A sexually transmitted disease: History of AIDS through philately.

PubMed

Vatanoğlu, Emine Elif; Ataman, Ahmet Doğan

2011-01-01

AIDS has become the new plague; a disease that is not only physically and psychologically debilitating, but culturally and socially devastating as well. Like the plague, AIDS has caused fear, prejudice and even panic in society. Although there are remarkable improvements in the diagnosis and treatment of the disease, AIDS continues its grim passage around the globe. After a slight downturn in the early 1990's, it then returned with a vengeance. By the end of the 20(th) century, AIDS was reliably estimated to have caused over 20 million deaths throughout the world. At the same time, 40 million people were estimated to be HIV positive. This paper provides an overview of the history of AIDS, including the discovery and its progress in the world through philately. Philately is the study of stamps and postal history and other related items. Philately involves more than just stamp collecting, it contains the study of the design and educational impact of a philatelic material. We have presented AIDS stamps produced world-wide to emphasize the history of AIDS.

Blood Ammonia as a Possible Etiological Agent for Alzheimer’s Disease

PubMed Central

Jin, Yan Yan; Singh, Parul; Chung, Hea-Jong; Hong, Seong-Tschool

2018-01-01

Alzheimer’s disease (AD), characterized by cognitive decline and devastating neurodegeneration, is the most common age-related dementia. Since AD is a typical example of a complex disease that is affected by various genetic and environmental factors, various factors could be involved in preventing and/or treating AD. Extracellular accumulation of beta-amyloid peptide (Aβ) and intracellular accumulation of tau undeniably play essential roles in the etiology of AD. However, interestingly enough, medications targeting Aβ or tau all failed and the only clinically efficient medications for AD are drugs targeting the cholinergic pathway. Also, a very intriguing discovery in AD is that the Mediterranean diet (MeDi), containing an unusually large quantity of Lactobacilli, is very effective in preventing AD. Based on recently emerging findings, it is our opinion that the reduction of blood ammonia levels by Lactobacilli in MeDi is the therapeutic agent of MeDi for AD. The recent evidence of Lactobacilli lowering blood ammonia level not only provides a link between AD and MeDi but also provides a foundation of pharmabiotics for hyperammonemia as well as various neurological diseases. PMID:29734664

Blood Ammonia as a Possible Etiological Agent for Alzheimer's Disease.

PubMed

Jin, Yan Yan; Singh, Parul; Chung, Hea-Jong; Hong, Seong-Tschool

2018-05-04

Alzheimer’s disease (AD), characterized by cognitive decline and devastating neurodegeneration, is the most common age-related dementia. Since AD is a typical example of a complex disease that is affected by various genetic and environmental factors, various factors could be involved in preventing and/or treating AD. Extracellular accumulation of beta-amyloid peptide (Aβ) and intracellular accumulation of tau undeniably play essential roles in the etiology of AD. However, interestingly enough, medications targeting Aβ or tau all failed and the only clinically efficient medications for AD are drugs targeting the cholinergic pathway. Also, a very intriguing discovery in AD is that the Mediterranean diet (MeDi), containing an unusually large quantity of Lactobacilli, is very effective in preventing AD. Based on recently emerging findings, it is our opinion that the reduction of blood ammonia levels by Lactobacilli in MeDi is the therapeutic agent of MeDi for AD. The recent evidence of Lactobacilli lowering blood ammonia level not only provides a link between AD and MeDi but also provides a foundation of pharmabiotics for hyperammonemia as well as various neurological diseases.

Carvedilol case history: the discovery and development of the first β-blocker for the treatment of congestive heart failure.

PubMed

Ruffolo, Robert R; Feuerstein, Giora Z

2006-06-01

Carvedilol is a multiple action drug that blocks β1-, β2- and α1- adrenoceptors, and has potent antioxidant properties. Carvedilol is the first drug of its kind to be approved for the treatment of congestive heart failure, and is now the standard of care for this devastating disease. The discovery and development of carvedilol encountered an adverse regulatory climate, skepticism by the cardiology community and hesitance by the company, and in the early 1990s, the fate of the drug was uncertain. Nonetheless, in the largest heart failure study conducted up until that point, carvedilol produced marked reductions in morbidity and mortality, and has given new hope to patients afflicted with congestive heart failure. The story behind carvedilol contains important observations and lessons for scientists, regulators and physicians.

Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder.

