presented days or weeks after discoveries are announced, and we can shorten this to hours or even minutes. The Data2Dome (D2D) initiative, led by the European Southern Observatory, proposes technical infrastructure and data standards that will streamline content flow from research institutions to planetariums, offering audiences a unique opportunity to access to the latest astronomical data in near real time.

Applications of patient-specific induced pluripotent stem cells; focused on disease modeling, drug screening and therapeutic potentials for liver disease.

PubMed

Chun, Yong Soon; Chaudhari, Pooja; Jang, Yoon-Young

2010-12-14

The recent advances in the induced pluripotent stem cell (iPSC) research have significantly changed our perspectives on regenerative medicine by providing researchers with a unique tool to derive disease-specific stem cells for study. In this review, we describe the human iPSC generation from developmentally diverse origins (i.e. endoderm-, mesoderm-, and ectoderm- tissue derived human iPSCs) and multistage hepatic differentiation protocols, and discuss both basic and clinical applications of these cells including disease modeling, drug toxicity screening/drug discovery, gene therapy and cell replacement therapy.

Design of the ARES Mars Airplane and Mission Architecture

NASA Technical Reports Server (NTRS)

Braun, Robert D.; Wright, Henry S.; Croom, Mark A.; Levine, Joel S.; Spencer, David A.

2006-01-01

Significant technology advances have enabled planetary aircraft to be considered as viable science platforms. Such systems fill a unique planetary science measurement gap, that of regional-scale, near-surface observation, while providing a fresh perspective for potential discovery. Recent efforts have produced mature mission and flight system concepts, ready for flight project implementation. This paper summarizes the development of a Mars airplane mission architecture that balances science, implementation risk and cost. Airplane mission performance, flight system design and technology maturation are described. The design, analysis and testing completed demonstrates the readiness of this science platform for use in a Mars flight project.

CSF proteomic fingerprints for HIV-associated cognitive impairment.

PubMed

Laspiur, Juliana Pérez; Anderson, Eric R; Ciborowski, Pawel; Wojna, Valerie; Rozek, Wojciech; Duan, Fenghai; Mayo, Raul; Rodríguez, Elaine; Plaud-Valentín, Marinés; Rodríguez-Orengo, José; Gendelman, Howard E; Meléndez, Loyda M

2007-12-01

Cognitive impairment remains a major complication of advanced human immunodeficiency virus (HIV) infection despite the widespread use of anti-retroviral therapy. Diagnosis is made by exclusion making biomarkers of great potential use. Thus, we used an integrated proteomics platform to assess cerebrospinal fluid protein profiles from 50 HIV-1 seropositive Hispanic women. Nine of 38 proteins identified were unique in those patients with cognitive impairment (CI). These proteins were linked to cell signaling, structural function, and antioxidant activities. This work highlights, in a preliminary manner, the utility of proteomic profiling for biomarker discovery for HIV-1 associated cognitive dysfunction.

Engineering Human Neural Tissue by 3D Bioprinting.

PubMed

Gu, Qi; Tomaskovic-Crook, Eva; Wallace, Gordon G; Crook, Jeremy M

2018-01-01

Bioprinting provides an opportunity to produce three-dimensional (3D) tissues for biomedical research and translational drug discovery, toxicology, and tissue replacement. Here we describe a method for fabricating human neural tissue by 3D printing human neural stem cells with a bioink, and subsequent gelation of the bioink for cell encapsulation, support, and differentiation to functional neurons and supporting neuroglia. The bioink uniquely comprises the polysaccharides alginate, water-soluble carboxymethyl-chitosan, and agarose. Importantly, the method could be adapted to fabricate neural and nonneural tissues from other cell types, with the potential to be applied for both research and clinical product development.

Crop status evaluations and yield predictions

NASA Technical Reports Server (NTRS)

Haun, J. R.

1976-01-01

One phase of the large area crop inventory project is presented. Wheat yield models based on the input of environmental variables potentially obtainable through the use of space remote sensing were developed and demonstrated. By the use of a unique method for visually qualifying daily plant development and subsequent multifactor computer analyses, it was possible to develop practical models for predicting crop development and yield. Development of wheat yield prediction models was based on the discovery that morphological changes in plants are detected and quantified on a daily basis, and that this change during a portion of the season was proportional to yield.

CSF proteomic fingerprints for HIV- associated cognitive impairment

PubMed Central

Laspiur, Juliana Pérez; Anderson, Eric R.; Ciborowski, Pawel; Wojna, Valerie; Rozek, Wojciech; Duan, Fenghai; Mayo, Raul; Rodríguez, Elaine; Plaud-Valentín, Marinés; Rodríguez-Orengo, José; Gendelman, Howard E.; Meléndez, Loyda M.

2008-01-01

Cognitive impairment remains a major complication of advanced human immunodeficiency virus (HIV) infection despite the wide spread use of anti-retroviral therapy. Diagnosis is made by exclusion making biomarkers of great potential use. Thus, we used an integrated proteomics platform to assess cerebrospinal fluid protein profiles from 50 HIV-1 seropositive Hispanic women. Nine of 38 proteins identified were unique in those patients with cognitive impairment. These proteins were linked to cell signaling, structural function, and antioxidant activities. This work highlights, in a preliminary manner, the utility of proteomic profiling for biomarker discovery for HIV-1 associated cognitive dysfunction. PMID:17950469

Proteomic characterisation of toxins isolated from nematocysts of the South Atlantic jellyfish Olindias sambaquiensis.

PubMed

Weston, Andrew J; Chung, Ray; Dunlap, Walter C; Morandini, André C; Marques, Antonio C; Moura-da-Silva, Ana M; Ward, Malcolm; Padilla, Gabriel; da Silva, Luiziana Ferreira; Andreakis, Nikos; Long, Paul F

2013-09-01

Surprisingly little is known of the toxic arsenal of cnidarian nematocysts compared to other venomous animals. Here we investigate the toxins of nematocysts isolated from the jellyfish Olindias sambaquiensis. A total of 29 unique ms/ms events were annotated as potential toxins homologous to the toxic proteins from diverse animal phyla, including cone-snails, snakes, spiders, scorpions, wasp, bee, parasitic worm and other Cnidaria. Biological activities of these potential toxins include cytolysins, neurotoxins, phospholipases and toxic peptidases. The presence of several toxic enzymes is intriguing, such as sphingomyelin phosphodiesterase B (SMase B) that has only been described in certain spider venoms, and a prepro-haystatin P-IIId snake venom metalloproteinase (SVMP) that activates coagulation factor X, which is very rare even in snake venoms. Our annotation reveals sequence orthologs to many representatives of the most important superfamilies of peptide venoms suggesting that their origins in higher organisms arise from deep eumetazoan innovations. Accordingly, cnidarian venoms may possess unique biological properties that might generate new leads in the discovery of novel pharmacologically active drugs. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

A semantic web ontology for small molecules and their biological targets.

PubMed

Choi, Jooyoung; Davis, Melissa J; Newman, Andrew F; Ragan, Mark A

2010-05-24

A wide range of data on sequences, structures, pathways, and networks of genes and gene products is available for hypothesis testing and discovery in biological and biomedical research. However, data describing the physical, chemical, and biological properties of small molecules have not been well-integrated with these resources. Semantically rich representations of chemical data, combined with Semantic Web technologies, have the potential to enable the integration of small molecule and biomolecular data resources, expanding the scope and power of biomedical and pharmacological research. We employed the Semantic Web technologies Resource Description Framework (RDF) and Web Ontology Language (OWL) to generate a Small Molecule Ontology (SMO) that represents concepts and provides unique identifiers for biologically relevant properties of small molecules and their interactions with biomolecules, such as proteins. We instanced SMO using data from three public data sources, i.e., DrugBank, PubChem and UniProt, and converted to RDF triples. Evaluation of SMO by use of predetermined competency questions implemented as SPARQL queries demonstrated that data from chemical and biomolecular data sources were effectively represented and that useful knowledge can be extracted. These results illustrate the potential of Semantic Web technologies in chemical, biological, and pharmacological research and in drug discovery.

From crystal to compound: structure-based antimalarial drug discovery.

PubMed

Drinkwater, Nyssa; McGowan, Sheena

2014-08-01

Despite a century of control and eradication campaigns, malaria remains one of the world's most devastating diseases. Our once-powerful therapeutic weapons are losing the war against the Plasmodium parasite, whose ability to rapidly develop and spread drug resistance hamper past and present malaria-control efforts. Finding new and effective treatments for malaria is now a top global health priority, fuelling an increase in funding and promoting open-source collaborations between researchers and pharmaceutical consortia around the world. The result of this is rapid advances in drug discovery approaches and technologies, with three major methods for antimalarial drug development emerging: (i) chemistry-based, (ii) target-based, and (iii) cell-based. Common to all three of these approaches is the unique ability of structural biology to inform and accelerate drug development. Where possible, SBDD (structure-based drug discovery) is a foundation for antimalarial drug development programmes, and has been invaluable to the development of a number of current pre-clinical and clinical candidates. However, as we expand our understanding of the malarial life cycle and mechanisms of resistance development, SBDD as a field must continue to evolve in order to develop compounds that adhere to the ideal characteristics for novel antimalarial therapeutics and to avoid high attrition rates pre- and post-clinic. In the present review, we aim to examine the contribution that SBDD has made to current antimalarial drug development efforts, covering hit discovery to lead optimization and prevention of parasite resistance. Finally, the potential for structural biology, particularly high-throughput structural genomics programmes, to identify future targets for drug discovery are discussed.

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

Bogomilov, M.; Matev, R.; Tsenov, R.

The properties of the neutrino provide a unique window on physics beyond that described by the standard model. The study of subleading effects in neutrino oscillations, and the race to discover CP-invariance violation in the lepton sector, has begun with the recent discovery that theta(13) > 0. The measured value of theta(13) is large, emphasizing the need for a facility at which the systematic uncertainties can be reduced to the percent level. The neutrino factory, in which intense neutrino beams are produced from the decay of muons, has been shown to outperform all realistic alternatives and to be capable ofmore » making measurements of the requisite precision. Its unique discovery potential arises from the fact that only at the neutrino factory is it practical to produce high-energy electron (anti) neutrino beams of the required intensity. This paper presents the conceptual design of the neutrino factory accelerator facility developed by the European Commission Framework Programme 7 EURO nu. Design Study consortium. EURO nu coordinated the European contributions to the International Design Study for the Neutrino Factory (the IDS-NF) collaboration. The EURO nu baseline accelerator facility will provide 10(21) muon decays per year from 12.6 GeV stored muon beams serving a single neutrino detector situated at a source-detector distance of between 1 500 km and 2 500 km. A suite of near detectors will allow definitive neutrino-scattering experiments to be performed.« less

Neutrino factory

DOE PAGES

Bogomilov, M.; Matev, R.; Tsenov, R.; ...

2014-12-08

The properties of the neutrino provide a unique window on physics beyond that described by the standard model. The study of subleading effects in neutrino oscillations, and the race to discover CP-invariance violation in the lepton sector, has begun with the recent discovery that theta(13) > 0. The measured value of theta(13) is large, emphasizing the need for a facility at which the systematic uncertainties can be reduced to the percent level. The neutrino factory, in which intense neutrino beams are produced from the decay of muons, has been shown to outperform all realistic alternatives and to be capable ofmore » making measurements of the requisite precision. Its unique discovery potential arises from the fact that only at the neutrino factory is it practical to produce high-energy electron (anti) neutrino beams of the required intensity. This paper presents the conceptual design of the neutrino factory accelerator facility developed by the European Commission Framework Programme 7 EURO nu. Design Study consortium. EURO nu coordinated the European contributions to the International Design Study for the Neutrino Factory (the IDS-NF) collaboration. The EURO nu baseline accelerator facility will provide 10(21) muon decays per year from 12.6 GeV stored muon beams serving a single neutrino detector situated at a source-detector distance of between 1 500 km and 2 500 km. A suite of near detectors will allow definitive neutrino-scattering experiments to be performed.« less

Plasticity and Kinky Chemistry of Carbon Nanotubes

NASA Technical Reports Server (NTRS)

Srivastava, Deepak; Dzegilenko, Fedor

2000-01-01

Since their discovery in 1991, carbon nanotubes have been the subject of intense research interest based on early predictions of their unique mechanical, electronic, and chemical properties. Materials with the predicted unique properties of carbon nanotubes are of great interest for use in future generations of aerospace vehicles. For their structural properties, carbon nanotubes could be used as reinforcing fibers in ultralight multifunctional composites. For their electronic properties, carbon nanotubes offer the potential of very high-speed, low-power computing elements, high-density data storage, and unique sensors. In a continuing effort to model and predict the properties of carbon nanotubes, Ames accomplished three significant results during FY99. First, accurate values of the nanomechanics and plasticity of carbon nanotubes based on quantum molecular dynamics simulations were computed. Second, the concept of mechanical deformation catalyzed-kinky-chemistry as a means to control local chemistry of nanotubes was discovered. Third, the ease of nano-indentation of silicon surfaces with carbon nanotubes was established. The elastic response and plastic failure mechanisms of single-wall nanotubes were investigated by means of quantum molecular dynamics simulations.

An integrated and accessible sample data library for Mars sample return science

NASA Astrophysics Data System (ADS)

Tuite, M. L., Jr.; Williford, K. H.

2015-12-01

Over the course of the next decade or more, many thousands of geological samples will be collected and analyzed in a variety of ways by researchers at the Jet Propulsion Laboratory (California Institute of Technology) in order to facilitate discovery and contextualize observations made of Mars rocks both in situ and here on Earth if samples are eventually returned. Integration of data from multiple analyses of samples including petrography, thin section and SEM imaging, isotope and organic geochemistry, XRF, XRD, and Raman spectrometry is a challenge and a potential obstacle to discoveries that require supporting lines of evidence. We report the development of a web-accessible repository, the Sample Data Library (SDL) for the sample-based data that are generated by the laboratories and instruments that comprise JPL's Center for Analysis of Returned Samples (CARS) in order to facilitate collaborative interpretation of potential biosignatures in Mars-analog geological samples. The SDL is constructed using low-cost, open-standards-based Amazon Web Services (AWS), including web-accessible storage, relational data base services, and a virtual web server. The data structure is sample-centered with a shared registry for assigning unique identifiers to all samples including International Geo-Sample Numbers. Both raw and derived data produced by instruments and post-processing workflows are automatically uploaded to online storage and linked via the unique identifiers. Through the web interface, users are able to find all the analyses associated with a single sample or search across features shared by multiple samples, sample localities, and analysis types. Planned features include more sophisticated search and analytical interfaces as well as data discoverability through NSF's EarthCube program.

Discovery of Anthelmintic Drug Targets and Drugs Using Chokepoints in Nematode Metabolic Pathways

PubMed Central

Taylor, Christina M.; Wang, Qi; Rosa, Bruce A.; Huang, Stanley Ching-Cheng; Powell, Kerrie; Schedl, Tim; Pearce, Edward J.; Abubucker, Sahar; Mitreva, Makedonka

2013-01-01

Parasitic roundworm infections plague more than 2 billion people (1/3 of humanity) and cause drastic losses in crops and livestock. New anthelmintic drugs are urgently needed as new drug resistance and environmental concerns arise. A “chokepoint reaction” is defined as a reaction that either consumes a unique substrate or produces a unique product. A chokepoint analysis provides a systematic method of identifying novel potential drug targets. Chokepoint enzymes were identified in the genomes of 10 nematode species, and the intersection and union of all chokepoint enzymes were found. By studying and experimentally testing available compounds known to target proteins orthologous to nematode chokepoint proteins in public databases, this study uncovers features of chokepoints that make them successful drug targets. Chemogenomic screening was performed on drug-like compounds from public drug databases to find existing compounds that target homologs of nematode chokepoints. The compounds were prioritized based on chemical properties frequently found in successful drugs and were experimentally tested using Caenorhabditis elegans. Several drugs that are already known anthelmintic drugs and novel candidate targets were identified. Seven of the compounds were tested in Caenorhabditis elegans and three yielded a detrimental phenotype. One of these three drug-like compounds, Perhexiline, also yielded a deleterious effect in Haemonchus contortus and Onchocerca lienalis, two nematodes with divergent forms of parasitism. Perhexiline, known to affect the fatty acid oxidation pathway in mammals, caused a reduction in oxygen consumption rates in C. elegans and genome-wide gene expression profiles provided an additional confirmation of its mode of action. Computational modeling of Perhexiline and its target provided structural insights regarding its binding mode and specificity. Our lists of prioritized drug targets and drug-like compounds have potential to expedite the discovery of new anthelmintic drugs with broad-spectrum efficacy. PMID:23935495

Olfactory Mechanisms for Discovery of Odorants to Reduce Insect-Host Contact

PubMed Central

Clark, Jonathan T.; Ray, Anandasankar

2016-01-01

Insects have developed highly sophisticated and sensitive olfactory systems to find animal or plant hosts for feeding. Some insects vector pathogens that cause diseases in hundreds of millions of people and destroy billions of dollars of food products every year. There is great interest, therefore, in understanding how the insect olfactory system can be manipulated to reduce their contact with hosts. Here, we review recent advances in our understanding of insect olfactory detection mechanisms, which may serve as a foundation for designing insect control programs based on manipulation of their behaviors by using odorants. Because every insect species has a unique set of olfactory receptors and olfactory-mediated behaviors, we focus primarily on general principles of odor detection that potentially apply to most insects. While these mechanisms have emerged from studies on model systems for study of insect olfaction, such as Drosophila melanogaster, they provide a foundation for discovery of odorants to repel insects or reduce host-seeking behavior. PMID:27628342

Induced Pluripotent Stem Cells in Huntington's Disease: Disease Modeling and the Potential for Cell-Based Therapy.

PubMed

Liu, Ling; Huang, Jin-Sha; Han, Chao; Zhang, Guo-Xin; Xu, Xiao-Yun; Shen, Yan; Li, Jie; Jiang, Hai-Yang; Lin, Zhi-Cheng; Xiong, Nian; Wang, Tao

2016-12-01

Huntington's disease (HD) is an incurable neurodegenerative disorder that is characterized by motor dysfunction, cognitive impairment, and behavioral abnormalities. It is an autosomal dominant disorder caused by a CAG repeat expansion in the huntingtin gene, resulting in progressive neuronal loss predominately in the striatum and cortex. Despite the discovery of the causative gene in 1993, the exact mechanisms underlying HD pathogenesis have yet to be elucidated. Treatments that slow or halt the disease process are currently unavailable. Recent advances in induced pluripotent stem cell (iPSC) technologies have transformed our ability to study disease in human neural cells. Here, we firstly review the progress made to model HD in vitro using patient-derived iPSCs, which reveal unique insights into illuminating molecular mechanisms and provide a novel human cell-based platform for drug discovery. We then highlight the promises and challenges for pluripotent stem cells that might be used as a therapeutic source for cell replacement therapy of the lost neurons in HD brains.

Targeting mammalian organelles with internalizing phage (iPhage) libraries

PubMed Central

Rangel, Roberto; Dobroff, Andrey S.; Guzman-Rojas, Liliana; Salmeron, Carolina C.; Gelovani, Juri G.; Sidman, Richard L.; Pasqualini, Renata; Arap, Wadih

2015-01-01

Techniques largely used for protein interaction studies and discovery of intracellular receptors, such as affinity capture complex purification and yeast two-hybrid, may produce inaccurate datasets due to protein insolubility, transient or weak protein interactions, or irrelevant intracellular context. A versatile tool to overcome these limitations as well as to potentially create vaccines and engineer peptides and antibodies as targeted diagnostic and therapeutic agents, is the phage display technique. We have recently developed a new technology for screening internalizing phage (iPhage) vectors and libraries utilizing a ligand/receptor-independent mechanism to penetrate eukaryotic cells. iPhage particles provide a unique discovery platform for combinatorial intracellular targeting of organelle ligands along with their corresponding receptors and to fingerprint functional protein domains in living cells. Here we explain the design, cloning, construction, and production of iPhage-based vectors and libraries, along with basic ligand-receptor identification and validation methodologies for organelle receptors. An iPhage library screening can be performed in ~8 weeks. PMID:24030441

An insight into the exploration of druggable genome of Streptococcus gordonii for the identification of novel therapeutic candidates.

PubMed

Azam, Syed Sikander; Shamim, Amen

2014-09-01

The discovery of novel drug targets of a genome that can bind with high affinity to drug-like compounds is a significant challenge in drug development. Streptococcus gordonii initiates dental plaque formation and endocarditis by entering into the blood stream, usually after oral trauma. The prolonged use of antibiotics is raising a problem of multi-drug resistance and lack of an optimal therapeutic regime that necessitates the drug discovery of vital importance in curing various infections. To overcome this dilemma, the in silico approach paves the way for identification and qualitative characterization of promising drug targets for S. gordonii that encompass three phases of analyses. The present study deciphers drug target genomes of S. gordonii in which 93 proteins were identified as potential drug targets and 16 proteins were found to be involved in unique metabolic pathways. Highlighted information will convincingly render to facilitate selection of S. gordonii proteins for successful entry into drug design pipelines. Copyright © 2014 Elsevier Inc. All rights reserved.

Mesoscopic superconductivity and high spin polarization coexisting at metallic point contacts on Weyl semimetal TaAs

PubMed Central

Aggarwal, Leena; Gayen, Sirshendu; Das, Shekhar; Kumar, Ritesh; Süß, Vicky; Felser, Claudia; Shekhar, Chandra; Sheet, Goutam

2017-01-01

A Weyl semimetal is a topologically non-trivial phase of matter that hosts mass-less Weyl fermions, the particles that remained elusive for more than 80 years since their theoretical discovery. The Weyl semimetals exhibit unique transport properties and remarkably high surface spin polarization. Here we show that a mesoscopic superconducting phase with critical temperature Tc=7 K can be realized by forming metallic point contacts with silver (Ag) on single crystals of TaAs, while neither Ag nor TaAs are superconductors. Andreev reflection spectroscopy of such point contacts reveals a superconducting gap of 1.2 meV that coexists with a high transport spin polarization of 60% indicating a highly spin-polarized supercurrent flowing through the point contacts on TaAs. Therefore, apart from the discovery of a novel mesoscopic superconducting phase, our results also show that the point contacts on Weyl semimetals are potentially important for applications in spintronics. PMID:28071685

Computer-aided discovery of a metal-organic framework with superior oxygen uptake.

PubMed

Moghadam, Peyman Z; Islamoglu, Timur; Goswami, Subhadip; Exley, Jason; Fantham, Marcus; Kaminski, Clemens F; Snurr, Randall Q; Farha, Omar K; Fairen-Jimenez, David

2018-04-11

Current advances in materials science have resulted in the rapid emergence of thousands of functional adsorbent materials in recent years. This clearly creates multiple opportunities for their potential application, but it also creates the following challenge: how does one identify the most promising structures, among the thousands of possibilities, for a particular application? Here, we present a case of computer-aided material discovery, in which we complete the full cycle from computational screening of metal-organic framework materials for oxygen storage, to identification, synthesis and measurement of oxygen adsorption in the top-ranked structure. We introduce an interactive visualization concept to analyze over 1000 unique structure-property plots in five dimensions and delimit the relationships between structural properties and oxygen adsorption performance at different pressures for 2932 already-synthesized structures. We also report a world-record holding material for oxygen storage, UMCM-152, which delivers 22.5% more oxygen than the best known material to date, to the best of our knowledge.

Symbolic Metal Bit and Saddlebag Fastenings in a Middle Bronze Age Donkey Burial

PubMed Central

Bar-Oz, Guy; Nahshoni, Pirhiya; Motro, Hadas; Oren, Eliezer D.

2013-01-01

Here we report the unprecedented discovery of the skeleton of a ritually interred donkey with a metal horse bit in association with its teeth and saddlebag fastenings on its back. This discovery in the Middle Bronze Age III sacred precinct (1700/1650-1550 BCE) at Tel Haror, Israel, presents a unique combination of evidence for the early employment of equid harnessing equipment, both for chariot bridling (horse bit) and pack animals (saddlebags). The ritually deposited donkey with its unique accoutrements advances our understanding of the broad social and religious significance of equids in the Levantine Bronze Age, previously known mainly from textual and iconographical sources. PMID:23484046

Discovery Bottles: A Unique Inexpensive Tool for the K-2 Science Classroom

ERIC Educational Resources Information Center

Watson, Sandy

2008-01-01

Discover discovery bottles! These wide-mouth plastic containers of any size filled with objects of different kinds can be terrific tools for science explorations and a great way to cultivate science minds in a K-2 science classroom. In addition, the author has found them to be a useful, inexpensive, and engaging way to help students develop skills…

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.

Ontology for Transforming Geo-Spatial Data for Discovery and Integration of Scientific Data

NASA Astrophysics Data System (ADS)

Nguyen, L.; Chee, T.; Minnis, P.

2013-12-01

Discovery and access to geo-spatial scientific data across heterogeneous repositories and multi-discipline datasets can present challenges for scientist. We propose to build a workflow for transforming geo-spatial datasets into semantic environment by using relationships to describe the resource using OWL Web Ontology, RDF, and a proposed geo-spatial vocabulary. We will present methods for transforming traditional scientific dataset, use of a semantic repository, and querying using SPARQL to integrate and access datasets. This unique repository will enable discovery of scientific data by geospatial bound or other criteria.

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.

A Recent History of HNO (Nitroxyl) Chemistry, Pharmacology and Therapeutic Potential.

PubMed

Fukuto, Jon M

2018-06-02

Due to the excitement surrounding the discovery of nitric oxide (NO) as an endogenously generated signaling molecule, numerous other nitrogen oxides were also investigated as possible physiological mediators. Among these was nitroxyl (HNO). Over the past 25 years or so, a significant amount of work by this lab and many others has discovered that HNO possesses unique chemical properties and important pharmacological utility. Indeed, the pharmacological potential for HNO as a treatment for heart failure, among other uses, has garnered this curious molecule tremendous recent attention. This review thus summarizes the events that led to this recent attention as well as pose remaining questions that are important to answer with regards to understanding the chemistry and biology of HNO. This article is protected by copyright. All rights reserved.

From Extrasolar Planets to Exo-Earths

NASA Astrophysics Data System (ADS)

Fischer, Debra

2018-06-01

The ancient Greeks debated whether the Earth was unique, or innumerable worlds existed around other Suns. Twenty five years ago, technology and human ingenuity enabled the discovery of the first extrasolar planet candidates. The architectures of these first systems, with gas giant planets in star-skirting orbits, were unexpected and again raised an echo of that ancient question: is the Earth typical or unique? We are interested in this seemingly anthropocentric question because with all of our searching and discoveries, Earth is the only place where life has been found. It is the question of whether life exists elsewhere that energizes the search for exoplanets. The trajectory of this field has been stunning. After a steady stream of detections with the radial velocity method, a burst of discovery was made possible with the NASA Kepler mission. While thousands of smaller planets have now been found, true Earth analogs have eluded robust detection. However, we are sharpening the knives of our technology and without a doubt we now stand at the threshold of detecting hundreds of Earth analogs. Using Gaia, TESS, WFIRST, JWST and new ground-based spectrographs, we will learn the names and addresses of the worlds that orbit nearby stars and we will be ready to probe their atmospheres. We will finally resolve the ancient question of whether life is unique or common.

Applications of ultrafast laser direct writing: from polarization control to data storage

NASA Astrophysics Data System (ADS)

Donko, A.; Gertus, T.; Brambilla, G.; Beresna, M.

2018-02-01

Ultrafast laser direct writing is a fascinating technology which emerged more than two decades from fundamental studies of material resistance to high-intensity optical fields. Its development saw the discovery of many puzzling phenomena and demonstration of useful applications. Today, ultrafast laser writing is seen as a technology with great potential and is rapidly entering the industrial environment. Whereas, less than 10 years ago, ultrafast lasers were still confined within the research labs. This talk will overview some of the unique features of ultrafast lasers and give examples of its applications in optical data storage, polarization control and optical fibers.

Traditional Medicine Collection Tracking System (TM-CTS): a database for ethnobotanically driven drug-discovery programs.

PubMed

Harris, Eric S J; Erickson, Sean D; Tolopko, Andrew N; Cao, Shugeng; Craycroft, Jane A; Scholten, Robert; Fu, Yanling; Wang, Wenquan; Liu, Yong; Zhao, Zhongzhen; Clardy, Jon; Shamu, Caroline E; Eisenberg, David M

2011-05-17

Ethnobotanically driven drug-discovery programs include data related to many aspects of the preparation of botanical medicines, from initial plant collection to chemical extraction and fractionation. The Traditional Medicine Collection Tracking System (TM-CTS) was created to organize and store data of this type for an international collaborative project involving the systematic evaluation of commonly used Traditional Chinese Medicinal plants. The system was developed using domain-driven design techniques, and is implemented using Java, Hibernate, PostgreSQL, Business Intelligence and Reporting Tools (BIRT), and Apache Tomcat. The TM-CTS relational database schema contains over 70 data types, comprising over 500 data fields. The system incorporates a number of unique features that are useful in the context of ethnobotanical projects such as support for information about botanical collection, method of processing, quality tests for plants with existing pharmacopoeia standards, chemical extraction and fractionation, and historical uses of the plants. The database also accommodates data provided in multiple languages and integration with a database system built to support high throughput screening based drug discovery efforts. It is accessed via a web-based application that provides extensive, multi-format reporting capabilities. This new database system was designed to support a project evaluating the bioactivity of Chinese medicinal plants. The software used to create the database is open source, freely available, and could potentially be applied to other ethnobotanically driven natural product collection and drug-discovery programs. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Traditional Medicine Collection Tracking System (TM-CTS): A Database for Ethnobotanically-Driven Drug-Discovery Programs

PubMed Central

Harris, Eric S. J.; Erickson, Sean D.; Tolopko, Andrew N.; Cao, Shugeng; Craycroft, Jane A.; Scholten, Robert; Fu, Yanling; Wang, Wenquan; Liu, Yong; Zhao, Zhongzhen; Clardy, Jon; Shamu, Caroline E.; Eisenberg, David M.

2011-01-01

Aim of the study. Ethnobotanically-driven drug-discovery programs include data related to many aspects of the preparation of botanical medicines, from initial plant collection to chemical extraction and fractionation. The Traditional Medicine-Collection Tracking System (TM-CTS) was created to organize and store data of this type for an international collaborative project involving the systematic evaluation of commonly used Traditional Chinese Medicinal plants. Materials and Methods. The system was developed using domain-driven design techniques, and is implemented using Java, Hibernate, PostgreSQL, Business Intelligence and Reporting Tools (BIRT), and Apache Tomcat. Results. The TM-CTS relational database schema contains over 70 data types, comprising over 500 data fields. The system incorporates a number of unique features that are useful in the context of ethnobotanical projects such as support for information about botanical collection, method of processing, quality tests for plants with existing pharmacopoeia standards, chemical extraction and fractionation, and historical uses of the plants. The database also accommodates data provided in multiple languages and integration with a database system built to support high throughput screening based drug discovery efforts. It is accessed via a web-based application that provides extensive, multi-format reporting capabilities. Conclusions. This new database system was designed to support a project evaluating the bioactivity of Chinese medicinal plants. The software used to create the database is open source, freely available, and could potentially be applied to other ethnobotanically-driven natural product collection and drug-discovery programs. PMID:21420479

A History and Informal Assessment of the "Slacker Astronomy" Podcast

ERIC Educational Resources Information Center

Price, Aaron; Gay, Pamela; Searle, Travis; Brissenden, Gina

2007-01-01

"Slacker Astronomy" is a weekly podcast that covers a recent astronomical news event or discovery. The show has a unique style consisting of irreverent, over-the-top humor combined with a healthy dose of hard science. According to our demographic analysis, the combination of this style and the unique podcasting distribution mechanism allows the…

Phenome-driven disease genetics prediction toward drug discovery.

PubMed

Chen, Yang; Li, Li; Zhang, Guo-Qiang; Xu, Rong

2015-06-15

Discerning genetic contributions to diseases not only enhances our understanding of disease mechanisms, but also leads to translational opportunities for drug discovery. Recent computational approaches incorporate disease phenotypic similarities to improve the prediction power of disease gene discovery. However, most current studies used only one data source of human disease phenotype. We present an innovative and generic strategy for combining multiple different data sources of human disease phenotype and predicting disease-associated genes from integrated phenotypic and genomic data. To demonstrate our approach, we explored a new phenotype database from biomedical ontologies and constructed Disease Manifestation Network (DMN). We combined DMN with mimMiner, which was a widely used phenotype database in disease gene prediction studies. Our approach achieved significantly improved performance over a baseline method, which used only one phenotype data source. In the leave-one-out cross-validation and de novo gene prediction analysis, our approach achieved the area under the curves of 90.7% and 90.3%, which are significantly higher than 84.2% (P < e(-4)) and 81.3% (P < e(-12)) for the baseline approach. We further demonstrated that our predicted genes have the translational potential in drug discovery. We used Crohn's disease as an example and ranked the candidate drugs based on the rank of drug targets. Our gene prediction approach prioritized druggable genes that are likely to be associated with Crohn's disease pathogenesis, and our rank of candidate drugs successfully prioritized the Food and Drug Administration-approved drugs for Crohn's disease. We also found literature evidence to support a number of drugs among the top 200 candidates. In summary, we demonstrated that a novel strategy combining unique disease phenotype data with system approaches can lead to rapid drug discovery. nlp. edu/public/data/DMN © The Author 2015. Published by Oxford University Press.

Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants.

PubMed

Srinivasan, Bharath; Rodrigues, João V; Tonddast-Navaei, Sam; Shakhnovich, Eugene; Skolnick, Jeffrey

2017-07-21

In drug discovery, systematic variations of substituents on a common scaffold and bioisosteric replacements are often used to generate diversity and obtain molecules with better biological effects. However, this could saturate the small-molecule diversity pool resulting in drug resistance. On the other hand, conventional drug discovery relies on targeting known pockets on protein surfaces leading to drug resistance by mutations of critical pocket residues. Here, we present a two-pronged strategy of designing novel drugs that target unique pockets on a protein's surface to overcome the above problems. Dihydrofolate reductase, DHFR, is a critical enzyme involved in thymidine and purine nucleotide biosynthesis. Several classes of compounds that are structural analogues of the substrate dihydrofolate have been explored for their antifolate activity. Here, we describe 10 novel small-molecule inhibitors of Escherichia coli DHFR, EcDHFR, belonging to the stilbenoid, deoxybenzoin, and chalcone family of compounds discovered by a combination of pocket-based virtual ligand screening and systematic scaffold hopping. These inhibitors show a unique uncompetitive or noncompetitive inhibition mechanism, distinct from those reported for all known inhibitors of DHFR, indicative of binding to a unique pocket distinct from either substrate or cofactor-binding pockets. Furthermore, we demonstrate that rescue mutants of EcDHFR, with reduced affinity to all known classes of DHFR inhibitors, are inhibited at the same concentration as the wild-type. These compounds also exhibit antibacterial activity against E. coli harboring the drug-resistant variant of DHFR. This discovery is the first report on a novel class of inhibitors targeting a unique pocket on EcDHFR.

Modeling & Informatics at Vertex Pharmaceuticals Incorporated: our philosophy for sustained impact

NASA Astrophysics Data System (ADS)

McGaughey, Georgia; Patrick Walters, W.

2017-03-01

Molecular modelers and informaticians have the unique opportunity to integrate cross-functional data using a myriad of tools, methods and visuals to generate information. Using their drug discovery expertise, information is transformed to knowledge that impacts drug discovery. These insights are often times formulated locally and then applied more broadly, which influence the discovery of new medicines. This is particularly true in an organization where the members are exposed to projects throughout an organization, such as in the case of the global Modeling & Informatics group at Vertex Pharmaceuticals. From its inception, Vertex has been a leader in the development and use of computational methods for drug discovery. In this paper, we describe the Modeling & Informatics group at Vertex and the underlying philosophy, which has driven this team to sustain impact on the discovery of first-in-class transformative medicines.

Binding Site Configurations Probe the Structure and Dynamics of the Zinc Finger of NEMO (NF-κB Essential Modulator).

PubMed

Godwin, Ryan C; Melvin, Ryan L; Gmeiner, William H; Salsbury, Freddie R

2017-01-31

Zinc-finger proteins are regulators of critical signaling pathways for various cellular functions, including apoptosis and oncogenesis. Here, we investigate how binding site protonation states and zinc coordination influence protein structure, dynamics, and ultimately function, as these pivotal regulatory proteins are increasingly important for protein engineering and therapeutic discovery. To better understand the thermodynamics and dynamics of the zinc finger of NEMO (NF-κB essential modulator), as well as the role of zinc, we present results of 20 μs molecular dynamics trajectories, 5 μs for each of four active site configurations. Consistent with experimental evidence, the zinc ion is essential for mechanical stabilization of the functional, folded conformation. Hydrogen bond motifs are unique for deprotonated configurations yet overlap in protonated cases. Correlated motions and principal component analysis corroborate the similarity of the protonated configurations and highlight unique relationships of the zinc-bound configuration. We hypothesize a potential mechanism for zinc binding from results of the thiol configurations. The deprotonated, zinc-bound configuration alone predominantly maintains its tertiary structure throughout all 5 μs and alludes rare conformations potentially important for (im)proper zinc-finger-related protein-protein or protein-DNA interactions.

Close up detail of the underside of the Orbiter Discovery ...

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

Close up detail of the underside of the Orbiter Discovery in the Vehicle Assembly Building at NASA's Kennedy Space Center. This view is from underneath the aft section looking forward. It is a close-up view of the High-temperature Reusable Surface Insulation tiles showing the wear patterns from the heat of reentry, consequential replacement of worn and damaged tiles. The wear and replacement patters are unique to each Orbiter which can serve as their particular "fingerprint". - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Perspectives on the recent developments with green tea polyphenols in drug discovery.

PubMed

Li, Feng; Wang, Yongli; Li, Dapeng; Chen, Yilun; Qiao, Xuguang; Fardous, Rania; Lewandowski, Ashton; Liu, Jinbao; Chan, Tak-Hang; Dou, Q Ping

2018-04-24

Increasing evidence has expanded the role of green tea from a traditional beverage to a source of pharmacologically active molecules with diverse health benefits. However, conclusive clinical results are needed to better elucidate the cancer-preventive and therapeutic effects of green tea polyphenols (GTPs). Areas covered: The authors describe GTPs' chemical compositions and metabolic biotransformations, and their recent developments in drug discovery, focusing on their cancer chemopreventive and therapeutic effects. They then review the recent development of GTP-loaded nanoparticles and GTP prodrugs. Expert opinion: GTPs possess potent anticarcinogenic activities through interfering with the initiation, development and progression phases of cancer. There are several challenges (e.g. poor bioavailability) in developing GTPs as therapeutic agents. Use of nanoparticle-based delivery systems has provided unique advantages over purified GTPs. However, there is still a need to determine the actual magnitude and pharmacological mechanisms of GTPs encapsulated in nanoparticles, in order to address newly emerging safety issues associated with the potential 'local overdose' effect. The use of Pro- epigallocatechin gallate (Pro-EGCG) as a prodrug appears to offer improved in vitro stability as well as better in vivo bioavailability and efficacies in a number of animal studies, suggesting its potential as a therapeutic agent for further study and development.

Protease‐activated receptor 4: from structure to function and back again

PubMed Central

French, Shauna L

2016-01-01

Protease‐activated receptors are a family of four GPCRs (PAR1–PAR4) with a number of unique attributes. Nearly two and a half decades after the discovery of the first PAR, an antagonist targeting this receptor has been approved for human use. The first‐in‐class PAR1 antagonist, vorapaxar, was approved for use in the USA in 2014 for the prevention of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. These recent developments indicate the clinical potential of manipulating PAR function. While much work has been aimed at uncovering the function of PAR1 and, to a lesser extent, PAR2, comparatively little is known regarding the pharmacology and physiology of PAR3 and PAR4. Recent studies have begun to develop the pharmacological and genetic tools required to study PAR4 function in detail, and there is now emerging evidence for the function of PAR4 in disease settings. In this review, we detail the discovery, structure, pharmacology, physiological significance and therapeutic potential of PAR4. 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:26844674

Unique disease heritage of the Dutch-German Mennonite population.

PubMed

Orton, Noelle C; Innes, A Micheil; Chudley, Albert E; Bech-Hansen, N Torben

2008-04-15

The Dutch-German Mennonites are a religious isolate with foundational roots in the 16th century. A tradition of endogamy, large families, detailed genealogical records, and a unique disease history all contribute to making this a valuable population for genetic studies. Such studies in the Dutch-German Mennonite population have already contributed to the identification of the causative genes in several conditions such as the incomplete form of X-linked congenital stationary night blindness (CSNB2; previously iCSNB) and hypophosphatasia (HOPS), as well as the discovery of founder mutations within established disease genes (MYBPC1, CYP17alpha). The Dutch-German Mennonite population provides a strong resource for gene discovery and could lead to the identification of additional disease genes with relevance to the general population. In addition, further research developments should enhance delivery of clinical genetic services to this unique community. In the current review we discuss 31 genetic conditions, including 17 with identified gene mutations, within the Dutch-German Mennonite population. Copyright 2008 Wiley-Liss, Inc.

Session Initiation Protocol Network Encryption Device Plain Text Domain Discovery Service

DTIC Science & Technology

2007-12-07

MONITOR’S REPORT NUMBER(S) 12. DISTRIBUTION / AVAILABILITY STATEMENT 13. SUPPLEMENTARY NOTES 14. ABSTRACT 15. SUBJECT TERMS 16. SECURITY CLASSIFICATION OF: a...such as the TACLANE, have developed unique discovery methods to establish Plain Text Domain (PTD) Security Associations (SA). All of these techniques...can include network and host Internet Protocol (IP) addresses, Information System Security Office (ISSO) point of contact information and PTD status

Modern Natural Products Drug Discovery and its Relevance to Biodiversity Conservation†

PubMed Central

Kingston, David G. I.

2010-01-01

Natural products continue to provide a diverse and unique source of bioactive lead compounds for drug discovery, but maintaining their continued eminence as source compounds is challenging in the face of the changing face of the pharmaceutical industry and the changing nature of biodiversity prospecting brought about by the Convention of Biodiversity. This review provides an overview of some of these challenges, and suggests ways in which they can be addressed so that natural products research can remain a viable and productive route to drug discovery. Results from International Cooperative Biodiversity Groups (ICBGs) working in Madagascar, Panama, and Suriname are used as examples of what can be achieved when biodiversity conservation is linked to drug discovery. PMID:21138324

Discovery, identification and mitigation of isobaric sulfate metabolite interference to a phosphate prodrug in LC-MS/MS bioanalysis: Critical role of method development in ensuring assay quality.

PubMed

Yuan, Long; Ji, Qin C

2018-06-05

Metabolite interferences represent a major risk of inaccurate quantification when using LC-MS/MS bioanalytical assays. During LC-MS/MS bioanalysis of BMS-919194, a phosphate ester prodrug, in plasma samples from rat and monkey GLP toxicology studies, an unknown peak was detected in the MRM channel of the prodrug. This peak was not observed in previous discovery toxicology studies, in which a fast gradient LC-MS/MS method was used. We found out that this unknown peak would co-elute with the prodrug peak when the discovery method was used, therefore, causing significant overestimation of the exposure of the prodrug in the discovery toxicology studies. To understand the nature of this interfering peak and its impact to bioanalytical assay, we further investigated its formation and identification. The interfering compound and the prodrug were found to be isobaric and to have the same major product ions in electrospray ionization positive mode, thus, could not be differentiated using a triple quadrupole mass spectrometer. By using high-resolution mass spectrometry (HRMS), the interfering metabolite was successfully identified to be an isobaric sulfate metabolite of BMS-919194. To the best of our knowledge, this is the first report that a phosphate prodrug was metabolized in vivo to an isobaric sulfate metabolite, and this metabolite caused significant interference to the analysis of the prodrug. This work demonstrated the presence of the interference risk from isobaric sulfate metabolites to the bioanalysis of phosphate prodrugs in real samples. It is critical to evaluate and mitigate potential metabolite interferences during method development, therefore, minimize the related bioanalytical risks and ensure assay quality. Our work also showed the unique advantages of HRMS in identifying potential metabolite interference during LC-MS/MS bioanalysis. Copyright © 2018 Elsevier B.V. All rights reserved.

Time is of the Essence: A Review of Electroencephalography (EEG) and Event-Related Brain Potentials (ERPs) in Language Research.

PubMed

Beres, Anna M

2017-12-01

The discovery of electroencephalography (EEG) over a century ago has changed the way we understand brain structure and function, in terms of both clinical and research applications. This paper starts with a short description of EEG and then focuses on the event-related brain potentials (ERPs), and their use in experimental settings. It describes the typical set-up of an ERP experiment. A description of a number of ERP components typically involved in language research is presented. Finally, the advantages and disadvantages of using ERPs in language research are discussed. EEG has an extensive use in today's world, including medical, psychology, or linguistic research. The excellent temporal resolution of EEG information allows one to track a brain response in milliseconds and therefore makes it uniquely suited to research concerning language processing.

Discovery stories in the science classroom

NASA Astrophysics Data System (ADS)

Arya, Diana Jaleh

School science has been criticized for its lack of emphasis on the tentative, dynamic nature of science as a process of learning more about our world. This criticism is the guiding force for this present body of work, which focuses on the question: what are the educational benefits for middle school students of reading texts that highlight the process of science in the form of a discovery narrative? This dissertation traces my journey through a review of theoretical perspectives of narrative, an analysis of first-hand accounts of scientific discovery, the complex process of developing age-appropriate, cohesive and engaging science texts for middle school students, and a comparison study (N=209) that seeks to determine the unique benefits of the scientific discovery narrative for the interest in and retained understanding of conceptual information presented in middle school science texts. A total of 209 middle school participants in nine different classrooms from two different schools participated in the experimental study. Each subject read two science texts that differed in topic (the qualities of and uses for radioactive elements and the use of telescopic technology to see planets in space) and genre (the discovery narrative and the "conceptually known exposition" comparison text). The differences between the SDN and CKE versions for each topic were equivalent in all possible ways (initial introduction, overall conceptual accuracy, elements of human interest, coherence and readability level), save for the unique components of the discovery narrative (i.e., love for their work, acknowledgement of the known, identification of the unknown and the explorative or experimental process to discovery). Participants generally chose the discovery narrative version as the more interesting of the two texts. Additional findings from the experimental study suggest that science texts in the form of SDNs elicit greater long-term retention of key conceptual information, especially when the readers have little prior knowledge of a given topic. Further, ethnic minority groups of lower socio-economic level (i.e., Latin and African-American origins) demonstrated an even greater benefit from the SDN texts, suggesting that a scientist's story of discovery can help to close the gap in academic performance in science.

The emergence of Clostridium thermocellum as a high utility candidate for consolidated bioprocessing applications

PubMed Central

Akinosho, Hannah; Yee, Kelsey; Close, Dan; Ragauskas, Arthur

2014-01-01

First isolated in 1926, Clostridium thermocellum has recently received increased attention as a high utility candidate for use in consolidated bioprocessing (CBP) applications. These applications, which seek to process lignocellulosic biomass directly into useful products such as ethanol, are gaining traction as economically feasible routes toward the production of fuel and other high value chemical compounds as the shortcomings of fossil fuels become evident. This review evaluates C. thermocellum's role in this transitory process by highlighting recent discoveries relating to its genomic, transcriptomic, proteomic, and metabolomic responses to varying biomass sources, with a special emphasis placed on providing an overview of its unique, multivariate enzyme cellulosome complex and the role that this structure performs during biomass degradation. Both naturally evolved and genetically engineered strains are examined in light of their unique attributes and responses to various biomass treatment conditions, and the genetic tools that have been employed for their creation are presented. Several future routes for potential industrial usage are presented, and it is concluded that, although there have been many advances to significantly improve C. thermocellum's amenability to industrial use, several hurdles still remain to be overcome as this unique organism enjoys increased attention within the scientific community. PMID:25207268

The emergence of Clostridium thermocellum as a high utility candidate for consolidated bioprocessing applications

NASA Astrophysics Data System (ADS)

Ragauskas, Arthur; Akinosho, Hannah; Yee, Kelsey; Close, Dan

2014-08-01

First isolated in 1926, Clostridium thermocellum has recently received increased attention as a high utility candidate for use in consolidated bioprocessing applications. These applications, which seek to process lignocellulosic biomass directly into useful products such as ethanol, are gaining traction as economically feasible routes towards the production of fuel and other high value chemical compounds as the shortcomings of fossil fuels become evident. This review evaluates C. thermocellum’s role in this transitory process by highlighting recent discoveries relating to its genomic, transcriptomic, proteomic, and metabolomic responses to varying biomass sources, with a special emphasis placed on providing an overview of its unique, multivariate enzyme cellulosome complex and the role that this structure performs during biomass degradation. Both naturally evolved and genetically engineered strains are examined in light of their unique attributes and responses to various biomass treatment conditions, and the genetic tools that have been employed for their creation are presented. Several future routes for potential industrial usage are presented, and it is concluded that, although there have been many advances to significantly improve C. thermocellum’s amenability to industrial use, several hurdles still remain to be overcome as this unique organism enjoys increased attention within the scientific community.

A concept for performance management for Federal science programs

USGS Publications Warehouse

Whalen, Kevin G.

2017-11-06

The demonstration of clear linkages between planning, funding, outcomes, and performance management has created unique challenges for U.S. Federal science programs. An approach is presented here that characterizes science program strategic objectives by one of five “activity types”: (1) knowledge discovery, (2) knowledge development and delivery, (3) science support, (4) inventory and monitoring, and (5) knowledge synthesis and assessment. The activity types relate to performance measurement tools for tracking outcomes of research funded under the objective. The result is a multi-time scale, integrated performance measure that tracks individual performance metrics synthetically while also measuring progress toward long-term outcomes. Tracking performance on individual metrics provides explicit linkages to root causes of potentially suboptimal performance and captures both internal and external program drivers, such as customer relations and science support for managers. Functionally connecting strategic planning objectives with performance measurement tools is a practical approach for publicly funded science agencies that links planning, outcomes, and performance management—an enterprise that has created unique challenges for public-sector research and development programs.

A designed inhibitor of a CLC antiporter blocks function through a unique binding mode

PubMed Central

Howery, Andrew E.; Elvington, Shelley; Abraham, Sherwin J.; Choi, Kee-Hyun; Phillips, Sabrina; Ryan, Christopher M.; Sanford, R. Lea; Simpson-Dworschak, Sierra; Almqvist, Jonas; Tran, Kevin; Chew, Thomas A.; Zachariae, Ulrich; Andersen, Olaf S.; Whitelegge, Julian; Matulef, Kimberly; Du Bois, Justin; Maduke, Merritt C.

2012-01-01

SUMMARY The lack of small-molecule inhibitors for anion-selective transporters and channels has impeded our understanding of the complex mechanisms that underlie ion passage. The ubiquitous CLC “Chloride Channel” family represents a unique target for biophysical and biochemical studies because its distinctive protein fold supports both passive chloride channels and secondary-active chloride-proton transporters. Here, we describe the synthesis and characterization of the first specific small-molecule inhibitor directed against a CLC antiporter (ClC-ec1). This compound, 4,4′-octanamidostilbene-2,2′-disulfonate (OADS), inhibits ClC-ec1 with low micromolar affinity and has no specific effect on a CLC channel (ClC-1). Inhibition of ClC-ec1 occurs by binding to two distinct intracellular sites. The location of these sites and the lipid-dependence of inhibition suggest potential mechanisms of action. The discovery of this compound will empower research to elucidate differences between antiporter and channel mechanisms and to develop treatments for CLC-mediated disorders. PMID:23177200

Translating Metabolomics to Cardiovascular Biomarkers

PubMed Central

Senn, Todd; Hazen, Stanley L.; Tang, W. H. Wilson

2012-01-01

Metabolomics is the systematic study of the unique chemical fingerprints of small-molecules, or metabolite profiles, that are related to a variety of cellular metabolic processes in a cell, organ, or organism. While mRNA gene expression data and proteomic analyses do not tell the whole story of what might be happening in a cell, metabolic profiling provides direct and indirect physiologic insights that can potentially be detectable in a wide range of biospecimens. Although not specific to cardiac conditions, translating metabolomics to cardiovascular biomarkers has followed the traditional path of biomarker discovery from identification and confirmation to clinical validation and bedside testing. With technological advances in metabolomic tools (such as nuclear magnetic resonance spectroscopy and mass spectrometry) and more sophisticated bioinformatics and analytical techniques, the ability to measure low-molecular-weight metabolites in biospecimens provides a unique insight into established and novel metabolic pathways. Systemic metabolomics may provide physiologic understanding of cardiovascular disease states beyond traditional profiling, and may involve descriptions of metabolic responses of an individual or population to therapeutic interventions or environmental exposures. PMID:22824112

Discovery and mechanistic study of a class of protein arginine methylation inhibitors.

PubMed

Feng, You; Li, Mingyong; Wang, Binghe; Zheng, Yujun George

2010-08-26

Protein arginine methylation regulates multiple biological processes such as chromatin remodeling and RNA splicing. Malfunction of protein arginine methyltransferases (PRMTs) is correlated with many human diseases. Thus, small molecule inhibitors of protein arginine methylation are of great potential for therapeutic development. Herein, we report a type of compound that blocks PRMT1-mediated arginine methylation at micromolar potency through a unique mechanism. Most of the discovered compounds bear naphthalene and sulfonate groups and are structurally different from typical PRMT substrates, for example, histone H4 and glycine- and arginine-rich sequences. To elucidate the molecular basis of inhibition, we conducted a variety of kinetic and biophysical assays. The combined data reveal that this type of naphthyl-sulfo (NS) molecule directly targets the substrates but not PRMTs for the observed inhibition. We also found that suramin effectively inhibited PRMT1 activity. These findings about novel PRMT inhibitors and their unique inhibition mechanism provide a new way for chemical regulation of protein arginine methylation.

Identification of Differentially Expressed Proteins in Direct Expressed Prostatic Secretions of Men with Organ-confined Versus Extracapsular Prostate Cancer*

PubMed Central

Kim, Yunee; Ignatchenko, Vladimir; Yao, Cindy Q.; Kalatskaya, Irina; Nyalwidhe, Julius O.; Lance, Raymond S.; Gramolini, Anthony O.; Troyer, Dean A.; Stein, Lincoln D.; Boutros, Paul C.; Medin, Jeffrey A.; Semmes, O. John; Drake, Richard R.; Kislinger, Thomas

2012-01-01

Current protocols for the screening of prostate cancer cannot accurately discriminate clinically indolent tumors from more aggressive ones. One reliable indicator of outcome has been the determination of organ-confined versus nonorgan-confined disease but even this determination is often only made following prostatectomy. This underscores the need to explore alternate avenues to enhance outcome prediction of prostate cancer patients. Fluids that are proximal to the prostate, such as expressed prostatic secretions (EPS), are attractive sources of potential prostate cancer biomarkers as these fluids likely bathe the tumor. Direct-EPS samples from 16 individuals with extracapsular (n = 8) or organ-confined (n = 8) prostate cancer were used as a discovery cohort, and were analyzed in duplicate by a nine-step MudPIT on a LTQ-Orbitrap XL mass spectrometer. A total of 624 unique proteins were identified by at least two unique peptides with a 0.2% false discovery rate. A semiquantitative spectral counting algorithm identified 133 significantly differentially expressed proteins in the discovery cohort. Integrative data mining prioritized 14 candidates, including two known prostate cancer biomarkers: prostate-specific antigen and prostatic acid phosphatase, which were significantly elevated in the direct-EPS from the organ-confined cancer group. These and five other candidates (SFN, MME, PARK7, TIMP1, and TGM4) were verified by Western blotting in an independent set of direct-EPS from patients with biochemically recurrent disease (n = 5) versus patients with no evidence of recurrence upon follow-up (n = 10). Lastly, we performed proof-of-concept SRM-MS-based relative quantification of the five candidates using unpurified heavy isotope-labeled synthetic peptides spiked into pools of EPS-urines from men with extracapsular and organ-confined prostate tumors. This study represents the first efforts to define the direct-EPS proteome from two major subclasses of prostate cancer using shotgun proteomics and verification in EPS-urine by SRM-MS. PMID:22986220

β-Cell Autophagy in Diabetes Pathogenesis.

PubMed

Marasco, Michelle R; Linnemann, Amelia K

2018-05-01

Nearly 100 years have passed since Frederick Banting and Charles Best first discovered and purified insulin. Their discovery and subsequent improvements revolutionized the treatment of diabetes, and the field continues to move at an ever-faster pace with respect to unique treatments for both type 1 and type 2 diabetes. Despite these advances, we still do not fully understand how apoptosis of the insulin-producing β-cells is triggered, presenting a challenge in the development of preventative measures. In recent years, the process of autophagy has generated substantial interest in this realm due to discoveries highlighting its clear role in the maintenance of cellular homeostasis. As a result, the number of studies focused on islet and β-cell autophagy has increased substantially in recent years. In this review, we will discuss what is currently known regarding the role of β-cell autophagy in type 1 and type 2 diabetes pathogenesis, with an emphasis on new and exciting developments over the past 5 years. Further, we will discuss how these discoveries might be translated into unique treatments in the coming years.

Collision or convergence?: beliefs and politics in neuroscience discovery, ethics, and intervention.

PubMed

Paylor, Ben; Longstaff, Holly; Rossi, Fabio; Illes, Judy

2014-08-01

Discovery and interventions for neurological disorders have a unique capacity to galvanize public opinion over issues of access, human rights, decision making, and the definition of disease. Here we highlight five cases where beliefs and politics prevailed over evidence and ethics. We examine lessons from them about the communication of risk and the power of public influence on science, society, and policy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Plants in space

NASA Technical Reports Server (NTRS)

Halstead, T. W.; Dutcher, F. R.

1987-01-01

Space may be, as some have called it, our last frontier. As such, it provides novel, even unique research opportunities. Plants are sure to figure significantly in these activities. The ability to manipulate the force of gravity from near zero to 1 g affords fresh opportunities to investigate gravity's physiological effects as well as a means of probing gravi- and phototropism, thigmo-morphogenesis, and other environmental effects in a state uncompromised by gravity. In this review we aim primarily to consider phenomenology, a goal that befits the state of our knowledge from space experiments. We intend to provide grist for future ground-based and space experiments and to reveal the potential for scientific discovery in this area.

Probing Higgs self-coupling of a classically scale invariant model in e+e- → Zhh: Evaluation at physical point

NASA Astrophysics Data System (ADS)

Fujitani, Y.; Sumino, Y.

2018-04-01

A classically scale invariant extension of the standard model predicts large anomalous Higgs self-interactions. We compute missing contributions in previous studies for probing the Higgs triple coupling of a minimal model using the process e+e- → Zhh. Employing a proper order counting, we compute the total and differential cross sections at the leading order, which incorporate the one-loop corrections between zero external momenta and their physical values. Discovery/exclusion potential of a future e+e- collider for this model is estimated. We also find a unique feature in the momentum dependence of the Higgs triple vertex for this class of models.

Stable isotopes in seafloor hydrothermal systems: Vent fluids, hydrothermal deposits, hydrothermal alteration, and microbial processes

USGS Publications Warehouse

Shanks, Wayne C.

2001-01-01

The recognition of abundant and widespread hydrothermal activity and associated unique life-forms on the ocean floor is one of the great scientific discoveries of the latter half of the twentieth century. Studies of seafloor hydrothermal processes have led to revolutions in understanding fluid convection and the cooling of the ocean crust, the chemical and isotopic mass balance of the oceans, the origin of stratiform and statabound massive-sulfide ore-deposits, the origin of greenstones and serpentinites, and the potential importance of the subseafloor biosphere. Stable isotope geochemistry has been a critical and definitive tool from the very beginning of the modern era of seafloor exploration.

Human pluripotent stem cells: an emerging model in developmental biology.

PubMed

Zhu, Zengrong; Huangfu, Danwei

2013-02-01

Developmental biology has long benefited from studies of classic model organisms. Recently, human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, have emerged as a new model system that offers unique advantages for developmental studies. Here, we discuss how studies of hPSCs can complement classic approaches using model organisms, and how hPSCs can be used to recapitulate aspects of human embryonic development 'in a dish'. We also summarize some of the recently developed genetic tools that greatly facilitate the interrogation of gene function during hPSC differentiation. With the development of high-throughput screening technologies, hPSCs have the potential to revolutionize gene discovery in mammalian development.

Diverse dinosaur-dominated ichnofaunas from the Potomac Group (Lower Cretaceous) Maryland

USGS Publications Warehouse

Stanford, Ray; Lockley, Martin G.; Weems, Robert E.

2007-01-01

Until recently fossil footprints were virtually unknown from the Cretaceous of the eastern United States. The discovery of about 300 footprints in iron-rich siliciclastic facies of the Patuxent Formation (Potomac Group) of Aptian age is undoubtedly one of the most significant Early Cretaceous track discoveries since the Paluxy track discoveries in Texas in the 1930s. The Patuxent tracks include theropod, sauropod, ankylosaur and ornithopod dinosaur footprints, pterosaur tracks, and miscellaneous mammal and other vertebrate ichnites that collectively suggest a diversity of about 14 morphotypes. This is about twice the previous maximum estimate for any known Early Cretaceous vertebrate ichnofauna. Among the more distinctive forms are excellent examples of hypsilophodontid tracks and a surprisingly large mammal footprint. A remarkable feature of the Patuxent track assemblage is the high proportion of small tracks indicative of hatchlings, independently verified by the discovery of a hatchling-sized dinosaur. Such evidence suggests the proximity of nest sites. The preservation of such small tracks is very rare in the Cretaceous track record, and indeed throughout most of the Mesozoic.This unusual preservation not only provides us with a window into a diverse Early Cretaceous ecosystem, but it also suggests the potential of such facies to provide ichnological bonanzas. A remarkable feature of the assemblage is that it consists largely of reworked nodules and clasts that may have previously been reworked within the Patuxent Formation. Such unusual contexts of preservation should provide intriguing research opportunities for sedimentologists interested in the diagenesis and taphonomy of a unique track-bearing facies.

25 Years of GenBank

MedlinePlus

... this page please turn Javascript on. Unique DNA database has helped advance scientific discoveries worldwide Since its origin 25 years ago, the database of nucleic acid sequences known as GenBank has ...

Anaerobic gut fungi: Advances in isolation, culture, and cellulolytic enzyme discovery for biofuel production.

PubMed

Haitjema, Charles H; Solomon, Kevin V; Henske, John K; Theodorou, Michael K; O'Malley, Michelle A

2014-08-01

Anaerobic gut fungi are an early branching family of fungi that are commonly found in the digestive tract of ruminants and monogastric herbivores. It is becoming increasingly clear that they are the primary colonizers of ingested plant biomass, and that they significantly contribute to the decomposition of plant biomass into fermentable sugars. As such, anaerobic fungi harbor a rich reservoir of undiscovered cellulolytic enzymes and enzyme complexes that can potentially transform the conversion of lignocellulose into bioenergy products. Despite their unique evolutionary history and cellulolytic activity, few species have been isolated and studied in great detail. As a result, their life cycle, cellular physiology, genetics, and cellulolytic metabolism remain poorly understood compared to aerobic fungi. To help address this limitation, this review briefly summarizes the current body of knowledge pertaining to anaerobic fungal biology, and describes progress made in the isolation, cultivation, molecular characterization, and long-term preservation of these microbes. We also discuss recent cellulase- and cellulosome-discovery efforts from gut fungi, and how these interesting, non-model microbes could be further adapted for biotechnology applications. © 2014 Wiley Periodicals, Inc.

Marine Algicolous Endophytic Fungi - A Promising Drug Resource of the Era.

PubMed

Sarasan, Manomi; Puthumana, Jayesh; Job, Neema; Han, Jeonghoon; Lee, Jae-Seong; Philip, Rosamma

2017-06-28

Endophytic fungi have currently been acknowledged as the most promising source of bioactive compounds for drug discovery, and considerable progress has been made in exploring their diversity, species richness, and bioprospecting. Fungal endophytes from unique environmental settings offer a pool of potentially useful medicinal entities. Owing to the constant stresses imposed on macroalgae by marine environments, it is believed that algae and their associated endophytic symbionts represent a good source of structurally diverse bioactive secondary metabolites. Despite the proven significance of active metabolites of algal endophytes, little have been exploited. This review highlights the latest discoveries in algicolous endophytic research, with particular focus on the bioactive metabolites from algal endophytes. Compounds are classified according to their reported biological activities, like anticancer, antibacterial, antifungal, and antioxidant properties. Present experimental evidence suggests that a majority of the bioactive metabolites were reported from Phaeophyceae followed by Rhodophyceae and Chlorophyceae. An intensive search for newer and more effective bioactive metabolites has generated a treasure trove of publications, and this review partially covers the literature published up to 2016.

First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass

PubMed Central

Wang, Guangliang; Rajpurohit, Surendra K; Delaspre, Fabien; Walker, Steven L; White, David T; Ceasrine, Alexis; Kuruvilla, Rejji; Li, Ruo-jing; Shim, Joong S; Liu, Jun O; Parsons, Michael J; Mumm, Jeff S

2015-01-01

Whole-organism chemical screening can circumvent bottlenecks that impede drug discovery. However, in vivo screens have not attained throughput capacities possible with in vitro assays. We therefore developed a method enabling in vivo high-throughput screening (HTS) in zebrafish, termed automated reporter quantification in vivo (ARQiv). In this study, ARQiv was combined with robotics to fully actualize whole-organism HTS (ARQiv-HTS). In a primary screen, this platform quantified cell-specific fluorescent reporters in >500,000 transgenic zebrafish larvae to identify FDA-approved (Federal Drug Administration) drugs that increased the number of insulin-producing β cells in the pancreas. 24 drugs were confirmed as inducers of endocrine differentiation and/or stimulators of β-cell proliferation. Further, we discovered novel roles for NF-κB signaling in regulating endocrine differentiation and for serotonergic signaling in selectively stimulating β-cell proliferation. These studies demonstrate the power of ARQiv-HTS for drug discovery and provide unique insights into signaling pathways controlling β-cell mass, potential therapeutic targets for treating diabetes. DOI: http://dx.doi.org/10.7554/eLife.08261.001 PMID:26218223

Managing the innovation supply chain to maximize personalized medicine.

PubMed

Waldman, S A; Terzic, A

2014-02-01

Personalized medicine epitomizes an evolving model of care tailored to the individual patient. This emerging paradigm harnesses radical technological advances to define each patient's molecular characteristics and decipher his or her unique pathophysiological processes. Translated into individualized algorithms, personalized medicine aims to predict, prevent, and cure disease without producing therapeutic adverse events. Although the transformative power of personalized medicine is generally recognized by physicians, patients, and payers, the complexity of translating discoveries into new modalities that transform health care is less appreciated. We often consider the flow of innovation and technology along a continuum of discovery, development, regulation, and application bridging the bench with the bedside. However, this process also can be viewed through a complementary prism, as a necessary supply chain of services and providers, each making essential contributions to the development of the final product to maximize value to consumers. Considering personalized medicine in this context of supply chain management highlights essential points of vulnerability and/or scalability that can ultimately constrain translation of the biological revolution or potentiate it into individualized diagnostics and therapeutics for optimized value creation and delivery.

Emerging Strategies and Integrated Systems Microbiology Technologies for Biodiscovery of Marine Bioactive Compounds

PubMed Central

Rocha-Martin, Javier; Harrington, Catriona; Dobson, Alan D.W.; O’Gara, Fergal

2014-01-01

Marine microorganisms continue to be a source of structurally and biologically novel compounds with potential use in the biotechnology industry. The unique physiochemical properties of the marine environment (such as pH, pressure, temperature, osmolarity) and uncommon functional groups (such as isonitrile, dichloroimine, isocyanate, and halogenated functional groups) are frequently found in marine metabolites. These facts have resulted in the production of bioactive substances with different properties than those found in terrestrial habitats. In fact, the marine environment contains a relatively untapped reservoir of bioactivity. Recent advances in genomics, metagenomics, proteomics, combinatorial biosynthesis, synthetic biology, screening methods, expression systems, bioinformatics, and the ever increasing availability of sequenced genomes provides us with more opportunities than ever in the discovery of novel bioactive compounds and biocatalysts. The combination of these advanced techniques with traditional techniques, together with the use of dereplication strategies to eliminate known compounds, provides a powerful tool in the discovery of novel marine bioactive compounds. This review outlines and discusses the emerging strategies for the biodiscovery of these bioactive compounds. PMID:24918453

Archaeology: formulation of a Roman cosmetic.

PubMed

Evershed, R P; Berstan, R; Grew, F; Copley, M S; Charmant, A J H; Barham, E; Mottram, H R; Brown, G

2004-11-04

The discovery of a small tin canister in London during archaeological excavations of a Roman temple precinct, dated to the middle of the second century AD, is a landmark in the study of this class of artefact. Such discoveries from the Roman world are rare and this is the only one to be found so far with its lid and contents--a whitish medicinal or cosmetic cream--providing a unique opportunity for us to study the ancient formulation.

Applications and toxicity of graphene family nanomaterials and their composites

PubMed Central

Singh, Zorawar

2016-01-01

Graphene has attracted much attention of scientific community due to its enormous potential in different fields, including medical sciences, agriculture, food safety, cancer research, and tissue engineering. The potential for widespread human exposure raises safety concerns about graphene and its derivatives, referred to as graphene family nanomaterials (GFNs). Due to their unique chemical and physical properties, graphene and its derivatives have found important places in their respective application fields, yet they are being found to have cytotoxic and genotoxic effects too. Since the discovery of graphene, a number of researches are being conducted to find out the toxic potential of GFNs to different cell and animal models, finding their suitability for being used in new and varied innovative fields. This paper presents a systematic review of the research done on GFNs and gives an insight into the mode and action of these nanosized moieties. The paper also emphasizes on the recent and up-to-date developments in research on GFNs and their nanocomposites for their toxic effects. PMID:27051278

Discovery of a Phosphodiesterase 9A Inhibitor as a Potential Hypoglycemic Agent

PubMed Central

2015-01-01

Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimer’s disease. Here we report a potent PDE9 inhibitor 3r that has an IC50 of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that 3r inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of 3r, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-3r reveals significantly different conformation and hydrogen bonding pattern of 3r from those of previously published 28s. Both 3r and 28s form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but 3r shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors. PMID:25432025

A single cell high content assay detects mitochondrial dysfunction in iPSC-derived neurons with mutations in SNCA.

PubMed

Little, Daniel; Luft, Christin; Mosaku, Olukunbi; Lorvellec, Maëlle; Yao, Zhi; Paillusson, Sébastien; Kriston-Vizi, Janos; Gandhi, Sonia; Abramov, Andrey Y; Ketteler, Robin; Devine, Michael J; Gissen, Paul

2018-06-13

Mitochondrial dysfunction is implicated in many neurodegenerative diseases including Parkinson's disease (PD). Induced pluripotent stem cells (iPSCs) provide a unique cell model for studying neurological diseases. We have established a high-content assay that can simultaneously measure mitochondrial function, morphology and cell viability in iPSC-derived dopaminergic neurons. iPSCs from PD patients with mutations in SNCA and unaffected controls were differentiated into dopaminergic neurons, seeded in 384-well plates and stained with the mitochondrial membrane potential dependent dye TMRM, alongside Hoechst-33342 and Calcein-AM. Images were acquired using an automated confocal screening microscope and single cells were analysed using automated image analysis software. PD neurons displayed reduced mitochondrial membrane potential and altered mitochondrial morphology compared to control neurons. This assay demonstrates that high content screening techniques can be applied to the analysis of mitochondria in iPSC-derived neurons. This technique could form part of a drug discovery platform to test potential new therapeutics for PD and other neurodegenerative diseases.

Novel bacteriocins from lactic acid bacteria (LAB): various structures and applications

PubMed Central

2014-01-01

Bacteriocins are heat-stable ribosomally synthesized antimicrobial peptides produced by various bacteria, including food-grade lactic acid bacteria (LAB). These antimicrobial peptides have huge potential as both food preservatives, and as next-generation antibiotics targeting the multiple-drug resistant pathogens. The increasing number of reports of new bacteriocins with unique properties indicates that there is still a lot to learn about this family of peptide antibiotics. In this review, we highlight our system of fast tracking the discovery of novel bacteriocins, belonging to different classes, and isolated from various sources. This system employs molecular mass analysis of supernatant from the candidate strain, coupled with a statistical analysis of their antimicrobial spectra that can even discriminate novel variants of known bacteriocins. This review also discusses current updates regarding the structural characterization, mode of antimicrobial action, and biosynthetic mechanisms of various novel bacteriocins. Future perspectives and potential applications of these novel bacteriocins are also discussed. PMID:25186038

Novel bacteriocins from lactic acid bacteria (LAB): various structures and applications.

PubMed

Perez, Rodney H; Zendo, Takeshi; Sonomoto, Kenji

2014-08-29

Bacteriocins are heat-stable ribosomally synthesized antimicrobial peptides produced by various bacteria, including food-grade lactic acid bacteria (LAB). These antimicrobial peptides have huge potential as both food preservatives, and as next-generation antibiotics targeting the multiple-drug resistant pathogens. The increasing number of reports of new bacteriocins with unique properties indicates that there is still a lot to learn about this family of peptide antibiotics. In this review, we highlight our system of fast tracking the discovery of novel bacteriocins, belonging to different classes, and isolated from various sources. This system employs molecular mass analysis of supernatant from the candidate strain, coupled with a statistical analysis of their antimicrobial spectra that can even discriminate novel variants of known bacteriocins. This review also discusses current updates regarding the structural characterization, mode of antimicrobial action, and biosynthetic mechanisms of various novel bacteriocins. Future perspectives and potential applications of these novel bacteriocins are also discussed.

Integrative Spatial Data Analytics for Public Health Studies of New York State

PubMed Central

Chen, Xin; Wang, Fusheng

2016-01-01

Increased accessibility of health data made available by the government provides unique opportunity for spatial analytics with much higher resolution to discover patterns of diseases, and their correlation with spatial impact indicators. This paper demonstrated our vision of integrative spatial analytics for public health by linking the New York Cancer Mapping Dataset with datasets containing potential spatial impact indicators. We performed spatial based discovery of disease patterns and variations across New York State, and identify potential correlations between diseases and demographic, socio-economic and environmental indicators. Our methods were validated by three correlation studies: the correlation between stomach cancer and Asian race, the correlation between breast cancer and high education population, and the correlation between lung cancer and air toxics. Our work will allow public health researchers, government officials or other practitioners to adequately identify, analyze, and monitor health problems at the community or neighborhood level for New York State. PMID:28269834

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

PubMed Central

Crane, Erika A.

2016-01-01

Abstract Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody–drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products. PMID:26833854

Liver-resident NK cells and their potential functions.

PubMed

Peng, Hui; Sun, Rui

2017-09-18

Natural killer (NK) cells represent a heterogeneous population of innate lymphocytes with phenotypically and functionally distinct subsets. In particular, recent studies have identified a unique subset of NK cells residing within the liver that are maintained as tissue-resident cells, confer antigen-specific memory responses and exhibit different phenotypical and developmental characteristics compared with conventional NK (cNK) cells. These findings have encouraged researchers to uncover tissue-resident NK cells at other sites, and detailed analyses have revealed that these tissue-resident NK cells share many similarities with liver-resident NK cells and tissue-resident memory T cells. Here, we present a brief historical perspective on the discovery of liver-resident NK cells and discuss their relationship to cNK cells and other emerging NK cell subsets and their potential functions.Cellular &Molecular Immunology advance online publication, 18 September 2017; doi:10.1038/cmi.2017.72.

Egg accumulation with 3D embryos provides insight into the life history of a pterosaur.

PubMed

Wang, Xiaolin; Kellner, Alexander W A; Jiang, Shunxing; Cheng, Xin; Wang, Qiang; Ma, Yingxia; Paidoula, Yahefujiang; Rodrigues, Taissa; Chen, He; Sayão, Juliana M; Li, Ning; Zhang, Jialiang; Bantim, Renan A M; Meng, Xi; Zhang, Xinjun; Qiu, Rui; Zhou, Zhonghe

2017-12-01

Fossil eggs and embryos that provide unique information about the reproduction and early growth of vertebrates are exceedingly rare, particularly for pterosaurs. Here we report on hundreds of three-dimensional (3D) eggs of the species Hamipterus tianshanensis from a Lower Cretaceous site in China, 16 of which contain embryonic remains. Computed tomography scanning, osteohistology, and micropreparation reveal that some bones lack extensive ossification in potentially late-term embryos, suggesting that hatchlings might have been flightless and less precocious than previously assumed. The geological context, including at least four levels with embryos and eggs, indicates that this deposit was formed by a rare combination of events, with storms acting on a nesting ground. This discovery supports colonial nesting behavior and potential nesting site fidelity in the Pterosauria. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

A Path to Discovery

ERIC Educational Resources Information Center

Stegemoller, William; Stegemoller, Rebecca

2004-01-01

The path taken and the turns made as a turtle traces a polygon are examined to discover an important theorem in geometry. A unique tool, the Angle Adder, is implemented in the investigation. (Contains 9 figures.)

Unique parasite aDNA in moa coprolites from New Zealand suggests mass parasite extinctions followed human-induced megafauna extinctions

USGS Publications Warehouse

Lafferty, Kevin D.; Hopkins, Skylar R.

2018-01-01

Having split early from Gondwana, Zealandia (now modern New Zealand) escaped discovery until the late 13th century, and therefore remains an important glimpse into a human-free world. Without humans or other land mammals, diverse and peculiar birds evolved in isolation, including several flightless moa species, the giant pouakai eagle (Harpagornis moorei), the kiwi (Apteryx mantelli), and the kakapo parrot (Strigops habroptila). This unique community has fascinated paleoecologists, who have spent almost two centuries devising new ways to glean information from ancient bird remains. In PNAS, Boast et al. (1) apply one recent technological advance, ancient DNA (aDNA) metabarcoding, to confirm previous discoveries and report new details about moa and kakapo diets, parasites, and niches. Their efforts confirm Zealandia was a lot different before humans arrived.

Comparative genomics uncovers the prolific and distinctive metabolic potential of the cyanobacterial genus Moorea

PubMed Central

Leao, Tiago; Castelão, Guilherme; Monroe, Emily A.; Podell, Sheila; Glukhov, Evgenia; Allen, Eric E.; Gerwick, William H.; Gerwick, Lena

2017-01-01

Cyanobacteria are major sources of oxygen, nitrogen, and carbon in nature. In addition to the importance of their primary metabolism, some cyanobacteria are prolific producers of unique and bioactive secondary metabolites. Chemical investigations of the cyanobacterial genus Moorea have resulted in the isolation of over 190 compounds in the last two decades. However, preliminary genomic analysis has suggested that genome-guided approaches can enable the discovery of novel compounds from even well-studied Moorea strains, highlighting the importance of obtaining complete genomes. We report a complete genome of a filamentous tropical marine cyanobacterium, Moorea producens PAL, which reveals that about one-fifth of its genome is devoted to production of secondary metabolites, an impressive four times the cyanobacterial average. Moreover, possession of the complete PAL genome has allowed improvement to the assembly of three other Moorea draft genomes. Comparative genomics revealed that they are remarkably similar to one another, despite their differences in geography, morphology, and secondary metabolite profiles. Gene cluster networking highlights that this genus is distinctive among cyanobacteria, not only in the number of secondary metabolite pathways but also in the content of many pathways, which are potentially distinct from all other bacterial gene clusters to date. These findings portend that future genome-guided secondary metabolite discovery and isolation efforts should be highly productive. PMID:28265051

SWATH-based proteomics identified carbonic anhydrase 2 as a potential diagnosis biomarker for nasopharyngeal carcinoma

PubMed Central

Luo, Yanzhang; Mok, Tin Seak; Lin, Xiuxian; Zhang, Wanling; Cui, Yizhi; Guo, Jiahui; Chen, Xing; Zhang, Tao; Wang, Tong

2017-01-01

Nasopharyngeal carcinoma (NPC) is a serious threat to public health, and the biomarker discovery is of urgent needs. The data-independent mode (DIA) based sequential window acquisition of all theoretical fragment-ion spectra (SWATH) mass spectrometry (MS) has been proved to be precise in protein quantitation and efficient for cancer biomarker researches. In this study, we performed the first SWATH-MS analysis comparing the NPC and normal tissues. Spike-in stable isotope labeling by amino acids in cell culture (super-SILAC) MS was used as a shotgun reference. We identified and quantified 1414 proteins across all SWATH-MS analyses. We found that SWATH-MS had a unique feature to preferentially detect proteins with smaller molecular weights than either super-SILAC MS or human proteome background. With SWATH-MS, 29 significant differentially express proteins (DEPs) were identified. Among them, carbonic anhydrase 2 (CA2) was selected for further validation per novelty, MS quality and other supporting rationale. With the tissue microarray analysis, we found that CA2 had an AUC of 0.94 in differentiating NPC from normal tissue samples. In conclusion, SWATH-MS has unique features in proteome analysis, and it leads to the identification of CA2 as a potentially new diagnostic biomarker for NPC. PMID:28117408

Lipids and Fatty Acids of Nudibranch Mollusks: Potential Sources of Bioactive Compounds

PubMed Central

Zhukova, Natalia V.

2014-01-01

The molecular diversity of chemical compounds found in marine animals offers a good chance for the discovery of novel bioactive compounds of unique structures and diverse biological activities. Nudibranch mollusks, which are not protected by a shell and produce chemicals for various ecological uses, including defense against predators, have attracted great interest for their lipid composition. Lipid analysis of eight nudibranch species revealed dominant phospholipids, sterols and monoalkyldiacylglycerols. Among polar lipids, 1-alkenyl-2-acyl glycerophospholipids (plasmalogens) and ceramide-aminoethyl phosphonates were found in the mollusks. The fatty acid compositions of the nudibranchs differed greatly from those of other marine gastropods and exhibited a wide diversity: very long chain fatty acids known as demospongic acids, a series of non-methylene-interrupted fatty acids, including unusual 21:2∆7,13, and an abundance of various odd and branched fatty acids typical of bacteria. Symbiotic bacteria revealed in some species of nudibranchs participate presumably in the production of some compounds serving as a chemical defense for the mollusks. The unique fatty acid composition of the nudibranchs is determined by food supply, inherent biosynthetic activities and intracellular symbiotic microorganisms. The potential of nudibranchs as a source of biologically active lipids and fatty acids is also discussed. PMID:25196731

Carbon nanotubes (CNTs) based advanced dermal therapeutics: current trends and future potential.

PubMed

Kuche, Kaushik; Maheshwari, Rahul; Tambe, Vishakha; Mak, Kit-Kay; Jogi, Hardi; Raval, Nidhi; Pichika, Mallikarjuna Rao; Kumar Tekade, Rakesh

2018-05-17

The search for effective and non-invasive delivery modules to transport therapeutic molecules across skin has led to the discovery of a number of nanocarriers (viz.: liposomes, ethosomes, dendrimers, etc.) in the last few decades. However, available literature suggests that these delivery modules face several issues including poor stability, low encapsulation efficiency, and scale-up hurdles. Recently, carbon nanotubes (CNTs) emerged as a versatile tool to deliver therapeutics across skin. Superior stability, high loading capacity, well-developed synthesis protocol as well as ease of scale-up are some of the reason for growing interest in CNTs. CNTs have a unique physical architecture and a large surface area with unique surface chemistry that can be tailored for vivid biomedical applications. CNTs have been thus largely engaged in the development of transdermal systems such as tuneable hydrogels, programmable nonporous membranes, electroresponsive skin modalities, protein channel mimetic platforms, reverse iontophoresis, microneedles, and dermal buckypapers. In addition, CNTs were also employed in the development of RNA interference (RNAi) based therapeutics for correcting defective dermal genes. This review expounds the state-of-art synthesis methodologies, skin penetration mechanism, drug liberation profile, loading potential, characterization techniques, and transdermal applications along with a summary on patent/regulatory status and future scope of CNT based skin therapeutics.

Growing with dinosaurs: natural products from the Cretaceous relict Metasequoia glyptostroboides Hu & Cheng-a molecular reservoir from the ancient world with potential in modern medicine.

PubMed

Juvik, Ole Johan; Nguyen, Xuan Hong Thy; Andersen, Heidi Lie; Fossen, Torgils

2016-01-01

After the sensational rediscovery of living exemplars of the Cretaceous relict Metasequoia glyptostroboides -a tree previously known exclusively from fossils from various locations in the northern hemisphere, there has been an increasing interest in discovery of novel natural products from this unique plant source. This article includes the first complete compilation of natural products reported from M. glyptostroboides during the entire period in which the tree has been investigated (1954-2014) with main focus on the compounds specific to this plant source. Studies on the biological activity of pure compounds and extracts derived from M. glyptostroboides are reviewed for the first time. The unique potential of M. glyptostroboides as a source of bioactive constituents is founded on the fact that the tree seems to have survived unchanged since the Cretaceous era. Since then, its molecular defense system has resisted the attacks of millions of generations of pathogens. In line with this, some recent landmarks in Metasequoia paleobotany are covered. Initial spectral analysis of recently discovered intact 53 million year old wood and amber of Metasequoia strongly indicate that the tree has remained unchanged for millions of years at the molecular level.

Lifeomics leads the age of grand discoveries.

PubMed

He, Fuchu

2013-03-01

When our knowledge of a field accumulates to a certain level, we are bound to see the rise of one or more great scientists. They will make a series of grand discoveries/breakthroughs and push the discipline into an 'age of grand discoveries'. Mathematics, geography, physics and chemistry have all experienced their ages of grand discoveries; and in life sciences, the age of grand discoveries has appeared countless times since the 16th century. Thanks to the ever-changing development of molecular biology over the past 50 years, contemporary life science is once again approaching its breaking point and the trigger for this is most likely to be 'lifeomics'. At the end of the 20th century, genomics wrote out the 'script of life'; proteomics decoded the script; and RNAomics, glycomics and metabolomics came into bloom. These 'omics', with their unique epistemology and methodology, quickly became the thrust of life sciences, pushing the discipline to new high. Lifeomics, which encompasses all omics, has taken shape and is now signalling the dawn of a new era, the age of grand discoveries.

Challenges of Antibacterial Discovery

PubMed Central

Silver, Lynn L.

2011-01-01

Summary: The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort. PMID:21233508

Manipulation of the mouse genome: a multiple impact resource for drug discovery and development.

PubMed

Prosser, Haydn; Rastan, Sohaila

2003-05-01

Few would deny that the pharmaceutical industry's investment in genomics throughout the 1990s has yet to deliver in terms of drugs on the market. The reasons are complex and beyond the scope of this review. The unique ability to manipulate the mouse genome, however, has already had a positive impact on all stages of the drug discovery process and, increasingly, on the drug development process too. We give an overview of some recent applications of so-called 'transgenic' mouse technology in pharmaceutical research and development. We show how genetic manipulation in the mouse can be employed at multiple points in the drug discovery and development process, providing new solutions to old problems.

Successes in drug discovery and design.

PubMed

2004-04-01

The Society for Medicines Research (SMR) held a one-day meeting on case histories in drug discovery on December 4, 2003, at the National Heart and Lung Institute in London. These meetings have been organized by the SMR biannually for many years, and this latest meeting proved extremely popular, attracting a capacity audience of more than 130 registrants. The purpose of these meetings is educational; they allow those interested in drug discovery to hear key learnings from recent successful drug discovery programs. There was no overall linking theme between the talks, other than each success story has led to the introduction of a new and improved product of therapeutic use. The drug discovery stories covered in the meeting were extremely varied and, put together, they emphasized that each successful story is unique and special. This meeting is also special for the SMR because it presents the "SMR Award for Drug Discovery" in recognition of outstanding achievement and contribution in the area. It should be remembered that drug discovery is an extremely risky business and an extremely costly and complicated process in which the success rate is, at best, low. (c) 2004 Prous Science. All rights reserved.

Mars scouts: an overview

NASA Technical Reports Server (NTRS)

Matousek, S.

2001-01-01

The Mars program institutes the Mars Scout Missions in order to address science goals in the program not otherwise covered in the baseline Mars plan. Mars Scout Missions will be Principle-Investigator (PI) led science missions. Analogous to the Discovery Program, PI led investigations optimize the use of limited resources to accomplish the best focused science and allow the flexibility to quickly respond to discoveries at Mars. Scout missions also require unique investments in technology and reliance upon Mars-based infrastructure such as telecom relay orbiters.

A deepwater fish with ‘lightsabers’ – dorsal spine-associated luminescence in a counterilluminating lanternshark

PubMed Central

Claes, Julien M.; Dean, Mason N.; Nilsson, Dan-Eric; Hart, Nathan S.; Mallefet, Jérôme

2013-01-01

We report the discovery of light organs (photophores) adjacent to the dorsal defensive spines of a small deep-sea lanternshark (Etmopterus spinax). Using a visual modeling based on in vivo luminescence recordings we show that this unusual light display would be detectable by the shark's potential predators from several meters away. We also demonstrate that the luminescence from the spine-associated photophores (SAPs) can be seen through the mineralized spines, which are partially translucent. These results suggest that the SAPs function, either by mimicking the spines' shape or by shining through them, as a unique visual deterrent for predators. This conspicuous dorsal warning display is a surprising complement to the ventral luminous camouflage (counterillumination) of the shark. PMID:23425862

Helping science to succeed: improving processes in R&D.

PubMed

Sewing, Andreas; Winchester, Toby; Carnell, Pauline; Hampton, David; Keighley, Wilma

2008-03-01

Bringing drugs to the market remains a costly and, until now, often unpredictable challenge. Although understanding the underlying science is key to further progress, our imperfect knowledge of disease and complex biological systems leaves excellence in execution as the most tangible lever to sustain our serendipitous approach to drug discovery. The problems encountered in pharmaceutical R&D are not unique, but to learn from other industries it is important to recognise similarity, rather than differences, and to advance industrialisation of R&D beyond technology and automation. Tools like Lean and Six Sigma, already applied to increase business excellence across diverse organisations, can equally be introduced to pharmaceutical R&D and offer the potential to transform operations without large-scale investment.

Thesis: A Combined-light Mission For Exoplanet Molecular Spectroscopy

NASA Astrophysics Data System (ADS)

Deroo, Pieter; Swain, M. R.; Tinetti, G.; Griffith, C.; Vasisht, G.; Deming, D.; Henning, T.; Beaulieu, J.

2010-01-01

THESIS, the Transiting Habitable-zone Exoplanet Spectroscopy Infrared Spacecraft, is a concept for a MIDEX/Discovery class exoplanet mission. Building on the recent Spitzer and Hubble successes in exoplanet characterization and molecular spectroscopy, THESIS would extend these types of measurements to a large population of planets including non-transiting planets and super-Earths. The ability to acquire high-stability, spectroscopic data from the near-visible to the mid-infrared is a unique aspect of THESIS. A strength of the THESIS concept is simplicity low technical risk, and modest cost. By enabling molecular spectroscopy of exoplanet atmospheres, THESIS mission has the potential to dramatically advance our understanding of conditions on extrasolar worlds while serving as a stepping stone to more ambitious future missions.

A deepwater fish with 'lightsabers'--dorsal spine-associated luminescence in a counterilluminating lanternshark.

PubMed

Claes, Julien M; Dean, Mason N; Nilsson, Dan-Eric; Hart, Nathan S; Mallefet, Jérôme

2013-01-01

We report the discovery of light organs (photophores) adjacent to the dorsal defensive spines of a small deep-sea lanternshark (Etmopterus spinax). Using a visual modeling based on in vivo luminescence recordings we show that this unusual light display would be detectable by the shark's potential predators from several meters away. We also demonstrate that the luminescence from the spine-associated photophores (SAPs) can be seen through the mineralized spines, which are partially translucent. These results suggest that the SAPs function, either by mimicking the spines' shape or by shining through them, as a unique visual deterrent for predators. This conspicuous dorsal warning display is a surprising complement to the ventral luminous camouflage (counterillumination) of the shark.

Human pluripotent stem cells: an emerging model in developmental biology

PubMed Central

Zhu, Zengrong; Huangfu, Danwei

2013-01-01

Developmental biology has long benefited from studies of classic model organisms. Recently, human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, have emerged as a new model system that offers unique advantages for developmental studies. Here, we discuss how studies of hPSCs can complement classic approaches using model organisms, and how hPSCs can be used to recapitulate aspects of human embryonic development ‘in a dish’. We also summarize some of the recently developed genetic tools that greatly facilitate the interrogation of gene function during hPSC differentiation. With the development of high-throughput screening technologies, hPSCs have the potential to revolutionize gene discovery in mammalian development. PMID:23362344

Sports Stars: Analyzing the Performance of Astronomers at Visualization-based Discovery

NASA Astrophysics Data System (ADS)

Fluke, C. J.; Parrington, L.; Hegarty, S.; MacMahon, C.; Morgan, S.; Hassan, A. H.; Kilborn, V. A.

2017-05-01

In this data-rich era of astronomy, there is a growing reliance on automated techniques to discover new knowledge. The role of the astronomer may change from being a discoverer to being a confirmer. But what do astronomers actually look at when they distinguish between “sources” and “noise?” What are the differences between novice and expert astronomers when it comes to visual-based discovery? Can we identify elite talent or coach astronomers to maximize their potential for discovery? By looking to the field of sports performance analysis, we consider an established, domain-wide approach, where the expertise of the viewer (i.e., a member of the coaching team) plays a crucial role in identifying and determining the subtle features of gameplay that provide a winning advantage. As an initial case study, we investigate whether the SportsCode performance analysis software can be used to understand and document how an experienced Hi astronomer makes discoveries in spectral data cubes. We find that the process of timeline-based coding can be applied to spectral cube data by mapping spectral channels to frames within a movie. SportsCode provides a range of easy to use methods for annotation, including feature-based codes and labels, text annotations associated with codes, and image-based drawing. The outputs, including instance movies that are uniquely associated with coded events, provide the basis for a training program or team-based analysis that could be used in unison with discipline specific analysis software. In this coordinated approach to visualization and analysis, SportsCode can act as a visual notebook, recording the insight and decisions in partnership with established analysis methods. Alternatively, in situ annotation and coding of features would be a valuable addition to existing and future visualization and analysis packages.

A knowledgebase system to enhance scientific discovery: Telemakus

PubMed Central

Fuller, Sherrilynne S; Revere, Debra; Bugni, Paul F; Martin, George M

2004-01-01

Background With the rapid expansion of scientific research, the ability to effectively find or integrate new domain knowledge in the sciences is proving increasingly difficult. Efforts to improve and speed up scientific discovery are being explored on a number of fronts. However, much of this work is based on traditional search and retrieval approaches and the bibliographic citation presentation format remains unchanged. Methods Case study. Results The Telemakus KnowledgeBase System provides flexible new tools for creating knowledgebases to facilitate retrieval and review of scientific research reports. In formalizing the representation of the research methods and results of scientific reports, Telemakus offers a potential strategy to enhance the scientific discovery process. While other research has demonstrated that aggregating and analyzing research findings across domains augments knowledge discovery, the Telemakus system is unique in combining document surrogates with interactive concept maps of linked relationships across groups of research reports. Conclusion Based on how scientists conduct research and read the literature, the Telemakus KnowledgeBase System brings together three innovations in analyzing, displaying and summarizing research reports across a domain: (1) research report schema, a document surrogate of extracted research methods and findings presented in a consistent and structured schema format which mimics the research process itself and provides a high-level surrogate to facilitate searching and rapid review of retrieved documents; (2) research findings, used to index the documents, allowing searchers to request, for example, research studies which have studied the relationship between neoplasms and vitamin E; and (3) visual exploration interface of linked relationships for interactive querying of research findings across the knowledgebase and graphical displays of what is known as well as, through gaps in the map, what is yet to be tested. The rationale and system architecture are described and plans for the future are discussed. PMID:15507158

Phenome-driven disease genetics prediction toward drug discovery

PubMed Central

Chen, Yang; Li, Li; Zhang, Guo-Qiang; Xu, Rong

2015-01-01

Motivation: Discerning genetic contributions to diseases not only enhances our understanding of disease mechanisms, but also leads to translational opportunities for drug discovery. Recent computational approaches incorporate disease phenotypic similarities to improve the prediction power of disease gene discovery. However, most current studies used only one data source of human disease phenotype. We present an innovative and generic strategy for combining multiple different data sources of human disease phenotype and predicting disease-associated genes from integrated phenotypic and genomic data. Results: To demonstrate our approach, we explored a new phenotype database from biomedical ontologies and constructed Disease Manifestation Network (DMN). We combined DMN with mimMiner, which was a widely used phenotype database in disease gene prediction studies. Our approach achieved significantly improved performance over a baseline method, which used only one phenotype data source. In the leave-one-out cross-validation and de novo gene prediction analysis, our approach achieved the area under the curves of 90.7% and 90.3%, which are significantly higher than 84.2% (P < e−4) and 81.3% (P < e−12) for the baseline approach. We further demonstrated that our predicted genes have the translational potential in drug discovery. We used Crohn’s disease as an example and ranked the candidate drugs based on the rank of drug targets. Our gene prediction approach prioritized druggable genes that are likely to be associated with Crohn’s disease pathogenesis, and our rank of candidate drugs successfully prioritized the Food and Drug Administration-approved drugs for Crohn’s disease. We also found literature evidence to support a number of drugs among the top 200 candidates. In summary, we demonstrated that a novel strategy combining unique disease phenotype data with system approaches can lead to rapid drug discovery. Availability and implementation: nlp.case.edu/public/data/DMN Contact: rxx@case.edu PMID:26072493

Recent advances in the discovery of potent and selective HDAC6 inhibitors.

PubMed

Wang, Xiu-Xiu; Wan, Ren-Zhong; Liu, Zhao-Peng

2018-01-01

Histone deacetylase HDAC6, a member of the class IIb HDAC family, is unique among HDAC enzymes in having two active catalytic domains, and has unique physiological function. In addition to the modification of histone, HDAC6 targets specific substrates including α-tubulin and HSP90, and are involved in protein trafficking and degradation, cell shape and migration. Selective HDAC6 inhibitors are an emerging class of pharmaceuticals due to the involvement of HDAC6 in different pathways related to neurodegenerative diseases, cancer, and immunology. Therefore, extensive investigations have been made in the discovery of selective HDAC6 inhibitors. Based on their different zinc binding groups (ZBGs), in this review, HDAC6 inhibitors are grouped as hydroxamic acids, a sulfur containing ZBG based derivatives and other ZBG-derived compounds, and their enzymatic inhibitory activity, selectivity and other biological activities are introduced and summarized. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Pharmacokinetic and pharmacodynamic considerations for the next generation protein therapeutics.

PubMed

Shah, Dhaval K

2015-10-01

Increasingly sophisticated protein engineering efforts have been undertaken lately to generate protein therapeutics with desired properties. This has resulted in the discovery of the next generation of protein therapeutics, which include: engineered antibodies, immunoconjugates, bi/multi-specific proteins, antibody mimetic novel scaffolds, and engineered ligands/receptors. These novel protein therapeutics possess unique physicochemical properties and act via a unique mechanism-of-action, which collectively makes their pharmacokinetics (PK) and pharmacodynamics (PD) different than other established biological molecules. Consequently, in order to support the discovery and development of these next generation molecules, it becomes important to understand the determinants controlling their PK/PD. This review discusses the determinants that a PK/PD scientist should consider during the design and development of next generation protein therapeutics. In addition, the role of systems PK/PD models in enabling rational development of the next generation protein therapeutics is emphasized.

Pharmacokinetic and pharmacodynamic considerations for the next generation protein therapeutics

PubMed Central

Shah, Dhaval K.

2015-01-01

Increasingly sophisticated protein engineering efforts have been undertaken lately to generate protein therapeutics with desired properties. This has resulted in the discovery of the next generation of protein therapeutics, which include: engineered antibodies, immunoconjugates, bi/multi-specific proteins, antibody mimetic novel scaffolds, and engineered ligands/receptors. These novel protein therapeutics possess unique physicochemical properties and act via a unique mechanism-of-action, which collectively makes their pharmacokinetics (PK) and pharmacodynamics (PD) different than other established biological molecules. Consequently, in order to support the discovery and development of these next generation molecules, it becomes important to understand the determinants controlling their PK/PD. This review discusses the determinants that a PK/PD scientist should consider during the design and development of next generation protein therapeutics. In addition, the role of systems PK/PD models in enabling rational development of the next generation protein therapeutics is emphasized. PMID:26373957

Treponema pallidum Putative Novel Drug Target Identification and Validation: Rethinking Syphilis Therapeutics with Plant-Derived Terpenoids

PubMed Central

Tiwari, Sameeksha; Singh, Priyanka; Singh, Swati; Awasthi, Manika; Pandey, Veda P.

2015-01-01

Abstract Syphilis, a slow progressive and the third most common sexually transmitted disease found worldwide, is caused by a spirochete gram negative bacteria Treponema pallidum. Emergence of antibiotic resistant T. pallidum has led to a search for novel drugs and their targets. Subtractive genomics analyses of pathogen T. pallidum and host Homo sapiens resulted in identification of 126 proteins essential for survival and viability of the pathogen. Metabolic pathway analyses of these essential proteins led to discovery of nineteen proteins distributed among six metabolic pathways unique to T. pallidum. One hundred plant-derived terpenoids, as potential therapeutic molecules against T. pallidum, were screened for their drug likeness and ADMET (absorption, distribution, metabolism, and toxicity) properties. Subsequently the resulting nine terpenoids were docked with five unique T. pallidum targets through molecular modeling approaches. Out of five targets analyzed, D-alanine:D-alanine ligase was found to be the most promising target, while terpenoid salvicine was the most potent inhibitor. A comparison of the inhibitory potential of the best docked readily available natural compound, namely pomiferin (flavonoid) with that of the best docked terpenoid salvicine, revealed that salvicine was a more potent inhibitor than that of pomiferin. To the best of our knowledge, this is the first report of a terpenoid as a potential therapeutic molecule against T. pallidum with D-alanine:D-alanine ligase as a novel target. Further studies are warranted to evaluate and explore the potential clinical ramifications of these findings in relation to syphilis that has public health importance worldwide. PMID:25683888

KSC-2011-6400

NASA Image and Video Library

2011-08-11

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center in Florida, space shuttles Discovery and Endeavour, their noses encased in protective plastic where their forward reaction control systems (FRCS) once resided, pause outside Orbiter Processing Facility-3 (OPF-3) for a unique photo opportunity. Discovery, which temporarily was being stored in the Vehicle Assembly Building (VAB), is switching places with Endeavour, which has been undergoing decommissioning in OPF-1. Discovery then will be rolled into OPF-1 and Endeavour into the VAB. In OPF-1, Discovery will undergo further preparations for public display at the Smithsonian's National Air and Space Museum Steven F. Udvar-Hazy Center in Virginia. Endeavour will be stored in the VAB until October when it will be moved into OPF-2 for further work to get it ready for public display at the California Science Center in Los Angeles. For more information, visit http://www.nasa.gov/shuttle. Photo credit: NASA/Jim Grossmann

[MicroRNAs in diagnosis and prognosis in lung cancer].

PubMed

Avila-Moreno, Federico; Urrea, Francisco; Ortiz-Quintero, Blanca

2011-01-01

MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that regulate gene expression at the posttranscriptional level by blocking translation or inducing degradation of messenger RNA targets. It has been shown that miRNAs participate in a wide spectrum of essential biologic processes including cell cycle, differentiation, development, apoptosis and hematopoiesis, revealing one of the major regulators of human gene expression. Recent studies have shown evidences of abnormal expression of miRNAs in solid and hematological tumors, as well as the association of altered miRNAs with oncogenic or tumor suppressor functions, suggesting a key role of miRNAs in carcinogenesis. Moreover, unique profiles of altered miRNAs expression seem to allow distinction from normal tissue, prediction of disease outcomes, and evaluation of tumor aggressiveness in several types of cancer, including lung cancer. These unique and highly stable miRNAs patterns seems not to depend of age and race, and these characteristics highlight their potential diagnostic and prognosis utility. These findings are particularly promising for lung cancer, a worldwide leading cause of cancer-related deaths with a poor survival rate, despite the discovery of novel therapies. This review describes the potential of miRNAs as biomarkers for diagnosis, cancer classification and estimation of prognosis in lung cancer; and the approaches used to detect and quantify these miRNAs; including the current information about circulating miRNAs as potential biomarkers in lung cancer. This review also provides a description of miRNAs biogenesis, nomenclature and available database for miRNA sequences.

Galactic Neighborhood and Laboratory Astrophysics

NASA Astrophysics Data System (ADS)

Wang, Q. D.

2011-05-01

The galactic neighborhood, extending from the Milky Way to redshifts of about 0.1, is our unique local laboratory for detailed study of galaxies and their interplay with the environment. Such study provides a foundation of knowledge for interpreting observations of more distant galaxies and their environment. The Astro 2010 Science Frontier Galactic Neighborhood Panel identified four key sci- entific questions: 1) What are the flows of matter and energy in the circumgalac- tic medium? 2) What controls the mass-energy-chemical cycles within galaxies? 3) What is the fossil record of galaxy assembly from first stars to present? 4) What are the connections between dark and luminous matter? These questions, essential to the understanding of galaxies as interconnected complexes, can be addressed most effectively and/or uniquely in the galactic neighborhood. The panel also highlighted the discovery potential of time-domain astronomy and astrometry with powerful new techniques and facilities to greatly advance our understanding of the precise connections among stars, galaxies, and newly dis- covered transient events. The relevant needs for laboratory astrophysics will be emphasized, especially in the context of supporting NASA missions.

Glutamine synthetase in Medicago truncatula, unveiling new secrets of a very old enzyme

PubMed Central

Seabra, Ana R.; Carvalho, Helena G.

2015-01-01

Glutamine synthetase (GS) catalyzes the first step at which nitrogen is brought into cellular metabolism and is also involved in the reassimilation of ammonium released by a number of metabolic pathways. Due to its unique position in plant nitrogen metabolism, GS plays essential roles in all aspects of plant development, from germination to senescence, and is a key component of nitrogen use efficiency (NUE) and plant yield. Understanding the mechanisms regulating GS activity is therefore of utmost importance and a great effort has been dedicated to understand how GS is regulated in different plant species. The present review summarizes exciting recent developments concerning the structure and regulation of GS isoenzymes, using the model legume Medicago truncatula. These include the understanding of the structural determinants of both the cytosolic and plastid located isoenzymes, the existence of a seed-specific GS gene unique to M. truncatula and closely related species and the discovery that GS isoenzymes are regulated by nitric oxide at the post-translational level. The data is discussed and integrated with the potential roles of the distinct GS isoenzymes within the whole plant context. PMID:26284094

Microbes: Agents of Isotopic Change

NASA Astrophysics Data System (ADS)

Fogel, M. L.

2012-12-01

Microbes drive many of the important oxidation and reduction reactions on Earth; digest almost all forms of organic matter; and can serve as both primary and secondary producers. Because of their versatile biochemistry and physiology, they impart unique isotopic signatures to organic and inorganic materials, which have proven to be key measurements for understanding elemental cycling now and throughout Earth's history. Understanding microbial isotope fractionations in laboratory experiments has been important for interpreting isotopic patterns measured in natural settings. In fact, the pairing of simple experiment with natural observation has been the pathway for interpreting the fingerprint of microbial processes in ancient sediments and rocks. Examples of how key experiments have explained stable isotope fractionations by microbes and advanced the field of microbial ecology will be presented. Learning the isotopic signatures of Earth's microbes is a valuable exercise for predicting what isotopic signatures could be displayed by possible extant or extinct extraterrestrial life. Given the potential for discovery on Mars, Enceladus, and other solar system bodies, new methods and techniques for pinpointing what is unique about microbial isotope signatures is particularly relevant.

Mining the human urine proteome for monitoring renal transplant injury

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

Sigdel, Tara K.; Gao, Yuqian; He, Jintang

The human urinary proteome reflects systemic and inherent renal injury perturbations and can be analyzed to harness specific biomarkers for different kidney transplant injury states. 396 unique urine samples were collected contemporaneously with an allograft biopsy from 396 unique kidney transplant recipients. Centralized, blinded histology on the graft was used to classify matched urine samples into categories of acute rejection (AR), chronic allograft nephropathy (CAN), BK virus nephritis (BKVN), and stable graft (STA). Liquid chromatography–mass spectrometry (LC-MS) based proteomics using iTRAQ based discovery (n=108) and global label-free LC-MS analyses of individual samples (n=137) for quantitative proteome assessment were used inmore » the discovery step. Selected reaction monitoring (SRM) was applied to identify and validate minimal urine protein/peptide biomarkers to accurately segregate organ injury causation and pathology on unique urine samples (n=151). A total of 958 proteins were initially quantified by iTRAQ, 87% of which were also identified among 1574 urine proteins detected in LC-MS validation. 103 urine proteins were significantly (p<0.05) perturbed in injury and enriched for humoral immunity, complement activation, and lymphocyte trafficking. A set of 131 peptides corresponding to 78 proteins were assessed by SRM for their significance in an independent sample cohort. A minimal set of 35 peptides mapping to 33 proteins, were modeled to segregate different injury groups (AUC =93% for AR, 99% for CAN, 83% for BKVN). Urinary proteome discovery and targeted validation identified urine protein fingerprints for non-invasive differentiation of kidney transplant injuries, thus opening the door for personalized immune risk assessment and therapy.« less

Keep Your Voice Sound: How to Prevent and Avoid Voice Problems

MedlinePlus

... ways, your voice is as unique as your fingerprint. It’s produced in your throat by 2 bands ... Act No Fear Act Office of Inspector General USA.gov – Government Made Easy NIH…Turning Discovery Into ...

Maturation inhibitors: a new therapeutic class targets the virus structure.

PubMed

Salzwedel, Karl; Martin, David E; Sakalian, Michael

2007-01-01

The current standard of care for HIV/AIDS in the developed world is HAART therapy, usually a combination of two reverse transcriptase inhibitors and a protease inhibitor. Despite the success of this regimen, there is a continuing need for new drug options to overcome problems with tolerability and the emergence of viral resistance. In this review we discuss the discovery of a potential new class of antiretroviral therapeutics, known as maturation inhibitors, and the development of the first-in-class compound, bevirimat. Bevirimat is distinguished from the currently available antiretrovirals by its unique target and mode of action. While the specific interactions responsible for activity have yet to be fully characterized, it is clear that the target for bevirimat is the Gag polyprotein precursor, the main structural protein responsible for assembly and budding of virion particles. As basic research continues on the precise mechanism of action of bevirimat, clinical development is progressing, with demonstration of both safety and efficacy in early-stage trials. These encouraging results, coupled with the discovery and development of future generations of maturation inhibitors, suggest that maturation inhibitors may be added to the growing set of tools available to control HIV/AIDS.

NASA Radioisotope Power System Program - Technology and Flight Systems

NASA Technical Reports Server (NTRS)

Sutliff, Thomas J.; Dudzinski, Leonard A.

2009-01-01

NASA sometimes conducts robotic science missions to solar system destinations for which the most appropriate power source is derived from thermal-to-electrical energy conversion of nuclear decay of radioactive isotopes. Typically the use of a radioisotope power system (RPS) has been limited to medium and large-scale missions, with 26 U,S, missions having used radioisotope power since 1961. A research portfolio of ten selected technologies selected in 2003 has progressed to a point of maturity, such that one particular technology may he considered for future mission use: the Advanced Stirling Converter. The Advanced Stirling Radioisotope Generator is a new power system in development based on this Stirling cycle dynamic power conversion technology. This system may be made available for smaller, Discovery-class NASA science missions. To assess possible uses of this new capability, NASA solicited and funded nine study teams to investigate unique opportunities for exploration of potential destinations for small Discovery-class missions. The influence of the results of these studies and the ongoing development of the Advanced Stirling Radioisotope Generator system are discussed in the context of an integrated Radioisotope Power System program. Discussion of other and future technology investments and program opportunities are provided.

Aerogel Development

NASA Technical Reports Server (NTRS)

Sahai, Rashmi K.

2005-01-01

Aerogel is one of the most promising materials of the future. It's unique properties, including high porosity, transparency, very high thermal tolerance, and environmental friendliness give it the potential of replacing many different products used in society today. However, the market for aerogel is still very limited because of the cost of producing the material and its fragility. The principle objective of my project has been to find new ways to apply aerogel in order to increase its practicality and appeal to different aspects of society. More specifically, I have focused on finding different chemicals that will coat aerogel and increase its durability. Because aerogel is so fragile and will crumble under the pressure of most coatings this has been no easy task. However, by experimenting with many different coatings and combinations of aerogel properties, I have made several significant discoveries. Aerogel (ideally, high density and hydrophobic) can be coated with several acrylic polymers, including artist's gel and nail polish. These materials provide a protective layering around the aerogel and keep it from breaking as easily. Because fragility is one of the main reasons applications of aerogel are limited, these discoveries will hopefully aid in finding future applications for this extraordinary material.

The Role of CRISPR-Cas Systems in Virulence of Pathogenic Bacteria

PubMed Central

Staals, Raymond H. J.; Endtz, Hubert P.; van Baarlen, Peter; van der Oost, John

2014-01-01

SUMMARY Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) genes are present in many bacterial and archaeal genomes. Since the discovery of the typical CRISPR loci in the 1980s, well before their physiological role was revealed, their variable sequences have been used as a complementary typing tool in diagnostic, epidemiologic, and evolutionary analyses of prokaryotic strains. The discovery that CRISPR spacers are often identical to sequence fragments of mobile genetic elements was a major breakthrough that eventually led to the elucidation of CRISPR-Cas as an adaptive immunity system. Key elements of this unique prokaryotic defense system are small CRISPR RNAs that guide nucleases to complementary target nucleic acids of invading viruses and plasmids, generally followed by the degradation of the invader. In addition, several recent studies have pointed at direct links of CRISPR-Cas to regulation of a range of stress-related phenomena. An interesting example concerns a pathogenic bacterium that possesses a CRISPR-associated ribonucleoprotein complex that may play a dual role in defense and/or virulence. In this review, we describe recently reported cases of potential involvement of CRISPR-Cas systems in bacterial stress responses in general and bacterial virulence in particular. PMID:24600041

The role of CRISPR-Cas systems in virulence of pathogenic bacteria.

PubMed

Louwen, Rogier; Staals, Raymond H J; Endtz, Hubert P; van Baarlen, Peter; van der Oost, John

2014-03-01

Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) genes are present in many bacterial and archaeal genomes. Since the discovery of the typical CRISPR loci in the 1980s, well before their physiological role was revealed, their variable sequences have been used as a complementary typing tool in diagnostic, epidemiologic, and evolutionary analyses of prokaryotic strains. The discovery that CRISPR spacers are often identical to sequence fragments of mobile genetic elements was a major breakthrough that eventually led to the elucidation of CRISPR-Cas as an adaptive immunity system. Key elements of this unique prokaryotic defense system are small CRISPR RNAs that guide nucleases to complementary target nucleic acids of invading viruses and plasmids, generally followed by the degradation of the invader. In addition, several recent studies have pointed at direct links of CRISPR-Cas to regulation of a range of stress-related phenomena. An interesting example concerns a pathogenic bacterium that possesses a CRISPR-associated ribonucleoprotein complex that may play a dual role in defense and/or virulence. In this review, we describe recently reported cases of potential involvement of CRISPR-Cas systems in bacterial stress responses in general and bacterial virulence in particular.

Measurements from an Aerial Vehicle: A New Tool for Planetary Exploration

NASA Technical Reports Server (NTRS)

Wright, Henry S.; Levine, Joel S.; Croom, Mark A.; Edwards, William C.; Qualls, Garry D.; Gasbarre, Joseph F.