PubMed

Papakostas, G I; Ionescu, D F

2015-10-01

Depression is a devastating disorder that places a significant burden on both the individual and society. As such, the discovery of novel therapeutics and innovative treatments--especially for treatment-resistant depression (TRD)--are essential. Research into antidepressant therapies for TRD has evolved from explorations of antidepressants with primary mechanisms of action on the monoaminergic neurotransmitter system to augmentation agents with primary mechanisms both within and outside of the serotonin/norepinephrine system. Now the field of antidepressant research has changed trajectories yet again; this time, compounds with primary mechanisms of action on the glutamatergic, cholinergic and opioid systems are in the forefront of antidepressant exploration. In this review, we will discuss the most recent research surrounding these novel compounds. In addition, we will discuss novel device-based therapeutics, with a particular focus on transcranial magnetic stimulation. In many cases of antidepressant drug discovery, the role of serendipity coupled with meticulous clinical observation in drug development in medicine was crucial. Moving forward, we must look toward the combination of innovation plus improvements on the remarkable discoveries thus far to advance the field of antidepressant research.

Development of Proteomics-Based Fungicides: New Strategies for Environmentally Friendly Control of Fungal Plant Diseases

PubMed Central

Acero, Francisco Javier Fernández; Carbú, María; El-Akhal, Mohamed Rabie; Garrido, Carlos; González-Rodríguez, Victoria E.; Cantoral, Jesús M.

2011-01-01

Proteomics has become one of the most relevant high-throughput technologies. Several approaches have been used for studying, for example, tumor development, biomarker discovery, or microbiology. In this “post-genomic” era, the relevance of these studies has been highlighted as the phenotypes determined by the proteins and not by the genotypes encoding them that is responsible for the final phenotypes. One of the most interesting outcomes of these technologies is the design of new drugs, due to the discovery of new disease factors that may be candidates for new therapeutic targets. To our knowledge, no commercial fungicides have been developed from targeted molecular research, this review will shed some light on future prospects. We will summarize previous research efforts and discuss future innovations, focused on the fight against one of the main agents causing a devastating crops disease, fungal phytopathogens. PMID:21340014

Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy.

PubMed

Hathout, Yetrib; Brody, Edward; Clemens, Paula R; Cripe, Linda; DeLisle, Robert Kirk; Furlong, Pat; Gordish-Dressman, Heather; Hache, Lauren; Henricson, Erik; Hoffman, Eric P; Kobayashi, Yvonne Monique; Lorts, Angela; Mah, Jean K; McDonald, Craig; Mehler, Bob; Nelson, Sally; Nikrad, Malti; Singer, Britta; Steele, Fintan; Sterling, David; Sweeney, H Lee; Williams, Steve; Gold, Larry

2015-06-09

Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases.

Metabolomics in cancer biomarker discovery: current trends and future perspectives.

PubMed

Armitage, Emily G; Barbas, Coral

2014-01-01

Cancer is one of the most devastating human diseases that causes a vast number of mortalities worldwide each year. Cancer research is one of the largest fields in the life sciences and despite many astounding breakthroughs and contributions over the past few decades, there is still a considerable amount to unveil on the function of cancer. It is well known that cancer metabolism differs from that of normal tissue and an important hypothesis published in the 1950s by Otto Warburg proposed that cancer cells rely on anaerobic metabolism as the source for energy, even under physiological oxygen levels. Following this, cancer central carbon metabolism has been researched extensively and beyond respiration, cancer has been found to involve a wide range of metabolic processes, and many more are still to be unveiled. Studying cancer through metabolomics could reveal new biomarkers for cancer that could be useful for its future prognosis, diagnosis and therapy. Metabolomics is becoming an increasingly popular tool in the life sciences since it is a relatively fast and accurate technique that can be applied with either a particular focus or in a global manner to reveal new knowledge about biological systems. There have been many examples of its application to reveal potential biomarkers in different cancers that have employed a range of different analytical platforms. In this review, approaches in metabolomics that have been employed in cancer biomarker discovery are discussed and some of the most noteworthy research in the field is highlighted. Copyright © 2013 Elsevier B.V. All rights reserved.

Collaboration for rare disease drug discovery research.