2004-01-01

Aerial vehicles fill a unique planetary science measurement gap, that of regional-scale, near-surface observation, while providing a fresh perspective for potential discovery. Aerial vehicles used in planetary exploration bridge the scale and resolution measurement gaps between orbiters (global perspective with limited spatial resolution) and landers (local perspective with high spatial resolution) thus complementing and extending orbital and landed measurements. Planetary aerial vehicles can also survey scientifically interesting terrain that is inaccessible or hazardous to landed missions. The use of aerial assets for performing observations on Mars, Titan, or Venus will enable direct measurements and direct follow-ons to recent discoveries. Aerial vehicles can be used for remote sensing of the interior, surface and atmosphere of Mars, Venus and Titan. Types of aerial vehicles considered are airplane "heavier than air" and airships and balloons "lighter than air". Interdependencies between the science measurements, science goals and objectives, and platform implementation illustrate how the proper balance of science, engineering, and cost, can be achieved to allow for a successful mission. Classification of measurement types along with how those measurements resolve science questions and how these instruments are accommodated within the mission context are discussed.

Schizophrenia-Associated hERG channel Kv11.1-3.1 Exhibits a Unique Trafficking Deficit that is Rescued Through Proteasome Inhibition for High Throughput Screening.

PubMed

Calcaterra, Nicholas E; Hoeppner, Daniel J; Wei, Huijun; Jaffe, Andrew E; Maher, Brady J; Barrow, James C

2016-02-16

The primate-specific brain voltage-gated potassium channel isoform Kv11.1-3.1 has been identified as a novel therapeutic target for the treatment of schizophrenia. While this ether-a-go-go related K(+)channel has shown clinical relevance, drug discovery efforts have been hampered due to low and inconsistent activity in cell-based assays. This poor activity is hypothesized to result from poor trafficking via the lack of an intact channel-stabilizing Per-Ant-Sim (PAS) domain. Here we characterize Kv11.1-3.1 cellular localization and show decreased channel expression and cell surface trafficking relative to the PAS-domain containing major isoform, Kv11.1-1A. Using small molecule inhibition of proteasome degradation, cellular expression and plasma membrane trafficking are rescued. These findings implicate the importance of the unfolded-protein response and endoplasmic reticulum associated degradation pathways in the expression and regulation of this schizophrenia risk factor. Utilizing this identified phenomenon, an electrophysiological and high throughput in-vitro fluorescent assay platform has been developed for drug discovery in order to explore a potentially new class of cognitive therapeutics.

Finding overlapping communities in multilayer networks

PubMed Central

Liu, Weiyi; Suzumura, Toyotaro; Ji, Hongyu; Hu, Guangmin

2018-01-01

Finding communities in multilayer networks is a vital step in understanding the structure and dynamics of these layers, where each layer represents a particular type of relationship between nodes in the natural world. However, most community discovery methods for multilayer networks may ignore the interplay between layers or the unique topological structure in a layer. Moreover, most of them can only detect non-overlapping communities. In this paper, we propose a new community discovery method for multilayer networks, which leverages the interplay between layers and the unique topology in a layer to reveal overlapping communities. Through a comprehensive analysis of edge behaviors within and across layers, we first calculate the similarities for edges from the same layer and the cross layers. Then, by leveraging these similarities, we can construct a dendrogram for the multilayer networks that takes both the unique topological structure and the important interplay into consideration. Finally, by introducing a new community density metric for multilayer networks, we can cut the dendrogram to get the overlapping communities for these layers. By applying our method on both synthetic and real-world datasets, we demonstrate that our method has an accurate performance in discovering overlapping communities in multilayer networks. PMID:29694387

Finding overlapping communities in multilayer networks.

PubMed

Liu, Weiyi; Suzumura, Toyotaro; Ji, Hongyu; Hu, Guangmin

2018-01-01

Finding communities in multilayer networks is a vital step in understanding the structure and dynamics of these layers, where each layer represents a particular type of relationship between nodes in the natural world. However, most community discovery methods for multilayer networks may ignore the interplay between layers or the unique topological structure in a layer. Moreover, most of them can only detect non-overlapping communities. In this paper, we propose a new community discovery method for multilayer networks, which leverages the interplay between layers and the unique topology in a layer to reveal overlapping communities. Through a comprehensive analysis of edge behaviors within and across layers, we first calculate the similarities for edges from the same layer and the cross layers. Then, by leveraging these similarities, we can construct a dendrogram for the multilayer networks that takes both the unique topological structure and the important interplay into consideration. Finally, by introducing a new community density metric for multilayer networks, we can cut the dendrogram to get the overlapping communities for these layers. By applying our method on both synthetic and real-world datasets, we demonstrate that our method has an accurate performance in discovering overlapping communities in multilayer networks.

SemaTyP: a knowledge graph based literature mining method for drug discovery.

PubMed

Sang, Shengtian; Yang, Zhihao; Wang, Lei; Liu, Xiaoxia; Lin, Hongfei; Wang, Jian

2018-05-30

Drug discovery is the process through which potential new medicines are identified. High-throughput screening and computer-aided drug discovery/design are the two main drug discovery methods for now, which have successfully discovered a series of drugs. However, development of new drugs is still an extremely time-consuming and expensive process. Biomedical literature contains important clues for the identification of potential treatments. It could support experts in biomedicine on their way towards new discoveries. Here, we propose a biomedical knowledge graph-based drug discovery method called SemaTyP, which discovers candidate drugs for diseases by mining published biomedical literature. We first construct a biomedical knowledge graph with the relations extracted from biomedical abstracts, then a logistic regression model is trained by learning the semantic types of paths of known drug therapies' existing in the biomedical knowledge graph, finally the learned model is used to discover drug therapies for new diseases. The experimental results show that our method could not only effectively discover new drug therapies for new diseases, but also could provide the potential mechanism of action of the candidate drugs. In this paper we propose a novel knowledge graph based literature mining method for drug discovery. It could be a supplementary method for current drug discovery methods.

No Limit: Exploring the Science of the Universe

ScienceCinema

Meinecke, Jena; Remington, Bruce; Zylstra, Alex; Falcone, Roger; Rinderknecht, Hans; Casner, Alexis

2018-06-13

Scientists who conduct unique, cutting-edge Discovery Science experiments on Lawrence Livermore National Laboratory’s National Ignition Facility (NIF) describe the excitement of doing research on the world’s largest and highest-energy laser system.

Interspecies chimeras.

PubMed

Suchy, Fabian; Nakauchi, Hiromitsu

2018-05-30

By probing early embryogenesis and regeneration, interspecies chimeras provide a unique platform for discovery and clinical use. Although efficient generation of human:animal chimeric embryos remains elusive, recent advancements attempt to overcome incompatibilities in xenogeneic development and transplantation. Copyright © 2018 Elsevier Ltd. All rights reserved.

Towards building a disease-phenotype knowledge base: extracting disease-manifestation relationship from literature

PubMed Central

Xu, Rong; Li, Li; Wang, QuanQiu

2013-01-01

Motivation: Systems approaches to studying phenotypic relationships among diseases are emerging as an active area of research for both novel disease gene discovery and drug repurposing. Currently, systematic study of disease phenotypic relationships on a phenome-wide scale is limited because large-scale machine-understandable disease–phenotype relationship knowledge bases are often unavailable. Here, we present an automatic approach to extract disease–manifestation (D-M) pairs (one specific type of disease–phenotype relationship) from the wide body of published biomedical literature. Data and Methods: Our method leverages external knowledge and limits the amount of human effort required. For the text corpus, we used 119 085 682 MEDLINE sentences (21 354 075 citations). First, we used D-M pairs from existing biomedical ontologies as prior knowledge to automatically discover D-M–specific syntactic patterns. We then extracted additional pairs from MEDLINE using the learned patterns. Finally, we analysed correlations between disease manifestations and disease-associated genes and drugs to demonstrate the potential of this newly created knowledge base in disease gene discovery and drug repurposing. Results: In total, we extracted 121 359 unique D-M pairs with a high precision of 0.924. Among the extracted pairs, 120 419 (99.2%) have not been captured in existing structured knowledge sources. We have shown that disease manifestations correlate positively with both disease-associated genes and drug treatments. Conclusions: The main contribution of our study is the creation of a large-scale and accurate D-M phenotype relationship knowledge base. This unique knowledge base, when combined with existing phenotypic, genetic and proteomic datasets, can have profound implications in our deeper understanding of disease etiology and in rapid drug repurposing. Availability: http://nlp.case.edu/public/data/DMPatternUMLS/ Contact: rxx@case.edu PMID:23828786

Genome Wide Methylome Alterations in Lung Cancer.

PubMed

Mullapudi, Nandita; Ye, Bin; Suzuki, Masako; Fazzari, Melissa; Han, Weiguo; Shi, Miao K; Marquardt, Gaby; Lin, Juan; Wang, Tao; Keller, Steven; Zhu, Changcheng; Locker, Joseph D; Spivack, Simon D

2015-01-01

Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)-non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.

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

Graphite from the University of Idaho Thermolyzed Asphalt Reaction (GUITAR): Fundamental Electrochemical Characterizations

NASA Astrophysics Data System (ADS)

Gyan, Isaiah Owusu

This dissertation details electrochemical characterization of GUITAR (Graphite from the University of Idaho Thermolyzed Asphalt Reaction), a new allotrope of carbon. Applications based on fundamental electrochemical properties of this material are also presented. The dissertation is presented in five chapters. Chapter one presents a summary of the discovery and physical characterizations of GUITAR and how its physical properties position it among carbon materials. In chapter two, fundamental electrochemical properties covering aqueous potential window and electron transfer kinetics with common dissolved redox couples are presented. This chapter highlights significant electrochemical differences between GUITAR and other sp2 carbon materials, notably, fast electron transfer across basal plane GUITAR, contrary to reports at basal planes of graphite and graphene electrodes. In chapter three, the concept of electron transfer facility is extended with biologically relevant molecules. GUITAR is shown to be suitable for biosensing with properties such as; facile electron transfer, low detection limit, high resistance to fouling and stability to anodic regeneration procedures. Chapter four presents further exploration of GUITAR's wide cathodic potential limits in other aqueous electrolytes and preliminary studies towards the exploitation of this property in the negative half of vanadium redox flow battery, where GUITAR-based electrodes are expected to increase coulombic efficiency and increase battery performance due to low hydrogen evolution. Chapter five concludes this dissertation with point-by-point presentation of significant discoveries that highlights GUITAR's uniqueness. This chapter also describes how the various fundamental electrochemical properties of GUITAR make it useful for various applications.

New cancer diagnostics and therapeutics from a ninth 'hallmark of cancer': symmetric self-renewal by mutated distributed stem cells.

PubMed

Sherley, James L

2013-11-01

A total of eight cellular alterations associated with human carcinogenesis have been framed as the 'hallmarks of cancer'. This representation overlooks a ninth hallmark of cancer: the requirement for tumor-originating distributed stem cells to shift sufficiently from asymmetric to symmetric self-renewal kinetics for attainment of the high cell production rate necessary to form clinically significant tumors within a human lifespan. Overlooking this ninth hallmark costs opportunities for discovery of more selective molecular targets for development of improved cancer therapeutics and missing cancer stem cell biomarkers of greater specificity. Here, the biological basis for the ninth hallmark of cancer is considered toward highlighting its importance in human carcinogenesis and, as such, its potential for revealing unique molecules for targeting cancer diagnostics and therapeutics.

Functional materials from cellulose-derived liquid-crystal templates.

PubMed

Giese, Michael; Blusch, Lina K; Khan, Mostofa K; MacLachlan, Mark J

2015-03-02

Cellulose nanocrystals (CNCs), known for more than 50 years, have attracted attention because of their unique properties such as high specific strength and modulus, high surface area, and fascinating optical properties. Just recently, however, their potential in supramolecular templating was identified by making use of their self-assembly behavior in aqueous dispersions in the presence of compatible precursors. The combination of the mesoporosity, photonic properties, and chiral nematic order of the materials, which are available as freestanding films, has led to a significant number of interesting and promising discoveries towards new functional materials. This Review summarizes the use of cellulose derivatives, especially CNCs, as novel templates and gives an overview of the recent developments toward new functional materials. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

REVIEWS OF TOPICAL PROBLEMS: Experimental tests of general relativity: recent progress and future directions

NASA Astrophysics Data System (ADS)

Turyshev, S. G.

2009-01-01

Einstein's general theory of relativity is the standard theory of gravity, especially where the needs of astronomy, astrophysics, cosmology, and fundamental physics are concerned. As such, this theory is used for many practical purposes involving spacecraft navigation, geodesy, and time transfer. We review the foundations of general relativity, discuss recent progress in tests of relativistic gravity, and present motivations for the new generation of high-accuracy tests of new physics beyond general relativity. Space-based experiments in fundamental physics are presently capable of uniquely addressing important questions related to the fundamental laws of nature. We discuss the advances in our understanding of fundamental physics that are anticipated in the near future and evaluate the discovery potential of a number of recently proposed space-based gravitational experiments.

Boronic acid-containing CXCR1/2 antagonists: optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model

PubMed Central

Maeda, Dean Y.; Peck, Angela M.; Schuler, Aaron D.; Quinn, Mark T.; Kirpotina, Liliya N.; Wicomb, Winston N.; Auten, Richard L.; Gundla, Rambabu; Zebala, John A.

2015-01-01

Blockade of undesired neutrophil migration to sites of inflammation remains an area of substantial pharmaceutical interest. To effect this blockade, a validated therapeutic target is antagonism of the chemokine receptor CXCR2. Herein we report the discovery of 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide 6, an antagonist with activity at both CXCR1 and CXCR2 receptors (IC50 values 31 and 21 nM, respectively). Compound 6 exhibited potent inhibition of neutrophil influx in a rat model of pulmonary inflammation, and is hypothesized to interact with a unique intracellular binding site on CXCR2. Compound 6 (SX-576) is undergoing further investigation as a potential therapy for pulmonary inflammation. PMID:25933594

Balmer Absorption Lines in FeLoBALs

NASA Astrophysics Data System (ADS)

Aoki, K.; Iwata, I.; Ohta, K.; Tamura, N.; Ando, M.; Akiyama, M.; Kiuchi, G.; Nakanishi, K.

2007-10-01

We discovered non-stellar Balmer absorption lines in two many-narrow-trough FeLoBALs (mntBALs) by the near-infrared spectroscopy with Subaru/CISCO. Presence of the non-stellar Balmer absorption lines is known to date only in the Seyfert galaxy NGC 4151; thus our discovery is the first cases for quasars. Since all known active galactic nuclei with Balmer absorption lines share similar characteristics, it is suggested that there is a population of BAL quasars which have unique structures at their nuclei or unique evolutionary phase.

Quantitative iTRAQ secretome analysis of Aspergillus niger reveals novel hydrolytic enzymes.

PubMed

Adav, Sunil S; Li, An A; Manavalan, Arulmani; Punt, Peter; Sze, Siu Kwan

2010-08-06

The natural lifestyle of Aspergillus niger made them more effective secretors of hydrolytic proteins and becomes critical when this species were exploited as hosts for the commercial secretion of heterologous proteins. The protein secretion profile of A. niger and its mutant at different pH was explored using iTRAQ-based quantitative proteomics approach coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). This study characterized 102 highly confident unique proteins in the secretome with zero false discovery rate based on decoy strategy. The iTRAQ technique identified and relatively quantified many hydrolyzing enzymes such as cellulases, hemicellulases, glycoside hydrolases, proteases, peroxidases, and protein translocating transporter proteins during fermentation. The enzymes have potential application in lignocellulosic biomass hydrolysis for biofuel production, for example, the cellulolytic and hemicellulolytic enzymes glucan 1,4-alpha-glucosidase, alpha-glucosidase C, endoglucanase, alpha l-arabinofuranosidase, beta-mannosidase, glycosyl hydrolase; proteases such as tripeptidyl-peptidase, aspergillopepsin, and other enzymes including cytochrome c oxidase, cytochrome c oxidase, glucose oxidase were highly expressed in A. niger and its mutant secretion. In addition, specific enzyme production can be stimulated by controlling pH of the culture medium. Our results showed comprehensive unique secretory protein profile of A. niger, its regulation at different pH, and the potential application of iTRAQ-based quantitative proteomics for the microbial secretome analysis.

A 2MASS/AllWISE Search for Extremely Red L Dwarfs: The Discovery of Several Likely L Type Members of β Pic, AB Dor, Tuc-Hor, Argus, and the Hyades

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

Schneider, Adam C.; Shkolnik, Evgenya L.; Windsor, James

Young brown dwarfs share many properties with directly imaged giant extrasolar planets. They therefore provide unique laboratories for investigating the full range of temperature and mass encompassed by the growing collection of planets discovered outside our Solar System. Furthermore, if they can be tied to a particular group of coeval stars, they also provide vital anchor points for low-mass empirical isochrones. We have developed a novel procedure for identifying such objects based on their unique 2MASS and AllWISE colors. Using our search criteria, we have identified 50 new, late-type L dwarf candidates, 47 of which are spectroscopically confirmed as Lmore » dwarfs with follow-up near-infrared spectroscopy. We evaluate the potential membership of these objects in nearby, young moving groups using their proper motions, photometric distance estimates, and spectroscopic indicators of youth, and find seven likely L-type members belonging to the β Pictoris moving group, the AB Doradus moving group, the Tucana-Horologium association, or the Argus association, in addition to several lower probability members. Also found are two late-type (L5 and L6) potential members of the nearby Hyades cluster (WISEA J043642.75+190134.8 and WISEA J044105.56+213001.5).« less

The unexpected discovery of the Mg(HMDS) 2 /MgCl 2 complex as a magnesium electrolyte for rechargeable magnesium batteries

DOE PAGES

Liao, Chen; Sa, Niya; Key, Baris; ...

2015-02-02

We developed a unique class of non-Grignard, aluminum-free magnesium electrolytes based on a simple mixture of magnesium compounds: magnesium hexamethyldisilazide (Mg(HMDS) 2) and magnesium chloride (MgCl 2).

Perspectives on NMR in drug discovery: a technique comes of age

PubMed Central

Pellecchia, Maurizio; Bertini, Ivano; Cowburn, David; Dalvit, Claudio; Giralt, Ernest; Jahnke, Wolfgang; James, Thomas L.; Homans, Steve W.; Kessler, Horst; Luchinat, Claudio; Meyer, Bernd; Oschkinat, Hartmut; Peng, Jeff; Schwalbe, Harald; Siegal, Gregg

2009-01-01

In the past decade, the potential of harnessing the ability of nuclear magnetic resonance (NMR) spectroscopy to monitor intermolecular interactions as a tool for drug discovery has been increasingly appreciated in academia and industry. In this Perspective, we highlight some of the major applications of NMR in drug discovery, focusing on hit and lead generation, and provide a critical analysis of its current and potential utility. PMID:19172689

Commentary: charting a course for success: excellence in clinical care and discovery in academic departments.

PubMed

Cooper, William O; Gitlin, Jonathan D

2011-05-01

The current shifts in academics not only invite new challenges but create previously unexplored opportunities for unique discoveries in health. Leaders in academic departments must consider changes in academic medicine as new courses to be charted rather than an inevitable shifting of the ground beneath them. Under this model, clinical excellence is coupled with discovery, where trainees, faculty, and patients and families are continually exposed to asking questions and identifying ways to move science forward to improve health. Academic pediatrics remains today a vibrant and exciting discipline with extraordinary leaders and committed trainees. We must continue to inspire on the voyage to excellence, keeping our eyes on the horizon and not the gathering storms. Copyright © by the Association of American medical Colleges.

General view of the underside of the Orbiter Discovery on ...

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

General view of the underside of the Orbiter Discovery on the port side looking toward the starboard side and slightly forward. Note the landing gear assemblies, the jack stands attached to the External Tank (ET) attach points in on the Orbiter/ET propellant interface plate and the black High-Temperature Reusable Surface Insulation. The varying degrees of darkness of the tiles is due to the age of the tiles, the more recently replaced tiles are darker than the older tiles. The pattern created by the tile replacement is unique to each orbiter and becomes their "fingerprint". This view was taken in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Changing the Scale and Efficiency of Chemical Warfare Countermeasure Discovery Using the Zebrafish

PubMed Central

Peterson, Randall T.; MacRae, Calum A.

2013-01-01

As the scope of potential chemical warfare agents grows rapidly and as the diversity of potential threat scenarios expands with non-state actors, so a need for innovative approaches to countermeasure development has emerged. In the last few years, the utility of the zebrafish as a model organism that is amenable to high-throughput screening has become apparent and this system has been applied to the unbiased discovery of chemical warfare countermeasures. This review summarizes the in vivo screening approach that has been pioneered in the countermeasure discovery arena, and highlights the successes to date as well as the potential challenges in moving the field forward. Importantly, the establishment of a zebrafish platform for countermeasure discovery would offer a rapid response system for the development of antidotes to the continuous stream of new potential chemical warfare agents. PMID:24273586

Recent Advances in Ultrathin Two-Dimensional Nanomaterials.

PubMed

Tan, Chaoliang; Cao, Xiehong; Wu, Xue-Jun; He, Qiyuan; Yang, Jian; Zhang, Xiao; Chen, Junze; Zhao, Wei; Han, Shikui; Nam, Gwang-Hyeon; Sindoro, Melinda; Zhang, Hua

2017-05-10

Since the discovery of mechanically exfoliated graphene in 2004, research on ultrathin two-dimensional (2D) nanomaterials has grown exponentially in the fields of condensed matter physics, material science, chemistry, and nanotechnology. Highlighting their compelling physical, chemical, electronic, and optical properties, as well as their various potential applications, in this Review, we summarize the state-of-art progress on the ultrathin 2D nanomaterials with a particular emphasis on their recent advances. First, we introduce the unique advances on ultrathin 2D nanomaterials, followed by the description of their composition and crystal structures. The assortments of their synthetic methods are then summarized, including insights on their advantages and limitations, alongside some recommendations on suitable characterization techniques. We also discuss in detail the utilization of these ultrathin 2D nanomaterials for wide ranges of potential applications among the electronics/optoelectronics, electrocatalysis, batteries, supercapacitors, solar cells, photocatalysis, and sensing platforms. Finally, the challenges and outlooks in this promising field are featured on the basis of its current development.

Beyond Agrobacterium-Mediated Transformation: Horizontal Gene Transfer from Bacteria to Eukaryotes.

PubMed

Lacroix, Benoît; Citovsky, Vitaly

2018-03-03

Besides the massive gene transfer from organelles to the nuclear genomes, which occurred during the early evolution of eukaryote lineages, the importance of horizontal gene transfer (HGT) in eukaryotes remains controversial. Yet, increasing amounts of genomic data reveal many cases of bacterium-to-eukaryote HGT that likely represent a significant force in adaptive evolution of eukaryotic species. However, DNA transfer involved in genetic transformation of plants by Agrobacterium species has traditionally been considered as the unique example of natural DNA transfer and integration into eukaryotic genomes. Recent discoveries indicate that the repertoire of donor bacterial species and of recipient eukaryotic hosts potentially are much wider than previously thought, including donor bacterial species, such as plant symbiotic nitrogen-fixing bacteria (e.g., Rhizobium etli) and animal bacterial pathogens (e.g., Bartonella henselae, Helicobacter pylori), and recipient species from virtually all eukaryotic clades. Here, we review the molecular pathways and potential mechanisms of these trans-kingdom HGT events and discuss their utilization in biotechnology and research.

Endophytic Fungi—Alternative Sources of Cytotoxic Compounds: A Review

PubMed Central

Uzma, Fazilath; Mohan, Chakrabhavi D.; Hashem, Abeer; Konappa, Narasimha M.; Rangappa, Shobith; Kamath, Praveen V.; Singh, Bhim P.; Mudili, Venkataramana; Gupta, Vijai K.; Siddaiah, Chandra N.; Chowdappa, Srinivas; Alqarawi, Abdulaziz A.; Abd_Allah, Elsayed F.

2018-01-01

Cancer is a major cause of death worldwide, with an increasing number of cases being reported annually. The elevated rate of mortality necessitates a global challenge to explore newer sources of anticancer drugs. Recent advancements in cancer treatment involve the discovery and development of new and improved chemotherapeutics derived from natural or synthetic sources. Natural sources offer the potential of finding new structural classes with unique bioactivities for cancer therapy. Endophytic fungi represent a rich source of bioactive metabolites that can be manipulated to produce desirable novel analogs for chemotherapy. This review offers a current and integrative account of clinically used anticancer drugs such as taxol, podophyllotoxin, camptothecin, and vinca alkaloids in terms of their mechanism of action, isolation from endophytic fungi and their characterization, yield obtained, and fungal strain improvement strategies. It also covers recent literature on endophytic fungal metabolites from terrestrial, mangrove, and marine sources as potential anticancer agents and emphasizes the findings for cytotoxic bioactive compounds tested against specific cancer cell lines. PMID:29755344

Stem cell therapy clinical research: A regulatory conundrum for academia.

PubMed

Nagpal, Anjali; Juttner, Chris; Hamilton-Bruce, Monica Anne; Rolan, Paul; Koblar, Simon A

2017-12-01

The encouraging pace of discovery and development in the field of regenerative medicine holds tremendous potential for bringing therapies to the clinic that may offer meaningful benefit to patients, particularly in diseases with no or suboptimal therapeutic options. Academic researchers will continue to play a critical role in developing concepts and therapies, thus determining whether regenerative medicine will be able to live up to this potential that clearly excites clinicians, researchers and patients alike. This review summarises recent developments in regulatory frameworks across different countries that aim to ensure adequate oversight of the development of regenerative medicine products, which are unique in structural and functional complexity when compared to traditional chemical drugs and fully characterised biological drugs. It discusses the implications of these developments for researchers aiming to make the challenging transition from laboratory to clinical development of these therapies and considers possible pragmatic solutions that could accelerate this process that is essential to maintain research credibility and ensure patient safety. Copyright © 2016 Elsevier B.V. All rights reserved.

Progress in bioleaching: part B: applications of microbial processes by the minerals industries.

PubMed

Brierley, Corale L; Brierley, James A

2013-09-01

This review presents developments and applications in bioleaching and mineral biooxidation since publication of a previous mini review in 2003 (Olson et al. Appl Microbiol Biotechnol 63:249-257, 2003). There have been discoveries of newly identified acidophilic microorganisms that have unique characteristics for effective bioleaching of sulfidic ores and concentrates. Progress has been made in understanding and developing bioleaching of copper from primary copper sulfide minerals, chalcopyrite, covellite, and enargite. These developments point to low oxidation-reduction potential in concert with thermophilic bacteria and archaea as a potential key to the leaching of these minerals. On the commercial front, heap bioleaching of nickel has been commissioned, and the mineral biooxidation pretreatment of sulfidic-refractory gold concentrates is increasingly used on a global scale to enhance precious metal recovery. New and larger stirred-tank reactors have been constructed since the 2003 review article. One biooxidation-heap process for pretreatment of sulfidic-refractory gold ores was also commercialized. A novel reductive approach to bioleaching nickel laterite minerals has been proposed.

Finding viable models in SUSY parameter spaces with signal specific discovery potential

NASA Astrophysics Data System (ADS)

Burgess, Thomas; Lindroos, Jan Øye; Lipniacka, Anna; Sandaker, Heidi

2013-08-01

Recent results from ATLAS giving a Higgs mass of 125.5 GeV, further constrain already highly constrained supersymmetric models such as pMSSM or CMSSM/mSUGRA. As a consequence, finding potentially discoverable and non-excluded regions of model parameter space is becoming increasingly difficult. Several groups have invested large effort in studying the consequences of Higgs mass bounds, upper limits on rare B-meson decays, and limits on relic dark matter density on constrained models, aiming at predicting superpartner masses, and establishing likelihood of SUSY models compared to that of the Standard Model vis-á-vis experimental data. In this paper a framework for efficient search for discoverable, non-excluded regions of different SUSY spaces giving specific experimental signature of interest is presented. The method employs an improved Markov Chain Monte Carlo (MCMC) scheme exploiting an iteratively updated likelihood function to guide search for viable models. Existing experimental and theoretical bounds as well as the LHC discovery potential are taken into account. This includes recent bounds on relic dark matter density, the Higgs sector and rare B-mesons decays. A clustering algorithm is applied to classify selected models according to expected phenomenology enabling automated choice of experimental benchmarks and regions to be used for optimizing searches. The aim is to provide experimentalist with a viable tool helping to target experimental signatures to search for, once a class of models of interest is established. As an example a search for viable CMSSM models with τ-lepton signatures observable with the 2012 LHC data set is presented. In the search 105209 unique models were probed. From these, ten reference benchmark points covering different ranges of phenomenological observables at the LHC were selected.

Drug Discovery in Fish, Flies, and Worms

PubMed Central

Strange, Kevin

2016-01-01

Abstract Nonmammalian model organisms such as the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the zebrafish Danio rerio provide numerous experimental advantages for drug discovery including genetic and molecular tractability, amenability to high-throughput screening methods and reduced experimental costs and increased experimental throughput compared to traditional mammalian models. An interdisciplinary approach that strategically combines the study of nonmammalian and mammalian animal models with diverse experimental tools has and will continue to provide deep molecular and genetic understanding of human disease and will significantly enhance the discovery and application of new therapies to treat those diseases. This review will provide an overview of C. elegans, Drosophila, and zebrafish biology and husbandry and will discuss how these models are being used for phenotype-based drug screening and for identification of drug targets and mechanisms of action. The review will also describe how these and other nonmammalian model organisms are uniquely suited for the discovery of drug-based regenerative medicine therapies. PMID:28053067

Integration of lyoplate based flow cytometry and computational analysis for standardized immunological biomarker discovery.

PubMed

Villanova, Federica; Di Meglio, Paola; Inokuma, Margaret; Aghaeepour, Nima; Perucha, Esperanza; Mollon, Jennifer; Nomura, Laurel; Hernandez-Fuentes, Maria; Cope, Andrew; Prevost, A Toby; Heck, Susanne; Maino, Vernon; Lord, Graham; Brinkman, Ryan R; Nestle, Frank O

2013-01-01

Discovery of novel immune biomarkers for monitoring of disease prognosis and response to therapy in immune-mediated inflammatory diseases is an important unmet clinical need. Here, we establish a novel framework for immunological biomarker discovery, comparing a conventional (liquid) flow cytometry platform (CFP) and a unique lyoplate-based flow cytometry platform (LFP) in combination with advanced computational data analysis. We demonstrate that LFP had higher sensitivity compared to CFP, with increased detection of cytokines (IFN-γ and IL-10) and activation markers (Foxp3 and CD25). Fluorescent intensity of cells stained with lyophilized antibodies was increased compared to cells stained with liquid antibodies. LFP, using a plate loader, allowed medium-throughput processing of samples with comparable intra- and inter-assay variability between platforms. Automated computational analysis identified novel immunophenotypes that were not detected with manual analysis. Our results establish a new flow cytometry platform for standardized and rapid immunological biomarker discovery with wide application to immune-mediated diseases.

Integration of Lyoplate Based Flow Cytometry and Computational Analysis for Standardized Immunological Biomarker Discovery

PubMed Central

Villanova, Federica; Di Meglio, Paola; Inokuma, Margaret; Aghaeepour, Nima; Perucha, Esperanza; Mollon, Jennifer; Nomura, Laurel; Hernandez-Fuentes, Maria; Cope, Andrew; Prevost, A. Toby; Heck, Susanne; Maino, Vernon; Lord, Graham; Brinkman, Ryan R.; Nestle, Frank O.

2013-01-01

Discovery of novel immune biomarkers for monitoring of disease prognosis and response to therapy in immune-mediated inflammatory diseases is an important unmet clinical need. Here, we establish a novel framework for immunological biomarker discovery, comparing a conventional (liquid) flow cytometry platform (CFP) and a unique lyoplate-based flow cytometry platform (LFP) in combination with advanced computational data analysis. We demonstrate that LFP had higher sensitivity compared to CFP, with increased detection of cytokines (IFN-γ and IL-10) and activation markers (Foxp3 and CD25). Fluorescent intensity of cells stained with lyophilized antibodies was increased compared to cells stained with liquid antibodies. LFP, using a plate loader, allowed medium-throughput processing of samples with comparable intra- and inter-assay variability between platforms. Automated computational analysis identified novel immunophenotypes that were not detected with manual analysis. Our results establish a new flow cytometry platform for standardized and rapid immunological biomarker discovery with wide application to immune-mediated diseases. PMID:23843942

Synthesis-Spectroscopy Roadmap Problems: Discovering Organic Chemistry

ERIC Educational Resources Information Center

Kurth, Laurie L.; Kurth, Mark J.

2014-01-01

Organic chemistry problems that interrelate and integrate synthesis with spectroscopy are presented. These synthesis-spectroscopy roadmap (SSR) problems uniquely engage second-year undergraduate organic chemistry students in the personal discovery of organic chemistry. SSR problems counter the memorize-or-bust strategy that many students tend to…

Revolutionary Science

PubMed Central

Fang, Ferric C.

2016-01-01

ABSTRACT On rare occasions in the history of science, remarkable discoveries transform human society and forever alter mankind’s view of the world. Examples of such discoveries include the heliocentric theory, Newtonian physics, the germ theory of disease, quantum theory, plate tectonics and the discovery that DNA carries genetic information. The science philosopher Thomas Kuhn famously described science as long periods of normality punctuated by times of crisis, when anomalous observations culminate in revolutionary changes that replace one paradigm with another. This essay examines several transformative discoveries in the light of Kuhn’s formulation. We find that each scientific revolution is unique, with disparate origins that may include puzzle solving, serendipity, inspiration, or a convergence of disparate observations. The causes of revolutionary science are varied and lack an obvious common structure. Moreover, it can be difficult to draw a clear distinction between so-called normal and revolutionary science. Revolutionary discoveries often emerge from basic science and are critically dependent on nonrevolutionary research. Revolutionary discoveries may be conceptual or technological in nature, lead to the creation of new fields, and have a lasting impact on many fields in addition to the field from which they emerge. In contrast to political revolutions, scientific revolutions do not necessarily require the destruction of the previous order. For humanity to continue to benefit from revolutionary discoveries, a broad palette of scientific inquiry with a particular emphasis on basic science should be supported. PMID:26933052

NCI Program for Natural Product Discovery: A Publicly-Accessible Library of Natural Product Fractions for High-Throughput Screening.

PubMed

Thornburg, Christopher C; Britt, John R; Evans, Jason R; Akee, Rhone K; Whitt, James A; Trinh, Spencer K; Harris, Matthew J; Thompson, Jerell R; Ewing, Teresa L; Shipley, Suzanne M; Grothaus, Paul G; Newman, David J; Schneider, Joel P; Grkovic, Tanja; O'Keefe, Barry R

2018-06-13

The US National Cancer Institute's (NCI) Natural Product Repository is one of the world's largest, most diverse collections of natural products containing over 230,000 unique extracts derived from plant, marine, and microbial organisms that have been collected from biodiverse regions throughout the world. Importantly, this national resource is available to the research community for the screening of extracts and the isolation of bioactive natural products. However, despite the success of natural products in drug discovery, compatibility issues that make extracts challenging for liquid handling systems, extended timelines that complicate natural product-based drug discovery efforts and the presence of pan-assay interfering compounds have reduced enthusiasm for the high-throughput screening (HTS) of crude natural product extract libraries in targeted assay systems. To address these limitations, the NCI Program for Natural Product Discovery (NPNPD), a newly launched, national program to advance natural product discovery technologies and facilitate the discovery of structurally defined, validated lead molecules ready for translation will create a prefractionated library from over 125,000 natural product extracts with the aim of producing a publicly-accessible, HTS-amenable library of >1,000,000 fractions. This library, representing perhaps the largest accumulation of natural-product based fractions in the world, will be made available free of charge in 384-well plates for screening against all disease states in an effort to reinvigorate natural product-based drug discovery.

Revolutionary Science.

PubMed

Casadevall, Arturo; Fang, Ferric C

2016-03-01

On rare occasions in the history of science, remarkable discoveries transform human society and forever alter mankind's view of the world. Examples of such discoveries include the heliocentric theory, Newtonian physics, the germ theory of disease, quantum theory, plate tectonics and the discovery that DNA carries genetic information. The science philosopher Thomas Kuhn famously described science as long periods of normality punctuated by times of crisis, when anomalous observations culminate in revolutionary changes that replace one paradigm with another. This essay examines several transformative discoveries in the light of Kuhn's formulation. We find that each scientific revolution is unique, with disparate origins that may include puzzle solving, serendipity, inspiration, or a convergence of disparate observations. The causes of revolutionary science are varied and lack an obvious common structure. Moreover, it can be difficult to draw a clear distinction between so-called normal and revolutionary science. Revolutionary discoveries often emerge from basic science and are critically dependent on nonrevolutionary research. Revolutionary discoveries may be conceptual or technological in nature, lead to the creation of new fields, and have a lasting impact on many fields in addition to the field from which they emerge. In contrast to political revolutions, scientific revolutions do not necessarily require the destruction of the previous order. For humanity to continue to benefit from revolutionary discoveries, a broad palette of scientific inquiry with a particular emphasis on basic science should be supported. Copyright © 2016 Casadevall and Fang.

Semantic Entity Pairing for Improved Data Validation and Discovery

NASA Astrophysics Data System (ADS)

Shepherd, Adam; Chandler, Cyndy; Arko, Robert; Chen, Yanning; Krisnadhi, Adila; Hitzler, Pascal; Narock, Tom; Groman, Robert; Rauch, Shannon

2014-05-01

One of the central incentives for linked data implementations is the opportunity to leverage the rich logic inherent in structured data. The logic embedded in semantic models can strengthen capabilities for data discovery and data validation when pairing entities from distinct, contextually-related datasets. The creation of links between the two datasets broadens data discovery by using the semantic logic to help machines compare similar entities and properties that exist on different levels of granularity. This semantic capability enables appropriate entity pairing without making inaccurate assertions as to the nature of the relationship. Entity pairing also provides a context to accurately validate the correctness of an entity's property values - an exercise highly valued by data management practices who seek to ensure the quality and correctness of their data. The Biological and Chemical Oceanography Data Management Office (BCO-DMO) semantically models metadata surrounding oceanographic researchcruises, but other sources outside of BCO-DMO exist that also model metadata about these same cruises. For BCO-DMO, the process of successfully pairing its entities to these sources begins by selecting sources that are decidedly trustworthy and authoritative for the modeled concepts. In this case, the Rolling Deck to Repository (R2R) program has a well-respected reputation among the oceanographic research community, presents a data context that is uniquely different and valuable, and semantically models its cruise metadata. Where BCO-DMO exposes the processed, analyzed data products generated by researchers, R2R exposes the raw shipboard data that was collected on the same research cruises. Interlinking these cruise entities expands data discovery capabilities but also allows for validating the contextual correctness of both BCO-DMO's and R2R's cruise metadata. Assessing the potential for a link between two datasets for a similar entity consists of aligning like properties and deciding on the appropriate semantic markup to describe the link. This highlights the desire for research organizations like BCO-DMO and R2R to ensure the complete accuracy of their exposed metadata, as it directly reflects on their reputations as successful and trustworthy source of research data. Therefore, data validation reaches beyond simple syntax of property values into contextual correctness. As a human process, this is a time-intensive task that does not scale well for finite human and funding resources. Therefore, to assess contextual correctness across datasets at different levels of granularity, BCO-DMO is developing a system that employs semantic technologies to aid the human process by organizing potential links and calculating a confidence coefficient as to the correctness of the potential pairing based on the distance between certain entity property values. The system allows humans to quickly scan potential links and their confidence coefficients for asserting persistence and correcting and investigating misaligned entity property values.

Hubble Space Telescope - Scientific, Technological and Social Contributions to the Public Discourse on Science

NASA Technical Reports Server (NTRS)

Wiseman, Jennifer

2012-01-01

The Hubble Space Telescope has unified the world with a sense of awe and wonder for 2 I years and is currently more scientifically powerful than ever. I will present highlights of discoveries made with the Hubble Space Telescope, including details of planetary weather, star formation, extra-solar planets, colliding galaxies, and a universe expanding with the acceleration of dark energy. I will also present the unique technical challenges and triumphs of this phenomenal observatory, and discuss how our discoveries in the cosmos affect our sense of human unity, significance, and wonder.

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

Insect-Specific Flaviviruses: A Systematic Review of Their Discovery, Host Range, Mode of Transmission, Superinfection Exclusion Potential and Genomic Organization

PubMed Central

Blitvich, Bradley J.; Firth, Andrew E.

2015-01-01

There has been a dramatic increase in the number of insect-specific flaviviruses (ISFs) discovered in the last decade. Historically, these viruses have generated limited interest due to their inability to infect vertebrate cells. This viewpoint has changed in recent years because some ISFs have been shown to enhance or suppress the replication of medically important flaviviruses in co-infected mosquito cells. Additionally, comparative studies between ISFs and medically important flaviviruses can provide a unique perspective as to why some flaviviruses possess the ability to infect and cause devastating disease in humans while others do not. ISFs have been isolated exclusively from mosquitoes in nature but the detection of ISF-like sequences in sandflies and chironomids indicates that they may also infect other dipterans. ISFs can be divided into two distinct phylogenetic groups. The first group currently consists of approximately 12 viruses and includes cell fusing agent virus, Kamiti River virus and Culex flavivirus. These viruses are phylogenetically distinct from all other known flaviviruses. The second group, which is apparently not monophyletic, currently consists of nine viruses and includes Chaoyang virus, Nounané virus and Lammi virus. These viruses phylogenetically affiliate with mosquito/vertebrate flaviviruses despite their apparent insect-restricted phenotype. This article provides a review of the discovery, host range, mode of transmission, superinfection exclusion ability and genomic organization of ISFs. This article also attempts to clarify the ISF nomenclature because some of these viruses have been assigned more than one name due to their simultaneous discoveries by independent research groups. PMID:25866904

Mitochondrial Flash: Integrative Reactive Oxygen Species and pH Signals in Cell and Organelle Biology

PubMed Central

Gong, Guohua; Wang, Xianhua; Wei-LaPierre, Lan; Cheng, Heping; Dirksen, Robert

2016-01-01

Abstract Significance: Recent breakthroughs in mitochondrial research have advanced, reshaped, and revolutionized our view of the role of mitochondria in health and disease. These discoveries include the development of novel tools to probe mitochondrial biology, the molecular identification of mitochondrial functional proteins, and the emergence of new concepts and mechanisms in mitochondrial function regulation. The discovery of “mitochondrial flash” activity has provided unique insights not only into real-time visualization of individual mitochondrial redox and pH dynamics in live cells but has also advanced understanding of the excitability, autonomy, and integration of mitochondrial function in vivo. Recent Advances: The mitochondrial flash is a transient and stochastic event confined within an individual mitochondrion and is observed in a wide range of organisms from plants to Caenorhabditis elegans to mammals. As flash events involve multiple transient concurrent changes within the mitochondrion (e.g., superoxide, pH, and membrane potential), a number of different mitochondrial targeted fluorescent indicators can detect flash activity. Accumulating evidence indicates that flash events reflect integrated snapshots of an intermittent mitochondrial process arising from mitochondrial respiration chain activity associated with the transient opening of the mitochondrial permeability transition pore. Critical Issues: We review the history of flash discovery, summarize current understanding of flash biology, highlight controversies regarding the relative roles of superoxide and pH signals during a flash event, and bring forth the integration of both signals in flash genesis. Future Directions: Investigations using flash as a biomarker and establishing its role in cell signaling pathway will move the field forward. Antioxid. Redox Signal. 25, 534–549. PMID:27245241

Phenomenological Research and Adolescent Female Sexuality: Discoveries and Applications

ERIC Educational Resources Information Center

Morrissey, Gabrielle; Higgs, Joy

2006-01-01

This paper presents research in female first sexual intercourse in Australia. Previous research in adolescent sexual behavior, particularly issues around first sexual intercourse behavior, has mainly utilized quantitative methodology. Our research adopted a qualitative approach to provide unique insight into adolescent sexual behavior, attitudes,…

Application of circular consensus sequencing and network analysis to characterize the bovine IgG repertoire

USDA-ARS?s Scientific Manuscript database

Background: Vertebrate immune systems generate diverse repertoires of antibodies capable of mediating response to a variety of antigens. Next generation sequencing methods provide unique approaches to a number of immuno-based research areas including antibody discovery and engineering, disease surve...

Ediacara Fossils

ERIC Educational Resources Information Center

Science Teacher, 2005

2005-01-01

Now, a research team from Virginia Tech and Nanjing Institute of Geology and Paleontology has discovered uniquely well-preserved fossil forms from 550-million-year-old rocks of the Ediacaran Period. The research appears in the Proceedings of the National Academy of Sciences. The discovery of these unusually preserved fossils reveals unprecedented…

Materials discovery guided by data-driven insights

NASA Astrophysics Data System (ADS)

Klintenberg, Mattias

As the computational power continues to grow systematic computational exploration has become an important tool for materials discovery. In this presentation the Electronic Structure Project (ESP/ELSA) will be discussed and a number of examples presented that show some of the capabilities of a data-driven methodology for guiding materials discovery. These examples include topological insulators, detector materials and 2D materials. ESP/ELSA is an initiative that dates back to 2001 and today contain many tens of thousands of materials that have been investigated using a robust and high accuracy electronic structure method (all-electron FP-LMTO) thus providing basic materials first-principles data for most inorganic compounds that have been structurally characterized. The web-site containing the ESP/ELSA data has as of today been accessed from more than 4,000 unique computers from all around the world.

Comparative Aspects of Osteosarcoma Pathogenesis in Humans and Dogs

PubMed Central

Fan, Timothy M.; Khanna, Chand

2015-01-01

Osteosarcoma (OS) is a primary and aggressive bone sarcoma affecting the skeleton of two principal species, human beings and canines. The biologic behavior of OS is conserved between people and dogs, and evidence suggests that fundamental discoveries in OS biology can be facilitated through detailed and comparative studies. In particular, the relative genetic homogeneity associated with specific dog breeds can provide opportunities to facilitate the discovery of key genetic drivers involved in OS pathogenesis, which, to-date, remain elusive. In this review, known causative factors that predispose to the development OS in human beings and dogs are summarized in detail. Based upon the commonalities shared in OS pathogenesis, it is likely that foundational discoveries in one species will be translationally relevant to the other and emphasizes the unique opportunities that might be gained through comparative scientific approaches. PMID:29061942

Bayesian Models Leveraging Bioactivity and Cytotoxicity Information for Drug Discovery

PubMed Central

Ekins, Sean; Reynolds, Robert C.; Kim, Hiyun; Koo, Mi-Sun; Ekonomidis, Marilyn; Talaue, Meliza; Paget, Steve D.; Woolhiser, Lisa K.; Lenaerts, Anne J.; Bunin, Barry A.; Connell, Nancy; Freundlich, Joel S.

2013-01-01

SUMMARY Identification of unique leads represents a significant challenge in drug discovery. This hurdle is magnified in neglected diseases such as tuberculosis. We have leveraged public high-throughput screening (HTS) data, to experimentally validate virtual screening approach employing Bayesian models built with bioactivity information (single-event model) as well as bioactivity and cytotoxicity information (dual-event model). We virtually screen a commercial library and experimentally confirm actives with hit rates exceeding typical HTS results by 1-2 orders of magnitude. The first dual-event Bayesian model identified compounds with antitubercular whole-cell activity and low mammalian cell cytotoxicity from a published set of antimalarials. The most potent hit exhibits the in vitro activity and in vitro/in vivo safety profile of a drug lead. These Bayesian models offer significant economies in time and cost to drug discovery. PMID:23521795

Nonpeptidic Delta (δ) Opioid Agonists and Antagonists of the Diarylmethylpiperazine Class: What Have We Learned?

NASA Astrophysics Data System (ADS)

Calderon, Silvia N.

The discovery of the selective delta (δ) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, represented a major advance in the field of δ-opioid ligands. Extensive research has recently been performed to uncover the structure-activity relationships (SAR) of this class of ligands, thereby providing valuable tools for the pharmacological characterization of the δ opioid receptor. This review focuses on the SAR of this unique series of ligands, and provides an overview of the various chemical routes that have been developed and optimized through the years to allow the syntheses of these ligands on a multigram scale. The search for selective δ opioid agonists and antagonists, as well as for those with mixed opioid agonist properties with potential therapeutic value, continues. Several questions regarding the interaction at the molecular level of diphenylmethylpiperazine derivatives and related analogs with opioid receptors and in particular with the δ opioid system still remain unanswered. Indeed, the development and pharmacological characterization of novel nonpeptidic δ opioid ligands remains an active area of research, as it may provide a better understanding of the role of this receptor in multiple disease states and disorders.

Inorganic Nitrite Therapy: Historical perspective and future directions

PubMed Central

Kevil, Christopher G.; Kolluru, Gopi K.; Pattillo, Christopher B.; Giordano, Tony

2015-01-01

Over the past several years, investigators studying nitric oxide (NO) biology and metabolism have come to learn that the one electron oxidation product of NO, nitrite anion, serves as a unique player in modulating tissue NO bioavailability. Numerous studies have examined how this oxidized metabolite of NO can act as a salvage pathway for maintaining NO equivalents through multiple reduction mechanisms in permissive tissue environments. Moreover, it is now clear that nitrite anion production and distribution throughout the body can act in an endocrine manner to augment NO bioavailability that is important for physiological and pathological processes. These discoveries have led to renewed hope and efforts for an effective NO based therapeutic agent through the unique action of sodium nitrite as an NO pro-drug. More recent studies also indicate that sodium nitrate may also increase plasma nitrite levels via the enterosalivary circulatory system resulting in nitrate reduction to nitrite by microorganisms found within the oral cavity. In this review, we discuss the importance of nitrite anion in several disease models along with an appraisal of sodium nitrite therapy in the clinic, potential caveats of such clinical uses, and future possibilities of nitrite based therapies. PMID:21619929

Shared mission operations concept

NASA Technical Reports Server (NTRS)

Spradlin, Gary L.; Rudd, Richard P.; Linick, Susan H.

1994-01-01

Historically, new JPL flight projects have developed a Mission Operations System (MOS) as unique as their spacecraft, and have utilized a mission-dedicated staff to monitor and control the spacecraft through the MOS. NASA budgetary pressures to reduce mission operations costs have led to the development and reliance on multimission ground system capabilities. The use of these multimission capabilities has not eliminated an ongoing requirement for a nucleus of personnel familiar with a given spacecraft and its mission to perform mission-dedicated operations. The high cost of skilled personnel required to support projects with diverse mission objectives has the potential for significant reduction through shared mission operations among mission-compatible projects. Shared mission operations are feasible if: (1) the missions do not conflict with one another in terms of peak activity periods, (2) a unique MOS is not required, and (3) there is sufficient similarity in the mission profiles so that greatly different skills would not be required to support each mission. This paper will further develop this shared mission operations concept. We will illustrate how a Discovery-class mission would enter a 'partner' relationship with the Voyager Project, and can minimize MOS development and operations costs by early and careful consideration of mission operations requirements.

Metabolomic profiling in perinatal asphyxia: a promising new field.

PubMed

Denihan, Niamh M; Boylan, Geraldine B; Murray, Deirdre M

2015-01-01

Metabolomics, the latest "omic" technology, is defined as the comprehensive study of all low molecular weight biochemicals, "metabolites" present in an organism. As a systems biology approach, metabolomics has huge potential to progress our understanding of perinatal asphyxia and neonatal hypoxic-ischaemic encephalopathy, by uniquely detecting rapid biochemical pathway alterations in response to the hypoxic environment. The study of metabolomic biomarkers in the immediate neonatal period is not a trivial task and requires a number of specific considerations, unique to this disease and population. Recruiting a clearly defined cohort requires standardised multicentre recruitment with broad inclusion criteria and the participation of a range of multidisciplinary staff. Minimally invasive biospecimen collection is a priority for biomarker discovery. Umbilical cord blood presents an ideal medium as large volumes can be easily extracted and stored and the sample is not confounded by postnatal disease progression. Pristine biobanking and phenotyping are essential to ensure the validity of metabolomic findings. This paper provides an overview of the current state of the art in the field of metabolomics in perinatal asphyxia and neonatal hypoxic-ischaemic encephalopathy. We detail the considerations required to ensure high quality sampling and analysis, to support scientific progression in this important field.

Metabolomic Profiling in Perinatal Asphyxia: A Promising New Field

PubMed Central

Denihan, Niamh M.; Boylan, Geraldine B.; Murray, Deirdre M.

2015-01-01

Metabolomics, the latest “omic” technology, is defined as the comprehensive study of all low molecular weight biochemicals, “metabolites” present in an organism. As a systems biology approach, metabolomics has huge potential to progress our understanding of perinatal asphyxia and neonatal hypoxic-ischaemic encephalopathy, by uniquely detecting rapid biochemical pathway alterations in response to the hypoxic environment. The study of metabolomic biomarkers in the immediate neonatal period is not a trivial task and requires a number of specific considerations, unique to this disease and population. Recruiting a clearly defined cohort requires standardised multicentre recruitment with broad inclusion criteria and the participation of a range of multidisciplinary staff. Minimally invasive biospecimen collection is a priority for biomarker discovery. Umbilical cord blood presents an ideal medium as large volumes can be easily extracted and stored and the sample is not confounded by postnatal disease progression. Pristine biobanking and phenotyping are essential to ensure the validity of metabolomic findings. This paper provides an overview of the current state of the art in the field of metabolomics in perinatal asphyxia and neonatal hypoxic-ischaemic encephalopathy. We detail the considerations required to ensure high quality sampling and analysis, to support scientific progression in this important field. PMID:25802843

Falsirhodobacter sp. alg1 Harbors Single Homologs of Endo and Exo-Type Alginate Lyases Efficient for Alginate Depolymerization

PubMed Central

Takahashi, Mami; Tanaka, Reiji; Miyake, Hideo; Shibata, Toshiyuki; Chow, Seinen; Kuroda, Kouichi; Ueda, Mitsuyoshi; Takeyama, Haruko

2016-01-01

Alginate-degrading bacteria play an important role in alginate degradation by harboring highly efficient and unique alginolytic genes. Although the general mechanism for alginate degradation by these bacteria is fairly understood, much is still required to fully exploit them. Here, we report the isolation of a novel strain, Falsirhodobacter sp. alg1, the first report for an alginate-degrading bacterium from the family Rhodobacteraceae. Genome sequencing reveals that strain alg1 harbors a primary alginate degradation pathway with only single homologs of an endo- and exo-type alginate lyase, AlyFRA and AlyFRB, which is uncommon among such bacteria. Subsequent functional analysis showed that both enzymes were extremely efficient to depolymerize alginate suggesting evolutionary interests in the acquirement of these enzymes. The exo-type alginate lyase, AlyFRB in particular could depolymerize alginate without producing intermediate products making it a highly efficient enzyme for the production of 4-deoxy-L-erythro-5-hexoseulose uronic acid (DEH). Based on our findings, we believe that the discovery of Falsirhodobacter sp. alg1 and its alginolytic genes hints at the potentiality of a more diverse and unique population of alginate-degrading bacteria. PMID:27176711

The Diagnostic and Prognostic Role of microRNA in Colorectal Cancer - a Comprehensive review.

PubMed

Mazeh, Haggi; Mizrahi, Ido; Ilyayev, Nadia; Halle, David; Brücher, Bjoern; Bilchik, Anton; Protic, Mladjan; Daumer, Martin; Stojadinovic, Alexander; Itzhak, Avital; Nissan, Aviram

2013-01-01

The discovery of microRNA, a group of regulatory short RNA fragments, has added a new dimension to the diagnosis and management of neoplastic diseases. Differential expression of microRNA in a unique pattern in a wide range of tumor types enables researches to develop a microRNA-based assay for source identification of metastatic disease of unknown origin. This is just one example of many microRNA-based cancer diagnostic and prognostic assays in various phases of clinical research.Since colorectal cancer (CRC) is a phenotypic expression of multiple molecular pathways including chromosomal instability (CIN), micro-satellite instability (MIS) and CpG islands promoter hypermethylation (CIMP), there is no one-unique pattern of microRNA expression expected in this disease and indeed, there are multiple reports published, describing different patterns of microRNA expression in CRC.The scope of this manuscript is to provide a comprehensive review of the scientific literature describing the dysregulation of and the potential role for microRNA in the management of CRC. A Pubmed search was conducted using the following MeSH terms, "microRNA" and "colorectal cancer". Of the 493 publications screened, there were 57 papers describing dysregulation of microRNA in CRC.

Top-down Proteomics in Health and Disease: Challenges and Opportunities

PubMed Central

Gregorich, Zachery R.; Ge, Ying

2014-01-01

Proteomics is essential for deciphering how molecules interact as a system and for understanding the functions of cellular systems in human disease; however, the unique characteristics of the human proteome, which include a high dynamic range of protein expression and extreme complexity due to a plethora of post-translational modifications (PTMs) and sequence variations, make such analyses challenging. An emerging “top-down” mass spectrometry (MS)-based proteomics approach, which provides a “bird’s eye” view of all proteoforms, has unique advantages for the assessment of PTMs and sequence variations. Recently, a number of studies have showcased the potential of top-down proteomics for unraveling of disease mechanisms and discovery of new biomarkers. Nevertheless, the top-down approach still faces significant challenges in terms of protein solubility, separation, and the detection of large intact proteins, as well as the under-developed data analysis tools. Consequently, new technological developments are urgently needed to advance the field of top-down proteomics. Herein, we intend to provide an overview of the recent applications of top-down proteomics in biomedical research. Moreover, we will outline the challenges and opportunities facing top-down proteomics strategies aimed at understanding and diagnosing human diseases. PMID:24723472

Cryptotephras: the revolution in correlation and precision dating1

PubMed Central

DAVIES, SIWAN M

2015-01-01

From its Icelandic origins in the study of visible tephra horizons, tephrochronology took a remarkable step in the late 1980 s with the discovery of a ca. 4300-year-old microscopic ash layer in a Scottish peat bog. Since then, the search for these cryptotephra deposits in distal areas has gone from strength to strength. Indeed, a recent discovery demonstrates how a few fine-grained glass shards from an Alaskan eruption have been dispersed more than 7000 km to northern Europe. Instantaneous deposition of geochemically distinct volcanic ash over such large geographical areas gives rise to a powerful correlation tool with considerable potential for addressing a range of scientific questions. A prerequisite of this work is the establishment of regional tephrochronological frameworks that include well-constrained age estimates and robust geochemical signatures for each deposit. With distal sites revealing a complex record of previously unknown volcanic events, frameworks are regularly revised, and it has become apparent that some closely timed eruptions have similar geochemical signatures. The search for unique and robust geochemical fingerprints thus hinges on rigorous analysis by electron microprobe and laser ablation-inductively coupled plasma-mass spectrometry. Historical developments and significant breakthroughs are presented to chart the revolution in correlation and precision dating over the last 50 years using tephrochronology and cryptotephrochronology. PMID:27512240

A targeted boost-and-sort immunization strategy using Escherichia coli BamA identifies rare growth inhibitory antibodies.