PubMed

Litterman, Nadia K; Rhee, Michele; Swinney, David C; Ekins, Sean

2014-01-01

Rare disease research has reached a tipping point, with the confluence of scientific and technologic developments that if appropriately harnessed, could lead to key breakthroughs and treatments for this set of devastating disorders. Industry-wide trends have revealed that the traditional drug discovery research and development (R&D) model is no longer viable, and drug companies are evolving their approach. Rather than only pursue blockbuster therapeutics for heterogeneous, common diseases, drug companies have increasingly begun to shift their focus to rare diseases. In academia, advances in genetics analyses and disease mechanisms have allowed scientific understanding to mature, but the lack of funding and translational capability severely limits the rare disease research that leads to clinical trials. Simultaneously, there is a movement towards increased research collaboration, more data sharing, and heightened engagement and active involvement by patients, advocates, and foundations. The growth in networks and social networking tools presents an opportunity to help reach other patients but also find researchers and build collaborations. The growth of collaborative software that can enable researchers to share their data could also enable rare disease patients and foundations to manage their portfolio of funded projects for developing new therapeutics and suggest drug repurposing opportunities. Still there are many thousands of diseases without treatments and with only fragmented research efforts. We will describe some recent progress in several rare diseases used as examples and propose how collaborations could be facilitated. We propose that the development of a center of excellence that integrates and shares informatics resources for rare diseases sponsored by all of the stakeholders would help foster these initiatives.

Collaboration for rare disease drug discovery research

PubMed Central

Litterman, Nadia K.; Rhee, Michele; Swinney, David C.; Ekins, Sean

2014-01-01

Rare disease research has reached a tipping point, with the confluence of scientific and technologic developments that if appropriately harnessed, could lead to key breakthroughs and treatments for this set of devastating disorders. Industry-wide trends have revealed that the traditional drug discovery research and development (R&D) model is no longer viable, and drug companies are evolving their approach. Rather than only pursue blockbuster therapeutics for heterogeneous, common diseases, drug companies have increasingly begun to shift their focus to rare diseases. In academia, advances in genetics analyses and disease mechanisms have allowed scientific understanding to mature, but the lack of funding and translational capability severely limits the rare disease research that leads to clinical trials. Simultaneously, there is a movement towards increased research collaboration, more data sharing, and heightened engagement and active involvement by patients, advocates, and foundations. The growth in networks and social networking tools presents an opportunity to help reach other patients but also find researchers and build collaborations. The growth of collaborative software that can enable researchers to share their data could also enable rare disease patients and foundations to manage their portfolio of funded projects for developing new therapeutics and suggest drug repurposing opportunities. Still there are many thousands of diseases without treatments and with only fragmented research efforts. We will describe some recent progress in several rare diseases used as examples and propose how collaborations could be facilitated. We propose that the development of a center of excellence that integrates and shares informatics resources for rare diseases sponsored by all of the stakeholders would help foster these initiatives. PMID:25685324

Molecular characterization of a heterothallic mating system in Pseudogymnoascus destructans, the Fungus causing white-nose syndrome of bats.

PubMed

Palmer, Jonathan M; Kubatova, Alena; Novakova, Alena; Minnis, Andrew M; Kolarik, Miroslav; Lindner, Daniel L

2014-07-21

White-nose syndrome (WNS) of bats has devastated bat populations in eastern North America since its discovery in 2006. WNS, caused by the fungus Pseudogymnoascus destructans, has spread quickly in North America and has become one of the most severe wildlife epidemics of our time. While P. destructans is spreading rapidly in North America, nothing is known about the sexual capacity of this fungus. To gain insight into the genes involved in sexual reproduction, we characterized the mating-type locus (MAT) of two Pseudogymnoascus spp. that are closely related to P. destructans and homothallic (self-fertile). As with other homothallic Ascomycota, the MAT locus of these two species encodes a conserved α-box protein (MAT1-1-1) as well as two high-mobility group (HMG) box proteins (MAT1-1-3 and MAT1-2-1). Comparisons with the MAT locus of the North American isolate of P. destructans (the ex-type isolate) revealed that this isolate of P. destructans was missing a clear homolog of the conserved HMG box protein (MAT1-2-1). These data prompted the discovery and molecular characterization of a heterothallic mating system in isolates of P. destructans from the Czech Republic. Both mating types of P. destructans were found to coexist within hibernacula, suggesting the presence of mating populations in Europe. Although populations of P. destructans in North America are thought to be clonal and of one mating type, the potential for sexual recombination indicates that continued vigilance is needed regarding introductions of additional isolates of this pathogen. Copyright © 2014 Palmer et al.

Molecular Characterization of a Heterothallic Mating System in Pseudogymnoascus destructans, the Fungus Causing White-Nose Syndrome of Bats

PubMed Central

Palmer, Jonathan M.; Kubatova, Alena; Novakova, Alena; Minnis, Andrew M.; Kolarik, Miroslav; Lindner, Daniel L.