PubMed

Vij, Rajesh; Lin, Zhonghua; Chiang, Nancy; Vernes, Jean-Michel; Storek, Kelly M; Park, Summer; Chan, Joyce; Meng, Y Gloria; Comps-Agrar, Laetitia; Luan, Peng; Lee, Sophia; Schneider, Kellen; Bevers, Jack; Zilberleyb, Inna; Tam, Christine; Koth, Christopher M; Xu, Min; Gill, Avinash; Auerbach, Marcy R; Smith, Peter A; Rutherford, Steven T; Nakamura, Gerald; Seshasayee, Dhaya; Payandeh, Jian; Koerber, James T

2018-05-08

Outer membrane proteins (OMPs) in Gram-negative bacteria are essential for a number of cellular functions including nutrient transport and drug efflux. Escherichia coli BamA is an essential component of the OMP β-barrel assembly machinery and a potential novel antibacterial target that has been proposed to undergo large (~15 Å) conformational changes. Here, we explored methods to isolate anti-BamA monoclonal antibodies (mAbs) that might alter the function of this OMP and ultimately lead to bacterial growth inhibition. We first optimized traditional immunization approaches but failed to identify mAbs that altered cell growth after screening >3000 hybridomas. We then developed a "targeted boost-and-sort" strategy that combines bacterial cell immunizations, purified BamA protein boosts, and single hybridoma cell sorting using amphipol-reconstituted BamA antigen. This unique workflow improves the discovery efficiency of FACS + mAbs by >600-fold and enabled the identification of rare anti-BamA mAbs with bacterial growth inhibitory activity in the presence of a truncated lipopolysaccharide layer. These mAbs represent novel tools for dissecting the BamA-mediated mechanism of β-barrel folding and our workflow establishes a new template for the efficient discovery of novel mAbs against other highly dynamic membrane proteins.

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

Cardio-Oncology: How New Targeted Cancer Therapies and Precision Medicine Can Inform Cardiovascular Discovery

PubMed Central

Bellinger, Andrew M.; Arteaga, Carlos L.; Force, Thomas; Humphreys, Benjamin D.; Demetri, George D.; Druker, Brian J.; Moslehi, Javid

2016-01-01

Cardio-Oncology (the cardiovascular care of cancer patients) has developed as a new translational and clinical field based on the expanding repertoire of mechanism-based cancer therapies. While these therapies have changed the natural course of many cancers, several may also lead to cardiovascular complications. Many new anti-cancer drugs approved over the past decade are “targeted” kinase inhibitors that interfere with intracellular signaling contributing to tumor progression. Unexpected cardiovascular and cardio-metabolic effects following patient treatment with these inhibitors have provided unique insights into the role of kinases in human cardiovascular biology. Today, an ever-expanding number of cancer therapies targeting novel kinases as well as other specific cellular and metabolic pathways are being developed and tested in oncology clinical trials. Some of these drugs may impact the cardiovascular system in detrimental and others perhaps in beneficial ways. We propose that the numerous ongoing oncology clinical trials are an opportunity for closer collaboration between cardiologists and oncologists to study the cardiovascular and cardio-metabolic changes due to modulation of these pathways in patients. In this regard, cardio-oncology represents an opportunity and a novel platform for basic and translational investigation and can serve as a potential avenue for optimization of anti-cancer therapies as well as for cardiovascular research and drug discovery. PMID:26644247

Metabolomics-based chemotaxonomy of root endophytic fungi for natural products discovery.

PubMed

Maciá-Vicente, Jose G; Shi, Yan-Ni; Cheikh-Ali, Zakaria; Grün, Peter; Glynou, Kyriaki; Kia, Sevda Haghi; Piepenbring, Meike; Bode, Helge B

2018-03-01

Fungi are prolific producers of natural products routinely screened for biotechnological applications, and those living endophytically within plants attract particular attention because of their purported chemical diversity. However, the harnessing of their biosynthetic potential is hampered by a large and often cryptic phylogenetic and ecological diversity, coupled with a lack of large-scale natural products' dereplication studies. To guide efforts to discover new chemistries among root-endophytic fungi, we analyzed the natural products produced by 822 strains using an untargeted UPLC-ESI-MS/MS-based approach and linked the patterns of chemical features to fungal lineages. We detected 17 809 compounds of which 7951 were classified in 1992 molecular families, whereas the remaining were considered unique chemistries. Our approach allowed to annotate 1191 compounds with different degrees of accuracy, many of which had known fungal origins. Approximately 61% of the compounds were specific of a fungal order, and differences were observed across lineages in the diversity and characteristics of their chemistries. Chemical profiles also showed variable chemosystematic values across lineages, ranging from relative homogeneity to high heterogeneity among related fungi. Our results provide an extensive resource to dereplicate fungal natural products and may assist future discovery programs by providing a guide for the selection of target fungi. © 2018 Society for Applied Microbiology and John Wiley & Sons Ltd.

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.

Microfluidic cell culture systems for drug research.

PubMed

Wu, Min-Hsien; Huang, Song-Bin; Lee, Gwo-Bin

2010-04-21

In pharmaceutical research, an adequate cell-based assay scheme to efficiently screen and to validate potential drug candidates in the initial stage of drug discovery is crucial. In order to better predict the clinical response to drug compounds, a cell culture model that is faithful to in vivo behavior is required. With the recent advances in microfluidic technology, the utilization of a microfluidic-based cell culture has several advantages, making it a promising alternative to the conventional cell culture methods. This review starts with a comprehensive discussion on the general process for drug discovery and development, the role of cell culture in drug research, and the characteristics of the cell culture formats commonly used in current microfluidic-based, cell-culture practices. Due to the significant differences in several physical phenomena between microscale and macroscale devices, microfluidic technology provides unique functionality, which is not previously possible by using traditional techniques. In a subsequent section, the niches for using microfluidic-based cell culture systems for drug research are discussed. Moreover, some critical issues such as cell immobilization, medium pumping or gradient generation in microfluidic-based, cell-culture systems are also reviewed. Finally, some practical applications of microfluidic-based, cell-culture systems in drug research particularly those pertaining to drug toxicity testing and those with a high-throughput capability are highlighted.

Human Exploration and Development of Space: Strategic Plan

NASA Technical Reports Server (NTRS)

Branscome, Darrell (Editor); Allen, Marc (Editor); Bihner, William (Editor); Cooke, Douglas (Editor); Craig, Mark (Editor); Crouch, Matthew (Editor); Crouch, Roger (Editor); Flaherty, Chris (Editor); Haynes, Norman (Editor); Horowitz, Steven (Editor)

2001-01-01

In order to make possible the permanent extension of human presence beyond the bounds of Earth and enable historic improvements in our understanding of our solar system and the universe, and the quality of life, NASA must: (1) Undertake, in partnership with the scientific community, sustained international explorations throughout the inner solar system by integrated human/robotic expeditions; (2) Achieve breakthrough discoveries and technology developments through basic, applied, and commercial research in the unique venue of space--exploiting characteristics such as microgravity, vacuum, radiation, and location; (3) Establish safe and routine access to space in support of permanent commercial human operations in low-Earth orbit and ongoing exploration activities at one or more sites beyond Earth orbit; (4) Engage the private sector in the commercial development of space and enable the creation of new space industries generating new wealth for the US economy; and (5) Communicate the excitement and importance of the discovery of new worlds and the profound insights we will gain into the origins of life and the universe. In order to guide planning, the Human Exploration and Development of Space (HEDS) Enterprise has identified some potential future targets and goals (e.g. 'Design Reference Points') beginning with the near-term and extending to the far-term and beyond.

Medicinal applications of fullerenes

PubMed Central

Bakry, Rania; Vallant, Rainer M; Najam-ul-Haq, Muhammad; Rainer, Matthias; Szabo, Zoltan; Huck, Christian W; Bonn, Günther K

2007-01-01

Fullerenes have attracted considerable attention in different fields of science since their discovery in 1985. Investigations of physical, chemical and biological properties of fullerenes have yielded promising information. It is inferred that size, hydrophobicity, three-dimensionality and electronic configurations make them an appealing subject in medicinal chemistry. Their unique carbon cage structure coupled with immense scope for derivatization make them a potential therapeutic agent. The study of biological applications has attracted increasing attention despite the low solubility of carbon spheres in physiological media. The fullerene family, and especially C60, has appealing photo, electrochemical and physical properties, which can be exploited in various medical fields. Fullerene is able to fit inside the hydrophobic cavity of HIV proteases, inhibiting the access of substrates to the catalytic site of enzyme. It can be used as radical scavenger and antioxidant. At the same time, if exposed to light, fullerene can produce singlet oxygen in high quantum yields. This action, together with direct electron transfer from excited state of fullerene and DNA bases, can be used to cleave DNA. In addition, fullerenes have been used as a carrier for gene and drug delivery systems. Also they are used for serum protein profiling as MELDI material for biomarker discovery. In this review we report the aspects of medicinal applications of fullerenes. PMID:18203430

Cassini’s Discoveries at Saturn and the Proposed Cassini Solstice Mission

NASA Astrophysics Data System (ADS)

Pappalardo, R. T.; Spilker, L. J.; Mitchell, R. T.; Cuzzi, J.; Gombosi, T. I.; Ingersoll, A. P.; Lunine, J. I.

2009-12-01

Understanding of the Saturn system has been greatly enhanced by the Cassini-Huygens mission. Fundamental discoveries have altered our views of Saturn, Titan and the other icy satellites, the rings, and magnetosphere of the system. Key discoveries include: water-rich plumes emanating from the south pole of Enceladus; hints of possible activity on Dione and of rings around Rhea; a methane hydrological cycle on Titan complete with fluvial erosion, lakes, and seas of liquid methane and ethane; non-axisymmetric ring microstructure in all moderate optical depth rings; south polar vortices on Saturn; and a unique magnetosphere that shares characteristics with both Earth’s and Jupiter’s magnetospheres. These new discoveries are directly relevant to current Solar System science goals including: planet and satellite formation processes, formation of gas giants, the nature of organic material, the history of volatiles, habitable zones and processes for life, processes that shape planetary bodies, and evolution of exoplanets. The proposed 7-year Cassini Solstice Mission would address new questions that have arisen during the Cassini Prime and Equinox Missions, and would observe seasonal and temporal change in the Saturn system to prepare for future missions to Saturn, Titan, and Enceladus. The proposed Cassini Solstice Mission would provide new science in three ways. First, it would observe seasonally and temporally dependent processes on Saturn, Titan and other icy satellites, and within the rings and magnetosphere, in a hitherto unobserved seasonal phase from equinox to solstice. Second, it would address new questions that have arisen during the mission thus far, providing qualitatively new measurements (e.g. of Enceladus and Titan) which could not be accommodated in the earlier mission phases. Tthird, it would conduct a close-in mission phase at Saturn that would provide unique science including comparison to the Juno observations at Jupiter.

SACCHARIS: an automated pipeline to streamline discovery of carbohydrate active enzyme activities within polyspecific families and de novo sequence datasets.

PubMed

Jones, Darryl R; Thomas, Dallas; Alger, Nicholas; Ghavidel, Ata; Inglis, G Douglas; Abbott, D Wade

2018-01-01

Deposition of new genetic sequences in online databases is expanding at an unprecedented rate. As a result, sequence identification continues to outpace functional characterization of carbohydrate active enzymes (CAZymes). In this paradigm, the discovery of enzymes with novel functions is often hindered by high volumes of uncharacterized sequences particularly when the enzyme sequence belongs to a family that exhibits diverse functional specificities (i.e., polyspecificity). Therefore, to direct sequence-based discovery and characterization of new enzyme activities we have developed an automated in silico pipeline entitled: Sequence Analysis and Clustering of CarboHydrate Active enzymes for Rapid Informed prediction of Specificity (SACCHARIS). This pipeline streamlines the selection of uncharacterized sequences for discovery of new CAZyme or CBM specificity from families currently maintained on the CAZy website or within user-defined datasets. SACCHARIS was used to generate a phylogenetic tree of a GH43, a CAZyme family with defined subfamily designations. This analysis confirmed that large datasets can be organized into sequence clusters of manageable sizes that possess related functions. Seeding this tree with a GH43 sequence from Bacteroides dorei DSM 17855 (BdGH43b, revealed it partitioned as a single sequence within the tree. This pattern was consistent with it possessing a unique enzyme activity for GH43 as BdGH43b is the first described α-glucanase described for this family. The capacity of SACCHARIS to extract and cluster characterized carbohydrate binding module sequences was demonstrated using family 6 CBMs (i.e., CBM6s). This CBM family displays a polyspecific ligand binding profile and contains many structurally determined members. Using SACCHARIS to identify a cluster of divergent sequences, a CBM6 sequence from a unique clade was demonstrated to bind yeast mannan, which represents the first description of an α-mannan binding CBM. Additionally, we have performed a CAZome analysis of an in-house sequenced bacterial genome and a comparative analysis of B. thetaiotaomicron VPI-5482 and B. thetaiotaomicron 7330, to demonstrate that SACCHARIS can generate "CAZome fingerprints", which differentiate between the saccharolytic potential of two related strains in silico. Establishing sequence-function and sequence-structure relationships in polyspecific CAZyme families are promising approaches for streamlining enzyme discovery. SACCHARIS facilitates this process by embedding CAZyme and CBM family trees generated from biochemically to structurally characterized sequences, with protein sequences that have unknown functions. In addition, these trees can be integrated with user-defined datasets (e.g., genomics, metagenomics, and transcriptomics) to inform experimental characterization of new CAZymes or CBMs not currently curated, and for researchers to compare differential sequence patterns between entire CAZomes. In this light, SACCHARIS provides an in silico tool that can be tailored for enzyme bioprospecting in datasets of increasing complexity and for diverse applications in glycobiotechnology.

Improving and Accelerating Drug Development for Nervous System Disorders

PubMed Central

Pankevich, Diana E.; Altevogt, Bruce M.; Dunlop, John; Gage, Fred H.; Hyman, Steve E.

2014-01-01

Advances in the neurosciences have placed the field in the position where it is poised to significantly reduce the burden of nervous system disorders. However, drug discovery, development and translation for nervous system disorders still pose many unique challenges. The key scientific challenges can be summarized as follows: mechanisms of disease, target identification and validation, predictive models, biomarkers for patient stratification and as endpoints for clinical trials, clear regulatory pathways, reliability and reproducibility of published data, and data sharing and collaboration. To accelerate nervous system drug development the Institute of Medicine’s Forum on Neuroscience and Nervous System Disorders has hosted a series of public workshops that brought together representatives of industry, government (including both research funding and regulatory agencies), academia, and patient groups to discuss these challenges and offer potential strategies to improve the translational neuroscience. PMID:25442933

Mechanisms of fatty acid synthesis in marine fungus-like protists.

PubMed

Xie, Yunxuan; Wang, Guangyi

2015-10-01

Thraustochytrids are unicellular fungus-like protists and are well known for their ability to produce interesting nutraceutical compounds. Significant efforts have been made to improve their efficient production of important fatty acids (FAs), mostly by optimizing fermentation conditions and selecting highly productive thraustochytrid strains. Furthermore, noticeable improvements have been made in understanding the mechanism of FA biosynthesis, allowing for a better understanding of how thraustochytrids assemble these unique metabolites and how their biosynthesis is coupled with other related pathways. This review summarizes recent achievements on two major FA biosynthesis pathways, the standard pathway and the polyketide synthase pathway, and detail features of individual enzymes involved in FA biosynthesis, biotechnological advances in pathway engineering and enzyme characterization, and the discovery of other pathways that affect the efficiency of FA accumulation. Perspectives of biotechnological potential application of thraustochytrids are also discussed.

Atypical Dopamine Uptake Inhibitors that Provide Clues About Cocaine's Mechanism at the Dopamine Transporter

NASA Astrophysics Data System (ADS)

Hauck Newman, Amy; Katz, Jonathan L.

The dopamine transporter (DAT) has been a primary target for cocaine abuse/addiction medication discovery. However predicted addiction liability and limited clinical evaluation has provided a formidable challenge for development of these agents for human use. The unique and atypical pharmacological profile of the benztropine (BZT) class of dopamine uptake inhibitors, in preclinical models of cocaine effects and abuse, has encouraged further development of these agents. Moreover, in vivo studies have challenged the original DAT hypothesis and demonstrated that DAT occupancy and subsequent increases in dopamine produced by BZT analogues are significantly delayed and long lasting, as compared to cocaine. These important and distinctive elements are critical to the lack of abuse liability among BZT analogues, and improve their potential for development as treatments for cocaine abuse and possibly other neuropsychiatric disorders.

DRESS syndrome with thrombotic microangiopathy revealing a Noonan syndrome: Case report.

PubMed

Bobot, Mickaël; Coen, Matteo; Simon, Clémentine; Daniel, Laurent; Habib, Gilbert; Serratrice, Jacques

2018-04-01

The life-threatening drug rash with eosinophilia and systemic symptoms (DRESS) syndrome occurs most commonly after exposure to drugs, clinical features mimic those found with other serious systemic disorders. It is rarely associated with thrombotic microangiopathy. We describe the unique case of a 44-year-old man who simultaneously experienced DRESS syndrome with thrombotic microangiopathy (TMA) after a 5 days treatment with fluindione. Clinical evaluation leads to the discovery of an underlying lymphangiomatosis, due to a Noonan syndrome. The anticoagulant was withdrawn, and corticosteroids (1 mg/kg/day) and acenocoumarol were started. Clinical improvement ensued. At follow-up the patient is well. The association of DRESS with TMA is a rare condition; we believe that the presence of the underlying Noonan syndrome could have been the trigger. Moreover, we speculate about the potential interrelations between these entities.

Friction Stir Welding and NASA

NASA Technical Reports Server (NTRS)

Horton, K Renee

2016-01-01

Friction stir welding (FSW) is a solid state welding process with potential advantages for aerospace and automotive industries dealing with light alloys. Self-reacting friction stir welding (SR-FSW) is one variation of the FSW process being developed at the National Aeronautics and Space Administration (NASA) for use in the fabrication of propellant tanks and other areas used on the Space Launch System (SLS) NASA's SLS is an advanced, heavy-lift launch vehicle which will provide an entirely new capability for science and human exploration beyond Earth's orbit. The SLS will give the nation a safe, affordable and sustainable means of reaching beyond our current limits and open new doors of discovery from the unique vantage point of space This talk will elaborate on the SR-FSW process and it's usage on the current Space Launch System Program at NASA.

FCDD: A Database for Fruit Crops Diseases.

PubMed

Chauhan, Rupal; Jasrai, Yogesh; Pandya, Himanshu; Chaudhari, Suman; Samota, Chand Mal

2014-01-01

Fruit Crops Diseases Database (FCDD) requires a number of biotechnology and bioinformatics tools. The FCDD is a unique bioinformatics resource that compiles information about 162 details on fruit crops diseases, diseases type, its causal organism, images, symptoms and their control. The FCDD contains 171 phytochemicals from 25 fruits, their 2D images and their 20 possible sequences. This information has been manually extracted and manually verified from numerous sources, including other electronic databases, textbooks and scientific journals. FCDD is fully searchable and supports extensive text search. The main focus of the FCDD is on providing possible information of fruit crops diseases, which will help in discovery of potential drugs from one of the common bioresource-fruits. The database was developed using MySQL. The database interface is developed in PHP, HTML and JAVA. FCDD is freely available. http://www.fruitcropsdd.com/

Targeting the Allosteric Site of Oncoprotein BCR-ABL as an Alternative Strategy for Effective Target Protein Degradation.

PubMed

Shimokawa, Kenichiro; Shibata, Norihito; Sameshima, Tomoya; Miyamoto, Naoki; Ujikawa, Osamu; Nara, Hiroshi; Ohoka, Nobumichi; Hattori, Takayuki; Cho, Nobuo; Naito, Mikihiko

2017-10-12

Protein degradation technology based on hybrid small molecules is an emerging drug modality that has significant potential in drug discovery and as a unique method of post-translational protein knockdown in the field of chemical biology. Here, we report the first example of a novel and potent protein degradation inducer that binds to an allosteric site of the oncogenic BCR-ABL protein. BCR-ABL allosteric ligands were incorporated into the SNIPER (Specific and Nongenetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers) platform, and a series of in vitro biological assays of binding affinity, target protein modulation, signal transduction, and growth inhibition were carried out. One of the designed compounds, 6 (SNIPER(ABL)-062), showed desirable binding affinities against ABL1, cIAP1/2, and XIAP and consequently caused potent BCR-ABL degradation.

Microbial Communities as Experimental Units

PubMed Central

DAY, MITCH D.; BECK, DANIEL; FOSTER, JAMES A.

2011-01-01

Artificial ecosystem selection is an experimental technique that treats microbial communities as though they were discrete units by applying selection on community-level properties. Highly diverse microbial communities associated with humans and other organisms can have significant impacts on the health of the host. It is difficult to find correlations between microbial community composition and community-associated diseases, in part because it may be impossible to define a universal and robust species concept for microbes. Microbial communities are composed of potentially thousands of unique populations that evolved in intimate contact, so it is appropriate in many situations to view the community as the unit of analysis. This perspective is supported by recent discoveries using metagenomics and pangenomics. Artificial ecosystem selection experiments can be costly, but they bring the logical rigor of biological model systems to the emerging field of microbial community analysis. PMID:21731083

An Overview of ARPA-E

NASA Astrophysics Data System (ADS)

Rohlfing, Eric

2015-04-01

In less than six years, the Advanced Research Projects Agency - Energy (ARPA-E) has developed and implemented a unique model for the support of energy research and development. ARPA-E funds R&D on high-potential, high-impact energy technologies that are too early for private-sector investment. The agency focuses on technologies that can be meaningfully advanced with a modest investment over a defined period of time in order to catalyze the translation from scientific discovery to early-stage technology. The fundamental question asked of every ARPA-E program and project is: ``If it works, will it matter?'' This talk will discuss the ARPA-E model, including the development of focused technology programs and the active management of projects for technical and market success. Highlights of programs and projects of particular interest to the physics community will be given.

Systematic and biotechnological aspects of halophilic and halotolerant actinomycetes.

PubMed

Hamedi, Javad; Mohammadipanah, Fatemeh; Ventosa, Antonio

2013-01-01

More than 70 species of halotolerant and halophilic actinomycetes belonging to at least 24 genera have been validly described. Halophilic actinomycetes are a less explored source of actinomycetes for discovery of novel bioactive secondary metabolites. Degradation of aliphatic and aromatic organic compounds, detoxification of pollutants, production of new enzymes and other metabolites such as antibiotics, compatible solutes and polymers are other potential industrial applications of halophilic and halotolerant actinomycetes. Especially new bioactive secondary metabolites that are derived from only a small fraction of the investigated halophilic actinomycetes, mainly from marine habitats, have revealed the huge capacity of this physiological group in production of new bioactive chemical entities. Combined high metabolic capacities of actinomycetes and unique features related to extremophilic nature of the halophilic actinomycetes have conferred on them an influential role for future biotechnological applications.

Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model.

PubMed

Maeda, Dean Y; Peck, Angela M; Schuler, Aaron D; Quinn, Mark T; Kirpotina, Liliya N; Wicomb, Winston N; Auten, Richard L; Gundla, Rambabu; Zebala, John A

2015-06-01

Blockade of undesired neutrophil migration to sites of inflammation remains an area of substantial pharmaceutical interest. To effect this blockade, a validated therapeutic target is antagonism of the chemokine receptor CXCR2. Herein we report the discovery of 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide 6, an antagonist with activity at both CXCR1 and CXCR2 receptors (IC50 values 31 and 21 nM, respectively). Compound 6 exhibited potent inhibition of neutrophil influx in a rat model of pulmonary inflammation, and is hypothesized to interact with a unique intracellular binding site on CXCR2. Compound 6 (SX-576) is undergoing further investigation as a potential therapy for pulmonary inflammation. Copyright © 2015 Elsevier Ltd. All rights reserved.

A high-throughput platform for population reformatting and mammalian expression of phage display libraries to enable functional screening as full-length IgG.

PubMed

Xiao, Xiaodong; Douthwaite, Julie A; Chen, Yan; Kemp, Ben; Kidd, Sara; Percival-Alwyn, Jennifer; Smith, Alison; Goode, Kate; Swerdlow, Bonnie; Lowe, David; Wu, Herren; Dall'Acqua, William F; Chowdhury, Partha S

Phage display antibody libraries are a rich resource for discovery of potential therapeutic antibodies. Single-chain variable fragment (scFv) libraries are the most common format due to the efficient display of scFv by phage particles and the ease by which soluble scFv antibodies can be expressed for high-throughput screening. Typically, a cascade of screening and triaging activities are performed, beginning with the assessment of large numbers of E. coli-expressed scFv, and progressing through additional assays with individual reformatting of the most promising scFv to full-length IgG. However, use of high-throughput screening of scFv for the discovery of full-length IgG is not ideal because of the differences between these molecules. Furthermore, the reformatting step represents a bottle neck in the process because each antibody has to be handled individually to preserve the unique VH and VL pairing. These problems could be resolved if populations of scFv could be reformatted to full-length IgG before screening without disrupting the variable region pairing. Here, we describe a novel strategy that allows the reformatting of diverse populations of scFv from phage selections to full-length IgG in a batch format. The reformatting process maintains the diversity and variable region pairing with high fidelity, and the resulted IgG pool enables high-throughput expression of IgG in mammalian cells and cell-based functional screening. The improved process led to the discovery of potent candidates that are comparable or better than those obtained by traditional methods. This strategy should also be readily applicable to Fab-based phage libraries. Our approach, Screening in Product Format (SiPF), represents a substantial improvement in the field of antibody discovery using phage display.

Proposal and Evaluation of BLE Discovery Process Based on New Features of Bluetooth 5.0.

PubMed

Hernández-Solana, Ángela; Perez-Diaz-de-Cerio, David; Valdovinos, Antonio; Valenzuela, Jose Luis

2017-08-30

The device discovery process is one of the most crucial aspects in real deployments of sensor networks. Recently, several works have analyzed the topic of Bluetooth Low Energy (BLE) device discovery through analytical or simulation models limited to version 4.x. Non-connectable and non-scannable undirected advertising has been shown to be a reliable alternative for discovering a high number of devices in a relatively short time period. However, new features of Bluetooth 5.0 allow us to define a variant on the device discovery process, based on BLE scannable undirected advertising events, which results in higher discovering capacities and also lower power consumption. In order to characterize this new device discovery process, we experimentally model the real device behavior of BLE scannable undirected advertising events. Non-detection packet probability, discovery probability, and discovery latency for a varying number of devices and parameters are compared by simulations and experimental measurements. We demonstrate that our proposal outperforms previous works, diminishing the discovery time and increasing the potential user device density. A mathematical model is also developed in order to easily obtain a measure of the potential capacity in high density scenarios.

Proposal and Evaluation of BLE Discovery Process Based on New Features of Bluetooth 5.0

PubMed Central

2017-01-01

The device discovery process is one of the most crucial aspects in real deployments of sensor networks. Recently, several works have analyzed the topic of Bluetooth Low Energy (BLE) device discovery through analytical or simulation models limited to version 4.x. Non-connectable and non-scannable undirected advertising has been shown to be a reliable alternative for discovering a high number of devices in a relatively short time period. However, new features of Bluetooth 5.0 allow us to define a variant on the device discovery process, based on BLE scannable undirected advertising events, which results in higher discovering capacities and also lower power consumption. In order to characterize this new device discovery process, we experimentally model the real device behavior of BLE scannable undirected advertising events. Non-detection packet probability, discovery probability, and discovery latency for a varying number of devices and parameters are compared by simulations and experimental measurements. We demonstrate that our proposal outperforms previous works, diminishing the discovery time and increasing the potential user device density. A mathematical model is also developed in order to easily obtain a measure of the potential capacity in high density scenarios. PMID:28867786

Simultaneous Proteomic Discovery and Targeted Monitoring using Liquid Chromatography, Ion Mobility Spectrometry, and Mass Spectrometry*

PubMed Central

Burnum-Johnson, Kristin E.; Nie, Song; Casey, Cameron P.; Monroe, Matthew E.; Orton, Daniel J.; Ibrahim, Yehia M.; Gritsenko, Marina A.; Clauss, Therese R. W.; Shukla, Anil K.; Moore, Ronald J.; Purvine, Samuel O.; Shi, Tujin; Qian, Weijun; Liu, Tao; Baker, Erin S.; Smith, Richard D.

2016-01-01

Current proteomic approaches include both broad discovery measurements and quantitative targeted analyses. In many cases, discovery measurements are initially used to identify potentially important proteins (e.g. candidate biomarkers) and then targeted studies are employed to quantify a limited number of selected proteins. Both approaches, however, suffer from limitations. Discovery measurements aim to sample the whole proteome but have lower sensitivity, accuracy, and quantitation precision than targeted approaches, whereas targeted measurements are significantly more sensitive but only sample a limited portion of the proteome. Herein, we describe a new approach that performs both discovery and targeted monitoring (DTM) in a single analysis by combining liquid chromatography, ion mobility spectrometry and mass spectrometry (LC-IMS-MS). In DTM, heavy labeled target peptides are spiked into tryptic digests and both the labeled and unlabeled peptides are detected using LC-IMS-MS instrumentation. Compared with the broad LC-MS discovery measurements, DTM yields greater peptide/protein coverage and detects lower abundance species. DTM also achieved detection limits similar to selected reaction monitoring (SRM) indicating its potential for combined high quality discovery and targeted analyses, which is a significant step toward the convergence of discovery and targeted approaches. PMID:27670688

Volta and Galvani: New Electricity from Old. Experiment No. 22.

ERIC Educational Resources Information Center

Devons, Samuel

Presented is a descriptive account of Alessandro Volta's first notable success in 1775, the invention of a unique method of generating electricity. Luigi Galvani's announcement of his theory of "animal electricity" in 1972 is integrated into this interpretation of Volta's discoveries with electricity. Five experiments are described: (1)…

The Promise for Geomorphic Discovery in the South.

ERIC Educational Resources Information Center

Mossa, Joann

1998-01-01

Presents an overview of current geomorphic research in the southern United States. Conveys that the limited historical effort offers both challenges and opportunities for conducting geomorphic work in the region; much is unknown about these unique landscapes. States applied and theoretical geomorphology will benefit the society and future of the…

The Biological Basis of Learning and Individuality.

ERIC Educational Resources Information Center

Kandel, Eric R.; Hawkins, Robert D.

1992-01-01

Describes the biological basis of learning and individuality. Presents an overview of recent discoveries that suggest learning engages a simple set of rules that modify the strength of connection between neurons in the brain. The changes are cited as playing an important role in making each individual unique. (MCO)

A Guided Discovery Approach for Learning Glycolysis.

ERIC Educational Resources Information Center

Schultz, Emeric

1997-01-01

Argues that more attention should be given to teaching students how to learn the rudiments of specific metabolic pathways. This approach describes a unique way of learning the glycolytic pathway in stepwise fashion. The pedagogy involves clear rote components that are connected to a set of generalizations that develop and enhance important…

Convergence of Two Independent Roads Leads to Collaboration between Education and Neuroscience

ERIC Educational Resources Information Center

Koch, Kourtland R.; Timmerman, L.; Peiffer, Ann M.; Laurienti, Paul J.

2013-01-01

Collaboration is the foundation for innovative discoveries, as individuals with different backgrounds come together and combine their unique expertise. In the current article, an educational researcher and two neuroscientists relate their experiences in establishing a successful collaborative effort. The marriage of neuroscientific findings with…

Creativity--A Dynamic Approach to Industrial Education

ERIC Educational Resources Information Center

Markowitz, John, Jr.

1974-01-01

The author presents a number of unique programs and projects which have proved successful in one high school's woodworking and graphic arts classes in terms of motivating high student interest, growth in skills, good community relations--and a financial profit. The chief objective is self-discovery, the model is Outward Bound. (AJ)

Human Disease Models in Drosophila melanogaster and the Role of the Fly in Therapeutic Drug Discovery

PubMed Central

Pandey, Udai Bhan

2011-01-01

The common fruit fly, Drosophila melanogaster, is a well studied and highly tractable genetic model organism for understanding molecular mechanisms of human diseases. Many basic biological, physiological, and neurological properties are conserved between mammals and D. melanogaster, and nearly 75% of human disease-causing genes are believed to have a functional homolog in the fly. In the discovery process for therapeutics, traditional approaches employ high-throughput screening for small molecules that is based primarily on in vitro cell culture, enzymatic assays, or receptor binding assays. The majority of positive hits identified through these types of in vitro screens, unfortunately, are found to be ineffective and/or toxic in subsequent validation experiments in whole-animal models. New tools and platforms are needed in the discovery arena to overcome these limitations. The incorporation of D. melanogaster into the therapeutic discovery process holds tremendous promise for an enhanced rate of discovery of higher quality leads. D. melanogaster models of human diseases provide several unique features such as powerful genetics, highly conserved disease pathways, and very low comparative costs. The fly can effectively be used for low- to high-throughput drug screens as well as in target discovery. Here, we review the basic biology of the fly and discuss models of human diseases and opportunities for therapeutic discovery for central nervous system disorders, inflammatory disorders, cardiovascular disease, cancer, and diabetes. We also provide information and resources for those interested in pursuing fly models of human disease, as well as those interested in using D. melanogaster in the drug discovery process. PMID:21415126

Physics with e{sup +}e{sup -} Linear Colliders

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

Barklow, Timothy L

2003-05-05

We describe the physics potential of e{sup +}e{sup -} linear colliders in this report. These machines are planned to operate in the first phase at a center-of-mass energy of 500 GeV, before being scaled up to about 1 TeV. In the second phase of the operation, a final energy of about 2 TeV is expected. The machines will allow us to perform precision tests of the heavy particles in the Standard Model, the top quark and the electroweak bosons. They are ideal facilities for exploring the properties of Higgs particles, in particular in the intermediate mass range. New vector bosonsmore » and novel matter particles in extended gauge theories can be searched for and studied thoroughly. The machines provide unique opportunities for the discovery of particles in supersymmetric extensions of the Standard Model, the spectrum of Higgs particles, the supersymmetric partners of the electroweak gauge and Higgs bosons, and of the matter particles. High precision analyses of their properties and interactions will allow for extrapolations to energy scales close to the Planck scale where gravity becomes significant. In alternative scenarios, like compositeness models, novel matter particles and interactions can be discovered and investigated in the energy range above the existing colliders up to the TeV scale. Whatever scenario is realized in Nature, the discovery potential of e{sup +}e{sup -} linear colliders and the high-precision with which the properties of particles and their interactions can be analyzed, define an exciting physics programme complementary to hadron machines.« less

Automatic and integrated micro-enzyme assay (AIμEA) platform for highly sensitive thrombin analysis via an engineered fluorescence protein-functionalized monolithic capillary column.

PubMed

Lin, Lihua; Liu, Shengquan; Nie, Zhou; Chen, Yingzhuang; Lei, Chunyang; Wang, Zhen; Yin, Chao; Hu, Huiping; Huang, Yan; Yao, Shouzhuo

2015-04-21

Nowadays, large-scale screening for enzyme discovery, engineering, and drug discovery processes require simple, fast, and sensitive enzyme activity assay platforms with high integration and potential for high-throughput detection. Herein, a novel automatic and integrated micro-enzyme assay (AIμEA) platform was proposed based on a unique microreaction system fabricated by a engineered green fluorescence protein (GFP)-functionalized monolithic capillary column, with thrombin as an example. The recombinant GFP probe was rationally engineered to possess a His-tag and a substrate sequence of thrombin, which enable it to be immobilized on the monolith via metal affinity binding, and to be released after thrombin digestion. Combined with capillary electrophoresis-laser-induced fluorescence (CE-LIF), all the procedures, including thrombin injection, online enzymatic digestion in the microreaction system, and label-free detection of the released GFP, were integrated in a single electrophoretic process. By taking advantage of the ultrahigh loading capacity of the AIμEA platform and the CE automatic programming setup, one microreaction column was sufficient for many times digestion without replacement. The novel microreaction system showed significantly enhanced catalytic efficiency, about 30 fold higher than that of the equivalent bulk reaction. Accordingly, the AIμEA platform was highly sensitive with a limit of detection down to 1 pM of thrombin. Moreover, the AIμEA platform was robust and reliable to detect thrombin in human serum samples and its inhibition by hirudin. Hence, this AIμEA platform exhibits great potential for high-throughput analysis in future biological application, disease diagnostics, and drug screening.

Retrospective analysis of natural products provides insights for future discovery trends.

PubMed

Pye, Cameron R; Bertin, Matthew J; Lokey, R Scott; Gerwick, William H; Linington, Roger G

2017-05-30

Understanding of the capacity of the natural world to produce secondary metabolites is important to a broad range of fields, including drug discovery, ecology, biosynthesis, and chemical biology, among others. Both the absolute number and the rate of discovery of natural products have increased significantly in recent years. However, there is a perception and concern that the fundamental novelty of these discoveries is decreasing relative to previously known natural products. This study presents a quantitative examination of the field from the perspective of both number of compounds and compound novelty using a dataset of all published microbial and marine-derived natural products. This analysis aimed to explore a number of key questions, such as how the rate of discovery of new natural products has changed over the past decades, how the average natural product structural novelty has changed as a function of time, whether exploring novel taxonomic space affords an advantage in terms of novel compound discovery, and whether it is possible to estimate how close we are to having described all of the chemical space covered by natural products. Our analyses demonstrate that most natural products being published today bear structural similarity to previously published compounds, and that the range of scaffolds readily accessible from nature is limited. However, the analysis also shows that the field continues to discover appreciable numbers of natural products with no structural precedent. Together, these results suggest that the development of innovative discovery methods will continue to yield compounds with unique structural and biological properties.

Eukaryogenesis, how special really?

PubMed

Booth, Austin; Doolittle, W Ford

2015-08-18

Eukaryogenesis is widely viewed as an improbable evolutionary transition uniquely affecting the evolution of life on this planet. However, scientific and popular rhetoric extolling this event as a singularity lacks rigorous evidential and statistical support. Here, we question several of the usual claims about the specialness of eukaryogenesis, focusing on both eukaryogenesis as a process and its outcome, the eukaryotic cell. We argue in favor of four ideas. First, the criteria by which we judge eukaryogenesis to have required a genuinely unlikely series of events 2 billion years in the making are being eroded by discoveries that fill in the gaps of the prokaryote:eukaryote "discontinuity." Second, eukaryogenesis confronts evolutionary theory in ways not different from other evolutionary transitions in individuality; parallel systems can be found at several hierarchical levels. Third, identifying which of several complex cellular features confer on eukaryotes a putative richer evolutionary potential remains an area of speculation: various keys to success have been proposed and rejected over the five-decade history of research in this area. Fourth, and perhaps most importantly, it is difficult and may be impossible to eliminate eukaryocentric bias from the measures by which eukaryotes as a whole are judged to have achieved greater success than prokaryotes as a whole. Overall, we question whether premises of existing theories about the uniqueness of eukaryogenesis and the greater evolutionary potential of eukaryotes have been objectively formulated and whether, despite widespread acceptance that eukaryogenesis was "special," any such notion has more than rhetorical value.

Eukaryogenesis, how special really?

PubMed Central

Booth, Austin; Doolittle, W. Ford

2015-01-01

Eukaryogenesis is widely viewed as an improbable evolutionary transition uniquely affecting the evolution of life on this planet. However, scientific and popular rhetoric extolling this event as a singularity lacks rigorous evidential and statistical support. Here, we question several of the usual claims about the specialness of eukaryogenesis, focusing on both eukaryogenesis as a process and its outcome, the eukaryotic cell. We argue in favor of four ideas. First, the criteria by which we judge eukaryogenesis to have required a genuinely unlikely series of events 2 billion years in the making are being eroded by discoveries that fill in the gaps of the prokaryote:eukaryote “discontinuity.” Second, eukaryogenesis confronts evolutionary theory in ways not different from other evolutionary transitions in individuality; parallel systems can be found at several hierarchical levels. Third, identifying which of several complex cellular features confer on eukaryotes a putative richer evolutionary potential remains an area of speculation: various keys to success have been proposed and rejected over the five-decade history of research in this area. Fourth, and perhaps most importantly, it is difficult and may be impossible to eliminate eukaryocentric bias from the measures by which eukaryotes as a whole are judged to have achieved greater success than prokaryotes as a whole. Overall, we question whether premises of existing theories about the uniqueness of eukaryogenesis and the greater evolutionary potential of eukaryotes have been objectively formulated and whether, despite widespread acceptance that eukaryogenesis was “special,” any such notion has more than rhetorical value. PMID:25883267

NanoLuc: A Small Luciferase is Brightening up the Field of Bioluminescence

PubMed Central

Cai, Weibo

2016-01-01

The biomedical field has greatly benefited from the discovery of bioluminescent proteins. Currently, scientists employ bioluminescent systems for numerous biomedical applications, ranging from highly sensitive cellular assays to bioluminescence-based molecular imaging. Traditionally, these systems are based on Firefly and Renilla luciferases; however, the applicability of these enzymes is limited by their size, stability, and luminescence efficiency. NanoLuc (NLuc), a novel bioluminescence platform, offers several advantages over established systems, including enhanced stability, smaller size, and >150-fold increase in luminescence. In addition, the substrate for NLuc displays enhanced stability and lower background activity, opening up new possibilities in the field of bioluminescence imaging. The NLuc system is incredibly versatile and may be utilized for a wide array of applications. The increased sensitivity, high stability, and small size of the NLuc system have the potential to drastically change the field of reporter assays in the future. However, as with all such technology, NLuc has limitations (including a non-ideal emission for in vivo applications and its unique substrate) which may cause it to find restricted use in certain areas of molecular biology. As this unique technology continues to broaden, NLuc may have a significant impact in both preclinical and clinical fields, with potential roles in disease detection, molecular imaging, and therapeutic monitoring. This review will present the NLuc technology to the scientific community in a non-biased manner, allowing the audience to adopt their own views of this novel system. PMID:27045664

Scientific Discovery through Citizen Science via Popular Amateur Astrophotography

NASA Astrophysics Data System (ADS)

Nemiroff, Robert J.; Bonnell, Jerry T.; Allen, Alice

2015-01-01

Can popular astrophotography stimulate real astronomical discovery? Perhaps surprisingly, in some cases, the answer is yes. Several examples are given using the Astronomy Picture of the Day (APOD) site as an example venue. One reason is angular -- popular wide and deep images sometimes complement professional images which typically span a more narrow field. Another reason is temporal -- an amateur is at the right place and time to take a unique and illuminating image. Additionally, popular venues can be informational -- alerting professionals to cutting-edge amateur astrophotography about which they might not have known previously. Methods of further encouraging this unusual brand of citizen science are considered.

Marshall M. Parks Memorial Lecture: Ocular Motor Misbehavior in Children: Where Neuro-Ophthalmology Meets Strabismus.

PubMed

Brodsky, Michael C

2017-06-01

Clinical diagnosis has been supplemented by neuroimaging advances, genetic discoveries, and molecular research to generate new neurobiological discoveries pertaining to early maldevelopment of ocular motor control systems. In this focused review, I examine recent paradigm shifts that have transformed our understanding of pediatric ocular motor disease at the prenuclear and infranuclear levels. The pathogenesis of complex ocular motor disorders, such as paradoxical pupillary constriction to darkness, benign tonic upgaze of infancy, congenital fibrosis syndrome, and the constellation of unique eye movements that accompany Joubert syndrome, are elucidated. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

The Impact of Students' Exploration Strategies on Discovery Learning Using Computer-Based Simulations

ERIC Educational Resources Information Center

Dalgarno, Barney; Kennedy, Gregor; Bennett, Sue

2014-01-01

Discovery-based learning designs incorporating active exploration are common within instructional software. However, researchers have highlighted empirical evidence showing that "pure" discovery learning is of limited value and strategies which reduce complexity and provide guidance to learners are important if potential learning…

Knowledge Discovery from Databases: An Introductory Review.

ERIC Educational Resources Information Center

Vickery, Brian

1997-01-01

Introduces new procedures being used to extract knowledge from databases and discusses rationales for developing knowledge discovery methods. Methods are described for such techniques as classification, clustering, and the detection of deviations from pre-established norms. Examines potential uses of knowledge discovery in the information field.…

Mitigating risk in academic preclinical drug discovery.

PubMed

Dahlin, Jayme L; Inglese, James; Walters, Michael A

2015-04-01

The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology.

Chiral Alkyl Halides: Underexplored Motifs in Medicine

PubMed Central

Gál, Bálint; Bucher, Cyril; Burns, Noah Z.

2016-01-01

While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in comparison. This is likely attributable to the common misconception that these compounds are merely non-specific alkylators in biological systems. A number of chlorinated compounds in the pharmaceutical and food industries, as well as a growing number of halogenated marine natural products showing unique bioactivity, illustrate the role that chiral alkyl halides can play in drug discovery. Through a series of case studies, we demonstrate in this review that these motifs can indeed be stable under physiological conditions, and that halogenation can enhance bioactivity through both steric and electronic effects. Our hope is that, by placing such compounds in the minds of the chemical community, they may gain more traction in drug discovery and inspire more synthetic chemists to develop methods for selective halogenation. PMID:27827902

The drug discovery portal: a computational platform for identifying drug leads from academia.

PubMed

Clark, Rachel L; Johnston, Blair F; Mackay, Simon P; Breslin, Catherine J; Robertson, Murray N; Sutcliffe, Oliver B; Dufton, Mark J; Harvey, Alan L

2010-05-01

The Drug Discovery Portal (DDP) is a research initiative based at the University of Strathclyde in Glasgow, Scotland. It was initiated in 2007 by a group of researchers with expertise in virtual screening. Academic research groups in the university working in drug discovery programmes estimated there was a historical collection of physical compounds going back 50 years that had never been adequately catalogued. This invaluable resource has been harnessed to form the basis of the DDP library, and has attracted a high-percentage uptake from the Universities and Research Groups internationally. Its unique attributes include the diversity of the academic database, sourced from synthetic, medicinal and phytochemists working an academic laboratories and the ability to link biologists with appropriate chemical expertise through a target-matching virtual screening approach, and has resulted in seven emerging hit development programmes between international contributors.

Streptomyces species: Ideal chassis for natural product discovery and overproduction.

PubMed

Liu, Ran; Deng, Zixin; Liu, Tiangang

2018-05-28

There is considerable interest in mining organisms for new natural products (NPs) and in improving methods to overproduce valuable NPs. Because of the rapid development of tools and strategies for metabolic engineering and the markedly increased knowledge of the biosynthetic pathways and genetics of NP-producing organisms, genome mining and overproduction of NPs can be dramatically accelerated. In particular, Streptomyces species have been proposed as suitable chassis organisms for NP discovery and overproduction because of their many unique characteristics not shared with yeast, Escherichia coli, or other microorganisms. In this review, we summarize the methods for genome sequencing, gene cluster prediction, and gene editing in Streptomyces, as well as metabolic engineering strategies for NP overproduction and approaches for generating new products. Finally, two strategies for utilizing Streptomyces as the chassis for NP discovery and overproduction are emphasized. Copyright © 2018 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Streptomyces artemisiae MCCB 248 isolated from Arctic fjord sediments has unique PKS and NRPS biosynthetic genes and produces potential new anticancer natural products.

PubMed

Dhaneesha, M; Benjamin Naman, C; Krishnan, K P; Sinha, Rupesh Kumar; Jayesh, P; Joseph, Valsamma; Bright Singh, I S; Gerwick, William H; Sajeevan, T P

2017-05-01

After screening marine actinomycetes isolated from sediment samples collected from the Arctic fjord Kongsfjorden for potential anticancer activity, an isolate identified as Streptomyces artemisiae MCCB 248 exhibited promising results against the NCI-H460 human lung cancer cell line. H460 cells treated with the ethyl acetate extract of strain MCCB 248 and stained with Hoechst 33342 showed clear signs of apoptosis, including shrinkage of the cell nucleus, DNA fragmentation and chromatin condensation. Further to this treated cells showed indications of early apoptotic cell death, including a significant proportion of Annexin V positive staining and evidence of DNA damage as observed in the TUNEL assay. Amplified PKS 1 and NRPS genes involved in secondary metabolite production showed only 82% similarity to known biosynthetic genes of Streptomyces, indicating the likely production of a novel secondary metabolite in this extract. Additionally, chemical dereplication efforts using LC-MS/MS molecular networking suggested the presence of a series of undescribed tetraene polyols. Taken together, these results revealed that this Arctic S. artemisiae strain MCCB 248 is a promising candidate for natural products drug discovery and genome mining for potential anticancer agents.

Phage Therapy in the Era of Synthetic Biology.

PubMed

Barbu, E Magda; Cady, Kyle C; Hubby, Bolyn

2016-10-03

For more than a century, bacteriophage (or phage) research has enabled some of the most important discoveries in biological sciences and has equipped scientists with many of the molecular biology tools that have advanced our understanding of replication, maintenance, and expression of genetic material. Phages have also been recognized and exploited as natural antimicrobial agents and nanovectors for gene therapy, but their potential as therapeutics has not been fully exploited in Western medicine because of challenges such as narrow host range, bacterial resistance, and unique pharmacokinetics. However, increasing concern related to the emergence of bacteria resistant to multiple antibiotics has heightened interest in phage therapy and the development of strategies to overcome hurdles associated with bacteriophage therapeutics. Recent progress in sequencing technologies, DNA manipulation, and synthetic biology allowed scientists to refactor the entire bacterial genome of Mycoplasma mycoides, thereby creating the first synthetic cell. These new strategies for engineering genomes may have the potential to accelerate the construction of designer phage genomes with superior therapeutic potential. Here, we discuss the use of phage as therapeutics, as well as how synthetic biology can create bacteriophage with desirable attributes. Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.

An Assessment of Research Gaps Related to Deep Water Wellbore Integrity

NASA Astrophysics Data System (ADS)

Tkach, M. K.; Radonjic, M.; Kutchko, B. G.

2017-12-01

In order for a deep-water wellbore to uphold its integrity under high pressure - high temperature conditions, the wellbore must possess complete zonal isolation while surrounded in an extreme environment. Highly variable temperature and pressure ranges, shallow flow zones, as well as potentially corrosive fluids and gasses all present unique challenges to the job of the cement which maintains that zonal isolation. As such, alternative options to mainstream choices often present themselves as attractive avenues of discovery. As it is of utmost importance to maintain structural integrity under HPHT conditions, cement slurries are pumped downhole to provide zonal isolation and structural support to offshore wells. The wellbore system potentially faces a variety of temperature and pressure fluctuations from the immediate onset. These fluctuations may affect the hydration properties of the cement. It is also important to consider the chemical interactions that the cement may have at the rock-cement interface where potential degradation or annulus gaps may occur further risking a decrease in zonal isolation. This presentation intends to review some of the important issues regarding zonal isolation in HPHT conditions and to highlight critical knowledge gaps in order to generate important research questions.

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

Viruses in the 21st Century: From the Curiosity-Driven Discovery of Giant Viruses to New Concepts and Definition of Life.

PubMed

Forterre, Patrick

2017-08-15

The curiosity-driven discovery of giant DNA viruses infecting amoebas has triggered an intense debate about the origin, nature, and definition of viruses. This discovery was delayed by the current paradigm confusing viruses with small virions. Several new definitions and concepts have been proposed either to reconcile the unique features of giant viruses with previous paradigms or to propose a completely new vision of the living world. I briefly review here how several other lines of research in virology converged during the last 2 decades with the discovery of giant viruses to change our traditional perception of the viral world. This story emphasizes the power of multidisciplinary curiosity-driven research, from the hospital to the field and the laboratory. Notably, some philosophers have now also joined biologists in their quest to make sense of the abundance and diversity of viruses and related capsidless mobile elements in the biosphere. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Discovery of novel drugs for promising targets.

PubMed

Martell, Robert E; Brooks, David G; Wang, Yan; Wilcoxen, Keith

2013-09-01

Once a promising drug target is identified, the steps to actually discover and optimize a drug are diverse and challenging. The goal of this study was to provide a road map to navigate drug discovery. Review general steps for drug discovery and provide illustrating references. A number of approaches are available to enhance and accelerate target identification and validation. Consideration of a variety of potential mechanisms of action of potential drugs can guide discovery efforts. The hit to lead stage may involve techniques such as high-throughput screening, fragment-based screening, and structure-based design, with informatics playing an ever-increasing role. Biologically relevant screening models are discussed, including cell lines, 3-dimensional culture, and in vivo screening. The process of enabling human studies for an investigational drug is also discussed. Drug discovery is a complex process that has significantly evolved in recent years. © 2013 Elsevier HS Journals, Inc. All rights reserved.

Simultaneous Proteomic Discovery and Targeted Monitoring using Liquid Chromatography, Ion Mobility Spectrometry, and Mass Spectrometry.

PubMed

Burnum-Johnson, Kristin E; Nie, Song; Casey, Cameron P; Monroe, Matthew E; Orton, Daniel J; Ibrahim, Yehia M; Gritsenko, Marina A; Clauss, Therese R W; Shukla, Anil K; Moore, Ronald J; Purvine, Samuel O; Shi, Tujin; Qian, Weijun; Liu, Tao; Baker, Erin S; Smith, Richard D

2016-12-01

Current proteomic approaches include both broad discovery measurements and quantitative targeted analyses. In many cases, discovery measurements are initially used to identify potentially important proteins (e.g. candidate biomarkers) and then targeted studies are employed to quantify a limited number of selected proteins. Both approaches, however, suffer from limitations. Discovery measurements aim to sample the whole proteome but have lower sensitivity, accuracy, and quantitation precision than targeted approaches, whereas targeted measurements are significantly more sensitive but only sample a limited portion of the proteome. Herein, we describe a new approach that performs both discovery and targeted monitoring (DTM) in a single analysis by combining liquid chromatography, ion mobility spectrometry and mass spectrometry (LC-IMS-MS). In DTM, heavy labeled target peptides are spiked into tryptic digests and both the labeled and unlabeled peptides are detected using LC-IMS-MS instrumentation. Compared with the broad LC-MS discovery measurements, DTM yields greater peptide/protein coverage and detects lower abundance species. DTM also achieved detection limits similar to selected reaction monitoring (SRM) indicating its potential for combined high quality discovery and targeted analyses, which is a significant step toward the convergence of discovery and targeted approaches. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

FOCU:S--future operator control unit: soldier

NASA Astrophysics Data System (ADS)

O'Brien, Barry J.; Karan, Cem; Young, Stuart H.

2009-05-01

The U.S. Army Research Laboratory's (ARL) Computational and Information Sciences Directorate (CISD) has long been involved in autonomous asset control, specifically as it relates to small robots. Over the past year, CISD has been making strides in the implementation of three areas of small robot autonomy, namely platform autonomy, Soldier-robot interface, and tactical behaviors. It is CISD's belief that these three areas must be considered as a whole in order to provide Soldiers with useful capabilities. In addressing the Soldier-robot interface aspect, CISD has begun development on a unique dismounted controller called the Future Operator Control Unit: Soldier (FOCU:S) that is based on an Apple iPod Touch. The iPod Touch's small form factor, unique touch-screen input device, and the presence of general purpose computing applications such as a web browser combine to give this device the potential to be a disruptive technology. Setting CISD's implementation apart from other similar iPod or iPhone-based devices is the ARL software that allows multiple robotic platforms to be controlled from a single OCU. The FOCU:S uses the same Agile Computing Infrastructure (ACI) that all other assets in the ARL robotic control system use, enabling automated asset discovery on any type of network. Further, a custom ad hoc routing implementation allows the FOCU:S to communicate with the ARL ad hoc communications system and enables it to extend the range of the network. This paper will briefly describe the current robotic control architecture employed by ARL and provide short descriptions of existing capabilities. Further, the paper will discuss FOCU:S specific software developed for the iPod Touch, including unique capabilities enabled by the device's unique hardware.

Applied genomics in ruminants-new discoveries and model for predictive medicine

USDA-ARS?s Scientific Manuscript database

An overview of the progress for Dr. Sonstegard’s work in applied genomics in dairy cattle will be presented. The overview will include how applied research in livestock offers unique investigative models to discover gene function as a result of genetic load or inbreeding and also how genome selectio...

Discovery of "Escherichia coli" CRISPR Sequences in an Undergraduate Laboratory

ERIC Educational Resources Information Center

Militello, Kevin T.; Lazatin, Justine C.

2017-01-01

Clustered regularly interspaced short palindromic repeats (CRISPRs) represent a novel type of adaptive immune system found in eubacteria and archaebacteria. CRISPRs have recently generated a lot of attention due to their unique ability to catalog foreign nucleic acids, their ability to destroy foreign nucleic acids in a mechanism that shares some…

Discovery of an acidic, thermostable and highly NADP+ dependent formate dehydrogenase from Lactobacillus buchneri NRRL B-30929

USDA-ARS?s Scientific Manuscript database

Objectives: To identify a robust NADP+ dependent formate dehydrogenase from Lactobacillus buchneri NRRL B-30929 (LbFDH) with unique biochemical properties. Results: A new NADP+ dependent formate dehydrogenase gene (fdh) was cloned from genomic DNA of L. buchneri NRRL B-30929. The recombinant constru...

Networking Antarctic Research Discoveries to a Science Classroom

ERIC Educational Resources Information Center

Podoll, Andrew; Olson, Barry; Montplaisir, Lisa; Schwert, Donald; McVicar, Kim; Comez, Dogan; Martin, William

2008-01-01

In 2006, a unique scenario transported eighth-grade Earth science students from the classroom into the cold, dry, pristine surroundings of Antarctica. The mission was to expose the students to hands-on science using satellite telephones, Contact 3.0 software, and some very creative improvisation. In addition, a detailed, well-illustrated blog…

Genetics of Mitochondrial Disease.

PubMed

Saneto, Russell P

2017-01-01

Mitochondria are intracellular organelles responsible for adenosine triphosphate production. The strict control of intracellular energy needs require proper mitochondrial functioning. The mitochondria are under dual controls of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Mitochondrial dysfunction can arise from changes in either mtDNA or nDNA genes regulating function. There are an estimated ∼1500 proteins in the mitoproteome, whereas the mtDNA genome has 37 proteins. There are, to date, ∼275 genes shown to give rise to disease. The unique physiology of mitochondrial functioning contributes to diverse gene expression. The onset and range of phenotypic expression of disease is diverse, with onset from neonatal to seventh decade of life. The range of dysfunction is heterogeneous, ranging from single organ to multisystem involvement. The complexity of disease expression has severely limited gene discovery. Combining phenotypes with improvements in gene sequencing strategies are improving the diagnosis process. This chapter focuses on the interplay of the unique physiology and gene discovery in the current knowledge of genetically derived mitochondrial disease. Copyright © 2017 Elsevier Inc. All rights reserved.

First fossil gravid turtle provides insight into the evolution of reproductive traits in turtles.

PubMed

Zelenitsky, Darla K; Therrien, Franc Ois; Joyce, Walter G; Brinkman, Donald B

2008-12-23

Here we report on the first discovery of shelled eggs inside the body cavity of a fossil turtle and on an isolated egg clutch, both referable to the Cretaceous turtle Adocus. These discoveries provide a unique opportunity to gain insight into the reproductive traits of an extinct turtle and to understand the evolution of such traits among living turtles. The gravid adult and egg clutch indicate that Adocus laid large clutches of rigid-shelled spherical eggs and established their nests near rivers, traits that are shared by its closest living relatives, the soft-shelled turtles. Adocus eggshell, however, was probably more rigid than that of living turtles, based on its great thickness and structure, features that may represent unique adaptations to intense predation or to arid nest environments. In light of the reproductive traits observed in Adocus, the distribution of reproductive traits among turtles reveals that large clutches of rigid-shelled eggs are primitive for hidden-necked turtles (cryptodirans) and that spherical eggs may have evolved independently within this group.

The European Lead Factory: A Blueprint for Public-Private Partnerships in Early Drug Discovery.

PubMed

Karawajczyk, Anna; Orrling, Kristina M; de Vlieger, Jon S B; Rijnders, Ton; Tzalis, Dimitrios

2016-01-01

The European Lead Factory (ELF) is a public-private partnership (PPP) that provides researchers in Europe with a unique platform for translation of innovative biology and chemistry into high-quality starting points for drug discovery. It combines an exceptional collection of small molecules, high-throughput screening (HTS) infrastructure, and hit follow-up capabilities to advance research projects from both private companies and publicly funded researchers. By active interactions with the wider European life science community, ELF connects and unites bright ideas, talent, and experience from several disciplines. As a result, ELF is a unique, collaborative lead generation engine that has so far resulted in >4,500 hit compounds with a defined biological activity from 83 successfully completed HTS and hit evaluation campaigns. The PPP has also produced more than 120,000 novel innovative library compounds that complement the 327,000 compounds contributed by the participating pharmaceutical companies. Intrinsic to its setup, ELF enables breakthroughs in areas with unmet medical and societal needs, where no individual entity would be able to create a comparable impact in such a short time.

The European Lead Factory: A Blueprint for Public–Private Partnerships in Early Drug Discovery

PubMed Central

Karawajczyk, Anna; Orrling, Kristina M.; de Vlieger, Jon S. B.; Rijnders, Ton; Tzalis, Dimitrios

2017-01-01

The European Lead Factory (ELF) is a public–private partnership (PPP) that provides researchers in Europe with a unique platform for translation of innovative biology and chemistry into high-quality starting points for drug discovery. It combines an exceptional collection of small molecules, high-throughput screening (HTS) infrastructure, and hit follow-up capabilities to advance research projects from both private companies and publicly funded researchers. By active interactions with the wider European life science community, ELF connects and unites bright ideas, talent, and experience from several disciplines. As a result, ELF is a unique, collaborative lead generation engine that has so far resulted in >4,500 hit compounds with a defined biological activity from 83 successfully completed HTS and hit evaluation campaigns. The PPP has also produced more than 120,000 novel innovative library compounds that complement the 327,000 compounds contributed by the participating pharmaceutical companies. Intrinsic to its setup, ELF enables breakthroughs in areas with unmet medical and societal needs, where no individual entity would be able to create a comparable impact in such a short time. PMID:28154815

Impact of the Choice of Normalization Method on Molecular Cancer Class Discovery Using Nonnegative Matrix Factorization.

PubMed

Yang, Haixuan; Seoighe, Cathal

2016-01-01

Nonnegative Matrix Factorization (NMF) has proved to be an effective method for unsupervised clustering analysis of gene expression data. By the nonnegativity constraint, NMF provides a decomposition of the data matrix into two matrices that have been used for clustering analysis. However, the decomposition is not unique. This allows different clustering results to be obtained, resulting in different interpretations of the decomposition. To alleviate this problem, some existing methods directly enforce uniqueness to some extent by adding regularization terms in the NMF objective function. Alternatively, various normalization methods have been applied to the factor matrices; however, the effects of the choice of normalization have not been carefully investigated. Here we investigate the performance of NMF for the task of cancer class discovery, under a wide range of normalization choices. After extensive evaluations, we observe that the maximum norm showed the best performance, although the maximum norm has not previously been used for NMF. Matlab codes are freely available from: http://maths.nuigalway.ie/~haixuanyang/pNMF/pNMF.htm.

Evaluation of solar electric propulsion technologies for discovery class missions

NASA Technical Reports Server (NTRS)

Oh, David Y.

2005-01-01

A detailed study examines the potential benefits that advanced electric propulsion (EP) technologies offer to the cost-capped missions in NASA's Discovery program. The study looks at potential cost and performance benefits provided by three EP technologies that are currently in development: NASA's Evolutionary Xenon Thruster (NEXT), an Enhanced NSTAR system, and a Low Power Hall effect thruster. These systems are analyzed on three straw man Discovery class missions and their performance is compared to a state of the art system using the NSTAR ion thruster. An electric propulsion subsystem cost model is used to conduct a cost-benefit analysis for each option. The results show that each proposed technology offers a different degree of performance and/or cost benefit for Discovery class missions.

Serum microRNAs as biomarkers for recurrence in melanoma

PubMed Central

2012-01-01

Background Identification of melanoma patients at high risk for recurrence and monitoring for recurrence are critical for informed management decisions. We hypothesized that serum microRNAs (miRNAs) could provide prognostic information at the time of diagnosis unaccounted for by the current staging system and could be useful in detecting recurrence after resection. Methods We screened 355 miRNAs in sera from 80 melanoma patients at primary diagnosis (discovery cohort) using a unique quantitative reverse transcription-PCR (qRT-PCR) panel. Cox proportional hazard models and Kaplan-Meier recurrence-free survival (RFS) curves were used to identify a miRNA signature with prognostic potential adjusting for stage. We then tested the miRNA signature in an independent cohort of 50 primary melanoma patients (validation cohort). Logistic regression analysis was performed to determine if the miRNA signature can determine risk of recurrence in both cohorts. Selected miRNAs were measured longitudinally in subsets of patients pre-/post-operatively and pre-/post-recurrence. Results A signature of 5 miRNAs successfully classified melanoma patients into high and low recurrence risk groups with significant separation of RFS in both discovery and validation cohorts (p = 0.0036, p = 0.0093, respectively). Significant separation of RFS was maintained when a logistic model containing the same signature set was used to predict recurrence risk in both discovery and validation cohorts (p < 0.0001, p = 0.033, respectively). Longitudinal expression of 4 miRNAs in a subset of patients was dynamic, suggesting miRNAs can be associated with tumor burden. Conclusion Our data demonstrate that serum miRNAs can improve accuracy in identifying primary melanoma patients with high recurrence risk and in monitoring melanoma tumor burden over time. PMID:22857597

Novel Substrates as Sources of Ancient DNA: Prospects and Hurdles

PubMed Central

Green, Eleanor Joan

2017-01-01

Following the discovery in the late 1980s that hard tissues such as bones and teeth preserve genetic information, the field of ancient DNA analysis has typically concentrated upon these substrates. The onset of high-throughput sequencing, combined with optimized DNA recovery methods, has enabled the analysis of a myriad of ancient species and specimens worldwide, dating back to the Middle Pleistocene. Despite the growing sophistication of analytical techniques, the genetic analysis of substrates other than bone and dentine remain comparatively “novel”. Here, we review analyses of other biological substrates which offer great potential for elucidating phylogenetic relationships, paleoenvironments, and microbial ecosystems including (1) archaeological artifacts and ecofacts; (2) calcified and/or mineralized biological deposits; and (3) biological and cultural archives. We conclude that there is a pressing need for more refined models of DNA preservation and bespoke tools for DNA extraction and analysis to authenticate and maximize the utility of the data obtained. With such tools in place the potential for neglected or underexploited substrates to provide a unique insight into phylogenetics, microbial evolution and evolutionary processes will be realized. PMID:28703741

A Critical Assessment of Combined Ligand-based and Structure-based Approaches to hERG Channel Blocker Modeling

PubMed Central

Du-Cuny, Lei; Chen, Lu; Zhang, Shuxing

2014-01-01

Blockade of hERG channel prolongs the duration of the cardiac action potential and is a common reason for drug failure in preclinical safety trials. Therefore, it is of great importance to develop robust in silico tools to predict potential hERG blockers in the early stages of drug discovery and development. Herein we described comprehensive approaches to assess the discrimination of hERG-active and -inactive compounds by combining QSAR modeling, pharmacophore analysis, and molecular docking. Our consensus models demonstrated high predictive capacity and improved enrichment, and they could correctly classify 91.8% of 147 hERG blockers from 351 inactives. To further enhance our modeling effort, hERG homology models were constructed and molecular docking studies were conducted, resulting in high correlations (R2=0.81) between predicted and experimental binding affinities. We expect our unique models can be applied to efficient screening for hERG blockades, and our extensive understanding of the hERG-inhibitor interactions will facilitate the rational design of drugs devoid of hERG channel activity and hence with reduced cardiac toxicities. PMID:21902220

The Eye As a Biomarker for Alzheimer's Disease

PubMed Central

Lim, Jeremiah K. H.; Li, Qiao-Xin; He, Zheng; Vingrys, Algis J.; Wong, Vickie H. Y.; Currier, Nicolas; Mullen, Jamie; Bui, Bang V.; Nguyen, Christine T. O.

2016-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in dementia and eventual death. It is the leading cause of dementia and the number of cases are projected to rise in the next few decades. Pathological hallmarks of AD include the presence of hyperphosphorylated tau and amyloid protein deposition. Currently, these pathological biomarkers are detected either through cerebrospinal fluid analysis, brain imaging or post-mortem. Though effective, these methods are not widely available due to issues such as the difficulty in acquiring samples, lack of infrastructure or high cost. Given that the eye possesses clear optics and shares many neural and vascular similarities to the brain, it offers a direct window to cerebral pathology. These unique characteristics lend itself to being a relatively inexpensive biomarker for AD which carries the potential for wide implementation. The development of ocular biomarkers can have far implications in the discovery of treatments which can improve the quality of lives of patients. In this review, we consider the current evidence for ocular biomarkers in AD and explore potential future avenues of research in this area. PMID:27909396

Genomes to natural products PRediction Informatics for Secondary Metabolomes (PRISM)

PubMed Central

Skinnider, Michael A.; Dejong, Chris A.; Rees, Philip N.; Johnston, Chad W.; Li, Haoxin; Webster, Andrew L. H.; Wyatt, Morgan A.; Magarvey, Nathan A.

2015-01-01

Microbial natural products are an invaluable source of evolved bioactive small molecules and pharmaceutical agents. Next-generation and metagenomic sequencing indicates untapped genomic potential, yet high rediscovery rates of known metabolites increasingly frustrate conventional natural product screening programs. New methods to connect biosynthetic gene clusters to novel chemical scaffolds are therefore critical to enable the targeted discovery of genetically encoded natural products. Here, we present PRISM, a computational resource for the identification of biosynthetic gene clusters, prediction of genetically encoded nonribosomal peptides and type I and II polyketides, and bio- and cheminformatic dereplication of known natural products. PRISM implements novel algorithms which render it uniquely capable of predicting type II polyketides, deoxygenated sugars, and starter units, making it a comprehensive genome-guided chemical structure prediction engine. A library of 57 tailoring reactions is leveraged for combinatorial scaffold library generation when multiple potential substrates are consistent with biosynthetic logic. We compare the accuracy of PRISM to existing genomic analysis platforms. PRISM is an open-source, user-friendly web application available at http://magarveylab.ca/prism/. PMID:26442528

DNA methylation in memory formation: Emerging insights

PubMed Central

Heyward, Frankie D.; Sweatt, J. David

2016-01-01

The establishment of synaptic plasticity and long-term memory requires lasting cellular and molecular modifications that, as a whole, must endure despite the rapid turnover of their constituent parts. Such a molecular feat must be mediated by a stable, self-perpetuating, cellular information storage mechanism. DNA methylation, being the archetypal cellular information storage mechanism, has been heavily implicated as being necessary for stable activity-dependent transcriptional alterations within the central nervous system (CNS). This review details the foundational discoveries from both gene-targeted, as well as whole-genome sequencing, studies that have successfully brought DNA methylation to our attention as a chief regulator of activity- and experience-dependent transcriptional alterations within the CNS. We present a hypothetical framework with which the disparate experimental findings dealing with distinct manipulations of the DNA methylation, and their effect on memory, might be resolved while taking into account the unique impact activity-dependent alterations in DNA methylation potentially have on both memory promoting and memory-suppressing gene expression. And last, we discuss potential avenues for future inquiry into the role of DNA methylation during remote memory formation. PMID:25832671

Quantifying Learning in Young Infants: Tracking Leg Actions During a Discovery-learning Task.

PubMed

Sargent, Barbara; Reimann, Hendrik; Kubo, Masayoshi; Fetters, Linda

2015-06-01

Task-specific actions emerge from spontaneous movement during infancy. It has been proposed that task-specific actions emerge through a discovery-learning process. Here a method is described in which 3-4 month old infants learn a task by discovery and their leg movements are captured to quantify the learning process. This discovery-learning task uses an infant activated mobile that rotates and plays music based on specified leg action of infants. Supine infants activate the mobile by moving their feet vertically across a virtual threshold. This paradigm is unique in that as infants independently discover that their leg actions activate the mobile, the infants' leg movements are tracked using a motion capture system allowing for the quantification of the learning process. Specifically, learning is quantified in terms of the duration of mobile activation, the position variance of the end effectors (feet) that activate the mobile, changes in hip-knee coordination patterns, and changes in hip and knee muscle torque. This information describes infant exploration and exploitation at the interplay of person and environmental constraints that support task-specific action. Subsequent research using this method can investigate how specific impairments of different populations of infants at risk for movement disorders influence the discovery-learning process for task-specific action.

Earth Science Keyword Stewardship: Access and Management through NASA's Global Change Master Directory (GCMD) Keyword Management System (KMS)

NASA Astrophysics Data System (ADS)

Stevens, T.; Olsen, L. M.; Ritz, S.; Morahan, M.; Aleman, A.; Cepero, L.; Gokey, C.; Holland, M.; Cordova, R.; Areu, S.; Cherry, T.; Tran-Ho, H.

2012-12-01

Discovering Earth science data can be complex if the catalog holding the data lacks structure. Controlled keyword vocabularies within metadata catalogues can improve data discovery. NASA's Global Change Master Directory's (GCMD) Keyword Management System (KMS) is a recently released a RESTful web service for managing and providing access to controlled keywords (science keywords, service keywords, platforms, instruments, providers, locations, projects, data resolution, etc.). The KMS introduces a completely new paradigm for the use and management of the keywords and allows access to these keywords as SKOS Concepts (RDF), OWL, standard XML, and CSV. A universally unique identifier (UUID) is automatically assigned to each keyword, which uniquely identifies each concept and its associated information. A component of the KMS is the keyword manager, an internal tool that allows GCMD science coordinators to manage concepts. This includes adding, modifying, and deleting broader, narrower, or related concepts and associated definitions. The controlled keyword vocabulary represents over 20 years of effort and collaboration with the Earth science community. The maintenance, stability, and ongoing vigilance in maintaining mutually exclusive and parallel keyword lists is important for a "normalized" search and discovery, and provides a unique advantage for the science community. Modifications and additions are made based on community suggestions and internal review. To help maintain keyword integrity, science keyword rules and procedures for modification of keywords were developed. This poster will highlight the use of the KMS as a beneficial service for the stewardship and access of the GCMD keywords. Users will learn how to access the KMS and utilize the keywords. Best practices for managing an extensive keyword hierarchy will also be discussed. Participants will learn the process for making keyword suggestions, which subsequently help in building a controlled keyword vocabulary to improve earth science data discovery and access.

Mitigating risk in academic preclinical drug discovery

PubMed Central

Dahlin, Jayme L.; Inglese, James; Walters, Michael A.

2018-01-01

The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology. PMID:25829283

Central ridge of Newfoundland: Little explored, potential large

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

Silva, N.R. De

The Central ridge on the northeastern Grand Banks off Newfoundland represents a large area with known hydrocarbon accumulations and the potential for giant fields. It covers some 17,000 sq km with water less than 400 m deep. The first major hydrocarbon discovery on the Newfoundland Grand Banks is giant Hibernia field in the Jeanne d'Arc basin. Hibernia field, discovered in 1979, has reserves of 666 million bbl and is due onstream in 1997. Since Hibernia, 14 other discoveries have been made on the Grand Banks, with three on the Central ridge. Oil was first discovered on Central Ridge in 1980more » with the Mobil et al. South Tempest G-88 well. In 1982 gas was discovered with the Mobil et al. North Dana I-43 well 30 km northeast of the earlier discovery. In 1983 gas and condensate were discovered with the Husky-Bow Valley et al. Trave E-87 well 20 km south of the South Tempest well. These discoveries are held under significant discovery licenses and an additional 2,400 sq km are held under exploration licenses. The paper discusses the history of the basin, the reservoir source traps, and the basin potential.« less

30 CFR 285.802 - What must I do if I discover a potential archaeological resource while conducting my approved...

Code of Federal Regulations, 2010 CFR

2010-07-01

... seafloor-disturbing activities within the area of the discovery; (2) Notify MMS of the discovery within 72 hours; and (3) Keep the location of the discovery confidential and not take any action that may... for carrying out preservation responsibilities under the OCS Lands Act. ...

Recent advances in inkjet dispensing technologies: applications in drug discovery.

PubMed

Zhu, Xiangcheng; Zheng, Qiang; Yang, Hu; Cai, Jin; Huang, Lei; Duan, Yanwen; Xu, Zhinan; Cen, Peilin

2012-09-01

Inkjet dispensing technology is a promising fabrication methodology widely applied in drug discovery. The automated programmable characteristics and high-throughput efficiency makes this approach potentially very useful in miniaturizing the design patterns for assays and drug screening. Various custom-made inkjet dispensing systems as well as specialized bio-ink and substrates have been developed and applied to fulfill the increasing demands of basic drug discovery studies. The incorporation of other modern technologies has further exploited the potential of inkjet dispensing technology in drug discovery and development. This paper reviews and discusses the recent developments and practical applications of inkjet dispensing technology in several areas of drug discovery and development including fundamental assays of cells and proteins, microarrays, biosensors, tissue engineering, basic biological and pharmaceutical studies. Progression in a number of areas of research including biomaterials, inkjet mechanical systems and modern analytical techniques as well as the exploration and accumulation of profound biological knowledge has enabled different inkjet dispensing technologies to be developed and adapted for high-throughput pattern fabrication and miniaturization. This in turn presents a great opportunity to propel inkjet dispensing technology into drug discovery.

The Geospace Dynamics Observatory; a Mission of Discovery for Geospace

NASA Technical Reports Server (NTRS)

Spann, James; Paxton, Larry; Burch, James; Reardon, Patrick; Krause, Linda; Gallagher, Dennis; Hopkins, Randall

2013-01-01

A few examples of potential advances include: 1. Unparalleled advances in the connection of the upper atmosphere to the Sun. In the aurora and lower latitudes, extending the duration of uninterrupted images would advance understanding of the transfer of energy from the Sun to the upper atmosphere and the response of the space environment. 2. Advances in the influence of waves and tides on the upper atmosphere. Increasing both the signal to noise and the duration ofthe observations would reveal contributions that are not identifiable using other approaches. 3. The ability to probe the mechanisms that control the evolution of planetary atmospheres. The vantage point provided by this mission allows the flux of hydrogen (which is tied to the escape of water from a planet) to be mapped globally. It also allows unique observations of changes in the atmospheric structure and their causes.

Development and Application of a Novel SPE-Method for Bioassay-Guided Fractionation of Marine Extracts

PubMed Central

Cutignano, Adele; Nuzzo, Genoveffa; Ianora, Adrianna; Luongo, Elvira; Romano, Giovanna; Gallo, Carmela; Sansone, Clementina; Aprea, Susanna; Mancini, Francesca; D’Oro, Ugo; Fontana, Angelo

2015-01-01

The biological diversity of marine habitats is a unique source of chemical compounds with potential use as pharmaceuticals, cosmetics and dietary supplements. However, biological screening and chemical analysis of marine extracts pose specific technical constraints and require adequate sample preparation. Here we report an improved method on Solid Phase Extraction (SPE) to fractionate organic extracts containing high concentration of salt that hampers the recovery of secondary metabolites. The procedure uses a water suspension to load the extracts on a poly(styrene-divynylbenzene)-based support and a stepwise organic solvent elution to effectively desalt and fractionate the organic components. The novel protocol has been tested on MeOH-soluble material from three model organisms (Reniera sarai, Dendrilla membranosa and Amphidinium carterae) and was validated on a small panel of 47 marine samples, including sponges and protists, within discovery programs for identification of immuno-stimulatory and anti-infective natural products. PMID:26378547

Perspectives and Peptides of the Next Generation

NASA Astrophysics Data System (ADS)

Brogden, Kim A.

Shortly after their discovery, antimicrobial peptides from prokaryotes and eukaryotes were recognized as the next potential generation of pharmaceuticals to treat antibiotic-resistant bacterial infections and septic shock, to preserve food, or to sanitize surfaces. Initial research focused on identifying the spectrum of antimicrobial agents, determining the range of antimicrobial activities against bacterial, fungal, and viral pathogens, and assessing the antimicrobial activity of synthetic peptides versus their natural counterparts. Subsequent research then focused on the mechanisms of antimicrobial peptide activity in model membrane systems not only to identify the mechanisms of antimicrobial peptide activity in microorganisms but also to discern differences in cytotoxicity for prokaryotic and eukaryotic cells. Recent, contemporary work now focuses on current and future efforts to construct hybrid peptides, peptide congeners, stabilized peptides, peptide conjugates, and immobilized peptides for unique and specific applications to control the growth of microorganisms in vitro and in vivo.

Perspectives: Nanofibers and nanowires for disordered photonics

NASA Astrophysics Data System (ADS)

Pisignano, Dario; Persano, Luana; Camposeo, Andrea

2017-03-01

As building blocks of microscopically non-homogeneous materials, semiconductor nanowires and polymer nanofibers are emerging component materials for disordered photonics, with unique properties of light emission and scattering. Effects found in assemblies of nanowires and nanofibers include broadband reflection, significant localization of light, strong and collective multiple scattering, enhanced absorption of incident photons, synergistic effects with plasmonic particles, and random lasing. We highlight recent related discoveries, with a focus on material aspects. The control of spatial correlations in complex assemblies during deposition, the coupling of modes with efficient transmission channels provided by nanofiber waveguides, and the embedment of random architectures into individually coded nanowires will allow the potential of these photonic materials to be fully exploited, unconventional physics to be highlighted, and next-generation optical devices to be achieved. The prospects opened by this technology include enhanced random lasing and mode-locking, multi-directionally guided coupling to sensors and receivers, and low-cost encrypting miniatures for encoders and labels.

DRESS syndrome with thrombotic microangiopathy revealing a Noonan syndrome

PubMed Central

Bobot, Mickaël; Coen, Matteo; Simon, Clémentine; Daniel, Laurent; Habib, Gilbert; Serratrice, Jacques

2018-01-01

Abstract Rationale: The life-threatening drug rash with eosinophilia and systemic symptoms (DRESS) syndrome occurs most commonly after exposure to drugs, clinical features mimic those found with other serious systemic disorders. It is rarely associated with thrombotic microangiopathy. Patient concerns: We describe the unique case of a 44-year-old man who simultaneously experienced DRESS syndrome with thrombotic microangiopathy (TMA) after a 5 days treatment with fluindione. Diagnoses: Clinical evaluation leads to the discovery of an underlying lymphangiomatosis, due to a Noonan syndrome. Intervetions: The anticoagulant was withdrawn, and corticosteroids (1 mg/kg/day) and acenocoumarol were started. Outcomes: Clinical improvement ensued. At follow-up the patient is well. Lessons: The association of DRESS with TMA is a rare condition; we believe that the presence of the underlying Noonan syndrome could have been the trigger. Moreover, we speculate about the potential interrelations between these entities. PMID:29642153

Kappa Opioid Receptor Agonist and Brain Ischemia

PubMed Central

Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

2014-01-01

Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

How the early voltage clamp studies of José del Castillo inform "modern" neuroscience.

PubMed

Zottoli, Steven J

2012-10-01

The description of ionic currents that flow across the membrane of the squid giant axon during an action potential sparked an interest in determining whether there were similar currents in vertebrates. The preparation of choice was the node of Ranvier in single myelinated fibers in frog. José del Castillo spent 3 years on the United States mainland from 1956 to 1959. During that time, he collaborated with Jerome Y. Lettvin and John W. Moore. I discuss how these individuals met one another and some of their scientific discoveries using the voltage clamp to study squid giant axons and frog nodes. Much of this work was conducted at the Marine Biological Laboratory in Woods Hole, MA, and I attempt to convey a sense of the unique scientific "melting pot" that existed at the Marine Biological Laboratory and the broader effect that del Castillo had on "modern" neuroscience.

Shifting the life-history paradigm: discovery of novel habitat use by hawksbill turtles.

PubMed

Gaos, Alexander R; Lewison, Rebecca L; Yañez, Ingrid L; Wallace, Bryan P; Liles, Michael J; Nichols, Wallace J; Baquero, Andres; Hasbún, Carlos R; Vasquez, Mauricio; Urteaga, José; Seminoff, Jeffrey A

2012-02-23

Adult hawksbill turtles (Eretmochelys imbricata) are typically described as open-coast, coral reef and hard substrate dwellers. Here, we report new satellite tracking data on female hawksbills from several countries in the eastern Pacific that revealed previously undocumented behaviour for adults of the species. In contrast to patterns of habitat use exhibited by their Caribbean and Indo-Pacific counterparts, eastern Pacific hawksbills generally occupied inshore estuaries, wherein they had strong associations with mangrove saltwater forests. The use of inshore habitats and affinities with mangrove saltwater forests presents a previously unknown life-history paradigm for adult hawksbill turtles and suggests a potentially unique evolutionary trajectory for the species. Our findings highlight the variability in life-history strategies that marine turtles and other wide-ranging marine wildlife may exhibit among ocean regions, and the importance of understanding such disparities from an ecological and management perspective.

Autoantibodies to Posttranslational Modifications in Rheumatoid Arthritis

PubMed Central

Burska, Agata N.; Hunt, Laura; Strollo, Rocky; Ryan, Brent J.; Vital, Ed; Nissim, Ahuva; Winyard, Paul G.; Emery, Paul; Ponchel, Frederique

2014-01-01

Autoantibodies have been associated with human pathologies for a long time, particularly with autoimmune diseases (AIDs). Rheumatoid factor (RF) is known since the late 1930s to be associated with rheumatoid arthritis (RA). The discovery of anticitrullinated protein antibodies in the last century has changed this and other posttranslational modifications (PTM) relevant to RA have since been described. Such PTM introduce neoepitopes in proteins that can generate novel autoantibody specificities. The recent recognition of these novel specificities in RA provides a unique opportunity to understand human B-cell development in vivo. In this paper, we will review the three of the main classes of PTMs already associated with RA: citrullination, carbamylation, and oxidation. With the advancement of research methodologies it should be expected that other autoantibodies against PTM proteins could be discovered in patients with autoimmune diseases. Many of such autoantibodies may provide significant biomarker potential. PMID:24782594

Development of Platinum(iv) Complexes as Anticancer Prodrugs: the Story so Far

NASA Astrophysics Data System (ADS)

Wong, Daniel Yuan Qiang; Ang, Wee Han

2012-06-01

The serendipitous discovery of the antitumor properties of cisplatin by Barnett Rosenberg some forty years ago brought about a paradigm shift in the field of medicinal chemistry and challenged conventional thinking regarding the role of potentially toxic heavy metals in drugs. Platinum(II)-based anticancer drugs have since become some of the most effective and widely-used drugs in a clinician's arsenal and have saved countless lives. However, they are limited by high toxicity, severe side-effects and the incidence of drug resistance. In recent years, attention has shifted to stable platinum(IV) complexes as anticancer prodrugs. By exploiting the unique chemical and structural attributes of their scaffolds, these platinum(IV) prodrugs offer new strategies of targeting and killing cancer cells. This review summarizes the development of anticancer platinum(IV) prodrugs to date and some of the exciting strategies that utilise the platinum(IV) construct as targeted chemotherapeutic agents against cancer.

Antimycobacterial Metabolites from Marine Invertebrates.

PubMed

Daletos, Georgios; Ancheeva, Elena; Chaidir, Chaidir; Kalscheuer, Rainer; Proksch, Peter

2016-10-01

Marine organisms play an important role in natural product-based drug research due to accumulation of structurally unique and bioactive metabolites. The exploration of marine-derived compounds may significantly extend the scientific knowledge of potential scaffolds for antibiotic drug discovery. Development of novel antitubercular agents is especially significant as the emergence of drug-resistant Mycobacterium tuberculosis strains remains threateningly high. Marine invertebrates (i.e., sponges, corals, gorgonians) as a source of new chemical entities are the center of research for several scientific groups, and the wide spectrum of biological activities of marine-derived compounds encourages scientists to carry out investigations in the field of antibiotic research, including tuberculosis treatment. The present review covers published data on antitubercular natural products from marine invertebrates grouped according to their biogenetic origin. Studies on the structure-activity relationships of these important leads are highlighted as well. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Marine snail venoms: use and trends in receptor and channel neuropharmacology.

PubMed

Favreau, Philippe; Stöcklin, Reto

2009-10-01

Venoms are rich mixtures of mainly peptides and proteins evolved by nature to catch and digest preys or for protection against predators. They represent extensive sources of potent and selective bioactive compounds that can lead to original active ingredients, for use as drugs, as pharmacological tools in research and for the biotechnology industry. Among the most fascinating venomous animals, marine snails offer a unique set of pharmacologically active components, targeting a wide diversity of receptors and ion channels. Recent advances still continue to demonstrate their huge neuropharmacological potential. In the quest for interesting pharmacological profiles, researchers face a vast number of venom components to investigate within time and technological constraints. A brief perspective on marine snail venom's complexity and features is given followed by the different discovery strategies and pharmacological approaches, exemplified with some recent developments. These advances will hopefully help further uncovering new pharmacologically important venom molecules.

Accelerating Precision Drug Development and Drug Repurposing by Leveraging Human Genetics

PubMed Central

Shirey-Rice, Jana K.; Lavieri, Robert R.; Jerome, Rebecca N.; Zaleski, Nicole M.; Aronoff, David M.; Bastarache, Lisa; Niu, Xinnan; Holroyd, Kenneth J.; Roden, Dan M.; Skaar, Eric P.; Niswender, Colleen M.; Marnett, Lawrence J.; Lindsley, Craig W.; Ekstrom, Leeland B.; Bentley, Alan R.; Bernard, Gordon R.; Hong, Charles C.; Denny, Joshua C.

2017-01-01

Abstract The potential impact of using human genetic data linked to longitudinal electronic medical records on drug development is extraordinary; however, the practical application of these data necessitates some organizational innovations. Vanderbilt has created resources such as an easily queried database of >2.6 million de-identified electronic health records linked to BioVU, which is a DNA biobank with more than 230,000 unique samples. To ensure these data are used to maximally benefit and accelerate both de novo drug discovery and drug repurposing efforts, we created the Accelerating Drug Development and Repurposing Incubator, a multidisciplinary think tank of experts in various therapeutic areas within both basic and clinical science as well as experts in legal, business, and other operational domains. The Incubator supports a diverse pipeline of drug indication finding projects, leveraging the natural experiment of human genetics. PMID:28379727

Modeling ALS and FTD with iPSC-derived Neurons

PubMed Central

Lee, Sebum; Huang, Eric J.

2015-01-01

Recent advances in genetics and neuropathology support the idea that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTD) are two ends of a disease spectrum. Although several animal models have been developed to investigate the pathogenesis and disease progression in ALS and FTD, there are significant limitations that hamper our ability to connect these models with the neurodegenerative processes in human diseases. With the technical breakthrough in reprogramming biology, it is now possible to generate patient-specific induced pluripotent stem cells (iPSCs) and disease-relevant neuron subtypes. This review provides a comprehensive summary of studies that use iPSC-derived neurons to model ALS and FTD. We discuss the unique capabilities of iPSC-derived neurons that capture some key features of ALS and FTD, and underscore their potential roles in drug discovery. There are, however, several critical caveats that require improvements before iPSC-derived neurons can become highly effective disease models. PMID:26462653

Shifting the life-history paradigm: discovery of novel habitat use by hawksbill turtles

PubMed Central

Gaos, Alexander R.; Lewison, Rebecca L.; Yañez, Ingrid L.; Wallace, Bryan P.; Liles, Michael J.; Nichols, Wallace J.; Baquero, Andres; Hasbún, Carlos R.; Vasquez, Mauricio; Urteaga, José; Seminoff, Jeffrey A.

2012-01-01

Adult hawksbill turtles (Eretmochelys imbricata) are typically described as open-coast, coral reef and hard substrate dwellers. Here, we report new satellite tracking data on female hawksbills from several countries in the eastern Pacific that revealed previously undocumented behaviour for adults of the species. In contrast to patterns of habitat use exhibited by their Caribbean and Indo-Pacific counterparts, eastern Pacific hawksbills generally occupied inshore estuaries, wherein they had strong associations with mangrove saltwater forests. The use of inshore habitats and affinities with mangrove saltwater forests presents a previously unknown life-history paradigm for adult hawksbill turtles and suggests a potentially unique evolutionary trajectory for the species. Our findings highlight the variability in life-history strategies that marine turtles and other wide-ranging marine wildlife may exhibit among ocean regions, and the importance of understanding such disparities from an ecological and management perspective. PMID:21880620

Biopolymer Aerogels and Foams: Chemistry, Properties, and Applications.

PubMed

Zhao, Shanyu; Malfait, Wim J; Guerrero-Alburquerque, Natalia; Koebel, Matthias M; Nyström, Gustav

2018-06-25

Biopolymer aerogels were among the first aerogels produced, but only in the last decade has research on biopolymer and biopolymer-composite aerogels become popular, motivated by sustainability arguments, their unique and tunable properties, and ease of functionalization. Biopolymer aerogels and open-cell foams have great potential for classical aerogel applications such as thermal insulation, as well as emerging applications in filtration, oil-water separation, CO 2 capture, catalysis, and medicine. The biopolymer aerogel field today is driven forward by empirical materials discovery at the laboratory scale, but requires a firmer theoretical basis and pilot studies to close the gap to market. This Review includes a database with over 3800 biopolymer aerogel properties, evaluates the state of the biopolymer aerogel field, and critically discusses the scientific, technological, and commercial barriers to the commercialization of these exciting materials. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Investigation of the Anti-Prostate Cancer Properties of Marine-Derived Compounds

PubMed Central

Fan, Meiqi; Nath, Amit Kumar; Tang, Yujiao; Choi, Young-Jin; Debnath, Trishna; Choi, Eun-Ju

2018-01-01

This review focuses on marine compounds with anti-prostate cancer properties. Marine species are unique and have great potential for the discovery of anticancer drugs. Marine sources are taxonomically diverse and include bacteria, cyanobacteria, fungi, algae, and mangroves. Marine-derived compounds, including nucleotides, amides, quinones, polyethers, and peptides are biologically active compounds isolated from marine organisms such as sponges, ascidians, gorgonians, soft corals, and bryozoans, including those mentioned above. Several compound classes such as macrolides and alkaloids include drugs with anti-cancer mechanisms, such as antioxidants, anti-angiogenics, antiproliferatives, and apoptosis-inducing drugs. Despite the diversity of marine species, most marine-derived bioactive compounds have not yet been evaluated. Our objective is to explore marine compounds to identify new treatment strategies for prostate cancer. This review discusses chemically and pharmacologically diverse marine natural compounds and their sources in the context of prostate cancer drug treatment. PMID:29757237

Patient Electronic Health Records as a Means to Approach Genetic Research in Gastroenterology

PubMed Central

Ananthakrishnan, Ashwin N; Lieberman, David

2015-01-01

Electronic health records (EHR) are being increasingly utilized and form a unique source of extensive data gathered during routine clinical care. Through use of codified and free text concepts identified using clinical informatics tools, disease labels can be assigned with a high degree of accuracy. Analysis linking such EHR-assigned disease labels to a biospecimen repository has demonstrated that genetic associations identified in prospective cohorts can be replicated with adequate statistical power, and novel phenotypic associations identified. In addition, genetic discovery research can be performed utilizing clinical, laboratory, and procedure data obtained during care. Challenges with such research include the need to tackle variability in quality and quantity of EHR data and importance of maintaining patient privacy and data security. With appropriate safeguards, this novel and emerging field of research offers considerable promise and potential to further scientific research in gastroenterology efficiently, cost-effectively, and with engagement of patients and communities. PMID:26073373

Retrospective analysis of natural products provides insights for future discovery trends

PubMed Central

Pye, Cameron R.; Bertin, Matthew J.; Lokey, R. Scott; Gerwick, William H.

2017-01-01

Understanding of the capacity of the natural world to produce secondary metabolites is important to a broad range of fields, including drug discovery, ecology, biosynthesis, and chemical biology, among others. Both the absolute number and the rate of discovery of natural products have increased significantly in recent years. However, there is a perception and concern that the fundamental novelty of these discoveries is decreasing relative to previously known natural products. This study presents a quantitative examination of the field from the perspective of both number of compounds and compound novelty using a dataset of all published microbial and marine-derived natural products. This analysis aimed to explore a number of key questions, such as how the rate of discovery of new natural products has changed over the past decades, how the average natural product structural novelty has changed as a function of time, whether exploring novel taxonomic space affords an advantage in terms of novel compound discovery, and whether it is possible to estimate how close we are to having described all of the chemical space covered by natural products. Our analyses demonstrate that most natural products being published today bear structural similarity to previously published compounds, and that the range of scaffolds readily accessible from nature is limited. However, the analysis also shows that the field continues to discover appreciable numbers of natural products with no structural precedent. Together, these results suggest that the development of innovative discovery methods will continue to yield compounds with unique structural and biological properties. PMID:28461474

Polyaniline nanofibers: a unique polymer nanostructure for versatile applications.

PubMed

Li, Dan; Huang, Jiaxing; Kaner, Richard B

2009-01-20

Known for more than 150 years, polyaniline is the oldest and potentially one of the most useful conducting polymers because of its facile synthesis, environmental stability, and simple acid/base doping/dedoping chemistry. Because a nanoform of this polymer could offer new properties or enhanced performance, nanostructured polyaniline has attracted a great deal of interest during the past few years. This Account summarizes our recent research on the syntheses, processing, properties, and applications of polyaniline nanofibers. By monitoring the nucleation behavior of polyaniline, we demonstrate that high-quality nanofibers can be readily produced in bulk quantity using the conventional chemical oxidative polymerization of aniline. The polyaniline nanostructures formed using this simple method have led to a number of exciting discoveries. For example, we can readily prepare aqueous polyaniline colloids by purifying polyaniline nanofibers and controlling the pH. The colloids formed are self-stabilized via electrostatic repulsions without the need for any chemical modification or steric stabilizer, thus providing a simple and environmentally friendly way to process this polymer. An unusual nanoscale photothermal effect called "flash welding", which we discovered with polyaniline nanofibers, has led to the development of new techniques for making asymmetric polymer membranes and patterned nanofiber films and creating polymer-based nanocomposites. We also demonstrate the use of flash-welded polyaniline films for monolithic actuators. Taking advantage of the unique reduction/oxidation chemistry of polyaniline, we can decorate polyaniline nanofibers with metal nanoparticles through in situ reduction of selected metal salts. The resulting polyaniline/metal nanoparticle composites show promise for use in ultrafast nonvolatile memory devices and for chemical catalysis. In addition, the use of polyaniline nanofibers or their composites can significantly enhance the sensitivity, selectivity, and response time of polyaniline-based chemical sensors. By combining straightforward synthesis and composite formation with exceptional solution processability, we have developed a range of new useful functionalities. Further research on nanostructured conjugated polymers holds promise for even more exciting discoveries and intriguing applications.

A frozen super-Earth orbiting a star at the bottom of the main sequence

NASA Astrophysics Data System (ADS)

Kubas, D.; Beaulieu, J. P.; Bennett, D. P.; Cassan, A.; Cole, A.; Lunine, J.; Marquette, J. B.; Dong, S.; Gould, A.; Sumi, T.; Batista, V.; Fouqué, P.; Brillant, S.; Dieters, S.; Coutures, C.; Greenhill, J.; Bond, I.; Nagayama, T.; Udalski, A.; Pompei, E.; Nürnberger, D. E. A.; Le Bouquin, J. B.

2012-04-01

Context. Microlensing is a unique method to probe low mass exoplanets beyond the snow line. However, the scientific potential of the new microlensing planet discovery is often unfulfilled due to lack of knowledge of the properties of the lens and source stars. The discovery light curve of the super Earth MOA-2007-BLG-192Lb suffers from significant degeneracies that limit what can be inferred about its physical properties. Aims: High resolution adaptive optics images allow us to solve this problem by resolving the microlensing target from all unrelated background stars, yielding the unique determination of magnified source and lens fluxes. This estimation permits the solution of our microlens model for the mass of the planet and its host and their physical projected separation. Methods: We observed the microlensing event MOA-2007-BLG-192 at high angular resolution in JHKs with the NACO adaptive optics system on the VLT while the object was still amplified by a factor 1.23 and then at baseline 18 months later. We analyzed and calibrated the NACO photometry in the standard 2MASS system in order to accurately constrain the source and the lens star fluxes. Results: We detect light from the host star of MOA-2007-BLG-192Lb, which significantly reduces the uncertainties in its characteristics as compared to earlier analyses. We find that MOA-2007-BLG-192L is most likely a very low mass late type M-dwarf (0.084-0.012+0.015 M⊙) at a distance of 660-70+100 pc orbited by a 3.2-1.8+5.2 M⊕ super-Earth at 0.66-0.22+0.51 AU. We then discuss the properties of this cold planetary system. Based on observations under ESO Prog.IDs: 279.C-5044(A) and 383-C.0495(A).

A new species of karst-adapted Cnemaspis Strauch, 1887 (Squamata: Gekkonidae) from a threatened karst region in Pahang, Peninsular Malaysia.

PubMed

Grismer, L Lee; Wood, Perry L; Mohamed, Maketab; Chan, Kin Onn; Heinz, Heather M; Sumarli, Alex S-I; Chan, Jacob A; Loredo, Ariel I

2013-12-12

A new species of karst-adapted gekkonid lizard of the genus Cnemaspis Strauch is described from Gua Gunting and Gua Goyang in a karst region of Merapoh, Pahang, Peninsular Malaysia whose unique limestone formations are in immediate danger of being quarried. The new species differs from all other species of Cnemaspis based on its unique suite of morphological and color pattern characters. Its discovery underscores the unique biodiversity endemic to karst regions and adds to a growing list of karst-adapted reptiles from Peninsular Malaysia. We posit that new karst-adapted species endemic to limestone forests will continue to be discovered and these regions will harbor a significant percentage of Peninsular Malaysia's biodiversity and thusly should be conserved rather than quarried.

Searching for human oncoviruses: Histories, challenges, and opportunities.

PubMed

Cao, Jian; Li, Dawei

2018-06-01

Oncoviruses contribute significantly to cancer burden. A century of tumor virological studies have led to the discovery of seven well-accepted human oncoviruses, cumulatively responsible for approximately 15% of human cancer cases. Virus-caused cancers are largely preventable through vaccination. Identifying additional oncoviruses and virus-caused tumors will advance cancer prevention and precision medicine, benefiting affected individuals, and society as a whole. The historic success of finding human oncoviruses has provided a unique lesson for directing new research efforts in the post-sequencing era. Combing the experiences from these pioneer studies with emerging high-throughput techniques will certainly accelerate new discovery and advance our knowledge of the remaining human oncoviruses. © 2018 Wiley Periodicals, Inc.

Recent Advances in the Discovery and Development of Marine Natural Products with Cardiovascular Pharmacological Effects.

PubMed

Zhou, Jie-Bin; Luo, Rong; Zheng, Ying-Lin; Pang, Ji-Yan

2018-01-01

Numerous studies have indicated that marine natural products are one of the most important sources of the lead compounds in drug discovery for their unique structures, various bioactivities and less side effects. In this review, the marine natural products with cardiovascular pharmacological effects reported after 2000 will be presented. Their structural types, relevant biological activities, origin of isolation and information of strain species will be discussed in detail. Finally, by describing our studies as an example, we also discuss the chances and challenges for translating marine-derived compounds into preclinical or clinical trials. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Making Friends and Buying Robots: How to Leverage Collaborations and Collections to Support STEM Learning

ERIC Educational Resources Information Center

Kvenild, Cassandra; Shepherd, Craig E.; Smith, Shannon M.; Thielk, Emma

2017-01-01

In a climate of increased interest in science, technology, engineering, and math (STEM), school libraries have unique opportunities to grow collections and cultivate partnerships in the sciences. At the federal level and in many states, STEM initiatives encourage hands-on exposure to technologies and open the door for student-led discovery of…

Robert Curl, Jr. and the Discovery of Fullerenes

Science.gov Websites

produced thousands of variations of the buckyball, including carbon sheets one atom thick and microscopic equilibrium in the carbon vapor that allowed the group to identify a unique, 60-atom configuration of carbon Interview with Robert F. Curl, Jr., nobelprize.org (video) Interview with Robert Curl (video) Buckyballs

Discovery of the first telemid spider (Araneae, Telemidae) from South America, and the first member of the family bearing a stridulatory organ.

PubMed

Dupérré, Nadine; Tapia, Elicio

2015-09-21

The genus Kinku n. gen. is established for the first telemid spider found in South America. The new species, Kinku turumanya n. sp. is characterized by the unique conformation of the male palp and the presence of an abdominal anterioventral stridulatory organ.

The discovery of resistant sources of spring barley, Hordeum vulgare ssp. spontaneum, and unique greenbug biotypes

USDA-ARS?s Scientific Manuscript database

The genetic sources for host-plant resistance to the greenbug (Schiazphis graminum Ronani) in barley (Hordeum vulgare ssp. spontaneum) are limited in that only two single dominant genes Rsg1 and Rsg2 are available for resistance to greenbug biotypes. We evaluated four new barley lines from the Wild...

[Activity of NTDs Drug-discovery Research Consortium].

PubMed

Namatame, Ichiji

2016-01-01

Neglected tropical diseases (NTDs) are an extremely important issue facing global health care. To improve "access to health" where people are unable to access adequate medical care due to poverty and weak healthcare systems, we have established two consortiums: the NTD drug discovery research consortium, and the pediatric praziquantel consortium. The NTD drug discovery research consortium, which involves six institutions from industry, government, and academia, as well as an international non-profit organization, is committed to developing anti-protozoan active compounds for three NTDs (Leishmaniasis, Chagas disease, and African sleeping sickness). Each participating institute will contribute their efforts to accomplish the following: selection of drug targets based on information technology, and drug discovery by three different approaches (in silico drug discovery, "fragment evolution" which is a unique drug designing method of Astellas Pharma, and phenotypic screening with Astellas' compound library). The consortium has established a brand new database (Integrated Neglected Tropical Disease Database; iNTRODB), and has selected target proteins for the in silico and fragment evolution drug discovery approaches. Thus far, we have identified a number of promising compounds that inhibit the target protein, and we are currently trying to improve the anti-protozoan activity of these compounds. The pediatric praziquantel consortium was founded in July 2012 to develop and register a new praziquantel pediatric formulation for the treatment of schistosomiasis. Astellas Pharma has been a core member in this consortium since its establishment, and has provided expertise and technology in the area of pediatric formulation development and clinical development.

Discovery of a Thorne-Żytkow object candidate in the Small Magellanic Cloud

NASA Astrophysics Data System (ADS)

Levesque, Emily M.; Massey, Philip; Żytkow, Anna N.; Morrell, Nidia

2015-01-01

Thorne-Żytkow objects (TŻOs) are a theoretical class of star in which a compact neutron star is surrounded by a large, diffuse envelope. Supergiant TŻOs are predicted to be almost identical in appearance to red supergiants (RSGs), with their very red colors and cool temperatures placing them at the Hayashi limit on the H-R diagram. The only features that can be used at present to distinguish TŻOs from the general RSG population are the unusually strong heavy-element and lithium lines present in their spectra. These elements are the unique products of the stars fully convective envelope linking the photosphere with the extraordinarily hot burning region in the vicinity of the neutron star core. We have recently discovered a TŻO candidate in the Small Magellanic Cloud. It is the first star to display the distinctive chemical profile of anomalous element enhancements thought to be characteristic of TŻOs however, up-to-date models and additional observable predictions (including potential asteroseismological signatures) are required to solidify this discovery. The definitive detection of a TŻO would provide the first direct evidence for a completely new model of stellar interiors, a theoretically predicted fate for massive binary systems, and never-before-seen nucleosynthesis processes that would offer a new channel for heavy-element and lithium production in our universe.

Camelid Single-Domain Antibodies: Historical Perspective and Future Outlook

PubMed Central

Arbabi-Ghahroudi, Mehdi

2017-01-01

Tremendous effort has been expended over the past two and a half decades to understand many aspects of camelid heavy chain antibodies, from their biology, evolution, and immunogenetics to their potential applications in various fields of research and medicine. In this article, I present a historical perspective on the development of camelid single-domain antibodies (sdAbs or VHHs, also widely known as nanobodies) since their discovery and discuss the advantages and disadvantages of these unique molecules in various areas of research, industry, and medicine. Commercialization of camelid sdAbs exploded in 2001 with a flurry of patents issued to the Vrije Universiteit Brussel (VUB) and later taken on by the Vlaams Interuniversitair Instituut voor Biotechnologie (VIB) and, after 2002, the VIB-founded spin-off company, Ablynx. While entrepreneurial spirit has certainly catalyzed the exploration of nanobodies as marketable products, IP restrictions may be partially responsible for the relatively long time span between the discovery of these biomolecules and their entry into the pharmaceutical market. It is now anticipated that the first VHH-based antibody drug, Caplacizumab, a bivalent anti-vWF antibody for treating rare blood clotting disorders, may be approved and commercialized in 2018 or shortly thereafter. This elusive first approval, along with the expiry of key patents, may substantially alter the scientific and biomedical landscape surrounding camelid sdAbs and pave the way for their emergence as mainstream biotherapeutics. PMID:29209322

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.

A Proteomic Analysis of Eccrine Sweat: Implications for the Discovery of Schizophrenia Biomarker Proteins

PubMed Central

Raiszadeh, Michelle M.; Ross, Mark M.; Russo, Paul S.; Schaepper, Mary Ann H.; Zhou, Weidong; Deng, Jianghong; Ng, Daniel; Dickson, April; Dickson, Cindy; Strom, Monica; Osorio, Carolina; Soeprono, Thomas; Wulfkuhle, Julia D.; Kabbani, Nadine; Petricoin, Emanuel F.; Liotta, Lance A.; Kirsch, Wolff M.

2012-01-01

Liquid chromatography tandem mass spectrometry (LC-MS/MS) and multiple reaction monitoring mass spectrometry (MRM-MS) proteomics analyses were performed on eccrine sweat of healthy controls, and the results were compared with those from individuals diagnosed with schizophrenia (SZ). This is the first large scale study of the sweat proteome. First, we performed LC-MS/MS on pooled SZ samples and pooled control samples for global proteomics analysis. Results revealed a high abundance of diverse proteins and peptides in eccrine sweat. Most of the proteins identified from sweat samples were found to be different than the most abundant proteins from serum, which indicates that eccrine sweat is not simply a plasma transudate, and may thereby be a source of unique disease-associated biomolecules. A second independent set of patient and control sweat samples were analyzed by LC-MS/MS and spectral counting to determine qualitative protein differential abundances between the control and disease groups. Differential abundances of selected proteins, initially determined by spectral counting, were verified by MRM-MS analyses. Seventeen proteins showed a differential abundance of approximately two-fold or greater between the SZ pooled sample and the control pooled sample. This study demonstrates the utility of LC-MS/MS and MRM-MS as a viable strategy for the discovery and verification of potential sweat protein disease biomarkers. PMID:22256890

Nonhuman Primate Models and Understanding the Pathogenesis of HIV Infection and AIDS.

PubMed

Veazey, Ronald S; Lackner, Andrew A

2017-12-01

Research using nonhuman primates (NHPs) as models for human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) has resulted in tremendous achievements not only in the prevention and treatment of HIV, but also in biomedical research more broadly. Once considered a death sentence, HIV infection is now fairly well controlled with combination antiretroviral treatments, almost all of which were first tested for efficacy and safety in nonhuman primates or other laboratory animals. Research in NHP has led to "dogma changing" discoveries in immunology, infectious disease, and even our own genetics. We now know that many of our genes are retroviral remnants, or developed in response to archaic HIV-like retroviral infections. Early studies involving blood from HIV patients and in experiments in cultured tissues contributed to confusion regarding the cause of AIDS and impeded progress in the development of effective interventions. Research on the many retroviruses of different NHP species have broadened our understanding of human immunology and perhaps even our origins and evolution as a species. In combination with recent advances in molecular biology and computational analytics, research in NHPs has unique potential for discoveries that will directly lead to new cures for old human and animal diseases, including HIV/AIDS. © The Author 2017. Published by Oxford University Press on behalf of the National Academy of Sciences. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Generation and analysis of expressed sequence tags from a cDNA library of the fruiting body of Ganoderma lucidum

PubMed Central

2010-01-01

Background Little genomic or trancriptomic information on Ganoderma lucidum (Lingzhi) is known. This study aims to discover the transcripts involved in secondary metabolite biosynthesis and developmental regulation of G. lucidum using an expressed sequence tag (EST) library. Methods A cDNA library was constructed from the G. lucidum fruiting body. Its high-quality ESTs were assembled into unique sequences with contigs and singletons. The unique sequences were annotated according to sequence similarities to genes or proteins available in public databases. The detection of simple sequence repeats (SSRs) was preformed by online analysis. Results A total of 1,023 clones were randomly selected from the G. lucidum library and sequenced, yielding 879 high-quality ESTs. These ESTs showed similarities to a diverse range of genes. The sequences encoding squalene epoxidase (SE) and farnesyl-diphosphate synthase (FPS) were identified in this EST collection. Several candidate genes, such as hydrophobin, MOB2, profilin and PHO84 were detected for the first time in G. lucidum. Thirteen (13) potential SSR-motif microsatellite loci were also identified. Conclusion The present study demonstrates a successful application of EST analysis in the discovery of transcripts involved in the secondary metabolite biosynthesis and the developmental regulation of G. lucidum. PMID:20230644

Digital Astronaut Photography: A Discovery Dataset for Archaeology

NASA Technical Reports Server (NTRS)

Stefanov, William L.

2010-01-01

Astronaut photography acquired from the International Space Station (ISS) using commercial off-the-shelf cameras offers a freely-accessible source for high to very high resolution (4-20 m/pixel) visible-wavelength digital data of Earth. Since ISS Expedition 1 in 2000, over 373,000 images of the Earth-Moon system (including land surface, ocean, atmospheric, and lunar images) have been added to the Gateway to Astronaut Photography of Earth online database (http://eol.jsc.nasa.gov ). Handheld astronaut photographs vary in look angle, time of acquisition, solar illumination, and spatial resolution. These attributes of digital astronaut photography result from a unique combination of ISS orbital dynamics, mission operations, camera systems, and the individual skills of the astronaut. The variable nature of astronaut photography makes the dataset uniquely useful for archaeological applications in comparison with more traditional nadir-viewing multispectral datasets acquired from unmanned orbital platforms. For example, surface features such as trenches, walls, ruins, urban patterns, and vegetation clearing and regrowth patterns may be accentuated by low sun angles and oblique viewing conditions (Fig. 1). High spatial resolution digital astronaut photographs can also be used with sophisticated land cover classification and spatial analysis approaches like Object Based Image Analysis, increasing the potential for use in archaeological characterization of landscapes and specific sites.

Constraining Binary Asteroid Mass Distributions Based On Mutual Motion

NASA Astrophysics Data System (ADS)

Davis, Alex B.; Scheeres, Daniel J.

2017-06-01

The mutual gravitational potential and torques of binary asteroid systems results in a complex coupling of attitude and orbital motion based on the mass distribution of each body. For a doubly-synchronous binary system observations of the mutual motion can be leveraged to identify and measure the unique mass distributions of each body. By implementing arbitrary shape and order computation of the full two-body problem (F2BP) equilibria we study the influence of asteroid asymmetries on separation and orientation of a doubly-synchronous system. Additionally, simulations of binary systems perturbed from doubly-synchronous behavior are studied to understand the effects of mass distribution perturbations on precession and nutation rates such that unique behaviors can be isolated and used to measure asteroid mass distributions. We apply our investigation to the Trojan binary asteroid system 617 Patroclus and Menoetius (1906 VY), which will be the final flyby target of the recently announced LUCY Discovery mission in March 2033. This binary asteroid system is of particular interest due to the results of a recent stellar occultation study (DPS 46, id.506.09) that suggests the system to be doubly-synchronous and consisting of two-similarly sized oblate ellipsoids, in addition to suggesting the presence mass asymmetries resulting from an impact crater on the southern limb of Menoetius.

Adaptive cultural transmission biases in children and nonhuman primates.

PubMed

Price, Elizabeth E; Wood, Lara A; Whiten, Andrew

2017-08-01

Comparative and evolutionary developmental analyses seek to discover the similarities and differences between humans and non-human species that might illuminate both the evolutionary foundations of our nature that we share with other animals, and the distinctive characteristics that make human development unique. As our closest animal relatives, with whom we last shared common ancestry, non-human primates have been particularly important in this endeavour. Such studies have focused on social learning, traditions, and culture, and have discovered much about the 'how' of social learning, concerned with key underlying processes such as imitation and emulation. One of the core discoveries is that the adaptive adjustment of social learning options to different contexts is not unique to human, therefore multiple new strands of research have begun to focus on more subtle questions about when, from whom, and why such learning occurs. Here we review illustrative studies on both human infants and young children and on non-human primates to identify the similarities shared more broadly across the primate order, and the apparent specialisms that distinguish human development. Adaptive biases in social learning discussed include those modulated by task comprehension, experience, conformity to majorities, and the age, skill, proficiency and familiarity of potential alternative cultural models. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

The Diagnostic and Prognostic Role of microRNA in Colorectal Cancer - a Comprehensive review

PubMed Central

Mazeh, Haggi; Mizrahi, Ido; Ilyayev, Nadia; Halle, David; Brücher, Björn LDM; Bilchik, Anton; Protic, Mladjan; Daumer, Martin; Stojadinovic, Alexander; Avital, Itzhak; Nissan, Aviram

2013-01-01

The discovery of microRNA, a group of regulatory short RNA fragments, has added a new dimension to the diagnosis and management of neoplastic diseases. Differential expression of microRNA in a unique pattern in a wide range of tumor types enables researches to develop a microRNA-based assay for source identification of metastatic disease of unknown origin. This is just one example of many microRNA-based cancer diagnostic and prognostic assays in various phases of clinical research. Since colorectal cancer (CRC) is a phenotypic expression of multiple molecular pathways including chromosomal instability (CIN), micro-satellite instability (MIS) and CpG islands promoter hypermethylation (CIMP), there is no one-unique pattern of microRNA expression expected in this disease and indeed, there are multiple reports published, describing different patterns of microRNA expression in CRC. The scope of this manuscript is to provide a comprehensive review of the scientific literature describing the dysregulation of and the potential role for microRNA in the management of CRC. A Pubmed search was conducted using the following MeSH terms, "microRNA" and "colorectal cancer". Of the 493 publications screened, there were 57 papers describing dysregulation of microRNA in CRC. PMID:23459799

RNA as a stable polymer to build controllable and defined nanostructures for material and biomedical applications

PubMed Central

Li, Hui; Lee, Taek; Dziubla, Thomas; Pi, Fengmei; Guo, Sijin; Xu, Jing; Li, Chan; Haque, Farzin; Liang, Xing-Jie; Guo, Peixuan

2015-01-01

Summary The value of polymers is manifested in their vital use as building blocks in material and life sciences. Ribonucleic acid (RNA) is a polynucleic acid, but its polymeric nature in materials and technological applications is often overlooked due to an impression that RNA is seemingly unstable. Recent findings that certain modifications can make RNA resistant to RNase degradation while retaining its authentic folding property and biological function, and the discovery of ultra-thermostable RNA motifs have adequately addressed the concerns of RNA unstability. RNA can serve as a unique polymeric material to build varieties of nanostructures including nanoparticles, polygons, arrays, bundles, membrane, and microsponges that have potential applications in biomedical and material sciences. Since 2005, more than a thousand publications on RNA nanostructures have been published in diverse fields, indicating a remarkable increase of interest in the emerging field of RNA nanotechnology. In this review, we aim to: delineate the physical and chemical properties of polymers that can be applied to RNA; introduce the unique properties of RNA as a polymer; review the current methods for the construction of RNA nanostructures; describe its applications in material, biomedical and computer sciences; and, discuss the challenges and future prospects in this field. PMID:26770259

Linking climate and environmental factors to the recent and surprising growth increase of red spruce trees across the northeastern US

NASA Astrophysics Data System (ADS)

Kosiba, A. M.; Schaberg, P. G.; Rayback, S. A.; Hawley, G. J.

2016-12-01

Recent investigations have uncovered an unanticipated trend: red spruce (Picea rubens Sarg.) trees in the northeastern US are undergoing a marked surge in growth. This discovery stands in contrast to the declines in growth and vigor for red spruce that were documented in the second half of the 20th century and quantitatively attributed to acid deposition-induced calcium depletion. Further, predictions of potential habitat due to climate change depict red spruce habitat constricting from low elevations and latitudes. Considering these conflicting findings, we asked: what factors are most likely stimulating growth increases for red spruce trees? Here we use a uniquely large and both spatially- and temporally-explicit tree ring dataset to assess changes in red spruce growth over time. We compare patterns in growth to local weather data, atmospheric deposition rates, and other environmental and forest-stand metrics, including nutrient soil status and buffering capacity. These results allow us to model areas in the region where we predict similar growth increases for red spruce trees. Through this study, we suggest that this temperate conifer may be uniquely posed to benefit from a lengthened functional growing season, increased annual temperatures, particularly in winter, and decreased atmospheric pollution levels that proved problematic in the past.

Comparative mass spectrometry-based metabolomics strategies for the investigation of microbial secondary metabolites.

PubMed

Covington, Brett C; McLean, John A; Bachmann, Brian O

2017-01-04

Covering: 2000 to 2016The labor-intensive process of microbial natural product discovery is contingent upon identifying discrete secondary metabolites of interest within complex biological extracts, which contain inventories of all extractable small molecules produced by an organism or consortium. Historically, compound isolation prioritization has been driven by observed biological activity and/or relative metabolite abundance and followed by dereplication via accurate mass analysis. Decades of discovery using variants of these methods has generated the natural pharmacopeia but also contributes to recent high rediscovery rates. However, genomic sequencing reveals substantial untapped potential in previously mined organisms, and can provide useful prescience of potentially new secondary metabolites that ultimately enables isolation. Recently, advances in comparative metabolomics analyses have been coupled to secondary metabolic predictions to accelerate bioactivity and abundance-independent discovery work flows. In this review we will discuss the various analytical and computational techniques that enable MS-based metabolomic applications to natural product discovery and discuss the future prospects for comparative metabolomics in natural product discovery.

A scientometric prediction of the discovery of the first potentially habitable planet with a mass similar to Earth.

PubMed

Arbesman, Samuel; Laughlin, Gregory

2010-10-04

The search for a habitable extrasolar planet has long interested scientists, but only recently have the tools become available to search for such planets. In the past decades, the number of known extrasolar planets has ballooned into the hundreds, and with it, the expectation that the discovery of the first Earth-like extrasolar planet is not far off. Here, we develop a novel metric of habitability for discovered planets and use this to arrive at a prediction for when the first habitable planet will be discovered. Using a bootstrap analysis of currently discovered exoplanets, we predict the discovery of the first Earth-like planet to be announced in the first half of 2011, with the likeliest date being early May 2011. Our predictions, using only the properties of previously discovered exoplanets, accord well with external estimates for the discovery of the first potentially habitable extrasolar planet and highlight the the usefulness of predictive scientometric techniques to understand the pace of scientific discovery in many fields.

Identification and characterization of potential druggable targets among hypothetical proteins of extensively drug resistant Mycobacterium tuberculosis (XDR KZN 605) through subtractive genomics approach.

PubMed

Uddin, Reaz; Siddiqui, Quratulain Nehal; Azam, Syed Sikander; Saima, Bibi; Wadood, Abdul

2018-03-01

Among the resistant isolates of tuberculosis (TB), the multidrug resistance tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) are the areas of growing concern for which the front-line antibiotics are no more effective. As a result, the search of new therapeutic targets against TB is an imperative need of time. On the other hand, the target identification is an a priori step in drug discovery based research. Furthermore, the availability of the complete proteomic data of extensively drug resistant Mycobacterium tuberculosis (XDR-MTB) made it possible to carry out in silico analysis for the discovery of new drug targets. In the current study, we aimed to prioritize the potential drug targets among the hypothetical proteins of XDR-TB via subtractive genomics approach. In the subtractive genomics, we stepwise reduced the complete proteome of XDR-MTB to only two hypothetical proteins and evidently proposed them as new therapeutic targets. The 3D structure of one of the two target proteins was predicted via homology modeling and later on, validated by various analysis tools. Our study suggested that the domains identified and the motif hits found in the sequences of the shortlisted drug targets are crucial for the survival of the XDR-MTB. To the best of our knowledge, the current study is the first attempt in which the complete proteomic data of XDR-MTB was subjected to the computational subtractive genomics approach and therefore, would provide an opportunity to identify the unique therapeutic targets against deadly XDR-MTB. Copyright © 2017 Elsevier B.V. All rights reserved.

Discovery of New Hydrothermal Activity and Chemosynthetic Fauna on the Central Indian Ridge at 18°–20°S

PubMed Central

Nakamura, Kentaro; Watanabe, Hiromi; Miyazaki, Junichi; Takai, Ken; Kawagucci, Shinsuke; Noguchi, Takuro; Nemoto, Suguru; Watsuji, Tomo-o; Matsuzaki, Takuya; Shibuya, Takazo; Okamura, Kei; Mochizuki, Masashi; Orihashi, Yuji; Ura, Tamaki; Asada, Akira; Marie, Daniel; Koonjul, Meera; Singh, Manvendra; Beedessee, Girish; Bhikajee, Mitrasen; Tamaki, Kensaku

2012-01-01

Indian Ocean hydrothermal vents are believed to represent a novel biogeographic province, and are host to many novel genera and families of animals, potentially indigenous to Indian Ocean hydrothermal systems. In particular, since its discovery in 2001, much attention has been paid to a so-called ‘scaly-foot’ gastropod because of its unique iron-sulfide-coated dermal sclerites and the chemosynthetic symbioses in its various tissues. Despite increasing interest in the faunal assemblages at Indian Ocean hydrothermal vents, only two hydrothermal vent fields have been investigated in the Indian Ocean. Here we report two newly discovered hydrothermal vent fields, the Dodo and Solitaire fields, which are located in the Central Indian Ridge (CIR) segments 16 and 15, respectively. Chemosynthetic faunal communities at the Dodo field are emaciated in size and composition. In contrast, at the Solitaire field, we observed faunal communities that potentially contained almost all genera found at CIR hydrothermal environments to date, and even identified previously unreported taxa. Moreover, a new morphotype of ‘scaly-foot’ gastropod has been found at the Solitaire field. The newly discovered ‘scaly-foot’ gastropod has similar morphological and anatomical features to the previously reported type that inhabits the Kairei field, and both types of ‘scaly-foot’ gastropods genetically belong to the same species according to analyses of their COI gene and nuclear SSU rRNA gene sequences. However, the new morphotype completely lacks an iron-sulfide coating on the sclerites, which had been believed to be a novel feature restricted to ‘scaly-foot’ gastropods. Our new findings at the two newly discovered hydrothermal vent sites provide important insights into the biodiversity and biogeography of vent-endemic ecosystems in the Indian Ocean. PMID:22431990

Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs.

PubMed

Löscher, Wolfgang

2017-07-01

The identification of potential therapeutic agents for the treatment of epilepsy requires the use of seizure models. Except for some early treatments, including bromides and phenobarbital, the antiseizure activity of all clinically used drugs was, for the most part, defined by acute seizure models in rodents using the maximal electroshock and subcutaneous pentylenetetrazole seizure tests and the electrically kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage patients with drug resistant seizures. Over the last 30 years, a number of animal models have been developed that display varying degrees of pharmacoresistance, such as the phenytoin- or lamotrigine-resistant kindled rat, the 6-Hz mouse model of partial seizures, the intrahippocampal kainate model in mice, or rats in which spontaneous recurrent seizures develops after inducing status epilepticus by chemical or electrical stimulation. As such, these models can be used to study mechanisms of drug resistance and may provide a unique opportunity for identifying a truly novel antiseizure drug (ASD), but thus far clinical evidence for this hope is lacking. Although animal models of drug resistant seizures are now included in ASD discovery approaches such as the ETSP (epilepsy therapy screening program), it is important to note that no single model has been validated for use to identify potential compounds for as yet drug resistant seizures, but rather a battery of such models should be employed, thus enhancing the sensitivity to discover novel, highly effective ASDs. The present review describes the previous and current approaches used in the search for new ASDs and offers some insight into future directions incorporating new and emerging animal models of therapy resistance.

A Feathered Dinosaur Tail with Primitive Plumage Trapped in Mid-Cretaceous Amber.

PubMed

Xing, Lida; McKellar, Ryan C; Xu, Xing; Li, Gang; Bai, Ming; Persons, W Scott; Miyashita, Tetsuto; Benton, Michael J; Zhang, Jianping; Wolfe, Alexander P; Yi, Qiru; Tseng, Kuowei; Ran, Hao; Currie, Philip J

2016-12-19

In the two decades since the discovery of feathered dinosaurs [1-3], the range of plumage known from non-avialan theropods has expanded significantly, confirming several features predicted by developmentally informed models of feather evolution [4-10]. However, three-dimensional feather morphology and evolutionary patterns remain difficult to interpret, due to compression in sedimentary rocks [9, 11]. Recent discoveries in Cretaceous amber from Canada, France, Japan, Lebanon, Myanmar, and the United States [12-18] reveal much finer levels of structural detail, but taxonomic placement is uncertain because plumage is rarely associated with identifiable skeletal material [14]. Here we describe the feathered tail of a non-avialan theropod preserved in mid-Cretaceous (∼99 Ma) amber from Kachin State, Myanmar [17], with plumage structure that directly informs the evolutionary developmental pathway of feathers. This specimen provides an opportunity to document pristine feathers in direct association with a putative juvenile coelurosaur, preserving fine morphological details, including the spatial arrangement of follicles and feathers on the body, and micrometer-scale features of the plumage. Many feathers exhibit a short, slender rachis with alternating barbs and a uniform series of contiguous barbules, supporting the developmental hypothesis that barbs already possessed barbules when they fused to form the rachis [19]. Beneath the feathers, carbonized soft tissues offer a glimpse of preservational potential and history for the inclusion; abundant Fe 2+ suggests that vestiges of primary hemoglobin and ferritin remain trapped within the tail. The new finding highlights the unique preservation potential of amber for understanding the morphology and evolution of coelurosaurian integumentary structures. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

Microfluidics for Drug Discovery and Development: From Target Selection to Product Lifecycle Management

PubMed Central

Kang, Lifeng; Chung, Bong Geun; Langer, Robert; Khademhosseini, Ali

2009-01-01

Microfluidic technologies’ ability to miniaturize assays and increase experimental throughput have generated significant interest in the drug discovery and development domain. These characteristics make microfluidic systems a potentially valuable tool for many drug discovery and development applications. Here, we review the recent advances of microfluidic devices for drug discovery and development and highlight their applications in different stages of the process, including target selection, lead identification, preclinical tests, clinical trials, chemical synthesis, formulations studies, and product management. PMID:18190858

Systems biology-embedded target validation: improving efficacy in drug discovery.

PubMed

Vandamme, Drieke; Minke, Benedikt A; Fitzmaurice, William; Kholodenko, Boris N; Kolch, Walter

2014-01-01

The pharmaceutical industry is faced with a range of challenges with the ever-escalating costs of drug development and a drying out of drug pipelines. By harnessing advances in -omics technologies and moving away from the standard, reductionist model of drug discovery, there is significant potential to reduce costs and improve efficacy. Embedding systems biology approaches in drug discovery, which seek to investigate underlying molecular mechanisms of potential drug targets in a network context, will reduce attrition rates by earlier target validation and the introduction of novel targets into the currently stagnant market. Systems biology approaches also have the potential to assist in the design of multidrug treatments and repositioning of existing drugs, while stratifying patients to give a greater personalization of medical treatment. © 2013 Wiley Periodicals, Inc.

Year of the Solar System: New Worlds, New Discoveries and Why People Should Care (Invited)

NASA Astrophysics Data System (ADS)

Green, J. L.; Adams, J.; McCuistion, D.; Erickson, K. J.

2010-12-01

The next two years represents a historic time in planetary science. In order to better communicate this period to our target audiences, NASA’s Planetary Science Division created the Year of the Solar System (YSS) initiative. YSS is being designed to raise awareness, build excitement and make connections with educators, students and the American public about planetary science events and discoveries. Over the next Martian year, with our international partners we will encounter two comets; orbit spacecraft around Venus, Mercury and Vesta; continue to explore Mars with rovers; and launch robotic explorers to Jupiter, Earth’s moon, and Mars. For the first time ever NASA will launch three planetary missions within four months of each other! With the successful accomplishment of these mission events will come a series of fabulous scientific discoveries. We must take advantage of this unique opportunity to get the word out about the scientific revolution occurring in planetary science. This presentation will also discuss the importance of providing relatable material through Earth analogs, comparative visuals, interactive web-based tools and other ideas to communicate, why people should care about these exciting discoveries to come.

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

Minireview: More Than Just a Hammer: Ligand “Bias” and Pharmaceutical Discovery

PubMed Central

2014-01-01

Conventional orthosteric drug development programs targeting G protein-coupled receptors (GPCRs) have focused on the concepts of agonism and antagonism, in which receptor structure determines the nature of the downstream signal and ligand efficacy determines its intensity. Over the past decade, the emerging paradigms of “pluridimensional efficacy” and “functional selectivity” have revealed that GPCR signaling is not monolithic, and that ligand structure can “bias” signal output by stabilizing active receptor states in different proportions than the native ligand. Biased ligands are novel pharmacologic entities that possess the unique ability to qualitatively change GPCR signaling, in effect creating “new receptors” with distinct efficacy profiles driven by ligand structure. The promise of biased agonism lies in this ability to engender “mixed” effects not attainable using conventional agonists or antagonists, promoting therapeutically beneficial signals while antagonizing deleterious ones. Indeed, arrestin pathway-selective agonists for the type 1 parathyroid hormone and angiotensin AT1 receptors, and G protein pathway-selective agonists for the GPR109A nicotinic acid and μ-opioid receptors, have demonstrated unique, and potentially therapeutic, efficacy in cell-based assays and preclinical animal models. Conversely, activating GPCRs in “unnatural” ways may lead to downstream biological consequences that cannot be predicted from prior knowledge of the actions of the native ligand, especially in the case of ligands that selectively activate as-yet poorly characterized G protein-independent signaling networks mediated via arrestins. Although much needs to be done to realize the clinical potential of functional selectivity, biased GPCR ligands nonetheless appear to be important new additions to the pharmacologic toolbox. PMID:24433041

A base-modified PNA-graphene oxide platform as a turn-on fluorescence sensor for the detection of human telomeric repeats

NASA Astrophysics Data System (ADS)

Sabale, Pramod M.; George, Jerrin Thomas; Srivatsan, Seergazhi G.

2014-08-01

Given the biological and therapeutic significance of telomeres and other G-quadruplex forming sequences in human genome, it is highly desirable to develop simple methods to study these structures, which can also be implemented in screening formats for the discovery of G-quadruplex binders. The majority of telomere detection methods developed so far are laborious and use elaborate assay and instrumental setups, and hence, are not amenable to discovery platforms. Here, we describe the development of a simple homogeneous fluorescence turn-on method, which uses a unique combination of an environment-sensitive fluorescent nucleobase analogue, the superior base pairing property of PNA, and DNA-binding and fluorescence quenching properties of graphene oxide, to detect human telomeric DNA repeats of varying lengths. Our results demonstrate that this method, which does not involve a rigorous assay setup, would provide new opportunities to study G-quadruplex structures.Given the biological and therapeutic significance of telomeres and other G-quadruplex forming sequences in human genome, it is highly desirable to develop simple methods to study these structures, which can also be implemented in screening formats for the discovery of G-quadruplex binders. The majority of telomere detection methods developed so far are laborious and use elaborate assay and instrumental setups, and hence, are not amenable to discovery platforms. Here, we describe the development of a simple homogeneous fluorescence turn-on method, which uses a unique combination of an environment-sensitive fluorescent nucleobase analogue, the superior base pairing property of PNA, and DNA-binding and fluorescence quenching properties of graphene oxide, to detect human telomeric DNA repeats of varying lengths. Our results demonstrate that this method, which does not involve a rigorous assay setup, would provide new opportunities to study G-quadruplex structures. Electronic supplementary information (ESI) available. Figures, tables, experimental procedures and NMR spectra. See DOI: 10.1039/c4nr00878b

Optimal False Discovery Rate Control for Dependent Data

PubMed Central

Xie, Jichun; Cai, T. Tony; Maris, John; Li, Hongzhe

2013-01-01

This paper considers the problem of optimal false discovery rate control when the test statistics are dependent. An optimal joint oracle procedure, which minimizes the false non-discovery rate subject to a constraint on the false discovery rate is developed. A data-driven marginal plug-in procedure is then proposed to approximate the optimal joint procedure for multivariate normal data. It is shown that the marginal procedure is asymptotically optimal for multivariate normal data with a short-range dependent covariance structure. Numerical results show that the marginal procedure controls false discovery rate and leads to a smaller false non-discovery rate than several commonly used p-value based false discovery rate controlling methods. The procedure is illustrated by an application to a genome-wide association study of neuroblastoma and it identifies a few more genetic variants that are potentially associated with neuroblastoma than several p-value-based false discovery rate controlling procedures. PMID:23378870

Scientific Discoveries: What Is Required for Lasting Impact.

PubMed

Lømo, Terje

2016-01-01

I have been involved in two scientific discoveries of some impact. One is the discovery of long-term potentiation (LTP), the phenomenon that brief, high-frequency impulse activity at synapses in the brain can lead to long-lasting increases in their efficiency of transmission. This finding demonstrated that synapses are plastic, a property thought to be necessary for learning and memory. The other discovery is that nerve-evoked muscle impulse activity, rather than putative trophic factors, controls the properties of muscle fibers. Here I describe how these two discoveries were made, the unexpected difficulties of reproducing the first discovery, and the controversies that followed the second discovery. I discuss why the first discovery took many years to become generally recognized, whereas the second caused an immediate sensation and entered textbooks and major reviews but is now largely forgotten. In the long run, discovering a new phenomenon has greater impact than falsifying a popular hypothesis.

Potential biological targets for bioassay development in drug discovery of Sturge-Weber syndrome.

PubMed

Mohammadipanah, Fatemeh; Salimi, Fatemeh

2018-02-01

Sturge-Weber Syndrome (SWS) is a neurocutaneous disease with clinical manifestations including ocular (glaucoma), cutaneous (port-wine birthmark), neurologic (seizures), and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against its progression. Development of such platforms of bioassay can bring along the implementation of high-throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of molecular targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholinesterase, alkaline phosphatase, GABAergic receptors, Hypoxia-Inducible Factor (HIF)-1α and 2α are suggested. © 2017 John Wiley & Sons A/S.

Lafora disease offers a unique window into neuronal glycogen metabolism.

PubMed

Gentry, Matthew S; Guinovart, Joan J; Minassian, Berge A; Roach, Peter J; Serratosa, Jose M

2018-05-11

Lafora disease (LD) is a fatal, autosomal recessive, glycogen-storage disorder that manifests as severe epilepsy. LD results from mutations in the gene encoding either the glycogen phosphatase laforin or the E3 ubiquitin ligase malin. Individuals with LD develop cytoplasmic, aberrant glycogen inclusions in nearly all tissues that more closely resemble plant starch than human glycogen. This Minireview discusses the unique window into glycogen metabolism that LD research offers. It also highlights recent discoveries, including that glycogen contains covalently bound phosphate and that neurons synthesize glycogen and express both glycogen synthase and glycogen phosphorylase. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Harnessing the potential of natural products in drug discovery from a cheminformatics vantage point.

PubMed

Rodrigues, Tiago

2017-11-15

Natural products (NPs) present a privileged source of inspiration for chemical probe and drug design. Despite the biological pre-validation of the underlying molecular architectures and their relevance in drug discovery, the poor accessibility to NPs, complexity of the synthetic routes and scarce knowledge of their macromolecular counterparts in phenotypic screens still hinder their broader exploration. Cheminformatics algorithms now provide a powerful means of circumventing the abovementioned challenges and unlocking the full potential of NPs in a drug discovery context. Herein, I discuss recent advances in the computer-assisted design of NP mimics and how artificial intelligence may accelerate future NP-inspired molecular medicine.

A brief history of Alzheimer's disease gene discovery.

PubMed

Tanzi, Rudolph E

2013-01-01

The rich and colorful history of gene discovery in Alzheimer's disease (AD) over the past three decades is as complex and heterogeneous as the disease, itself. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations inAPP, PSEN1, and PSEN2 are fully penetrant for early-onset (<60 years) familial AD, which represents <5% of AD. On the other hand, common gene polymorphisms, such as the 4 and 2 variants of the APOE gene, influence susceptibility for common (>95%) late-onset AD. These four genes account for 30-50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of additional highly confirmed AD candidate genes. Here, I review the past, present, and future of attempts to elucidate the complex and heterogeneous genetic underpinnings of AD along with some of the unique events that made these discoveries possible.

The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis.

PubMed

Wacleche, Vanessa Sue; Landay, Alan; Routy, Jean-Pierre; Ancuta, Petronela

2017-10-19

The T helper 17 (Th17) cells represent a subset of CD4+ T-cells with unique effector functions, developmental plasticity, and stem-cell features. Th17 cells bridge innate and adaptive immunity against fungal and bacterial infections at skin and mucosal barrier surfaces. Although Th17 cells have been extensively studied in the context of autoimmunity, their role in various other pathologies is underexplored and remains an area of open investigation. This review summarizes the history of Th17 cell discovery and the current knowledge relative to the beneficial role of Th17 cells in maintaining mucosal immunity homeostasis. We further discuss the concept of Th17 pathogenicity in the context of autoimmunity, cancer, and HIV infection, and we review the most recent discoveries on molecular mechanisms regulating HIV replication/persistence in pathogenic Th17 cells. Finally, we stress the need for novel fundamental research discovery-based Th17-specific therapeutic interventions to treat pathogenic conditions associated with Th17 abnormalities, including HIV infection.

Induced Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Neurodegenerative Diseases.

PubMed

Cao, Lei; Tan, Lan; Jiang, Teng; Zhu, Xi-Chen; Yu, Jin-Tai

2015-08-01

Although most neurodegenerative diseases have been closely related to aberrant accumulation of aggregation-prone proteins in neurons, understanding their pathogenesis remains incomplete, and there is no treatment to delay the onset or slow the progression of many neurodegenerative diseases. The availability of induced pluripotent stem cells (iPSCs) in recapitulating the phenotypes of several late-onset neurodegenerative diseases marks the new era in in vitro modeling. The iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in these diseases and provides a novel human stem cell platform for screening new candidate therapeutics. Modeling human diseases using iPSCs has created novel opportunities for both mechanistic studies as well as for the discovery of new disease therapies. In this review, we introduce iPSC-based disease modeling in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In addition, we discuss the implementation of iPSCs in drug discovery associated with some new techniques.

RAS - Screens & Assays - Drug Discovery

Cancer.gov

The RAS Drug Discovery group aims to develop assays that will reveal aspects of RAS biology upon which cancer cells depend. Successful assay formats are made available for high-throughput screening programs to yield potentially effective drug compounds.

Quantifying the Ease of Scientific Discovery

PubMed Central

Arbesman, Samuel

2012-01-01

It has long been known that scientific output proceeds on an exponential increase, or more properly, a logistic growth curve. The interplay between effort and discovery is clear, and the nature of the functional form has been thought to be due to many changes in the scientific process over time. Here I show a quantitative method for examining the ease of scientific progress, another necessary component in understanding scientific discovery. Using examples from three different scientific disciplines – mammalian species, chemical elements, and minor planets – I find the ease of discovery to conform to an exponential decay. In addition, I show how the pace of scientific discovery can be best understood as the outcome of both scientific output and ease of discovery. A quantitative study of the ease of scientific discovery in the aggregate, such as done here, has the potential to provide a great deal of insight into both the nature of future discoveries and the technical processes behind discoveries in science. PMID:22328796

Quantifying the Ease of Scientific Discovery.

PubMed

Arbesman, Samuel

2011-02-01

It has long been known that scientific output proceeds on an exponential increase, or more properly, a logistic growth curve. The interplay between effort and discovery is clear, and the nature of the functional form has been thought to be due to many changes in the scientific process over time. Here I show a quantitative method for examining the ease of scientific progress, another necessary component in understanding scientific discovery. Using examples from three different scientific disciplines - mammalian species, chemical elements, and minor planets - I find the ease of discovery to conform to an exponential decay. In addition, I show how the pace of scientific discovery can be best understood as the outcome of both scientific output and ease of discovery. A quantitative study of the ease of scientific discovery in the aggregate, such as done here, has the potential to provide a great deal of insight into both the nature of future discoveries and the technical processes behind discoveries in science.

Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents

PubMed Central

Cragg, Gordon M.; Pezzuto, John M.

2016-01-01

Throughout history, natural products have played a dominant role in the treatment of human ailments. For example, the legendary discovery of penicillin transformed global existence. Presently, natural products comprise a large portion of current-day pharmaceutical agents, most notably in the area of cancer therapy. Examples include Taxol, vinblastine, and camptothecin. These structurally unique agents function by novel mechanisms of action; isolation from natural sources is the only plausible method that could have led to their discovery. In addition to terrestrial plants as sources for starting materials, the marine environment (e.g., ecteinascidin 743, halichondrin B, and dolastatins), microbes (e.g., bleomycin, doxorubicin, and staurosporin), and slime molds (e.g., epothilone B) have yielded remarkable cancer chemotherapeutic agents. Irrespective of these advances, cancer remains a leading cause of death worldwide. Undoubtedly, the prevention of human cancer is highly preferable to treatment. Cancer chemoprevention, the use of vaccines or pharmaceutical agents to inhibit, retard, or reverse the process of carcinogenesis, is another important approach for easing this formidable public health burden. Similar to cancer chemotherapeutic agents, natural products play an important role in this field. There are many examples, including dietary phytochemicals such as sulforaphane and phenethyl isothiocyanate (cruciferous vegetables) and resveratrol (grapes and grape products). Overall, natural product research is a powerful approach for discovering biologically active compounds with unique structures and mechanisms of action. Given the unfathomable diversity of nature, it is reasonable to suggest that chemical leads can be generated that are capable of interacting with most or possibly all therapeutic targets. PMID:26679767

Sequence-Based Discovery Demonstrates That Fixed Light Chain Human Transgenic Rats Produce a Diverse Repertoire of Antigen-Specific Antibodies.

PubMed

Harris, Katherine E; Aldred, Shelley Force; Davison, Laura M; Ogana, Heather Anne N; Boudreau, Andrew; Brüggemann, Marianne; Osborn, Michael; Ma, Biao; Buelow, Benjamin; Clarke, Starlynn C; Dang, Kevin H; Iyer, Suhasini; Jorgensen, Brett; Pham, Duy T; Pratap, Payal P; Rangaswamy, Udaya S; Schellenberger, Ute; van Schooten, Wim C; Ugamraj, Harshad S; Vafa, Omid; Buelow, Roland; Trinklein, Nathan D

2018-01-01

We created a novel transgenic rat that expresses human antibodies comprising a diverse repertoire of heavy chains with a single common rearranged kappa light chain (IgKV3-15-JK1). This fixed light chain animal, called OmniFlic, presents a unique system for human therapeutic antibody discovery and a model to study heavy chain repertoire diversity in the context of a constant light chain. The purpose of this study was to analyze heavy chain variable gene usage, clonotype diversity, and to describe the sequence characteristics of antigen-specific monoclonal antibodies (mAbs) isolated from immunized OmniFlic animals. Using next-generation sequencing antibody repertoire analysis, we measured heavy chain variable gene usage and the diversity of clonotypes present in the lymph node germinal centers of 75 OmniFlic rats immunized with 9 different protein antigens. Furthermore, we expressed 2,560 unique heavy chain sequences sampled from a diverse set of clonotypes as fixed light chain antibody proteins and measured their binding to antigen by ELISA. Finally, we measured patterns and overall levels of somatic hypermutation in the full B-cell repertoire and in the 2,560 mAbs tested for binding. The results demonstrate that OmniFlic animals produce an abundance of antigen-specific antibodies with heavy chain clonotype diversity that is similar to what has been described with unrestricted light chain use in mammals. In addition, we show that sequence-based discovery is a highly effective and efficient way to identify a large number of diverse monoclonal antibodies to a protein target of interest.

AtPDS over-expression in tomato: exposing unique patterns of carotenoid self-regulation and an alternative strategy for the enhancement of fruit carotenoid content

USDA-ARS?s Scientific Manuscript database

The regulation of plant carotenogenesis is an active research area for both biological discovery and practical implementation. In tomato, we demonstrate additional bottlenecks exist in the poly-cis-transformation of phytoene to lycopene in the context of ripening-induced PSY1 expression and activity...

Lesson Two: Terra Australis. Australian Studies High School Series. History Unit.

ERIC Educational Resources Information Center

Waldron, John

This lesson, one of four stand-alone lessons that examine Australia as an aspect of world history, points out that Australia's unique geographic characteristics and history serve as a useful case study of key global concepts. The lesson focuses on exploration and control of trade routes during the Age of Discovery. The lesson has two parts. In…

Chandra’s first decade of discovery

PubMed Central

Swartz, Douglas A.; Wolk, Scott J.; Fruscione, Antonella

2010-01-01

We review some of the many scientific results reported at a symposium held in September 2009 celebrating the 10th anniversary of National Aeronautics and Space Administration's (NASA's) Chandra X-ray Observatory. These results were contributed by scientists who were among the more than 300 symposium participants. We highlight those results that most emphasize the unique imaging and spectroscopic capabilities of Chandra. PMID:20406906

2017 - The Year @NASA

NASA Image and Video Library

2017-12-07

2017: A year of groundbreaking discoveries and record-setting exploration at NASA. The Moon became a focal point for the agency, we brought you unique coverage of the first coast-to-coast total solar eclipse in the U.S. in 99 years, we announced the most Earth-size planets ever found in the habitable zone of a star outside our solar system, and more!

The astrophysical science case for a decihertz gravitational-wave detector

NASA Astrophysics Data System (ADS)

Mandel, Ilya; Sesana, Alberto; Vecchio, Alberto

2018-03-01

We discuss the astrophysical science case for a decihertz gravitational-wave mission. We focus on unique opportunities for scientific discovery in this frequency range, including probes of type IA supernova progenitors, mergers in the presence of third bodies, intermediate mass black holes, seeds of massive black holes, improved sky localization, and tracking the population of merging compact binaries.

Tunable and label-free virus enrichment for ultrasensitive virus detection using carbon nanotube arrays

PubMed Central

Yeh, Yin-Ting; Tang, Yi; Sebastian, Aswathy; Dasgupta, Archi; Perea-Lopez, Nestor; Albert, Istvan; Lu, Huaguang; Terrones, Mauricio; Zheng, Si-Yang

2016-01-01

Viral infectious diseases can erupt unpredictably, spread rapidly, and ravage mass populations. Although established methods, such as polymerase chain reaction, virus isolation, and next-generation sequencing have been used to detect viruses, field samples with low virus count pose major challenges in virus surveillance and discovery. We report a unique carbon nanotube size-tunable enrichment microdevice (CNT-STEM) that efficiently enriches and concentrates viruses collected from field samples. The channel sidewall in the microdevice was made by growing arrays of vertically aligned nitrogen-doped multiwalled CNTs, where the intertubular distance between CNTs could be engineered in the range of 17 to 325 nm to accurately match the size of different viruses. The CNT-STEM significantly improves detection limits and virus isolation rates by at least 100 times. Using this device, we successfully identified an emerging avian influenza virus strain [A/duck/PA/02099/2012(H11N9)] and a novel virus strain (IBDV/turkey/PA/00924/14). Our unique method demonstrates the early detection of emerging viruses and the discovery of new viruses directly from field samples, thus creating a universal platform for effectively remediating viral infectious diseases. PMID:27730213

Discovery of a Xylooligosaccharide Oxidase from Myceliophthora thermophila C1.

PubMed

Ferrari, Alessandro R; Rozeboom, Henriëtte J; Dobruchowska, Justyna M; van Leeuwen, Sander S; Vugts, Aniek S C; Koetsier, Martijn J; Visser, Jaap; Fraaije, Marco W

2016-11-04

By inspection of the predicted proteome of the fungus Myceliophthora thermophila C1 for vanillyl-alcohol oxidase (VAO)-type flavoprotein oxidases, a putative oligosaccharide oxidase was identified. By homologous expression and subsequent purification, the respective protein could be obtained. The protein was found to contain a bicovalently bound FAD cofactor. By screening a large number of carbohydrates, several mono- and oligosaccharides could be identified as substrates. The enzyme exhibits a strong substrate preference toward xylooligosaccharides; hence it is named xylooligosaccharide oxidase (XylO). Chemical analyses of the product formed upon oxidation of xylobiose revealed that the oxidation occurs at C1, yielding xylobionate as product. By elucidation of several XylO crystal structures (in complex with a substrate mimic, xylose, and xylobiose), the residues that tune the unique substrate specificity and regioselectivity could be identified. The discovery of this novel oligosaccharide oxidase reveals that the VAO-type flavoprotein family harbors oxidases tuned for specific oligosaccharides. The unique substrate profile of XylO hints at a role in the degradation of xylan-derived oligosaccharides by the fungus M. thermophila C1. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

The origin and development of extragalactic radio astronomy: the role of CSIRO's Division of Radiophysics Dover Heights Field Station in Sydney

NASA Astrophysics Data System (ADS)

Orchiston, Wayne; Robertson, Peter

2017-12-01

Initial post-war developments in non-solar radio astronomy were inspired by Hey, Phillips and Parson’s report in 1946 of an intense source of radio emission in Cygnus. This so-called ‘radio star’ was unique, and questions immediately were raised about its true nature. But it did not remain unique for long. Observing from Sydney, John Bolton, Gordon Stanley and Bruce Slee followed up the Cygnus discovery with more radio star detections, beginning what would evolve into a long-term multi-faceted research program and one of the mainstays of the CSIRO’s Division of Radiophysics. But more than this, these early discoveries in England and in Sydney opened up a whole new field of investigation, extragalactic radio astronomy, which has remained a major area of investigation through to the present day. This paper focusses on the early years of this program when the observations were carried out at Dover Heights Field Station in Sydney, and the ways in which new developments in instrumentation that allowed a major expansion of the program eventually led to the closure of Dover Heights and the founding of the Fleurs Field Station.

A 28,000 Years Old Cro-Magnon mtDNA Sequence Differs from All Potentially Contaminating Modern Sequences

PubMed Central

Caramelli, David; Milani, Lucio; Vai, Stefania; Modi, Alessandra; Pecchioli, Elena; Girardi, Matteo; Pilli, Elena; Lari, Martina; Lippi, Barbara; Ronchitelli, Annamaria; Mallegni, Francesco; Casoli, Antonella; Bertorelle, Giorgio; Barbujani, Guido

2008-01-01

Background DNA sequences from ancient speciments may in fact result from undetected contamination of the ancient specimens by modern DNA, and the problem is particularly challenging in studies of human fossils. Doubts on the authenticity of the available sequences have so far hampered genetic comparisons between anatomically archaic (Neandertal) and early modern (Cro-Magnoid) Europeans. Methodology/Principal Findings We typed the mitochondrial DNA (mtDNA) hypervariable region I in a 28,000 years old Cro-Magnoid individual from the Paglicci cave, in Italy (Paglicci 23) and in all the people who had contact with the sample since its discovery in 2003. The Paglicci 23 sequence, determined through the analysis of 152 clones, is the Cambridge reference sequence, and cannot possibly reflect contamination because it differs from all potentially contaminating modern sequences. Conclusions/Significance: The Paglicci 23 individual carried a mtDNA sequence that is still common in Europe, and which radically differs from those of the almost contemporary Neandertals, demonstrating a genealogical continuity across 28,000 years, from Cro-Magnoid to modern Europeans. Because all potential sources of modern DNA contamination are known, the Paglicci 23 sample will offer a unique opportunity to get insight for the first time into the nuclear genes of early modern Europeans. PMID:18628960

Discovery of pyridyl sulfonamide 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors for the treatment of metabolic disorders.

PubMed

Yoon, David S; Wu, Shung C; Seethala, Ramakrishna; Golla, Rajasree; Nayeem, Akbar; Everlof, John G; Gordon, David A; Hamann, Lawrence G; Robl, Jeffrey A

2014-11-01

A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11β-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO2) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability. Copyright © 2014 Elsevier Ltd. All rights reserved.

Overview of the Inland California Translational Consortium

NASA Astrophysics Data System (ADS)

Malkas, Linda H.

2017-05-01

The mission of the Inland California Translational Consortium (ICTC), an independent research consortium comprising a unique hub of regional institutions (City of Hope [COH], California Institute of Technology [Caltech], Jet Propulsion Laboratory [JPL], University of California Riverside [UCR], and Claremont Colleges Keck Graduate Institute [KGI], is to institute a new paradigm within the academic culture to accelerate translation of innovative biomedical discoveries into clinical applications that positively affect human health and life. The ICTC actively supports clinical translational research as well as the implementation and advancement of novel education and training models for the translation of basic discoveries into workable products and practices that preserve and improve human health while training and educating at all levels of the workforce using innovative forward-thinking approaches.

Mars Scout 2007 - a current status

NASA Technical Reports Server (NTRS)

Matousek, Steve

2003-01-01

The Mars Program institutes the Mars Scout Missions in order to address science goals in the program not otherwise covered in baseline Mars plans. Mars Scout missions will be Principal-Investigator (PI) led science missions. Analogous to the Discovery Program, PI-led investigations optimize the use of limited resources to accomplish focused science and allow the flexibility to quickly respond to discoveries at Mars. Scout missions also require unique investments in technology and reliance upon Mars-based infrastructure such as telecom relay orbiters. Scouts utilize a two-step competitive process for selection. In Dec, 2002, the Step 2 selections by NASA were announced and then approximately five month studies will result in a selection for flight around August, 2003 for a mission to be launched in 2007.

Simultaneous Proteomic Discovery and Targeted Monitoring using Liquid Chromatography, Ion Mobility Spectrometry, and Mass Spectrometry

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

Burnum-Johnson, Kristin E.; Nie, Song; Casey, Cameron P.

Current proteomics approaches are comprised of both broad discovery measurements as well as more quantitative targeted measurements. These two different measurement types are used to initially identify potentially important proteins (e.g., candidate biomarkers) and then enable improved quantification for a limited number of selected proteins. However, both approaches suffer from limitations, particularly the lower sensitivity, accuracy, and quantitation precision for discovery approaches compared to targeted approaches, and the limited proteome coverage provided by targeted approaches. Herein, we describe a new proteomics approach that allows both discovery and targeted monitoring (DTM) in a single analysis using liquid chromatography, ion mobility spectrometrymore » and mass spectrometry (LC-IMS-MS). In DTM, heavy labeled peptides for target ions are spiked into tryptic digests and both the labeled and unlabeled peptides are broadly detected using LC-IMS-MS instrumentation, allowing the benefits of discovery and targeted approaches. To understand the possible improvement of the DTM approach, it was compared to LC-MS broad measurements using an accurate mass and time tag database and selected reaction monitoring (SRM) targeted measurements. The DTM results yielded greater peptide/protein coverage and a significant improvement in the detection of lower abundance species compared to LC-MS discovery measurements. DTM was also observed to have similar detection limits as SRM for the targeted measurements indicating its potential for combining the discovery and targeted approaches.« less

The discovery of long-term potentiation.

PubMed

Lømo, Terje

2003-04-29

This paper describes circumstances around the discovery of long-term potentiation (LTP). In 1966, I had just begun independent work for the degree of Dr medicinae (PhD) in Per Andersen's laboratory in Oslo after an eighteen-month apprenticeship with him. Studying the effects of activating the perforant path to dentate granule cells in the hippocampus of anaesthetized rabbits, I observed that brief trains of stimuli resulted in increased efficiency of transmission at the perforant path-granule cell synapses that could last for hours. In 1968, Tim Bliss came to Per Andersen's laboratory to learn about the hippocampus and field potential recording for studies of possible memory mechanisms. The two of us then followed up my preliminary results from 1966 and did the experiments that resulted in a paper that is now properly considered to be the basic reference for the discovery of LTP.

Accessing Nature’s diversity through metabolic engineering and synthetic biology

PubMed Central

King, Jason R.; Edgar, Steven; Qiao, Kangjian; Stephanopoulos, Gregory

2016-01-01

In this perspective, we highlight recent examples and trends in metabolic engineering and synthetic biology that demonstrate the synthetic potential of enzyme and pathway engineering for natural product discovery. In doing so, we introduce natural paradigms of secondary metabolism whereby simple carbon substrates are combined into complex molecules through “scaffold diversification”, and subsequent “derivatization” of these scaffolds is used to synthesize distinct complex natural products. We provide examples in which modern pathway engineering efforts including combinatorial biosynthesis and biological retrosynthesis can be coupled to directed enzyme evolution and rational enzyme engineering to allow access to the “privileged” chemical space of natural products in industry-proven microbes. Finally, we forecast the potential to produce natural product-like discovery platforms in biological systems that are amenable to single-step discovery, validation, and synthesis for streamlined discovery and production of biologically active agents. PMID:27081481

A Scientometric Prediction of the Discovery of the First Potentially Habitable Planet with a Mass Similar to Earth

PubMed Central

Arbesman, Samuel; Laughlin, Gregory

2010-01-01

Background The search for a habitable extrasolar planet has long interested scientists, but only recently have the tools become available to search for such planets. In the past decades, the number of known extrasolar planets has ballooned into the hundreds, and with it, the expectation that the discovery of the first Earth-like extrasolar planet is not far off. Methodology/Principal Findings Here, we develop a novel metric of habitability for discovered planets and use this to arrive at a prediction for when the first habitable planet will be discovered. Using a bootstrap analysis of currently discovered exoplanets, we predict the discovery of the first Earth-like planet to be announced in the first half of 2011, with the likeliest date being early May 2011. Conclusions/Significance Our predictions, using only the properties of previously discovered exoplanets, accord well with external estimates for the discovery of the first potentially habitable extrasolar planet and highlight the the usefulness of predictive scientometric techniques to understand the pace of scientific discovery in many fields. PMID:20957226

Therapeutics discovery: From bench to first in-human trials*

PubMed Central

Al-Hujaily, Ensaf M.; Khatlani, Tanvir; Alehaideb, Zeyad; Ali, Rizwan; Almuzaini, Bader; Alrfaei, Bahauddeen M; Iqbal, Jahangir; Islam, Imadul; Malik, Shuja; Marwani, Bader A; Massadeh, Salam; Nehdi, Atef; Alsomaie, Barrak; Debasi, Bader; Bushnak, Ibraheem; Noibi, Saeed; Hussain, Syed; Wajid, Wahid Abdul; Armand, Jean-Pierre; Gul, Sheraz; Oyarzabal, Julen; Rais, Rana; Bountra, Chas; Alaskar, Ahmed; Knawy, Bander Al; Boudjelal, Mohamed

2018-01-01

The ‘Therapeutics discovery: From bench to first in-human trials’ conference, held at the King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard Health Affairs (MNGHA), Kingdom of Saudi Arabia (KSA) from October 10–12, 2017, provided a unique opportunity for experts worldwide to discuss advances in drug discovery and development, focusing on phase I clinical trials. It was the first event of its kind to be hosted at the new research center, which was constructed to boost drug discovery and development in the KSA in collaboration with institutions, such as the Academic Drug Discovery Consortium in the United States of America (USA), Structural Genomics Consortium of the University of Oxford in the United Kingdom (UK), and Institute of Materia Medica of the Chinese Academy of Medical Sciences in China. The program was divided into two parts. A pre-symposium day took place on October 10, during which courses were conducted on clinical trials, preclinical drug discovery, molecular biology and nanofiber research. The attendees had the opportunity for one-to-one meetings with international experts to exchange information and foster collaborations. In the second part of the conference, which took place on October 11 and 12, the clinical trials pipeline, design and recruitment of volunteers, and economic impact of clinical trials were discussed. The Saudi Food and Drug Administration presented the regulations governing clinical trials in the KSA. The process of preclinical drug discovery from small molecules, cellular and immunologic therapies, and approaches to identifying new targets were also presented. The recommendation of the conference was that researchers in the KSA must invest more fund, talents and infrastructure to lead the region in phase I clinical trials and preclinical drug discovery. Diseases affecting the local population, such as Middle East Respiratory Syndrome and resistant bacterial infections, represent the optimal starting point. PMID:29564125

Therapeutics discovery: From bench to first in-human trials.

PubMed

Al-Hujaily, Ensaf M; Khatlani, Tanvir; Alehaideb, Zeyad; Ali, Rizwan; Almuzaini, Bader; Alrfaei, Bahauddeen M; Iqbal, Jahangir; Islam, Imadul; Malik, Shuja; Marwani, Bader A; Massadeh, Salam; Nehdi, Atef; Alsomaie, Barrak; Debasi, Bader; Bushnak, Ibraheem; Noibi, Saeed; Hussain, Syed; Wajid, Wahid Abdul; Armand, Jean-Pierre; Gul, Sheraz; Oyarzabal, Julen; Rais, Rana; Bountra, Chas; Alaskar, Ahmed; Knawy, Bander Al; Boudjelal, Mohamed

2018-03-01

The 'Therapeutics discovery: From bench to first in-human trials' conference, held at the King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard Health Affairs (MNGHA), Kingdom of Saudi Arabia (KSA) from October 10-12, 2017, provided a unique opportunity for experts worldwide to discuss advances in drug discovery and development, focusing on phase I clinical trials. It was the first event of its kind to be hosted at the new research center, which was constructed to boost drug discovery and development in the KSA in collaboration with institutions, such as the Academic Drug Discovery Consortium in the United States of America (USA), Structural Genomics Consortium of the University of Oxford in the United Kingdom (UK), and Institute of Materia Medica of the Chinese Academy of Medical Sciences in China. The program was divided into two parts. A pre-symposium day took place on October 10, during which courses were conducted on clinical trials, preclinical drug discovery, molecular biology and nanofiber research. The attendees had the opportunity for one-to-one meetings with international experts to exchange information and foster collaborations. In the second part of the conference, which took place on October 11 and 12, the clinical trials pipeline, design and recruitment of volunteers, and economic impact of clinical trials were discussed. The Saudi Food and Drug Administration presented the regulations governing clinical trials in the KSA. The process of preclinical drug discovery from small molecules, cellular and immunologic therapies, and approaches to identifying new targets were also presented. The recommendation of the conference was that researchers in the KSA must invest more fund, talents and infrastructure to lead the region in phase I clinical trials and preclinical drug discovery. Diseases affecting the local population, such as Middle East Respiratory Syndrome and resistant bacterial infections, represent the optimal starting point.

Ketamine and phencyclidine: the good, the bad and the unexpected

PubMed Central

Lodge, D; Mercier, M S

2015-01-01

The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The findings of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms. PMID:26075331

The Impact of Chemical Probes in Drug Discovery: A Pharmaceutical Industry Perspective.

PubMed

Garbaccio, Robert M; Parmee, Emma R

2016-01-21

Chemical probes represent an important component of both academic and pharmaceutical drug discovery research. As a complement to prior reviews that have defined this scientific field, we aim to provide an industry perspective on the value of having high-quality chemical probes throughout the course of preclinical research. By studying examples from the internal Merck pipeline, we recognize that these probes require significant collaborative investment to realize their potential impact in clarifying the tractability and translation of a given therapeutic target. This perspective concludes with recommendations for chemical probe discovery aimed toward maximizing their potential to identify targets that result in the successful delivery of novel therapeutics. Copyright © 2016 Elsevier Ltd. All rights reserved.

Metagenomics and novel gene discovery

PubMed Central

Culligan, Eamonn P; Sleator, Roy D; Marchesi, Julian R; Hill, Colin

2014-01-01

Metagenomics provides a means of assessing the total genetic pool of all the microbes in a particular environment, in a culture-independent manner. It has revealed unprecedented diversity in microbial community composition, which is further reflected in the encoded functional diversity of the genomes, a large proportion of which consists of novel genes. Herein, we review both sequence-based and functional metagenomic methods to uncover novel genes and outline some of the associated problems of each type of approach, as well as potential solutions. Furthermore, we discuss the potential for metagenomic biotherapeutic discovery, with a particular focus on the human gut microbiome and finally, we outline how the discovery of novel genes may be used to create bioengineered probiotics. PMID:24317337

A systematic study of chemogenomics of carbohydrates.

PubMed

Gu, Jiangyong; Luo, Fang; Chen, Lirong; Yuan, Gu; Xu, Xiaojie

2014-03-04

Chemogenomics focuses on the interactions between biologically active molecules and protein targets for drug discovery. Carbohydrates are the most abundant compounds in natural products. Compared with other drugs, the carbohydrate drugs show weaker side effects. Searching for multi-target carbohydrate drugs can be regarded as a solution to improve therapeutic efficacy and safety. In this work, we collected 60 344 carbohydrates from the Universal Natural Products Database (UNPD) and explored the chemical space of carbohydrates by principal component analysis. We found that there is a large quantity of potential lead compounds among carbohydrates. Then we explored the potential of carbohydrates in drug discovery by using a network-based multi-target computational approach. All carbohydrates were docked to 2389 target proteins. The most potential carbohydrates for drug discovery and their indications were predicted based on a docking score-weighted prediction model. We also explored the interactions between carbohydrates and target proteins to find the pathological networks, potential drug candidates and new indications.

Radiation Detection Material Discovery Initiative at PNNL

NASA Astrophysics Data System (ADS)

Milbrath, Brian

2006-05-01

Today's security threats are being met with 30-year old radiation technology. Discovery of new radiation detection materials is currently a slow and Edisonian process. With heightened concerns over nuclear proliferation, terrorism and unconventional warfare, an alternative strategy for identification and development of potential radiation detection materials must be adopted. Through the Radiation Detection Materials Discovery Initiative, PNNL focuses on the science-based discovery of next generation materials for radiation detection by addressing three ``grand challenges'': fundamental understanding of radiation detection, identification of new materials, and accelerating the discovery process. The new initiative has eight projects addressing these challenges, which will be described, including early work, paths forward and the opportunities for collaboration.

Nexus Between Protein–Ligand Affinity Rank-Ordering, Biophysical Approaches, and Drug Discovery

PubMed Central

2013-01-01

The confluence of computational and biophysical methods to accurately rank-order the binding affinities of small molecules and determine structures of macromolecular complexes is a potentially transformative advance in the work flow of drug discovery. This viewpoint explores the impact that advanced computational methods may have on the efficacy of small molecule drug discovery and optimization, particularly with respect to emerging fragment-based methods. PMID:24900579

Updates on Managing Type 2 Diabetes Mellitus with Natural Products: Towards Antidiabetic Drug Development.

PubMed

Alam, Fahmida; Islam, Md Asiful; Kamal, M A; Gan, Siew Hua

2016-08-13

Over the years, natural products have shown success as antidiabetics in vitro, in vivo and in clinical trials. Because natural product-derived drugs are more affordable and effective with fewer side-effects compared to conventional therapies, pharmaceutical research is increasingly leaning towards the discovery of new antidiabetic drugs from natural products targeting pathways or components associated with type 2 diabetes mellitus (T2DM) pathophysiology. However, the drug discovery process is very lengthy and costly with significant challenges. Therefore, various techniques are currently being developed for the preclinical research phase of drug discovery with the aim of drug development with less time and efforts from natural products. In this review, we have provided an update on natural products including fruits, vegetables, spices, nuts, beverages and mushrooms with potential antidiabetic activities from in vivo, in vitro and clinical studies. Synergistic interactions between natural products and antidiabetic drugs; and potential antidiabetic active compounds from natural products are also documented to pave the way for combination treatment and new drug discovery, respectively. Additionally, a brief idea of the drug discovery process along with the challenges that arise during drug development from natural products and the methods to conquer those challenges are discussed to create a more convenient future drug discovery process.

High-field MRS in clinical drug development.

PubMed

Ross, Brian D

2013-07-01

Magnetic resonance spectroscopy (MRS) will continue to play an ever increasing role in drug discovery because MRS does readily define biomarkers for several hundreds of clinically distinct diseases. Published evidence based medicine (EBM) surveys, which generally conclude the opposite, are seriously flawed and do a disservice to the field of drug discovery. This article presents MRS and how it has guided several hundreds of practical human 'drug discovery' endeavors since its development. Specifically, the author looks at the process of 'reverse-translation' and its influence in the expansion of the number of preclinical drug discoveries from in vivo MRS. The author also provides a structured approach of eight criteria, including EBM acceptance, which could potentially re-open the field of MRS for productive exploration of existing and repurposed drugs and cost-effective drug-discovery. MRS-guided drug discovery is poised for future expansion. The cost of clinical trials has escalated and the use of biomarkers has become increasingly useful in improving patient selection for drug trials. Clinical MRS has uncovered a treasure-trove of novel biomarkers and clinical MRS itself has become better standardized and more widely available on 'routine' clinical MRI scanners. When combined with available new MRI sequences, MRS can provide a 'one stop shop' with multiple potential outcome measures for the disease and the drug in question.

Potential biological targets for bioassay development in drug discovery of Sturge-Weber syndrome.

PubMed

Mohammadipanah, Fatemeh; Salimi, Fatemeh

2017-04-29

Sturge-Weber Syndrome (SWS) is among the neurocutaneous diseases, which has several clinical manifestations of ocular (glaucoma), cutaneous (port-wine stain), neurological (seizures) and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for the SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against this syndrome. Development of such platforms of bioassay can bring along the implementation of high throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of biological targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholine esterase, alkaline phosphatase, gamma-aminobutyricacidergic, Hypoxia-Inducible Factor (HIF) -1α and 2α are suggested. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool.

PubMed

Karthigeyan, Dhanasekaran; Siddhanta, Soumik; Kishore, Annavarapu Hari; Perumal, Sathya S R R; Ågren, Hans; Sudevan, Surabhi; Bhat, Akshay V; Balasubramanyam, Karanam; Subbegowda, Rangappa Kanchugarakoppal; Kundu, Tapas K; Narayana, Chandrabhas

2014-07-22

We demonstrate the use of surface-enhanced Raman spectroscopy (SERS) as an excellent tool for identifying the binding site of small molecules on a therapeutically important protein. As an example, we show the specific binding of the common antihypertension drug felodipine to the oncogenic Aurora A kinase protein via hydrogen bonding interactions with Tyr-212 residue to specifically inhibit its activity. Based on SERS studies, molecular docking, molecular dynamics simulation, biochemical assays, and point mutation-based validation, we demonstrate the surface-binding mode of this molecule in two similar hydrophobic pockets in the Aurora A kinase. These binding pockets comprise the same unique hydrophobic patches that may aid in distinguishing human Aurora A versus human Aurora B kinase in vivo. The application of SERS to identify the specific interactions between small molecules and therapeutically important proteins by differentiating competitive and noncompetitive inhibition demonstrates its ability as a complementary technique. We also present felodipine as a specific inhibitor for oncogenic Aurora A kinase. Felodipine retards the rate of tumor progression in a xenografted nude mice model. This study reveals a potential surface pocket that may be useful for developing small molecules by selectively targeting the Aurora family kinases.

Genomes to natural products PRediction Informatics for Secondary Metabolomes (PRISM).

PubMed

Skinnider, Michael A; Dejong, Chris A; Rees, Philip N; Johnston, Chad W; Li, Haoxin; Webster, Andrew L H; Wyatt, Morgan A; Magarvey, Nathan A

2015-11-16

Microbial natural products are an invaluable source of evolved bioactive small molecules and pharmaceutical agents. Next-generation and metagenomic sequencing indicates untapped genomic potential, yet high rediscovery rates of known metabolites increasingly frustrate conventional natural product screening programs. New methods to connect biosynthetic gene clusters to novel chemical scaffolds are therefore critical to enable the targeted discovery of genetically encoded natural products. Here, we present PRISM, a computational resource for the identification of biosynthetic gene clusters, prediction of genetically encoded nonribosomal peptides and type I and II polyketides, and bio- and cheminformatic dereplication of known natural products. PRISM implements novel algorithms which render it uniquely capable of predicting type II polyketides, deoxygenated sugars, and starter units, making it a comprehensive genome-guided chemical structure prediction engine. A library of 57 tailoring reactions is leveraged for combinatorial scaffold library generation when multiple potential substrates are consistent with biosynthetic logic. We compare the accuracy of PRISM to existing genomic analysis platforms. PRISM is an open-source, user-friendly web application available at http://magarveylab.ca/prism/. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

The Top 10 List of Gravitational Lens Candidates from the HUBBLE SPACE TELESCOPE Medium Deep Survey

NASA Astrophysics Data System (ADS)

Ratnatunga, Kavan U.; Griffiths, Richard E.; Ostrander, Eric J.

1999-05-01

A total of 10 good candidates for gravitational lensing have been discovered in the WFPC2 images from the Hubble Space Telescope (HST) Medium Deep Survey (MDS) and archival primary observations. These candidate lenses are unique HST discoveries, i.e., they are faint systems with subarcsecond separations between the lensing objects and the lensed source images. Most of them are difficult objects for ground-based spectroscopic confirmation or for measurement of the lens and source redshifts. Seven are ``strong lens'' candidates that appear to have multiple images of the source. Three are cases in which the single image of the source galaxy has been significantly distorted into an arc. The first two quadruply lensed candidates were reported by Ratnatunga et al. We report on the subsequent eight candidates and describe them with simple models based on the assumption of singular isothermal potentials. Residuals from the simple models for some of the candidates indicate that a more complex model for the potential will probably be required to explain the full structural detail of the observations once they are confirmed to be lenses. We also discuss the effective survey area that was searched for these candidate lens objects.

Can the silkworm (Bombyx mori) be used as a human disease model?

PubMed

Tabunoki, Hiroko; Bono, Hidemasa; Ito, Katsuhiko; Yokoyama, Takeshi

2016-02-01

Bombyx mori (silkworm) is the most famous lepidopteran in Japan. B. mori has long been used in the silk industry and also as a model insect for agricultural research. In recent years, B. mori has attracted interest in its potential for use in pathological analysis of model animals. For example, the human macular carotenoid transporter was discovered using information of B. mori carotenoid transporter derived from yellow-cocoon strain. The B. mori carotenoid transport system is useful in human studies. To develop a human disease model, we characterized the human homologs of B. mori, and by constructing KAIKO functional annotation pipeline, and to analyze gene expression profile of a unique B. mori mutant strain using microarray analysis. As a result, we identified a novel molecular network involved in Parkinson's disease. Here we describe the potential use of a spontaneous mutant silkworm strain as a human disease model. We also summarize recent progress in the application of genomic information for annotation of human homologs in B. mori. The B. mori mutant will provide a clue to pathological mechanisms, and the findings will be helpful for the development of therapies and for medical drug discovery.

Trimetallic nitride template endohedral metallofullerenes: discovery, structural characterization, reactivity, and applications.

PubMed

Zhang, Jianyuan; Stevenson, Steven; Dorn, Harry C

2013-07-16

Shortly after the discovery of the carbon fullerene allotrope, C₆₀, researchers recognized that the hollow spheroidal shape could accommodate metal atoms, or clusters, which quickly led to the discovery of endohedral metallofullerenes (EMFs). In the past 2 decades, the unique features of EMFs have attracted broad interest in many fields, including inorganic chemistry, organic chemistry, materials chemistry, and biomedical chemistry. Some EMFs produce new metallic clusters that do not exist outside of a fullerene cage, and some other EMFs can boost the efficiency of magnetic resonance (MR) imaging 10-50-fold, in comparison with commercial contrast agents. In 1999, the Dorn laboratory discovered the trimetallic nitride template (TNT) EMFs, which consist of a trimetallic nitride cluster and a host fullerene cage. The TNT-EMFs (A₃N@C2n, n = 34-55, A = Sc, Y, or lanthanides) are typically formed in relatively high yields (sometimes only exceeded by empty-cage C₆₀ and C₇₀, but yields may decrease with increasing TNT cluster size), and exhibit high chemical and thermal stability. In this Account, we give an overview of TNT-EMF research, starting with the discovery of these structures and then describing their synthesis and applications. First, we describe our serendipitous discovery of the first member of this class, Sc₃N@Ih-C₈₀. Second, we discuss the methodology for the synthesis of several TNT-EMFs. These results emphasize the importance of chemically adjusting plasma temperature, energy, and reactivity (CAPTEAR) to optimize the type and yield of TNT-EMFs produced. Third, we review the approaches that are used to separate and purify pristine TNT-EMF molecules from their corresponding product mixtures. Although we used high-performance liquid chromatography (HPLC) to separate TNT-EMFs in early studies, we have more recently achieved facile separation based on the reduced chemical reactivity of the TNT-EMFs. These improved production yields and separation protocols have allowed industrial researchers to scale up the production of TNT-EMFs for commercial use. Fourth, we summarize the structural features of individual members of the TNT-EMF class, including cage structures, cluster arrangement, and dynamics. Fifth, we illustrate typical functionalization reactions of the TNT-EMFs, particularly cycloadditions and radical reactions, and describe the characterization of their derivatives. Finally, we illustrate the unique magnetic and electronic properties of specific TNT-EMFs for biomedicine and molecular device applications.

Ensuring the Quality of Outreach: The Critical Role of Evaluating Individual and Collective Initiatives and Performance

ERIC Educational Resources Information Center

Lynton, Ernest A.

2016-01-01

New knowledge is created in the course of the application of outreach. Each complex problem in the real world is likely to have unique aspects and thus it requires some modification of standard approaches. Hence, each engagement in outreach is likely to have an element of inquiry and discovery, leading to new knowledge. The flow of knowledge is in…

Quantitative Systems Pharmacology: A Case for Disease Models

PubMed Central

Ramanujan, S; Schmidt, BJ; Ghobrial, OG; Lu, J; Heatherington, AC

2016-01-01

Quantitative systems pharmacology (QSP) has emerged as an innovative approach in model‐informed drug discovery and development, supporting program decisions from exploratory research through late‐stage clinical trials. In this commentary, we discuss the unique value of disease‐scale “platform” QSP models that are amenable to reuse and repurposing to support diverse clinical decisions in ways distinct from other pharmacometrics strategies. PMID:27709613

2017 - The Year @NASA - [Updated 12-12-2017

NASA Image and Video Library

2017-12-12

2017: A year of groundbreaking discoveries and record-setting exploration at NASA. The Moon became a focal point for the agency, we brought you unique coverage of the first coast-to-coast total solar eclipse in the U.S. in 99 years, we announced the most Earth-size planets ever found in the habitable zone of a star outside our solar system, and more!

The MEDEA/JASON remotely operated vehicle system

NASA Astrophysics Data System (ADS)

Ballard, Robert D.

1993-08-01

The remotely operated vehicle (ROV) system MEDEA/JASON has been under development for the last decade. Adter a number of engineering test cruises, including the discovery of the R.M.S. Titanic and the German Battleship Bismarck, this ROV system is now being implemented in oceanographic investigations. This paper explains its development history and its unique ability to carry out a broad range of scientific research.

Collection and Retention Procedures for Electronically Stored Information (ESI) Collected Using E-Discovery Tools

EPA Pesticide Factsheets

This procedure is designed to support the collection of potentially responsive information using automated E-Discovery tools that rely on keywords, key phrases, index queries, or other technological assistance to retrieve Electronically Stored Information

The discovery of long-term potentiation.

PubMed Central

Lømo, Terje

2003-01-01

This paper describes circumstances around the discovery of long-term potentiation (LTP). In 1966, I had just begun independent work for the degree of Dr medicinae (PhD) in Per Andersen's laboratory in Oslo after an eighteen-month apprenticeship with him. Studying the effects of activating the perforant path to dentate granule cells in the hippocampus of anaesthetized rabbits, I observed that brief trains of stimuli resulted in increased efficiency of transmission at the perforant path-granule cell synapses that could last for hours. In 1968, Tim Bliss came to Per Andersen's laboratory to learn about the hippocampus and field potential recording for studies of possible memory mechanisms. The two of us then followed up my preliminary results from 1966 and did the experiments that resulted in a paper that is now properly considered to be the basic reference for the discovery of LTP. PMID:12740104

Therapeutic Potential of Foldamers: From Chemical Biology Tools To Drug Candidates?

PubMed

Gopalakrishnan, Ranganath; Frolov, Andrey I; Knerr, Laurent; Drury, William J; Valeur, Eric

2016-11-10

Over the past decade, foldamers have progressively emerged as useful architectures to mimic secondary structures of proteins. Peptidic foldamers, consisting of various amino acid based backbones, have been the most studied from a therapeutic perspective, while polyaromatic foldamers have barely evolved from their nascency and remain perplexing for medicinal chemists due to their poor drug-like nature. Despite these limitations, this compound class may still offer opportunities to study challenging targets or provide chemical biology tools. The potential of foldamer drug candidates reaching the clinic is still a stretch. Nevertheless, advances in the field have demonstrated their potential for the discovery of next generation therapeutics. In this perspective, the current knowledge of foldamers is reviewed in a drug discovery context. Recent advances in the early phases of drug discovery including hit finding, target validation, and optimization and molecular modeling are discussed. In addition, challenges and focus areas are debated and gaps highlighted.

Improving Cardiac Action Potential Measurements: 2D and 3D Cell Culture.

PubMed

Daily, Neil J; Yin, Yue; Kemanli, Pinar; Ip, Brian; Wakatsuki, Tetsuro

2015-11-01

Progress in the development of assays for measuring cardiac action potential is crucial for the discovery of drugs for treating cardiac disease and assessing cardiotoxicity. Recently, high-throughput methods for assessing action potential using induced pluripotent stem cell (iPSC) derived cardiomyocytes in both two-dimensional monolayer cultures and three-dimensional tissues have been developed. We describe an improved method for assessing cardiac action potential using an ultra-fast cost-effective plate reader with commercially available dyes. Our methods improve dramatically the detection of the fluorescence signal from these dyes and make way for the development of more high-throughput methods for cardiac drug discovery and cardiotoxicity.

New Meteorite Type NWA 8159 Augite Basalt: Specimen from a Previously Unsampled Location on Mars?

NASA Technical Reports Server (NTRS)

Agee, C. B.; Muttik, N.; Ziegler, K.; Walton, E. L.; Herd, C. D. K.; McCubbin, F. M.; Santos, A. R.; Simon, J. I.; Peters, T. J.; Tappa, M. J.;

Strategies for target identification of antimicrobial natural products.

PubMed

Farha, Maya A; Brown, Eric D

2016-05-04

Covering: 2000 to 2015Despite a pervasive decline in natural product research at many pharmaceutical companies over the last two decades, natural products have undeniably been a prolific and unsurpassed source for new lead antibacterial compounds. Due to their inherent complexity, natural extracts face several hurdles in high-throughout discovery programs, including target identification. Target identification and validation is a crucial process for advancing hits through the discovery pipeline, but has remained a major bottleneck. In the case of natural products, extremely low yields and limited compound supply further impede the process. Here, we review the wealth of target identification strategies that have been proposed and implemented for the characterization of novel antibacterials. Traditionally, these have included genomic and biochemical-based approaches, which, in recent years, have been improved with modern-day technology and better honed for natural product discovery. Further, we discuss the more recent innovative approaches for uncovering the target of new antibacterial natural products, which have resulted from modern advances in chemical biology tools. Finally, we present unique screening platforms implemented to streamline the process of target identification. The different innovative methods to respond to the challenge of characterizing the mode of action for antibacterial natural products have cumulatively built useful frameworks that may advocate a renovated interest in natural product drug discovery programs.

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.

The prepared mind. [Serendipitous discovery of demulsifier

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

Thompson, N.E.S.

Products derived from the work of scientists with serendipity, or an imagined faculty for making fluke discoveries by looking for one thing and finding another, include the well-known examples of Teflon, penicillin, X-rays, Velcro, nylon, saccharin, and Nutrasweet. This dream of every scientist came true for the author in the discovery of a dithiocarbamate compound that could be used as a water-clarifying agent for oil fields that produce water. The new agent enables oil companies to discharge water produced in offshore drilling facilities without upsetting the clarity of the aquatic environment. The EPA limit for oil in discharged water ismore » 48 ppm. Failure to maintain this limit will result in shutdown of the platform. The alternative is to pipe the produced water to onshore facilities for treatment before discharge, which costs a good bit more. The serendipitous discovery of the dithiocarbamate compound discussed here as a unique water-clarifying agent has also led to important fundamental advances. The new agent allows producers to use existing water treatment equipment and remain in compliance with the latest limits on oil content. This compound has made it more economical to operate offshore oil and gas production facilities in the Gulf of Mexico and the North Sea.« less

Unique Cellular Organization in the Oldest Root Meristem.

PubMed

Hetherington, Alexander J; Dubrovsky, Joseph G; Dolan, Liam

2016-06-20

Roots and shoots of plant bodies develop from meristems-cell populations that self-renew and produce cells that undergo differentiation-located at the apices of axes [1].The oldest preserved root apices in which cellular anatomy can be imaged are found in nodules of permineralized fossil soils called coal balls [2], which formed in the Carboniferous coal swamp forests over 300 million years ago [3-9]. However, no fossil root apices described to date were actively growing at the time of preservation [3-10]. Because the cellular organization of meristems changes when root growth stops, it has been impossible to compare cellular dynamics as stem cells transition to differentiated cells in extinct and extant taxa [11]. We predicted that meristems of actively growing roots would be preserved in coal balls. Here we report the discovery of the first fossilized remains of an actively growing root meristem from permineralized Carboniferous soil with detail of the stem cells and differentiating cells preserved. The cellular organization of the meristem is unique. The position of the Körper-Kappe boundary, discrete root cap, and presence of many anticlinal cell divisions within a broad promeristem distinguish it from all other known root meristems. This discovery is important because it demonstrates that the same general cellular dynamics are conserved between the oldest extinct and extant root meristems. However, its unique cellular organization demonstrates that extant root meristem organization and development represents only a subset of the diversity that has existed since roots first evolved. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

James C. McGroddy Prize Lecutre: Iron-Based Superconductors: Discovery and Progress

NASA Astrophysics Data System (ADS)

Hosono, Hideo

2015-03-01

The largest breakthrough in the history is the discovery of high Tc Cuprates by G.Bednorz and A.Muller in 1986 and the maximum Tc exceeded 77K, boiling temperature of liquid nitrogen in 1987. However, no new superconductors with high Tc had been reported since then except MgB2 (Tc =39K) discovered by J.Akimitsu in 2001.We found LaFePO superconductor with Tc =3K in 2006 and LaFeAsO1-xFx with Tc =26K (42K at under high pressure of 5GPa) in early 2008. The latter discovery rekindled the extensive superconductivity research globally, and more than 10,000 papers have been published to now. This excitement originates from disprovement of a widely accepted belief that iron with a large magnetic moment is harmful for emergence of superconductivity and relatively high Tc. Extensive research on iron-based superconductors pushed up the maximal Tc to 56K, which is next to high Tc cuprates and has led to the discovery of more than 50 new iron-based superconducting materials to date. Seen are so many advances in elucidation of superconducting properties and pairing mechanism. In this talk, I introduce a tale to the discovery and show the current status by reviewing progresses in materials, properties, mechanism and the application covering the recent hot topics. Emphases are placed on the unique characteristics arising from multi-orbital nature which totally differs from high Tc cuprates.

Connection Map for Compounds (CMC): A Server for Combinatorial Drug Toxicity and Efficacy Analysis.

PubMed

Liu, Lei; Tsompana, Maria; Wang, Yong; Wu, Dingfeng; Zhu, Lixin; Zhu, Ruixin

2016-09-26

Drug discovery and development is a costly and time-consuming process with a high risk for failure resulting primarily from a drug's associated clinical safety and efficacy potential. Identifying and eliminating inapt candidate drugs as early as possible is an effective way for reducing unnecessary costs, but limited analytical tools are currently available for this purpose. Recent growth in the area of toxicogenomics and pharmacogenomics has provided with a vast amount of drug expression microarray data. Web servers such as CMap and LTMap have used this information to evaluate drug toxicity and mechanisms of action independently; however, their wider applicability has been limited by the lack of a combinatorial drug-safety type of analysis. Using available genome-wide drug transcriptional expression profiles, we developed the first web server for combinatorial evaluation of toxicity and efficacy of candidate drugs named "Connection Map for Compounds" (CMC). Using CMC, researchers can initially compare their query drug gene signatures with prebuilt gene profiles generated from two large-scale toxicogenomics databases, and subsequently perform a drug efficacy analysis for identification of known mechanisms of drug action or generation of new predictions. CMC provides a novel approach for drug repositioning and early evaluation in drug discovery with its unique combination of toxicity and efficacy analyses, expansibility of data and algorithms, and customization of reference gene profiles. CMC can be freely accessed at http://cadd.tongji.edu.cn/webserver/CMCbp.jsp .

Amblypygids: Model Organisms for the Study of Arthropod Navigation Mechanisms in Complex Environments?

PubMed Central

Wiegmann, Daniel D.; Hebets, Eileen A.; Gronenberg, Wulfila; Graving, Jacob M.; Bingman, Verner P.

2016-01-01

Navigation is an ideal behavioral model for the study of sensory system integration and the neural substrates associated with complex behavior. For this broader purpose, however, it may be profitable to develop new model systems that are both tractable and sufficiently complex to ensure that information derived from a single sensory modality and path integration are inadequate to locate a goal. Here, we discuss some recent discoveries related to navigation by amblypygids, nocturnal arachnids that inhabit the tropics and sub-tropics. Nocturnal displacement experiments under the cover of a tropical rainforest reveal that these animals possess navigational abilities that are reminiscent, albeit on a smaller spatial scale, of true-navigating vertebrates. Specialized legs, called antenniform legs, which possess hundreds of olfactory and tactile sensory hairs, and vision appear to be involved. These animals also have enormous mushroom bodies, higher-order brain regions that, in insects, integrate contextual cues and may be involved in spatial memory. In amblypygids, the complexity of a nocturnal rainforest may impose navigational challenges that favor the integration of information derived from multimodal cues. Moreover, the movement of these animals is easily studied in the laboratory and putative neural integration sites of sensory information can be manipulated. Thus, amblypygids could serve as model organisms for the discovery of neural substrates associated with a unique and potentially sophisticated navigational capability. The diversity of habitats in which amblypygids are found also offers an opportunity for comparative studies of sensory integration and ecological selection pressures on navigation mechanisms. PMID:27014008

Novel paths towards neural cellular products for neurological disorders.

PubMed

Daadi, Marcel M

2011-11-01

The prospect of using neural cells derived from stem cells or from reprogrammed adult somatic cells provides a unique opportunity in cell therapy and drug discovery for developing novel strategies for brain repair. Cell-based therapeutic approaches for treating CNS afflictions caused by disease or injury aim to promote structural repair of the injured or diseased neural tissue, an outcome currently not achieved by drug therapy. Preclinical research in animal models of various diseases or injuries report that grafts of neural cells enhance endogenous repair, provide neurotrophic support to neurons undergoing degeneration and replace lost neural cells. In recent years, the sources of neural cells for treating neurological disorders have been rapidly expanding and in addition to offering therapeutic potential, neural cell products hold promise for disease modeling and drug discovery use. Specific neural cell types have been derived from adult or fetal brain, from human embryonic stem cells, from induced pluripotent stem cells and directly transdifferentiated from adult somatic cells, such as skin cells. It is yet to be determined if the latter approach will evolve into a paradigm shift in the fields of stem cell research and regenerative medicine. These multiple sources of neural cells cover a wide spectrum of safety that needs to be balanced with efficacy to determine the viability of the cellular product. In this article, we will review novel sources of neural cells and discuss current obstacles to developing them into viable cellular products for treating neurological disorders.

Exploration in petroleum development in Oman: Getting a kick into the creaming curve

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

Knox, G.J.

1993-09-01

Petroleum Development Oman (PDO) currently explores an 80,000 mi[sup 2] concession area. Major discoveries were made in the early 1960s in north Oman and in south Oman in the 1970s. However, in the middle to late 1980s, discovery sizes decreased, consistent with classical creaming curves, particularly as exploration concentrated on areas around the hydrocarbon fairways. With a flattening creaming curve, the outlook did not look rosy. PDO faced the question, [open quotes]Does this curve represent the future or could new ideas, a change in approach, or application of newer technologies give an upward kick to the creaming curve [close quotes]more » A major strategy review took place in which the potential of all plays was reviewed. Prospects were place into frontier, conventional, and exploratory appraisal types. String time was allocated over a five-year period on a basis of play testing for frontier plays and a steady realization of conventional and exploratory appraisal drilling as partial fulfillment of the annual exploration reserves replenishment target. Initial results are promising, and specific challenges including new plays, one unique to Oman, have been defined beyond the aims of the original strategy. Resolution of these challenges will lead to delineation of new hydrocarbon resources in Oman. At the same time, technological advances such as slim-hole drilling and extensive three-dimensional seismic, in concert with work-station interpretation, are being used, in order to minimize costs and increase the success ratio.« less

Advanced Visualization and Interactive Display Rapid Innovation and Discovery Evaluation Research (VISRIDER) Program Task 6: Point Cloud Visualization Techniques for Desktop and Web Platforms

DTIC Science & Technology

2017-04-01

ADVANCED VISUALIZATION AND INTERACTIVE DISPLAY RAPID INNOVATION AND DISCOVERY EVALUATION RESEARCH (VISRIDER) PROGRAM TASK 6: POINT CLOUD...To) OCT 2013 – SEP 2014 4. TITLE AND SUBTITLE ADVANCED VISUALIZATION AND INTERACTIVE DISPLAY RAPID INNOVATION AND DISCOVERY EVALUATION RESEARCH...various point cloud visualization techniques for viewing large scale LiDAR datasets. Evaluate their potential use for thick client desktop platforms

5 CFR 1201.72 - Explanation and scope of discovery.

Code of Federal Regulations, 2010 CFR

2010-01-01

... obtain relevant information, including the identification of potential witnesses, from another person or a party, that the other person or party has not otherwise provided. Relevant information includes information that appears reasonably calculated to lead to the discovery of admissible evidence. This...

Phenotypic mutant library: potential for gene discovery

USDA-ARS?s Scientific Manuscript database

The rapid development of high throughput and affordable Next- Generation Sequencing (NGS) techniques has renewed interest in gene discovery using forward genetics. The conventional forward genetic approach starts with isolation of mutants with a phenotype of interest, mapping the mutation within a s...

Lurking in the Shadows: Emerging Rodent Infectious Diseases

PubMed Central

Besselsen, David G.; Franklin, Craig L.; Livingston, Robert S.; Riley, Lela K.

2013-01-01

Rodent parvoviruses, Helicobacter spp., murine norovirus, and several other previously unknown infectious agents have “emerged” in laboratory rodents relatively recently. These agents have been discovered serendipitously or through active investigation of atypical serology results, cell culture contamination, unexpected histopathology, or previously unrecognized clinical disease syndromes. The potential research impact of these agents is not fully known. Infected rodents have demonstrated immunomodulation, tumor suppression, clinical disease (particularly in immunodeficient rodents), and histopathology. Perturbations of organismal and cellular physiology also likely occur. These agents posed unique challenges to laboratory animal resource programs once discovered; it was necessary to develop specific diagnostic assays and an understanding of their epidemiology and transmission routes before attempting eradication, and then evaluate eradication methods for efficacy. Even then management approaches varied significantly, from apathy to total exclusion, and such inconsistency has hindered the sharing and transfer of rodents among institutions, particularly for genetically modified rodent models that may not be readily available. As additional infectious agents are discovered in laboratory rodents in coming years, much of what researchers have learned from experiences with the recently identified pathogens will be applicable. This article provides an overview of the discovery, detection, and research impact of infectious agents recently identified in laboratory rodents. We also discuss emerging syndromes for which there is a suspected infectious etiology, and the unique challenges of managing newly emerging infectious agents. PMID:18506061

Carbohydrate Polymers for Nonviral Nucleic Acid Delivery

PubMed Central

Sizovs, Antons; McLendon, Patrick M.; Srinivasachari, Sathya

2014-01-01

Carbohydrates have been investigated and developed as delivery vehicles for shuttling nucleic acids into cells. In this review, we present the state of the art in carbohydrate-based polymeric vehicles for nucleic acid delivery, with the focus on the recent successes in preclinical models, both in vitro and in vivo. Polymeric scaffolds based on the natural polysaccharides chitosan, hyaluronan, pullulan, dextran, and schizophyllan each have unique properties and potential for modification, and these results are discussed with the focus on facile synthetic routes and favorable performance in biological systems. Many of these carbohydrates have been used to develop alternative types of biomaterials for nucleic acid delivery to typical polyplexes, and these novel materials are discussed. Also presented are polymeric vehicles that incorporate copolymerized carbohydrates into polymer backbones based on polyethylenimine and polylysine and their effect on transfection and biocompatibility. Unique scaffolds, such as clusters and polymers based on cyclodextrin (CD), are also discussed, with the focus on recent successes in vivo and in the clinic. These results are presented with the emphasis on the role of carbohydrate and charge on transfection. Use of carbohydrates as molecular recognition ligands for cell-type specific delivery is also briefly reviewed. We contend that carbohydrates have contributed significantly to progress in the field of non-viral DNA delivery, and these new discoveries are impactful for developing new vehicles and materials for treatment of human disease. PMID:21504102

A new approach to aid the characterisation and identification of metabolites of a model drug; partial isotope enrichment combined with novel formula elucidation software.

PubMed

Hobby, Kirsten; Gallagher, Richard T; Caldwell, Patrick; Wilson, Ian D

2009-01-01

This work describes the identification of 'isotopically enriched' metabolites of 4-cyanoaniline using the unique features of the software package 'Spectral Simplicity'. The software is capable of creating the theoretical mass spectra for partially isotope-enriched compounds, and subsequently performing an elemental composition analysis to give the elemental formula for the 'isotopically enriched' metabolite. A novel mass spectral correlation method, called 'FuzzyFit', was employed. 'FuzzyFit' utilises the expected experimental distribution of errors in both mass accuracy and isotope pattern and enables discrimination between statistically probable and improbable candidate formulae. The software correctly determined the molecular formulae of ten previously described metabolites of 4-cyanoaniline confirming the technique of partial isotope enrichment can produce results analogous to standard methodologies. Six previously unknown species were also identified, based on the presence of the unique 'designer' isotope ratio. Three of the unknowns were tentatively identified as N-acetylglutamine, O-methyl-N acetylglucuronide and a putative fatty acid conjugate. The discovery of a significant number of unknown species of a model drug with a comprehensive history of investigation highlights the potential for enhancement to the analytical process by the use of 'designer' isotope ratio compounds. The 'FuzzyFit' methodology significantly aided the elucidation of candidate formulae, by provision of a vastly simplified candidate formula data set. Copyright (c) 2008 John Wiley & Sons, Ltd.

Okadaic acid and microcystin insensitive PPP-family phosphatases may represent novel biotechnology targets.

PubMed

Uhrig, R Glen; Moorhead, Greg B

2011-12-01

Reversible protein phosphorylation is of central importance to the proper cellular functioning of all living organisms. Catalyzed by the opposing reactions of protein kinases and phosphatases, dysfunction in reversible protein phosphorylation can result in a wide variety of cellular aberrations. In eukaryotic organisms there exists four classes of protein phosphatases, of which the PPP-family protein phosphatases have documented susceptibility to a range of protein and small molecule inhibitors. These inhibitors have been of great importance to the biochemical characterization of PPP-family protein phosphatases since their discovery, but also maintain in natura biological significance with their endogenous regulatory properties (protein inhibitors) and toxicity (small molecule inhibitors). Recently, two unique PPP-family protein phosphatases, named the Shewanella-like protein phosphatases (SLP phosphatases), from Arabidopsis thaliana were characterized and found to be phylogenetically similar to the PPP-family protein phosphatases protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), while completely lacking sensitivity to the classic PPP-family phosphatase small molecule inhibitors okadaic acid and microcystin-LR. SLP phosphatases were also found to be absent in metazoans, but present in a wide range of bacteria, fungi and protozoa responsible for human disease. The unique biochemical properties and evolutionary heritage of SLP phosphatases suggests they could not only be potential biotechnology targets for agriculture, but may also prove to be of interest for future therapeutic drug development. © 2011 Landes Bioscience

Magnetic exploration of a low-temperature ultramafic-hosted hydrothermal site (Lost City, 30°N, MAR)

NASA Astrophysics Data System (ADS)

Szitkar, Florent; Tivey, Maurice A.; Kelley, Deborah S.; Karson, Jeffrey A.; Früh-Green, Gretchen L.; Denny, Alden R.

2017-03-01

A 2003 high-resolution magnetic survey conducted by the Autonomous Underwater Vehicle ABE over the low-temperature, ultramafic-hosted hydrothermal field Lost City reveals a weak positive magnetic anomaly. This observation is in direct contrast to recent observations of strong positive magnetic anomalies documented over the high-temperature ultramafic-hosted hydrothermal vents fields Rainbow and Ashadze, which indicates that temperature may control the production of magnetization at these sites. The Lost City survey provides a unique opportunity to study a field that is, to date, one of a kind, and is an end member of ultramafic-hosted hydrothermal systems. Our results highlight the key contribution of temperature on magnetite production resulting from serpentinization reactions. Whereas high temperature promotes significant production and partitioning of iron into magnetite, low temperature favors iron partitioning into various alteration phases, resulting in a magnetite-poor rock. Moreover, the distribution of magnetic anomalies confirms results of a previous geological survey indicating the progressive migration of hydrothermal activity upslope. These discoveries contribute to the results of 25 yrs of magnetic exploration of a wide range of hydrothermal sites, from low- to high-temperature and from basalt- to ultramafic-hosted, and thereby validate using high-resolution magnetics as a crucial parameter for locating and characterizing hydrothermal sites hosting unique chemosynthetic-based ecosystems and potentially mineral-rich deposits.

The rhizospheres of traditional medicinal plants in Panxi, China, host a diverse selection of actinobacteria with antimicrobial properties.

PubMed

Zhao, Ke; Penttinen, Petri; Chen, Qiang; Guan, Tongwei; Lindström, Kristina; Ao, Xiaoling; Zhang, Lili; Zhang, Xiaoping

2012-06-01

Actinobacteria are a prolific source of antibiotics. Since the rate of discovery of novel antibiotics is decreasing, actinobacteria from unique environments need to be explored. In particular, actinobacterial biocontrol strains from medicinal plants need to be studied as they can be a source of potent antibiotics. We combined culture-dependent and culture-independent methods in analyzing the actinobacterial diversity in the rhizosphere of seven traditional medicinal plant species from Panxi, China, and assessed the antimicrobial activity of the isolates. Each of the plant species hosted a unique set of actinobacterial strains. Out of the 64 morphologically distinct isolates, half were Streptomyces sp., eight were Micromonospora sp., and the rest were members of 18 actinobacterial genera. In particular, Ainsliaea henryi Diels. hosted a diverse selection of actinobacteria, although the 16S ribosomal RNA (rRNA) sequence identity ranges of the isolates and of the 16S rRNA gene clone library were not congruent. In the clone library, 40% of the sequences were related to uncultured actinobacteria, emphasizing the need to develop isolation methods to assess the full potential of the actinobacteria. All Streptomyces isolates showed antimicrobial activity. While the antimicrobial activities of the rare actinobacteria were limited, the growth of Escherichia coli, Verticillium dahliae, and Fusarium oxysporum were inhibited only by rare actinobacteria, and strains related to Saccharopolyspora shandongensis and Streptosporangium roseum showed broad antimicrobial activity.

Classical many-particle systems with unique disordered ground states

NASA Astrophysics Data System (ADS)

Zhang, G.; Stillinger, F. H.; Torquato, S.

2017-10-01

Classical ground states (global energy-minimizing configurations) of many-particle systems are typically unique crystalline structures, implying zero enumeration entropy of distinct patterns (aside from trivial symmetry operations). By contrast, the few previously known disordered classical ground states of many-particle systems are all high-entropy (highly degenerate) states. Here we show computationally that our recently proposed "perfect-glass" many-particle model [Sci. Rep. 6, 36963 (2016), 10.1038/srep36963] possesses disordered classical ground states with a zero entropy: a highly counterintuitive situation . For all of the system sizes, parameters, and space dimensions that we have numerically investigated, the disordered ground states are unique such that they can always be superposed onto each other or their mirror image. At low energies, the density of states obtained from simulations matches those calculated from the harmonic approximation near a single ground state, further confirming ground-state uniqueness. Our discovery provides singular examples in which entropy and disorder are at odds with one another. The zero-entropy ground states provide a unique perspective on the celebrated Kauzmann-entropy crisis in which the extrapolated entropy of a supercooled liquid drops below that of the crystal. We expect that our disordered unique patterns to be of value in fields beyond glass physics, including applications in cryptography as pseudorandom functions with tunable computational complexity.

NASA's Discovery Program: Moving Toward the Edge (of the Solar System)

NASA Technical Reports Server (NTRS)

Johnson, Les; Gilbert, Paul

2007-01-01

NASA's Planetary Science , Division sponsors a competitive program of small spacecraft missions with the goal of performing focused science investigations that complement NASA's larger planetary science explorations at relatively low cost. The goal of the Discovery program is to launch many smaller missions with fast development times to increase our understanding of the solar system by exploring the planets, dwarf planets, their moons, and small bodies such as comets and asteroids. Discovery missions are solicited from the broad planetary science community approximately every 2 years. Active missions within the Discovery program include several with direct scientific or engineering connections to potential future missions to the edge of the solar system and beyond. In addition to those in the Discovery program are the missions of the New Frontiers program. The first New Frontiers mission. is the New Horizons mission to Pluto, which will explore this 38-AU distant dwarf planet and potentially some Kuiper Belt objects beyond. The Discovery program's Dawn mission, when launched in mid-2007, will use ion drive as its primary propulsion system. Ion propulsion is one of only two technologies that appear feasible for early interstellar precursor missions with practical flight times. The Kepler mission will explore the structure and diversity of extrasolar planetary systems, with an emphasis on the detection of Earth-size planets around other stars. Kepler will survey nearby solar systems searching for planets that may fall within the habitable zone,' a region surrounding a star within which liquid water may exist on a planet's surface - an essential ingredient for life as we know it. With its open and competitive approach to mission selections, the Discovery program affords scientists the opportunity to propose missions to virtually any solar system destination. With its emphasis on science and proven openness to the use of new technologies such as ion propulsion, missions flown as part of the program will test out technologies needed for future very deep-space exploration and potentially take us to these difficult and distant destinations.

Discovery of metabolic signatures for predicting whole organism toxicology.

PubMed

Hines, Adam; Staff, Fred J; Widdows, John; Compton, Russell M; Falciani, Francesco; Viant, Mark R

2010-06-01

Toxicological studies in sentinel organisms frequently use biomarkers to assess biological effect. Development of "omic" technologies has enhanced biomarker discovery at the molecular level, providing signatures unique to toxicant mode-of-action (MOA). However, these signatures often lack relevance to organismal responses, such as growth or reproduction, limiting their value for environmental monitoring. Our primary objective was to discover metabolic signatures in chemically exposed organisms that can predict physiological toxicity. Marine mussels (Mytilus edulis) were exposed for 7 days to 12 and 50 microg/l copper and 50 and 350 microg/l pentachlorophenol (PCP), toxicants with unique MOAs. Physiological responses comprised an established measure of organism energetic fitness, scope for growth (SFG). Metabolic fingerprints were measured in the same individuals using nuclear magnetic resonance-based metabolomics. Metabolic signatures predictive of SFG were sought using optimal variable selection strategies and multivariate regression and then tested upon independently field-sampled mussels from rural and industrialized sites. Copper and PCP induced rational metabolic and physiological changes. Measured and predicted SFG were highly correlated for copper (r(2) = 0.55, P = 2.82 x 10(-7)) and PCP (r(2) = 0.66, P = 3.20 x 10(-6)). Predictive metabolites included methionine and arginine/phosphoarginine for copper and allantoin, valine, and methionine for PCP. When tested on field-sampled animals, metabolic signatures predicted considerably reduced fitness of mussels from the contaminated (SFG = 6.0 J/h/g) versus rural (SFG = 15.2 J/h/g) site. We report the first successful discovery of metabolic signatures in chemically exposed environmental organisms that inform on molecular MOA and that can predict physiological toxicity. This could have far-reaching implications for monitoring impacts on environmental health.

Rational design of an enzyme mutant for anti-cocaine therapeutics

NASA Astrophysics Data System (ADS)

Zheng, Fang; Zhan, Chang-Guo

2008-09-01

(-)-Cocaine is a widely abused drug and there is no available anti-cocaine therapeutic. The disastrous medical and social consequences of cocaine addiction have made the development of an effective pharmacological treatment a high priority. An ideal anti-cocaine medication would be to accelerate (-)-cocaine metabolism producing biologically inactive metabolites. The main metabolic pathway of cocaine in body is the hydrolysis at its benzoyl ester group. Reviewed in this article is the state-of-the-art computational design of high-activity mutants of human butyrylcholinesterase (BChE) against (-)-cocaine. The computational design of BChE mutants have been based on not only the structure of the enzyme, but also the detailed catalytic mechanisms for BChE-catalyzed hydrolysis of (-)-cocaine and (+)-cocaine. Computational studies of the detailed catalytic mechanisms and the structure-and-mechanism-based computational design have been carried out through the combined use of a variety of state-of-the-art techniques of molecular modeling. By using the computational insights into the catalytic mechanisms, a recently developed unique computational design strategy based on the simulation of the rate-determining transition state has been employed to design high-activity mutants of human BChE for hydrolysis of (-)-cocaine, leading to the exciting discovery of BChE mutants with a considerably improved catalytic efficiency against (-)-cocaine. One of the discovered BChE mutants (i.e., A199S/S287G/A328W/Y332G) has a ˜456-fold improved catalytic efficiency against (-)-cocaine. The encouraging outcome of the computational design and discovery effort demonstrates that the unique computational design approach based on the transition-state simulation is promising for rational enzyme redesign and drug discovery.

Financing drug discovery for orphan diseases.

PubMed

Fagnan, David E; Gromatzky, Austin A; Stein, Roger M; Fernandez, Jose-Maria; Lo, Andrew W

2014-05-01

Recently proposed 'megafund' financing methods for funding translational medicine and drug development require billions of dollars in capital per megafund to de-risk the drug discovery process enough to issue long-term bonds. Here, we demonstrate that the same financing methods can be applied to orphan drug development but, because of the unique nature of orphan diseases and therapeutics (lower development costs, faster FDA approval times, lower failure rates and lower correlation of failures among disease targets) the amount of capital needed to de-risk such portfolios is much lower in this field. Numerical simulations suggest that an orphan disease megafund of only US$575 million can yield double-digit expected rates of return with only 10-20 projects in the portfolio. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

UCLA's Molecular Screening Shared Resource: enhancing small molecule discovery with functional genomics and new technology.

PubMed

Damoiseaux, Robert

2014-05-01

The Molecular Screening Shared Resource (MSSR) offers a comprehensive range of leading-edge high throughput screening (HTS) services including drug discovery, chemical and functional genomics, and novel methods for nano and environmental toxicology. The MSSR is an open access environment with investigators from UCLA as well as from the entire globe. Industrial clients are equally welcome as are non-profit entities. The MSSR is a fee-for-service entity and does not retain intellectual property. In conjunction with the Center for Environmental Implications of Nanotechnology, the MSSR is unique in its dedicated and ongoing efforts towards high throughput toxicity testing of nanomaterials. In addition, the MSSR engages in technology development eliminating bottlenecks from the HTS workflow and enabling novel assays and readouts currently not available.

The promise of disease gene discovery in South Asia

PubMed Central

Nakatsuka, Nathan; Moorjani, Priya; Rai, Niraj; Sarkar, Biswanath; Tandon, Arti; Patterson, Nick; Bhavani, Gandham SriLakshmi; Girisha, Katta Mohan; Mustak, Mohammed S; Srinivasan, Sudha; Kaushik, Amit; Vahab, Saadi Abdul; Jagadeesh, Sujatha M.; Satyamoorthy, Kapaettu; Singh, Lalji; Reich, David; Thangaraj, Kumarasamy

2017-01-01

The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population, but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identify 81 unique groups, of which 14 have estimated census sizes of more than a million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identify multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an under-appreciated opportunity for reducing disease burden among South Asians through the discovery of and testing for recessive disease genes. PMID:28714977

The Late Devonian Gogo Formation Lägerstatte of Western Australia: Exceptional Early Vertebrate Preservation and Diversity

NASA Astrophysics Data System (ADS)

Long, John A.; Trinajstic, Kate

2010-05-01

The Gogo Formation of Western Australia preserves a unique Late Devonian (Frasnian) reef fauna. The exceptional three-dimensional preservation of macrofossils combined with unprecedented soft-tissue preservation (including muscle bundles, nerve cells, and umbilical structures) has yielded a particularly rich assemblage with almost 50 species of fishes described. The most significant discoveries have contributed to resolving placoderm phylogeny and elucidating their reproductive physiology. Specifically, these discoveries have produced data on the oldest known vertebrate embryos; the anatomy of the primitive actinopterygian neurocranium and phylogeny of the earliest actinopterygians; the histology, radiation, and plasticity of dipnoan (lungfish) dental and cranial structures; the anatomy and functional morphology of the extinct onychodonts; and the anatomy of the primitive tetrapodomorph head and pectoral fin.

Blueprint for antimicrobial hit discovery targeting metabolic networks.

PubMed

Shen, Y; Liu, J; Estiu, G; Isin, B; Ahn, Y-Y; Lee, D-S; Barabási, A-L; Kapatral, V; Wiest, O; Oltvai, Z N

2010-01-19

Advances in genome analysis, network biology, and computational chemistry have the potential to revolutionize drug discovery by combining system-level identification of drug targets with the atomistic modeling of small molecules capable of modulating their activity. To demonstrate the effectiveness of such a discovery pipeline, we deduced common antibiotic targets in Escherichia coli and Staphylococcus aureus by identifying shared tissue-specific or uniformly essential metabolic reactions in their metabolic networks. We then predicted through virtual screening dozens of potential inhibitors for several enzymes of these reactions and showed experimentally that a subset of these inhibited both enzyme activities in vitro and bacterial cell viability. This blueprint is applicable for any sequenced organism with high-quality metabolic reconstruction and suggests a general strategy for strain-specific antiinfective therapy.

Accelerating the Rate of Astronomical Discovery

NASA Astrophysics Data System (ADS)

Norris, Ray P. Ruggles, Clive L. N.

2010-05-01

Special Session 5 on Accelerating the Rate of Astronomical Discovery addressed a range of potential limits to progress - paradigmatic, technological, organisational, and political - examining each issue both from modern and historical perspectives, and drawing lessons to guide future progress. A number of issues were identified which potentially regulate the flow of discoveries, such as the balance between large strongly-focussed projects and instruments, designed to answer the most fundamental questions confronting us, and the need to maintain a creative environment with room for unorthodox thinkers and bold, high risk, projects. Also important is the need to maintain historical and cultural perspectives, and the need to engage the minds of the most brilliant young people on the planet, regardless of their background, ethnicity, gender, or geography.

Chemical Space of DNA-Encoded Libraries.

PubMed

Franzini, Raphael M; Randolph, Cassie

2016-07-28

In recent years, DNA-encoded chemical libraries (DECLs) have attracted considerable attention as a potential discovery tool in drug development. Screening encoded libraries may offer advantages over conventional hit discovery approaches and has the potential to complement such methods in pharmaceutical research. As a result of the increased application of encoded libraries in drug discovery, a growing number of hit compounds are emerging in scientific literature. In this review we evaluate reported encoded library-derived structures and identify general trends of these compounds in relation to library design parameters. We in particular emphasize the combinatorial nature of these libraries. Generally, the reported molecules demonstrate the ability of this technology to afford hits suitable for further lead development, and on the basis of them, we derive guidelines for DECL design.

Strategic Protein Target Analysis for Developing Drugs to Stop Dental Caries

PubMed Central

Horst, J.A.; Pieper, U.; Sali, A.; Zhan, L.; Chopra, G.; Samudrala, R.; Featherstone, J.D.B.

2012-01-01

Dental caries is the most common disease to cause irreversible damage in humans. Several therapeutic agents are available to treat or prevent dental caries, but none besides fluoride has significantly influenced the disease burden globally. Etiologic mechanisms of the mutans group streptococci and specific Lactobacillus species have been characterized to various degrees of detail, from identification of physiologic processes to specific proteins. Here, we analyze the entire Streptococcus mutans proteome for potential drug targets by investigating their uniqueness with respect to non-cariogenic dental plaque bacteria, quality of protein structure models, and the likelihood of finding a drug for the active site. Our results suggest specific targets for rational drug discovery, including 15 known virulence factors, 16 proteins for which crystallographic structures are available, and 84 previously uncharacterized proteins, with various levels of similarity to homologs in dental plaque bacteria. This analysis provides a map to streamline the process of clinical development of effective multispecies pharmacologic interventions for dental caries. PMID:22899687

(Per)chlorate in Biology on Earth and Beyond.

PubMed

Youngblut, Matthew D; Wang, Ouwei; Barnum, Tyler P; Coates, John D

2016-09-08

Respiration of perchlorate and chlorate [collectively, (per)chlorate] was only recognized in the last 20 years, yet substantial advances have been made in our understanding of the underlying metabolisms. Although it was once considered solely anthropogenic, pervasive natural sources, both terrestrial and extraterrestrial, indicate an ancient (per)chlorate presence across our solar system. These discoveries stimulated interest in (per)chlorate microbiology, and the application of advanced approaches highlights exciting new facets. Forward and reverse genetics revealed new information regarding underlying molecular biology and associated regulatory mechanisms. Structural and functional analysis characterized core enzymes and identified novel reaction sequences. Comparative genomics elucidated evolutionary aspects, and stress analysis identified novel response mechanisms to reactive chlorine species. Finally, systems biology identified unique metabolic versatility and novel mechanisms of (per)chlorate respiration, including symbiosis and a hybrid enzymatic-abiotic metabolism. While many published studies focus on (per)chlorate and their basic metabolism, this review highlights seminal advances made over the last decade and identifies new directions and potential novel applications.

The Effect of Hypoxia on Mesenchymal Stem Cell Biology

PubMed Central

Ejtehadifar, Mostafa; Shamsasenjan, Karim; Movassaghpour, Aliakbar; Akbarzadehlaleh, Parvin; Dehdilani, Nima; Abbasi, Parvaneh; Molaeipour, Zahra; Saleh, Mahshid

2015-01-01

Although physiological and pathological role of hypoxia have been appreciated in mammalians for decades however the cellular biology of hypoxia more clarified in the past 20 years. Discovery of the transcription factor hypoxia-inducible factor (HIF)-1, in the 1990s opened a new window to investigate the mechanisms behind hypoxia. In different cellular contexts HIF-1 activation show variable results by impacting various aspects of cell biology such as cell cycle, apoptosis, differentiation and etc. Mesenchymal stem cells (MSC) are unique cells which take important role in tissue regeneration. They are characterized by self-renewal capacity, multilineage potential, and immunosuppressive property. Like so many kind of cells, hypoxia induces different responses in MSCs by HIF- 1 activation. The activation of this molecule changes the growth, multiplication, differentiation and gene expression profile of MSCs in their niche by a complex of signals. This article briefly discusses the most important effects of hypoxia in growth kinetics, signalling pathways, cytokine secretion profile and expression of chemokine receptors in different conditions. PMID:26236651

The Role, Involvement and Function(s) of Interleukin-35 and Interleukin-37 in Disease Pathogenesis.

PubMed

Bello, Ramatu Omenesa; Chin, Voon Kin; Abd Rachman Isnadi, Mohammad Faruq; Abd Majid, Roslaini; Atmadini Abdullah, Maizaton; Lee, Tze Yan; Amiruddin Zakaria, Zainul; Hussain, Mohd Khairi; Basir, Rusliza

2018-04-11

The recently identified cytokines-interleukin (IL)-35 and interleukin (IL)-37-have been described for their anti-inflammatory and immune-modulating actions in numerous inflammatory diseases, auto-immune disorders, malignancies, infectious diseases and sepsis. Either cytokine has been reported to be reduced and in some cases elevated and consequently contributed towards disease pathogenesis. In view of the recent advances in utilizing cytokine profiles for the development of biological macromolecules, beneficial in the management of certain intractable immune-mediated disorders, these recently characterized cytokines (IL-35 and IL-37) offer potential as reasonable targets for the discovery of novel immune-modulating anti-inflammatory therapies. A detailed comprehension of their sophisticated regulatory mechanisms and patterns of expression may provide unique opportunities for clinical application as highly selective and target specific therapeutic agents. This review seeks to summarize the recent advancements in discerning the dynamics, mechanisms, immunoregulatory and anti-inflammatory actions of IL-35 and IL-37 as they relate to disease pathogenesis.

Culture and neuroscience: additive or synergistic?

PubMed Central

Dapretto, Mirella; Iacoboni, Marco

2010-01-01

The investigation of cultural phenomena using neuroscientific methods—cultural neuroscience (CN)—is receiving increasing attention. Yet it is unclear whether the integration of cultural study and neuroscience is merely additive, providing additional evidence of neural plasticity in the human brain, or truly synergistic, yielding discoveries that neither discipline could have achieved alone. We discuss how the parent fields to CN: cross-cultural psychology, psychological anthropology and cognitive neuroscience inform the investigation of the role of cultural experience in shaping the brain. Drawing on well-established methodologies from cross-cultural psychology and cognitive neuroscience, we outline a set of guidelines for CN, evaluate 17 CN studies in terms of these guidelines, and provide a summary table of our results. We conclude that the combination of culture and neuroscience is both additive and synergistic; while some CN methodologies and findings will represent the direct union of information from parent fields, CN studies employing the methodological rigor required by this logistically challenging new field have the potential to transform existing methodologies and produce unique findings. PMID:20083533

Immunology of Pediatric HIV Infection

PubMed Central

Tobin, Nicole H.; Aldrovandi, Grace M.

2013-01-01

Summary Most infants born to human immunodeficiency virus (HIV)-infected women escape HIV infection. Infants evade infection despite an immature immune system and, in the case of breastfeeding, prolonged repetitive, exposure. If infants become infected, the course of their infection and response to treatment differs dramatically depending upon the timing (in utero, intrapartum, or during breastfeeding) and potentially the route of their infection. Perinatally acquired HIV infection occurs during a critical window of immune development. HIV’s perturbation of this dynamic process may account for the striking age-dependent differences in HIV disease progression. HIV infection also profoundly disrupts the maternal immune system upon which infants rely for protection and immune instruction. Therefore, it is not surprising that infants who escape HIV infection still suffer adverse effects. In this review, we highlight the unique aspects of pediatric HIV transmission and pathogenesis with a focus on mechanisms by which HIV infection during immune ontogeny may allow discovery of key elements for protection and control from HIV. PMID:23772619

Viruses associated with Antarctic wildlife: From serology based detection to identification of genomes using high throughput sequencing.

PubMed

Smeele, Zoe E; Ainley, David G; Varsani, Arvind

2018-01-02

The Antarctic, sub-Antarctic islands and surrounding sea-ice provide a unique environment for the existence of organisms. Nonetheless, birds and seals of a variety of species inhabit them, particularly during their breeding seasons. Early research on Antarctic wildlife health, using serology-based assays, showed exposure to viruses in the families Birnaviridae, Flaviviridae, Herpesviridae, Orthomyxoviridae and Paramyxoviridae circulating in seals (Phocidae), penguins (Spheniscidae), petrels (Procellariidae) and skuas (Stercorariidae). It is only during the last decade or so that polymerase chain reaction-based assays have been used to characterize viruses associated with Antarctic animals. Furthermore, it is only during the last five years that full/whole genomes of viruses (adenoviruses, anelloviruses, orthomyxoviruses, a papillomavirus, paramyoviruses, polyomaviruses and a togavirus) have been sequenced using Sanger sequencing or high throughput sequencing (HTS) approaches. This review summaries the knowledge of animal Antarctic virology and discusses potential future directions with the advent of HTS in virus discovery and ecology. Copyright © 2017 Elsevier B.V. All rights reserved.

Borophene as a prototype for synthetic 2D materials development.

PubMed

Mannix, Andrew J; Zhang, Zhuhua; Guisinger, Nathan P; Yakobson, Boris I; Hersam, Mark C

2018-06-01

The synthesis of 2D materials with no analogous bulk layered allotropes promises a substantial breadth of physical and chemical properties through the diverse structural options afforded by substrate-dependent epitaxy. However, despite the joint theoretical and experimental efforts to guide materials discovery, successful demonstrations of synthetic 2D materials have been rare. The recent synthesis of 2D boron polymorphs (that is, borophene) provides a notable example of such success. In this Perspective, we discuss recent progress and future opportunities for borophene research. Borophene combines unique mechanical properties with anisotropic metallicity, which complements the canon of conventional 2D materials. The multi-centre characteristics of boron-boron bonding lead to the formation of configurationally varied, vacancy-mediated structural motifs, providing unprecedented diversity in a mono-elemental 2D system with potential for electronic applications, chemical functionalization, materials synthesis and complex heterostructures. With its foundations in computationally guided synthesis, borophene can serve as a prototype for ongoing efforts to discover and exploit synthetic 2D materials.

Self-assembled Nanofibrils for Immunomodulation

NASA Astrophysics Data System (ADS)

Zhao, Fan

This thesis has been mainly focused on applying self-assembled nanofibrils as unique depots for controlled release to modulate immune system, with two major chapters on modulation of innate immunity in chapter 2 and adaptive immunity in chapter 3, respectively. There are 5 chapters in the thesis. Chapter 1 gives a detailed review on the discovery, synthesis and application of self-assembled nanofibrils of therapeutic agents (termed as "self-delivery drugs"), including bioactive molecules; Chapter 2 demonstrates the supramolecular hydrogel of chemotactic peptides as a prolonged inflammation model through proper molecular engineering; Chapter 3 reports a suppressive antibody response achieved by encapsulation of antigens by supramolecular hydrogel of glycopeptide; Chapter 4 illustrates an example of supramolecular hydrogel formation of molecules with extremely low solubility, based on the fact that many small organic drugs have poor solubility. Chapter 5 used beta-galatosidase as a model to study glycosidase-instructed supramolecular hydrogel formation, with potential to target cancer cells due to their distinct metabolic profile.

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

NASA Astrophysics Data System (ADS)

McLaughlin, Russell L.; Schijven, Dick; van Rheenen, Wouter; van Eijk, Kristel R.; O'Brien, Margaret; Kahn, René S.; Ophoff, Roel A.; Goris, An; Bradley, Daniel G.; Al-Chalabi, Ammar; van den Berg, Leonard H.; Luykx, Jurjen J.; Hardiman, Orla; Veldink, Jan H.; Shatunov, Aleksey; Dekker, Annelot M.; Diekstra, Frank P.; Pulit, Sara L.; van der Spek, Rick A. A.; van Doormaal, Perry T. C.; Sproviero, William; Jones, Ashley R.; Nicholson, Garth A.; Rowe, Dominic B.; Pamphlett, Roger; Kiernan, Matthew C.; Bauer, Denis; Kahlke, Tim; Williams, Kelly; Eftimov, Filip; Fogh, Isabella; Ticozzi, Nicola; Lin, Kuang; Millecamps, Stéphanie; Salachas, François; Meininger, Vincent; de Carvalho, Mamede; Pinto, Susana; Mora, Jesus S.; Rojas-García, Ricardo; Polak, Meraida; Chandran, Siddharthan; Colville, Shuna; Swingler, Robert; Morrison, Karen E.; Shaw, Pamela J.; Hardy, John; Orrell, Richard W.; Pittman, Alan; Sidle, Katie; Fratta, Pietro; Malaspina, Andrea; Petri, Susanne; Abdulla, Susanna; Drepper, Carsten; Sendtner, Michael; Meyer, Thomas; Wiedau-Pazos, Martina; Lomen-Hoerth, Catherine; van Deerlin, Vivianna M.; Trojanowski, John Q.; Elman, Lauren; McCluskey, Leo; Basak, Nazli; Meitinger, Thomas; Lichtner, Peter; Blagojevic-Radivojkov, Milena; Andres, Christian R.; Maurel, Cindy; Bensimon, Gilbert; Landwehrmeyer, Bernhard; Brice, Alexis; Payan, Christine A. M.; Saker-Delye, Safa; Dürr, Alexandra; Wood, Nicholas; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Nöuthen, Markus M.; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean-François; Uitterlinden, Andre G.; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; van der Kooi, Anneke J.; de Visser, Marianne; Weber, Markus; Shaw, Christopher E.; Smith, Bradley N.; Pansarasa, Orietta; Cereda, Cristina; Del Bo, Roberto; Comi, Giacomo P.; D'Alfonso, Sandra; Bertolin, Cinzia; Sorarù, Gianni; Mazzini, Letizia; Pensato, Viviana; Gellera, Cinzia; Tiloca, Cinzia; Ratti, Antonia; Calvo, Andrea; Moglia, Cristina; Brunetti, Maura; Arcuti, Simon; Capozzo, Rosa; Zecca, Chiara; Lunetta, Christian; Penco, Silvana; Riva, Nilo; Padovani, Alessandro; Filosto, Massimiliano; Blair, Ian; Leigh, P. Nigel; Casale, Federico; Chio, Adriano; Beghi, Ettore; Pupillo, Elisabetta; Tortelli, Rosanna; Logroscino, Giancarlo; Powell, John; Ludolph, Albert C.; Weishaupt, Jochen H.; Robberecht, Wim; van Damme, Philip; Brown, Robert H.; Glass, Jonathan; Landers, John E.; Andersen, Peter M.; Corcia, Philippe; Vourc'h, Patrick; Silani, Vincenzo; van Es, Michael A.; Pasterkamp, R. Jeroen; Lewis, Cathryn M.; Breen, Gerome; Ripke, Stephan; Neale, Benjamin M.; Corvin, Aiden; Walters, James T. R.; Farh, Kai-How; Holmans, Peter A.; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A.; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberley D.; Chan, Raymond C. K.; Chan, Ronald Y. L.; Chen, Eric Y. H.; Cheng, Wei; Cheung, Eric F. C.; Chong, Siow Ann; Cloninger, C. Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L.; Degenhardt, Franziska; Del Favero, Jurgen; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Durmishi, Naser; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H.; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Friedman, Joseph I.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Giegling, Ina; Giusti-Rodríguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Golimbet, Vera; Gopal, Srihari; Gratten, Jacob; de Haan, Lieuwe; Hammer, Christian; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan; Hirschhorn, Joel N.; Hoffmann, Per; Hofman, Andrea; Hollegaard, Mads V.; Hougaard, David M.; Ikeda, Masashi; Joa, Inge; Julià, Antonio; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kennedy, James L.; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles, James A.; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kuzelova-Ptackova, Hana; Kähler, Anna K.; Laurent, Claudine; Lee, Jimmy; Lee, S. Hong; Legge, Sophie E.; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang, Kung-Yee; Lieberman, Jeffrey; Limborska, Svetlana; Loughland, Carmel M.; Lubinski, Jan; Lönnqvist, Jouko; Macek, Milan; Magnusson, Patrik K. E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W.; McDonald, Colm; McIntosh, Andrew M.; Meier, Sandra; Meijer, Carin J.; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Mors, Ole; Murphy, Kieran C.; Murray, Robin M.; Myin-Germeys, Inez; Müller-Myhsok, Bertram; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O'Callaghan, Eadbhard; O'Dushlaine, Colm; O'Neill, F. Anthony; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; van Os, Jim; Pantelis, Christos; Papadimitriou, George N.; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Pejovic-Milovancevic, Milica; Perkins, Diana O.; Pietiläinen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Schall, Ulrich; Schubert, Christian R.; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Sigurdsson, Engilbert; Silagadze, Teimuraz; Silverman, Jeremy M.; Sim, Kang; Slominsky, Petr; Smoller, Jordan W.; So, Hon-Cheong; Spencer, Chris C. A.; Stahl, Eli A.; Stefansson, Hreinn; Steinberg, Stacy; Stogmann, Elisabeth; Straub, Richard E.; Strengman, Eric; Strohmaier, Jana; Stroup, T. Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Söderman, Erik; Thirumalai, Srinivas; Toncheva, Draga; Tosato, Sarah; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wong, Emily H. M.; Wormley, Brandon K.; Xi, Hualin Simon; Zai, Clement C.; Zheng, Xuebin; Zimprich, Fritz; Wray, Naomi R.; Stefansson, Kari; Visscher, Peter M.; Adolfsson, Rolf; Andreassen, Ole A.; Blackwood, Douglas H. R.; Bramon, Elvira; Buxbaum, Joseph D.; Børglum, Anders D.; Darvasi, Ariel; Domenici, Enrico; Ehrenreich, Hannelore; Esko, Tõnu; Gejman, Pablo V.; Gill, Michael; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Jönsson, Erik G.; Kendler, Kenneth S.; Kirov, George; Knight, Jo; Lencz, Todd; Levinson, Douglas F.; Li, Qingqin S.; Liu, Jianjun; Malhotra, Anil K.; McCarroll, Steven A.; McQuillin, Andrew; Moran, Jennifer L.; Mortensen, Preben B.; Mowry, Bryan J.; Owen, Michael J.; Palotie, Aarno; Pato, Carlos N.; Petryshen, Tracey L.; Posthuma, Danielle; Riley, Brien P.; Rujescu, Dan; Sham, Pak C.; Sklar, Pamela; St Clair, David; Weinberger, Daniel R.; Wendland, Jens R.; Werge, Thomas; Daly, Mark J.; Sullivan, Patrick F.; O'Donovan, Michael C.

2017-03-01

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6 P=1 × 10-4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10-7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

Fluorescent techniques for discovery and characterization of phosphopantetheinyl transferase inhibitors

PubMed Central

Kosa, Nicolas M.; Foley, Timothy L.; Burkart, Michael D.

2016-01-01

Phosphopantetheinyl transferase (E.C. 2.7.8.-) activates biosynthetic pathways that synthesize both primary and secondary metabolites in bacteria. Inhibitors of these enzymes have the potential to serve as antibiotic compounds that function through a unique mode of action and possess clinical utility. Here we report a direct and continuous assay for this enzyme class based upon monitoring polarization of a fluorescent phosphopantetheine analog as it is transferred from a low molecular weight coenzyme A substrate to higher molecular weight protein acceptor. We demonstrate the utility of this method for the biochemical characterization of phosphopantetheinyl transferase Sfp, a canonical representative from this class. We also establish the portability of this technique to other homologs by adapting the assay to function with the human phosphopantetheinyl transferase, a target for which a microplate detection method does not currently exist. Comparison of these targets provides a basis to predict therapeutic index of inhibitor candidates and offers a valuable characterization of enzyme activity. PMID:24192555

Genetically Engineered Mouse Models of Pancreatic Cancer: The KPC Model (LSL-Kras(G12D/+) ;LSL-Trp53(R172H/+) ;Pdx-1-Cre), Its Variants, and Their Application in Immuno-oncology Drug Discovery.

PubMed

Lee, Jae W; Komar, Chad A; Bengsch, Fee; Graham, Kathleen; Beatty, Gregory L

2016-06-01

Pancreatic ductal adenocarcinoma (PDAC) ranks fourth among cancer-related deaths in the United States. For patients with unresectable disease, treatment options are limited and lack curative potential. Preclinical mouse models of PDAC that recapitulate the biology of human pancreatic cancer offer an opportunity for the rational development of novel treatment approaches that may improve patient outcomes. With the recent success of immunotherapy for subsets of patients with solid malignancies, interest is mounting in the possible use of immunotherapy for the treatment of PDAC. Considered in this unit is the value of genetic mouse models for characterizing the immunobiology of PDAC and for investigating novel immunotherapeutics. Several variants of these models are described, all of which may be used in drug development and for providing information on unique aspects of disease biology and therapeutic responsiveness. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

Borophene as a prototype for synthetic 2D materials development

NASA Astrophysics Data System (ADS)

Mannix, Andrew J.; Zhang, Zhuhua; Guisinger, Nathan P.; Yakobson, Boris I.; Hersam, Mark C.

2018-06-01

The synthesis of 2D materials with no analogous bulk layered allotropes promises a substantial breadth of physical and chemical properties through the diverse structural options afforded by substrate-dependent epitaxy. However, despite the joint theoretical and experimental efforts to guide materials discovery, successful demonstrations of synthetic 2D materials have been rare. The recent synthesis of 2D boron polymorphs (that is, borophene) provides a notable example of such success. In this Perspective, we discuss recent progress and future opportunities for borophene research. Borophene combines unique mechanical properties with anisotropic metallicity, which complements the canon of conventional 2D materials. The multi-centre characteristics of boron-boron bonding lead to the formation of configurationally varied, vacancy-mediated structural motifs, providing unprecedented diversity in a mono-elemental 2D system with potential for electronic applications, chemical functionalization, materials synthesis and complex heterostructures. With its foundations in computationally guided synthesis, borophene can serve as a prototype for ongoing efforts to discover and exploit synthetic 2D materials.

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia.

PubMed

McLaughlin, Russell L; Schijven, Dick; van Rheenen, Wouter; van Eijk, Kristel R; O'Brien, Margaret; Kahn, René S; Ophoff, Roel A; Goris, An; Bradley, Daniel G; Al-Chalabi, Ammar; van den Berg, Leonard H; Luykx, Jurjen J; Hardiman, Orla; Veldink, Jan H

2017-03-21

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10 -4 ) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10 -7 ). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.

Patient Electronic Health Records as a Means to Approach Genetic Research in Gastroenterology.

PubMed

Ananthakrishnan, Ashwin N; Lieberman, David

2015-10-01

Electronic health records (EHRs) are being increasingly utilized and form a unique source of extensive data gathered during routine clinical care. Through use of codified and free text concepts identified using clinical informatics tools, disease labels can be assigned with a high degree of accuracy. Analysis linking such EHR-assigned disease labels to a biospecimen repository has demonstrated that genetic associations identified in prospective cohorts can be replicated with adequate statistical power and novel phenotypic associations identified. In addition, genetic discovery research can be performed utilizing clinical, laboratory, and procedure data obtained during care. Challenges with such research include the need to tackle variability in quality and quantity of EHR data and importance of maintaining patient privacy and data security. With appropriate safeguards, this novel and emerging field of research offers considerable promise and potential to further scientific research in gastroenterology efficiently, cost-effectively, and with engagement of patients and communities. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

The Reinvention of General Relativity: A Historiographical Framework for Assessing One Hundred Years of Curved Space-time.

PubMed

Blum, Alexander; Lalli, Roberto; Renn, M Jürgen

2015-09-01

The history of the theory of general relativity presents unique features. After its discovery, the theory was immediately confirmed and rapidly changed established notions of space and time. The further implications of general relativity, however, remained largely unexplored until the mid 1950s, when it came into focus as a physical theory and gradually returned to the mainstream of physics. This essay presents a historiographical framework for assessing the history of general relativity by taking into account in an integrated narrative intellectual developments, epistemological problems, and technological advances; the characteristics of post-World War II and Cold War science; and newly emerging institutional settings. It argues that such a framework can help us understand this renaissance of general relativity as a result of two main factors: the recognition of the untapped potential of general relativity and an explicit effort at community building, which allowed this formerly disparate and dispersed field to benefit from the postwar changes in the scientific landscape.

Oligonucleotide Aptamers: New Tools for Targeted Cancer Therapy

PubMed Central

Sun, Hongguang; Zhu, Xun; Lu, Patrick Y; Rosato, Roberto R; Tan, Wen; Zu, Youli

2014-01-01

Aptamers are a class of small nucleic acid ligands that are composed of RNA or single-stranded DNA oligonucleotides and have high specificity and affinity for their targets. Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed “chemical antibodies.” In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties. Hence, they are more suitable for the development of novel clinical applications. Aptamer technology has been widely investigated in various biomedical fields for biomarker discovery, in vitro diagnosis, in vivo imaging, and targeted therapy. This review will discuss the potential applications of aptamer technology as a new tool for targeted cancer therapy with emphasis on the development of aptamers that are able to specifically target cell surface biomarkers. Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy. PMID:25093706

The chronic mild stress (CMS) model of depression: History, evaluation and usage.

PubMed

Willner, Paul

2017-02-01

Now 30 years old, the chronic mild stress (CMS) model of depression has been used in >1300 published studies, with a year-on-year increase rising to >200 papers in 2015. Data from a survey of users show that while a variety of names are in use (chronic mild/unpredictable/varied stress), these describe essentially the same procedure. This paper provides an update on the validity and reliability of the CMS model, and reviews recent data on the neurobiological basis of CMS effects and the mechanisms of antidepressant action: the volume of this research may be unique in providing a comprehensive account of antidepressant action within a single model. Also discussed is the use of CMS in drug discovery, with particular reference to hippocampal and extra-hippocampal targets. The high translational potential of the CMS model means that the neurobiological mechanisms described may be of particular relevance to human depression and mechanisms of clinical antidepressant action.

From embryonic stem cells to functioning germ cells: science, clinical and ethical perspectives.

PubMed

Kiatpongsan, Sorapop

2007-10-01

Embryonic stem cells have been well recognized as cells having a versatile potential to differentiate into all types of cells in the body including germ cells. There are many research studies focusing on the differentiation processes and protocols to derive various types of somatic cells from embryonic stem cells. However, germ cells have unique differentiation process and developmental pathway compared with somatic cells. Consequently, they will require different differentiation protocols and special culture techniques. More understanding and established in vitro systems for gametogenesis will greatly contribute to further progression of knowledge and technology in germ cell biology, reproductive biology and reproductive medicine. Moreover if oocytes can be efficiently produced in vitro, this will play an important role on progression in nuclear transfer and nuclear reprogramming technology. The present article will provide concise review on past important discoveries, current ongoing studies and future views of this challenging research area. An ethical perspective has also been proposed to give comprehensive summary and viewpoint for future clinical application.

Mesenchymal stem cell-derived microparticles: a promising therapeutic strategy.

PubMed

Tan, Xi; Gong, Yong-Zhen; Wu, Ping; Liao, Duan-Fang; Zheng, Xi-Long

2014-08-18

Mesenchymal stem cells (MSCs) are multipotent stem cells that give rise to various cell types of the mesodermal germ layer. Because of their unique ability to home in on injured and cancerous tissues, MSCs are of great potential in regenerative medicine. MSCs also contribute to reparative processes in different pathological conditions, including cardiovascular diseases and cancer. However, many studies have shown that only a small proportion of transplanted MSCs can actually survive and be incorporated into host tissues. The effects of MSCs cannot be fully explained by their number. Recent discoveries suggest that microparticles (MPs) derived from MSCs may be important for the physiological functions of their parent. Though the physiological role of MSC-MPs is currently not well understood, inspiring results indicate that, in tissue repair and anti-cancer therapy, MSC-MPs have similar pro-regenerative and protective properties as their cellular counterparts. Thus, MSC-MPs represent a promising approach that may overcome the obstacles and risks associated with the use of native or engineered MSCs.

Mesenchymal Stem Cell-Derived Microparticles: A Promising Therapeutic Strategy

PubMed Central

Tan, Xi; Gong, Yong-Zhen; Wu, Ping; Liao, Duan-Fang; Zheng, Xi-Long

2014-01-01

Mesenchymal stem cells (MSCs) are multipotent stem cells that give rise to various cell types of the mesodermal germ layer. Because of their unique ability to home in on injured and cancerous tissues, MSCs are of great potential in regenerative medicine. MSCs also contribute to reparative processes in different pathological conditions, including cardiovascular diseases and cancer. However, many studies have shown that only a small proportion of transplanted MSCs can actually survive and be incorporated into host tissues. The effects of MSCs cannot be fully explained by their number. Recent discoveries suggest that microparticles (MPs) derived from MSCs may be important for the physiological functions of their parent. Though the physiological role of MSC-MPs is currently not well understood, inspiring results indicate that, in tissue repair and anti-cancer therapy, MSC-MPs have similar pro-regenerative and protective properties as their cellular counterparts. Thus, MSC-MPs represent a promising approach that may overcome the obstacles and risks associated with the use of native or engineered MSCs. PMID:25196436

Climbing plants: attachment adaptations and bioinspired innovations.

PubMed

Burris, Jason N; Lenaghan, Scott C; Stewart, C Neal

2018-04-01

Climbing plants have unique adaptations to enable them to compete for sunlight, for which they invest minimal resources for vertical growth. Indeed, their stems bear relatively little weight, as they traverse their host substrates skyward. Climbers possess high tensile strength and flexibility, which allows them to utilize natural and manmade structures for support and growth. The climbing strategies of plants have intrigued scientists for centuries, yet our understanding about biochemical adaptations and their molecular undergirding is still in the early stages of research. Nonetheless, recent discoveries are promising, not only from a basic knowledge perspective, but also for bioinspired product development. Several adaptations, including nanoparticle and adhesive production will be reviewed, as well as practical translation of these adaptations to commercial applications. We will review the botanical literature on the modes of adaptation to climb, as well as specialized organs-and cellular innovations. Finally, recent molecular and biochemical data will be reviewed to assess the future needs and new directions for potential practical products that may be bioinspired by climbing plants.

The Role of Venezuelan Space Technology in Promoting Development in Latin America

NASA Astrophysics Data System (ADS)

Pena, J. A.; Yumin, T.

2017-09-01

Space technology and resources are used around the world to address societal challenges. Space provides valuable satellite services, unique scientific discoveries, surprising technology applications and new economic opportunities. Venezuela formally recognizes the advantages of space resources and pursues national level activity to harness them. Venezuela space cooperation has grown in the past several years, contributing to debates over Venezuela's rising influence in the Latin America. This paper summarizes the establishment and current development of space activities in the Bolivarian Republic of Venezuela, these activities are focused on the areas of telecommunications, Earth observation, research and development space and has as a primary goal the satisfaction of social needs. This analysis offers the elements most important of the Venezuelan space policy: technological transfer, capacity building and human training and international cooperation including the new participation of Venezuela in the international charter on space and major disasters. Our analysis shows that Venezuela has the potential to become a space leadership country, promoting the social welfare, integration, and sustainable development of Latin American countries.

Innovative Methodology in the Discovery of Novel Drug Targets in the Free-Living Amoebae

PubMed

Baig, Abdul Mannan

2018-04-25

Despite advances in drug discovery and modifications in the chemotherapeutic regimens, human infections caused by free-living amoebae (FLA) have high mortality rates (~95%). The FLA that cause fatal human cerebral infections include Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba spp. Novel drug-target discovery remains the only viable option to tackle these central nervous system (CNS) infection in order to lower the mortality rates caused by the FLA. Of these FLA, N. fowleri causes primary amoebic meningoencephalitis (PAM), while the A. castellanii and B. Mandrillaris are known to cause granulomatous amoebic encephalitis (GAE). The infections caused by the FLA have been treated with drugs like Rifampin, Fluconazole, Amphotericin-B and Miltefosine. Miltefosine is an anti-leishmanial agent and an experimental anti-cancer drug. With only rare incidences of success, these drugs have remained unsuccessful to lower the mortality rates of the cerebral infection caused by FLA. Recently, with the help of bioinformatic computational tools and the discovered genomic data of the FLA, discovery of newer drug targets has become possible. These cellular targets are proteins that are either unique to the FLA or shared between the humans and these unicellular eukaryotes. The latter group of proteins has shown to be targets of some FDA approved drugs prescribed in non-infectious diseases. This review out-lines the bioinformatic methodologies that can be used in the discovery of such novel drug-targets, their chronicle by in-vitro assays done in the past and the translational value of such target discoveries in human diseases caused by FLA. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Comparative genomics reveals phylogenetic distribution patterns of secondary metabolites in Amycolatopsis species.

PubMed

Adamek, Martina; Alanjary, Mohammad; Sales-Ortells, Helena; Goodfellow, Michael; Bull, Alan T; Winkler, Anika; Wibberg, Daniel; Kalinowski, Jörn; Ziemert, Nadine

2018-06-01

Genome mining tools have enabled us to predict biosynthetic gene clusters that might encode compounds with valuable functions for industrial and medical applications. With the continuously increasing number of genomes sequenced, we are confronted with an overwhelming number of predicted clusters. In order to guide the effective prioritization of biosynthetic gene clusters towards finding the most promising compounds, knowledge about diversity, phylogenetic relationships and distribution patterns of biosynthetic gene clusters is necessary. Here, we provide a comprehensive analysis of the model actinobacterial genus Amycolatopsis and its potential for the production of secondary metabolites. A phylogenetic characterization, together with a pan-genome analysis showed that within this highly diverse genus, four major lineages could be distinguished which differed in their potential to produce secondary metabolites. Furthermore, we were able to distinguish gene cluster families whose distribution correlated with phylogeny, indicating that vertical gene transfer plays a major role in the evolution of secondary metabolite gene clusters. Still, the vast majority of the diverse biosynthetic gene clusters were derived from clusters unique to the genus, and also unique in comparison to a database of known compounds. Our study on the locations of biosynthetic gene clusters in the genomes of Amycolatopsis' strains showed that clusters acquired by horizontal gene transfer tend to be incorporated into non-conserved regions of the genome thereby allowing us to distinguish core and hypervariable regions in Amycolatopsis genomes. Using a comparative genomics approach, it was possible to determine the potential of the genus Amycolatopsis to produce a huge diversity of secondary metabolites. Furthermore, the analysis demonstrates that horizontal and vertical gene transfer play an important role in the acquisition and maintenance of valuable secondary metabolites. Our results cast light on the interconnections between secondary metabolite gene clusters and provide a way to prioritize biosynthetic pathways in the search and discovery of novel compounds.

Navigating tissue chips from development to dissemination: A pharmaceutical industry perspective

PubMed Central

Fabre, Kristin; Chakilam, Ananthsrinivas; Dragan, Yvonne; Duignan, David B; Eswaraka, Jeetu; Gan, Jinping; Guzzie-Peck, Peggy; Otieno, Monicah; Jeong, Claire G; Keller, Douglas A; de Morais, Sonia M; Phillips, Jonathan A; Proctor, William; Sura, Radhakrishna; Van Vleet, Terry; Watson, David; Will, Yvonne; Tagle, Danilo; Berridge, Brian

2017-01-01

Tissue chips are poised to deliver a paradigm shift in drug discovery. By emulating human physiology, these chips have the potential to increase the predictive power of preclinical modeling, which in turn will move the pharmaceutical industry closer to its aspiration of clinically relevant and ultimately animal-free drug discovery. Despite the tremendous science and innovation invested in these tissue chips, significant challenges remain to be addressed to enable their routine adoption into the industrial laboratory. This article describes the main steps that need to be taken and highlights key considerations in order to transform tissue chip technology from the hands of the innovators into those of the industrial scientists. Written by scientists from 13 pharmaceutical companies and partners at the National Institutes of Health, this article uniquely captures a consensus view on the progression strategy to facilitate and accelerate the adoption of this valuable technology. It concludes that success will be delivered by a partnership approach as well as a deep understanding of the context within which these chips will actually be used. Impact statement The rapid pace of scientific innovation in the tissue chip (TC) field requires a cohesive partnership between innovators and end users. Near term uptake of these human-relevant platforms will fill gaps in current capabilities for assessing important properties of disposition, efficacy and safety liabilities. Similarly, these platforms could support mechanistic studies which aim to resolve challenges later in development (e.g. assessing the human relevance of a liability identified in animal studies). Building confidence that novel capabilities of TCs can address real world challenges while they themselves are being developed will accelerate their application in the discovery and development of innovative medicines. This article outlines a strategic roadmap to unite innovators and end users thus making implementation smooth and rapid. With the collective contributions from multiple international pharmaceutical companies and partners at National Institutes of Health, this article should serve as an invaluable resource to the multi-disciplinary field of TC development. PMID:28622731

Navigating tissue chips from development to dissemination: A pharmaceutical industry perspective.

PubMed

Ewart, Lorna; Fabre, Kristin; Chakilam, Ananthsrinivas; Dragan, Yvonne; Duignan, David B; Eswaraka, Jeetu; Gan, Jinping; Guzzie-Peck, Peggy; Otieno, Monicah; Jeong, Claire G; Keller, Douglas A; de Morais, Sonia M; Phillips, Jonathan A; Proctor, William; Sura, Radhakrishna; Van Vleet, Terry; Watson, David; Will, Yvonne; Tagle, Danilo; Berridge, Brian

2017-10-01

Tissue chips are poised to deliver a paradigm shift in drug discovery. By emulating human physiology, these chips have the potential to increase the predictive power of preclinical modeling, which in turn will move the pharmaceutical industry closer to its aspiration of clinically relevant and ultimately animal-free drug discovery. Despite the tremendous science and innovation invested in these tissue chips, significant challenges remain to be addressed to enable their routine adoption into the industrial laboratory. This article describes the main steps that need to be taken and highlights key considerations in order to transform tissue chip technology from the hands of the innovators into those of the industrial scientists. Written by scientists from 13 pharmaceutical companies and partners at the National Institutes of Health, this article uniquely captures a consensus view on the progression strategy to facilitate and accelerate the adoption of this valuable technology. It concludes that success will be delivered by a partnership approach as well as a deep understanding of the context within which these chips will actually be used. Impact statement The rapid pace of scientific innovation in the tissue chip (TC) field requires a cohesive partnership between innovators and end users. Near term uptake of these human-relevant platforms will fill gaps in current capabilities for assessing important properties of disposition, efficacy and safety liabilities. Similarly, these platforms could support mechanistic studies which aim to resolve challenges later in development (e.g. assessing the human relevance of a liability identified in animal studies). Building confidence that novel capabilities of TCs can address real world challenges while they themselves are being developed will accelerate their application in the discovery and development of innovative medicines. This article outlines a strategic roadmap to unite innovators and end users thus making implementation smooth and rapid. With the collective contributions from multiple international pharmaceutical companies and partners at National Institutes of Health, this article should serve as an invaluable resource to the multi-disciplinary field of TC development.

Biotechnological Applications of Marine Enzymes From Algae, Bacteria, Fungi, and Sponges.

PubMed

Parte, S; Sirisha, V L; D'Souza, J S

Diversity is the hallmark of all life forms that inhabit the soil, air, water, and land. All these habitats pose their unique inherent challenges so as to breed the "fittest" creatures. Similarly, the biodiversity from the marine ecosystem has evolved unique properties due to challenging environment. These challenges include permafrost regions to hydrothermal vents, oceanic trenches to abyssal plains, fluctuating saline conditions, pH, temperature, light, atmospheric pressure, and the availability of nutrients. Oceans occupy 75% of the earth's surface and harbor most ancient and diverse forms of organisms (algae, bacteria, fungi, sponges, etc.), serving as an excellent source of natural bioactive molecules, novel therapeutic compounds, and enzymes. In this chapter, we introduce enzyme technology, its current state of the art, unique enzyme properties, and the biocatalytic potential of marine algal, bacterial, fungal, and sponge enzymes that have indeed boosted the Marine Biotechnology Industry. Researchers began exploring marine enzymes, and today they are preferred over the chemical catalysts for biotechnological applications and functions, encompassing various sectors, namely, domestic, industrial, commercial, and healthcare. Next, we summarize the plausible pros and cons: the challenges encountered in the process of discovery of the potent compounds and bioactive metabolites such as biocatalysts/enzymes of biomedical, therapeutic, biotechnological, and industrial significance. The field of Marine Enzyme Technology has recently assumed importance, and if it receives further boost, it could successfully substitute other chemical sources of enzymes useful for industrial and commercial purposes and may prove as a beneficial and ecofriendly option. With appropriate directions and encouragement, marine enzyme technology can sustain the rising demand for enzyme production while maintaining the ecological balance, provided any undesired exploitation of the marine ecosystem is avoided. © 2017 Elsevier Inc. All rights reserved.

Structural Analysis of PTM Hotspots (SAPH-ire) – A Quantitative Informatics Method Enabling the Discovery of Novel Regulatory Elements in Protein Families*

PubMed Central

Dewhurst, Henry M.; Choudhury, Shilpa; Torres, Matthew P.

2015-01-01

Predicting the biological function potential of post-translational modifications (PTMs) is becoming increasingly important in light of the exponential increase in available PTM data from high-throughput proteomics. We developed structural analysis of PTM hotspots (SAPH-ire)—a quantitative PTM ranking method that integrates experimental PTM observations, sequence conservation, protein structure, and interaction data to allow rank order comparisons within or between protein families. Here, we applied SAPH-ire to the study of PTMs in diverse G protein families, a conserved and ubiquitous class of proteins essential for maintenance of intracellular structure (tubulins) and signal transduction (large and small Ras-like G proteins). A total of 1728 experimentally verified PTMs from eight unique G protein families were clustered into 451 unique hotspots, 51 of which have a known and cited biological function or response. Using customized software, the hotspots were analyzed in the context of 598 unique protein structures. By comparing distributions of hotspots with known versus unknown function, we show that SAPH-ire analysis is predictive for PTM biological function. Notably, SAPH-ire revealed high-ranking hotspots for which a functional impact has not yet been determined, including phosphorylation hotspots in the N-terminal tails of G protein gamma subunits—conserved protein structures never before reported as regulators of G protein coupled receptor signaling. To validate this prediction we used the yeast model system for G protein coupled receptor signaling, revealing that gamma subunit–N-terminal tail phosphorylation is activated in response to G protein coupled receptor stimulation and regulates protein stability in vivo. These results demonstrate the utility of integrating protein structural and sequence features into PTM prioritization schemes that can improve the analysis and functional power of modification-specific proteomics data. PMID:26070665

Rare k-mer DNA: Identification of sequence motifs and prediction of CpG island and promoter.

PubMed

Mohamed Hashim, Ezzeddin Kamil; Abdullah, Rosni

2015-12-21

Empirical analysis on k-mer DNA has been proven as an effective tool in finding unique patterns in DNA sequences which can lead to the discovery of potential sequence motifs. In an extensive study of empirical k-mer DNA on hundreds of organisms, the researchers found unique multi-modal k-mer spectra occur in the genomes of organisms from the tetrapod clade only which includes all mammals. The multi-modality is caused by the formation of the two lowest modes where k-mers under them are referred as the rare k-mers. The suppression of the two lowest modes (or the rare k-mers) can be attributed to the CG dinucleotide inclusions in them. Apart from that, the rare k-mers are selectively distributed in certain genomic features of CpG Island (CGI), promoter, 5' UTR, and exon. We correlated the rare k-mers with hundreds of annotated features using several bioinformatic tools, performed further intrinsic rare k-mer analyses within the correlated features, and modeled the elucidated rare k-mer clustering feature into a classifier to predict the correlated CGI and promoter features. Our correlation results show that rare k-mers are highly associated with several annotated features of CGI, promoter, 5' UTR, and open chromatin regions. Our intrinsic results show that rare k-mers have several unique topological, compositional, and clustering properties in CGI and promoter features. Finally, the performances of our RWC (rare-word clustering) method in predicting the CGI and promoter features are ranked among the top three, in eight of the CGI and promoter evaluations, among eight of the benchmarked datasets. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Induced pluripotent stem cells for regenerative cardiovascular therapies and biomedical discovery.

PubMed

Nsair, Ali; MacLellan, W Robb

2011-04-30

The discovery of induced pluripotent stem cells (iPSC) has, in the short time since their discovery, revolutionized the field of stem cell biology. This technology allows the generation of a virtually unlimited supply of cells with pluripotent potential similar to that of embryonic stem cells (ESC). However, in contrast to ESC, iPSC are not subject to the same ethical concerns and can be easily generated from living individuals. For the first time, patient-specific iPSC can be generated and offer a supply of genetically identical cells that can be differentiated into all somatic cell types for potential use in regenerative therapies or drug screening and testing. As the techniques for generation of iPSC lines are constantly evolving, new uses for human iPSC are emerging from in-vitro disease modeling to high throughput drug discovery and screening. This technology promises to revolutionize the field of medicine and offers new hope for understanding and treatment of numerous diseases. Copyright © 2011 Elsevier B.V. All rights reserved.

Bioinformatics in protein kinases regulatory network and drug discovery.

PubMed

Chen, Qingfeng; Luo, Haiqiong; Zhang, Chengqi; Chen, Yi-Ping Phoebe

2015-04-01

Protein kinases have been implicated in a number of diseases, where kinases participate many aspects that control cell growth, movement and death. The deregulated kinase activities and the knowledge of these disorders are of great clinical interest of drug discovery. The most critical issue is the development of safe and efficient disease diagnosis and treatment for less cost and in less time. It is critical to develop innovative approaches that aim at the root cause of a disease, not just its symptoms. Bioinformatics including genetic, genomic, mathematics and computational technologies, has become the most promising option for effective drug discovery, and has showed its potential in early stage of drug-target identification and target validation. It is essential that these aspects are understood and integrated into new methods used in drug discovery for diseases arisen from deregulated kinase activity. This article reviews bioinformatics techniques for protein kinase data management and analysis, kinase pathways and drug targets and describes their potential application in pharma ceutical industry. Copyright © 2015 Elsevier Inc. All rights reserved.

A Relevancy Algorithm for Curating Earth Science Data Around Phenomenon

NASA Technical Reports Server (NTRS)

Maskey, Manil; Ramachandran, Rahul; Li, Xiang; Weigel, Amanda; Bugbee, Kaylin; Gatlin, Patrick; Miller, J. J.

2017-01-01

Earth science data are being collected for various science needs and applications, processed using different algorithms at multiple resolutions and coverages, and then archived at different archiving centers for distribution and stewardship causing difficulty in data discovery. Curation, which typically occurs in museums, art galleries, and libraries, is traditionally defined as the process of collecting and organizing information around a common subject matter or a topic of interest. Curating data sets around topics or areas of interest addresses some of the data discovery needs in the field of Earth science, especially for unanticipated users of data. This paper describes a methodology to automate search and selection of data around specific phenomena. Different components of the methodology including the assumptions, the process, and the relevancy ranking algorithm are described. The paper makes two unique contributions to improving data search and discovery capabilities. First, the paper describes a novel methodology developed for automatically curating data around a topic using Earthscience metadata records. Second, the methodology has been implemented as a standalone web service that is utilized to augment search and usability of data in a variety of tools.

A relevancy algorithm for curating earth science data around phenomenon

NASA Astrophysics Data System (ADS)

Maskey, Manil; Ramachandran, Rahul; Li, Xiang; Weigel, Amanda; Bugbee, Kaylin; Gatlin, Patrick; Miller, J. J.

2017-09-01

Earth science data are being collected for various science needs and applications, processed using different algorithms at multiple resolutions and coverages, and then archived at different archiving centers for distribution and stewardship causing difficulty in data discovery. Curation, which typically occurs in museums, art galleries, and libraries, is traditionally defined as the process of collecting and organizing information around a common subject matter or a topic of interest. Curating data sets around topics or areas of interest addresses some of the data discovery needs in the field of Earth science, especially for unanticipated users of data. This paper describes a methodology to automate search and selection of data around specific phenomena. Different components of the methodology including the assumptions, the process, and the relevancy ranking algorithm are described. The paper makes two unique contributions to improving data search and discovery capabilities. First, the paper describes a novel methodology developed for automatically curating data around a topic using Earth science metadata records. Second, the methodology has been implemented as a stand-alone web service that is utilized to augment search and usability of data in a variety of tools.

FoldMiner and LOCK 2: protein structure comparison and motif discovery on the web.

PubMed

Shapiro, Jessica; Brutlag, Douglas

2004-07-01

The FoldMiner web server (http://foldminer.stanford.edu/) provides remote access to methods for protein structure alignment and unsupervised motif discovery. FoldMiner is unique among such algorithms in that it improves both the motif definition and the sensitivity of a structural similarity search by combining the search and motif discovery methods and using information from each process to enhance the other. In a typical run, a query structure is aligned to all structures in one of several databases of single domain targets in order to identify its structural neighbors and to discover a motif that is the basis for the similarity among the query and statistically significant targets. This process is fully automated, but options for manual refinement of the results are available as well. The server uses the Chime plugin and customized controls to allow for visualization of the motif and of structural superpositions. In addition, we provide an interface to the LOCK 2 algorithm for rapid alignments of a query structure to smaller numbers of user-specified targets.

[Drug innovation and reverse thinking].

PubMed

Guo, Zong-ru

2016-03-01

Drug innovation involves an individual molecular operation, and every new molecular entity features a hard-duplicated track of R&D. The transformation from an active compound to a new medicine carries out almost in a chaotic system devoid of regularity and periodic alteration. Since new millennium the dominant position in drug innovation has been occupied by the first-in-class drugs, yet the number of launched follow-on drugs has been distinctly decreased. The innovation of first-in-class drugs is characterized by a high risk throughout the whole process. To achieve initiative and uniqueness of drug discovery, the strategy and method of the inverse thinking might be a feasible way, because the inertial and conformity thinkings in drug discovery normally lead to ensemble with similar drug category. However, the study from the flipside or opposite of things(e.g. targets or effects) brand new routes might be opened. This article is to describe the strategy of reverse thinking in drug discovery by some examples including opioid receptor antagonist eluxadoline, HSP90 activator, h ERG channel agonist, covalent drugs, and ultra-small drugs.

60 YEARS OF POMC: Regulation of feeding and energy homeostasis by α-MSH.

PubMed

Anderson, Erica J P; Çakir, Isin; Carrington, Sheridan J; Cone, Roger D; Ghamari-Langroudi, Masoud; Gillyard, Taneisha; Gimenez, Luis E; Litt, Michael J

2016-05-01

The melanocortin peptides derived from pro-opiomelanocortin (POMC) were originally understood in terms of the biological actions of α-melanocyte-stimulating hormone (α-MSH) on pigmentation and adrenocorticotrophic hormone on adrenocortical glucocorticoid production. However, the discovery of POMC mRNA and melanocortin peptides in the CNS generated activities directed at understanding the direct biological actions of melanocortins in the brain. Ultimately, discovery of unique melanocortin receptors expressed in the CNS, the melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors, led to the development of pharmacological tools and genetic models leading to the demonstration that the central melanocortin system plays a critical role in the regulation of energy homeostasis. Indeed, mutations in MC4R are now known to be the most common cause of early onset syndromic obesity, accounting for 2-5% of all cases. This review discusses the history of these discoveries, as well as the latest work attempting to understand the molecular and cellular basis of regulation of feeding and energy homeostasis by the predominant melanocortin peptide in the CNS, α-MSH. © 2016 Society for Endocrinology.

Opportunities for Science on the ISS: A Unique Laboratory Environment

NASA Technical Reports Server (NTRS)

Kugler, Justin; Edeen, Marybeth

2010-01-01

This slide presentation reviews the opportunities for scientific discoveries on the International Space Station (ISS). With the crew tended, and availability of long-term studies and the capabilities of the ISS (i.e. microgravity, exposure to the thermosphere and observations at high altitude and velocity) there are many examples of scientific experiments. There are several examples showing that microgravity is different from the effects of gravity.

Penicillin Until 1957,

DTIC Science & Technology

1983-01-01

but also with those which, in certain respects, are so far advanced that the field perceives them as "unzeitgemgss" or premature. In fact, Stent (1972...were treated intravenously, a baby with a persistant staphylococal urinary infection, by mouth and four cases of eye infections by local application. In...the binding of penicillin to bacterial cells. J. Bacteriol. 71, 84-90 (1956) Stent , G.S.: Prematurity and uniqueness in scientific discovery. Sci. Am

JPL-20180410-GRACEFOf-0001-Facebook

NASA Image and Video Library

2018-04-10

GRACE-Follow On (GRACE-FO) is a satellite mission scheduled for launch in May 2018. GRACE-FO will continue the work of the GRACE satellite mission tracking Earth's water movement around the globe. These discoveries provide a unique view of Earth's climate and have far-reaching benefits to society and the world's population. For more information about this mission, visit https://www.nasa.gov/missions/grace-fo and https://gracefo.jpl.nasa.gov/

Shape memory effect and super elasticity. Its dental applications.

PubMed

Kotian, R

2001-01-01

The shape memory alloys are quite fascinating materials characterized by a shape memory effect and super elasticity which ordinary metals do not have. This unique behaviour was first found in a Au-47.5 at % Cd alloy in 1951, and was published in 1963 by the discovery of Ti-Ni alloy. Shape memory alloys now being practically used as new functional alloys for various dental and medical applications.

The Cosmology of Edgar Allan Poe

NASA Astrophysics Data System (ADS)

Cappi, Alberto

2011-06-01

Eureka is a ``prose poem'' published in 1848, where Edgar Allan Poe presents his original cosmology. While starting from metaphysical assumptions, Poe develops an evolving Newtonian model of the Universe which has many and non casual analogies with modern cosmology. Poe was well informed about astronomical and physical discoveries, and he was influenced by both contemporary science and ancient ideas. For these reasons, Eureka is a unique synthesis of metaphysics, art and science.

The Recruitment and Retention of the 180A: The Special Forces Warrant Officer

DTIC Science & Technology

2015-03-01

that are gained through unique institutions associated with the vocation itself. The professional individual is an expert who performs a service that...Warrant Officer. Research Report 1851. U.S. Army Research Institute . Glaser, B., & Strauss, A. (1967). The discovery of grounded theory : Strategies...the Special Forces Regiment. The watrant officer’s institutional knowledge--developed over years of operational experience-is essential to the success

Mass spectrometry-based biomarker discovery: toward a global proteome index of individuality.

PubMed

Hawkridge, Adam M; Muddiman, David C

2009-01-01

Biomarker discovery and proteomics have become synonymous with mass spectrometry in recent years. Although this conflation is an injustice to the many essential biomolecular techniques widely used in biomarker-discovery platforms, it underscores the power and potential of contemporary mass spectrometry. Numerous novel and powerful technologies have been developed around mass spectrometry, proteomics, and biomarker discovery over the past 20 years to globally study complex proteomes (e.g., plasma). However, very few large-scale longitudinal studies have been carried out using these platforms to establish the analytical variability relative to true biological variability. The purpose of this review is not to cover exhaustively the applications of mass spectrometry to biomarker discovery, but rather to discuss the analytical methods and strategies that have been developed for mass spectrometry-based biomarker-discovery platforms and to place them in the context of the many challenges and opportunities yet to be addressed.

Analysis of latency performance of bluetooth low energy (BLE) networks.

PubMed

Cho, Keuchul; Park, Woojin; Hong, Moonki; Park, Gisu; Cho, Wooseong; Seo, Jihoon; Han, Kijun

2014-12-23

Bluetooth Low Energy (BLE) is a short-range wireless communication technology aiming at low-cost and low-power communication. The performance evaluation of classical Bluetooth device discovery have been intensively studied using analytical modeling and simulative methods, but these techniques are not applicable to BLE, since BLE has a fundamental change in the design of the discovery mechanism, including the usage of three advertising channels. Recently, there several works have analyzed the topic of BLE device discovery, but these studies are still far from thorough. It is thus necessary to develop a new, accurate model for the BLE discovery process. In particular, the wide range settings of the parameters introduce lots of potential for BLE devices to customize their discovery performance. This motivates our study of modeling the BLE discovery process and performing intensive simulation. This paper is focused on building an analytical model to investigate the discovery probability, as well as the expected discovery latency, which are then validated via extensive experiments. Our analysis considers both continuous and discontinuous scanning modes. We analyze the sensitivity of these performance metrics to parameter settings to quantitatively examine to what extent parameters influence the performance metric of the discovery processes.

Analysis of Latency Performance of Bluetooth Low Energy (BLE) Networks

PubMed Central

Cho, Keuchul; Park, Woojin; Hong, Moonki; Park, Gisu; Cho, Wooseong; Seo, Jihoon; Han, Kijun

2015-01-01

Bluetooth Low Energy (BLE) is a short-range wireless communication technology aiming at low-cost and low-power communication. The performance evaluation of classical Bluetooth device discovery have been intensively studied using analytical modeling and simulative methods, but these techniques are not applicable to BLE, since BLE has a fundamental change in the design of the discovery mechanism, including the usage of three advertising channels. Recently, there several works have analyzed the topic of BLE device discovery, but these studies are still far from thorough. It is thus necessary to develop a new, accurate model for the BLE discovery process. In particular, the wide range settings of the parameters introduce lots of potential for BLE devices to customize their discovery performance. This motivates our study of modeling the BLE discovery process and performing intensive simulation. This paper is focused on building an analytical model to investigate the discovery probability, as well as the expected discovery latency, which are then validated via extensive experiments. Our analysis considers both continuous and discontinuous scanning modes. We analyze the sensitivity of these performance metrics to parameter settings to quantitatively examine to what extent parameters influence the performance metric of the discovery processes. PMID:25545266

Flexible Design and Manufacturing Systems for Automotive Components and Sheet Metal Parts

DTIC Science & Technology

1999-10-01

sometimes shocking discoveries you will make, discoveries that can help you avoid potential crises down the road if you take the necessary steps now...ISSUE Guest Lecture John Swanson, VP Qualcomm 10-Feb Fast, Flexible, Lilly, US Robotics, Economist, Upton & Agile Manufacturing Readings

Implementation of false discovery rate for exploring novel paradigms and trait dimensions with ERPs.

PubMed

Crowley, Michael J; Wu, Jia; McCreary, Scott; Miller, Kelly; Mayes, Linda C

2012-01-01

False discovery rate (FDR) is a multiple comparison procedure that targets the expected proportion of false discoveries among the discoveries. Employing FDR methods in event-related potential (ERP) research provides an approach to explore new ERP paradigms and ERP-psychological trait/behavior relations. In Study 1, we examined neural responses to escape behavior from an aversive noise. In Study 2, we correlated a relatively unexplored trait dimension, ostracism, with neural response. In both situations we focused on the frontal cortical region, applying a channel by time plots to display statistically significant uncorrected data and FDR corrected data, controlling for multiple comparisons.

From Toxins Targeting Ligand Gated Ion Channels to Therapeutic Molecules

PubMed Central

Nasiripourdori, Adak; Taly, Valérie; Grutter, Thomas; Taly, Antoine

2011-01-01

Ligand-gated ion channels (LGIC) play a central role in inter-cellular communication. This key function has two consequences: (i) these receptor channels are major targets for drug discovery because of their potential involvement in numerous human brain diseases; (ii) they are often found to be the target of plant and animal toxins. Together this makes toxin/receptor interactions important to drug discovery projects. Therefore, toxins acting on LGIC are presented and their current/potential therapeutic uses highlighted. PMID:22069709

Ligand-based receptor tyrosine kinase partial agonists: New paradigm for cancer drug discovery?

PubMed

Riese, David J

2011-02-01

INTRODUCTION: Receptor tyrosine kinases (RTKs) are validated targets for oncology drug discovery and several RTK antagonists have been approved for the treatment of human malignancies. Nonetheless, the discovery and development of RTK antagonists has lagged behind the discovery and development of agents that target G-protein coupled receptors. In part, this is because it has been difficult to discover analogs of naturally-occurring RTK agonists that function as antagonists. AREAS COVERED: Here we describe ligands of ErbB receptors that function as partial agonists for these receptors, thereby enabling these ligands to antagonize the activity of full agonists for these receptors. We provide insights into the mechanisms by which these ligands function as antagonists. We discuss how information concerning these mechanisms can be translated into screens for novel small molecule- and antibody-based antagonists of ErbB receptors and how such antagonists hold great potential as targeted cancer chemotherapeutics. EXPERT OPINION: While there have been a number of important key findings into this field, the identification of the structural basis of ligand functional specificity is still of the greatest importance. While it is true that, with some notable exceptions, peptide hormones and growth factors have not proven to be good platforms for oncology drug discovery; addressing the fundamental issues of antagonistic partial agonists for receptor tyrosine kinases has the potential to steer oncology drug discovery in new directions. Mechanism based approaches are now emerging to enable the discovery of RTK partial agonists that may antagonize both agonist-dependent and -independent RTK signaling and may hold tremendous promise as targeted cancer chemotherapeutics.

Computer-aided drug discovery.

PubMed

Bajorath, Jürgen

2015-01-01

Computational approaches are an integral part of interdisciplinary drug discovery research. Understanding the science behind computational tools, their opportunities, and limitations is essential to make a true impact on drug discovery at different levels. If applied in a scientifically meaningful way, computational methods improve the ability to identify and evaluate potential drug molecules, but there remain weaknesses in the methods that preclude naïve applications. Herein, current trends in computer-aided drug discovery are reviewed, and selected computational areas are discussed. Approaches are highlighted that aid in the identification and optimization of new drug candidates. Emphasis is put on the presentation and discussion of computational concepts and methods, rather than case studies or application examples. As such, this contribution aims to provide an overview of the current methodological spectrum of computational drug discovery for a broad audience.

Blueprint for antimicrobial hit discovery targeting metabolic networks

PubMed Central

Shen, Y.; Liu, J.; Estiu, G.; Isin, B.; Ahn, Y-Y.; Lee, D-S.; Barabási, A-L.; Kapatral, V.; Wiest, O.; Oltvai, Z. N.

2010-01-01

Advances in genome analysis, network biology, and computational chemistry have the potential to revolutionize drug discovery by combining system-level identification of drug targets with the atomistic modeling of small molecules capable of modulating their activity. To demonstrate the effectiveness of such a discovery pipeline, we deduced common antibiotic targets in Escherichia coli and Staphylococcus aureus by identifying shared tissue-specific or uniformly essential metabolic reactions in their metabolic networks. We then predicted through virtual screening dozens of potential inhibitors for several enzymes of these reactions and showed experimentally that a subset of these inhibited both enzyme activities in vitro and bacterial cell viability. This blueprint is applicable for any sequenced organism with high-quality metabolic reconstruction and suggests a general strategy for strain-specific antiinfective therapy. PMID:20080587

Stem cell technology for drug discovery and development.

PubMed

Hook, Lilian A

2012-04-01

Stem cells have enormous potential to revolutionise the drug discovery process at all stages, from target identification through to toxicology studies. Their ability to generate physiologically relevant cells in limitless supply makes them an attractive alternative to currently used recombinant cell lines or primary cells. However, realisation of the full potential of stem cells is currently hampered by the difficulty in routinely directing stem cell differentiation to reproducibly and cost effectively generate pure populations of specific cell types. In this article we discuss how stem cells have already been used in the drug discovery process and how novel technologies, particularly in relation to stem cell differentiation, can be applied to attain widespread adoption of stem cell technology by the pharmaceutical industry. Copyright © 2011 Elsevier Ltd. All rights reserved.

Typhoid toxin provides a window into typhoid fever and the biology of Salmonella Typhi.

PubMed

Galán, Jorge E

2016-06-07

Salmonella Typhi is the cause of typhoid fever, a disease that has challenged humans throughout history and continues to be a major public health concern. Unlike infections with most other Salmonellae, which result in self-limiting gastroenteritis, typhoid fever is a life-threatening systemic disease. Furthermore, in contrast to most Salmonellae, which can infect a broad range of hosts, S. Typhi is a strict human pathogen. The unique features of S. Typhi pathogenesis and its stringent host specificity have been a long-standing puzzle. The discovery of typhoid toxin not only has provided major insight into these questions but also has offered unique opportunities to develop novel therapeutic and prevention strategies to combat typhoid fever.

Typhoid toxin provides a window into typhoid fever and the biology of Salmonella Typhi

PubMed Central

Galán, Jorge E.

2016-01-01

Salmonella Typhi is the cause of typhoid fever, a disease that has challenged humans throughout history and continues to be a major public health concern. Unlike infections with most other Salmonellae, which result in self-limiting gastroenteritis, typhoid fever is a life-threatening systemic disease. Furthermore, in contrast to most Salmonellae, which can infect a broad range of hosts, S. Typhi is a strict human pathogen. The unique features of S. Typhi pathogenesis and its stringent host specificity have been a long-standing puzzle. The discovery of typhoid toxin not only has provided major insight into these questions but also has offered unique opportunities to develop novel therapeutic and prevention strategies to combat typhoid fever. PMID:27222578

Polygenic risk score, genome-wide association, and gene set analyses of cognitive domain deficits in schizophrenia.

PubMed

Nakahara, Soichiro; Medland, Sarah; Turner, Jessica A; Calhoun, Vince D; Lim, Kelvin O; Mueller, Bryon A; Bustillo, Juan R; O'Leary, Daniel S; Vaidya, Jatin G; McEwen, Sarah; Voyvodic, James; Belger, Aysenil; Mathalon, Daniel H; Ford, Judith M; Guffanti, Guia; Macciardi, Fabio; Potkin, Steven G; van Erp, Theo G M

2018-06-12

This study assessed genetic contributions to six cognitive domains, identified by the MATRICS Cognitive Consensus Battery as relevant for schizophrenia, cognition-enhancing, clinical trials. Psychiatric Genomics Consortium Schizophrenia polygenic risk scores showed significant negative correlations with each cognitive domain. Genome-wide association analyses identified loci associated with attention/vigilance (rs830786 within HNF4G), verbal memory (rs67017972 near NDUFS4), and reasoning/problem solving (rs76872642 within HDAC9). Gene set analysis identified unique and shared genes across cognitive domains. These findings suggest involvement of common and unique mechanisms across cognitive domains and may contribute to the discovery of new therapeutic targets to treat cognitive deficits in schizophrenia. Copyright © 2018 Elsevier B.V. All rights reserved.

Pythons in Burma: Short-tailed python (Reptilia: Squamata)

USGS Publications Warehouse

Zug, George R.; Gotte, Steve W.; Jacobs, Jeremy F.

2011-01-01

Short-tailed pythons, Python curtus species group, occur predominantly in the Malayan Peninsula, Sumatra, and Borneo. The discovery of an adult female in Mon State, Myanmar, led to a review of the distribution of all group members (spot-mapping of all localities of confirmed occurrence) and an examination of morphological variation in P. brongersmai. The resulting maps demonstrate a limited occurrence of these pythons within peninsular Malaya, Sumatra, and Borneo with broad absences in these regions. Our small samples limit the recognition of regional differentiation in the morphology of P. brongersmai populations; however, the presence of unique traits in the Myanmar python and its strong allopatry indicate that it is a unique genetic lineage, and it is described as Python kyaiktiyo new species.

Fermi-LAT Gamma-ray Bursts and Insight from Swift

NASA Technical Reports Server (NTRS)

Racusin, Judith L.

2011-01-01

A new revolution in GRB observation and theory has begun over the last 3 years since the launch of the Fermi gamma-ray space telescope. The new window into high energy gamma-rays opened by the Fermi-LAT is providing insight into prompt emission mechanisms and possibly also afterglow physics. The LAT detected GRBs appear to be a new unique subset of extremely energetic and bright bursts. In this talk I will discuss the context and recent discoveries from these LAT GRBs and the large database of broadband observations collected by Swift over the last 7 years and how through comparisons between the Swift, GBM, and LAT GRB samples, we can learn about the unique characteristics and relationships between each population.

[Gastrointestinal stromal tumor with primary hepatic unique location--clinical case].

PubMed

Alecu, L; Tulin, A; Ursut, Beatrice; Ursut, B; Oproiu, Al; Obrocea, F; Ionescu, M

2011-01-01

The gastrointestinal stromal tumors are mesenchymal tumors whose primary extradigestive location is very rare (less than 10% primary liver localization). We present a clinical case of primary hepatic location of GIST in a 28 year-old patient. The discovery of this tumor is a chance, the patient presenting for non-specific dyspeptic syndrome and epigastralgia. During the presentation an abdominal ultrasound is performed which identifies an whell-delineated hepatic mass - 5/4 cm. Clinical and paraclinical investigations (CT, EDS, EDI, examination of the intestinal lumen with the videocapsula), confirm the diagnosis of unique hepatic mass of segments III-IV. The diagnosis is confirmed intraoperatory and we perform an atypical liver resection of segments III-IV (with 1 cm safety-margin). The histopatologic exam: GIST.

BluePen Biomarkers LLC: integrated biomarker solutions

PubMed Central

Blair, Ian A; Mesaros, Clementina; Lilley, Patrick; Nunez, Matthew

2016-01-01

BluePen Biomarkers provides a unique comprehensive multi-omics biomarker discovery and validation platform. We can quantify, integrate and analyze genomics, proteomics, metabolomics and lipidomics biomarkers, alongside clinical data, demographics and other phenotypic data. A unique bio-inspired signal processing analytic approach is used that has the proven ability to identify biomarkers in a wide variety of diseases. The resulting biomarkers can be used for diagnosis, prognosis, mechanistic studies and predicting treatment response, in contexts from core research through clinical trials. BluePen Biomarkers provides an additional groundbreaking research goal: identifying surrogate biomarkers from different modalities. This not only provides new biological insights, but enables least invasive, least-cost tests that meet or exceed the predictive quality of current tests. PMID:28031971