2014-01-01

White-nose syndrome (WNS) of bats has devastated bat populations in eastern North America since its discovery in 2006. WNS, caused by the fungus Pseudogymnoascus destructans, has spread quickly in North America and has become one of the most severe wildlife epidemics of our time. While P. destructans is spreading rapidly in North America, nothing is known about the sexual capacity of this fungus. To gain insight into the genes involved in sexual reproduction, we characterized the mating-type locus (MAT) of two Pseudogymnoascus spp. that are closely related to P. destructans and homothallic (self-fertile). As with other homothallic Ascomycota, the MAT locus of these two species encodes a conserved α-box protein (MAT1-1-1) as well as two high-mobility group (HMG) box proteins (MAT1-1-3 and MAT1-2-1). Comparisons with the MAT locus of the North American isolate of P. destructans (the ex-type isolate) revealed that this isolate of P. destructans was missing a clear homolog of the conserved HMG box protein (MAT1-2-1). These data prompted the discovery and molecular characterization of a heterothallic mating system in isolates of P. destructans from the Czech Republic. Both mating types of P. destructans were found to coexist within hibernacula, suggesting the presence of mating populations in Europe. Although populations of P. destructans in North America are thought to be clonal and of one mating type, the potential for sexual recombination indicates that continued vigilance is needed regarding introductions of additional isolates of this pathogen. PMID:25053709

Next-generation sequencing in schizophrenia and other neuropsychiatric disorders.

PubMed

Schreiber, Matthew; Dorschner, Michael; Tsuang, Debby

2013-10-01

Schizophrenia is a debilitating lifelong illness that lacks a cure and poses a worldwide public health burden. The disease is characterized by a heterogeneous clinical and genetic presentation that complicates research efforts to identify causative genetic variations. This review examines the potential of current findings in schizophrenia and in other related neuropsychiatric disorders for application in next-generation technologies, particularly whole-exome sequencing (WES) and whole-genome sequencing (WGS). These approaches may lead to the discovery of underlying genetic factors for schizophrenia and may thereby identify and target novel therapeutic targets for this devastating disorder. © 2013 Wiley Periodicals, Inc.

Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders

PubMed Central

Han, Chanshuai; Chaineau, Mathilde; Chen, Carol X.-Q.; Beitel, Lenore K.; Durcan, Thomas M.

2018-01-01

Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs) from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop “first-of-their-kind” disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI) and its partners are piloting an “Open Science” model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders. PMID:29467610

Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders.

PubMed

Han, Chanshuai; Chaineau, Mathilde; Chen, Carol X-Q; Beitel, Lenore K; Durcan, Thomas M

2018-01-01

Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs) from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop "first-of-their-kind" disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI) and its partners are piloting an "Open Science" model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders.

Hazard potential of volcanic flank collapses raised by new megatsunami evidence

PubMed Central

Ramalho, Ricardo S.; Winckler, Gisela; Madeira, José; Helffrich, George R.; Hipólito, Ana; Quartau, Rui; Adena, Katherine; Schaefer, Joerg M.

2015-01-01

Large-scale gravitational flank collapses of steep volcanic islands are hypothetically capable of triggering megatsunamis with highly catastrophic effects. Yet, evidence for the generation and impact of collapse-triggered megatsunamis and their high run-ups remains scarce or is highly controversial. Therefore, doubts remain on whether island flank failures truly generate enough volume flux to trigger giant tsunamis, leading to diverging opinions concerning the real hazard potential of such collapses. We show that one of the most prominent oceanic volcanoes on Earth—Fogo, in the Cape Verde Islands—catastrophically collapsed and triggered a megatsunami with devastating effects ~73,000 years ago. Our deductions are based on the recent discovery and cosmogenic 3He dating of tsunamigenic deposits found on nearby Santiago Island, which attest to the impact of this giant tsunami and document wave run-up heights exceeding 270 m. The evidence reported here implies that Fogo’s flank failure involved at least one fast and voluminous event that led to a giant tsunami, in contrast to what has been suggested before. Our observations therefore further demonstrate that flank collapses may indeed catastrophically happen and are capable of triggering tsunamis of enormous height and energy, adding to their hazard potential. PMID:26601287

Culture conditions defining glioblastoma cells behavior: what is the impact for novel discoveries?

PubMed

Ledur, Pítia Flores; Onzi, Giovana Ravizzoni; Zong, Hui; Lenz, Guido

2017-09-15

In cancer research, the use of established cell lines has gradually been replaced by primary cell cultures due to their better representation of in vivo cancer cell behaviors. However, a major challenge with primary culture involves the finding of growth conditions that minimize alterations in the biological state of the cells. To ensure reproducibility and translational potentials for research findings, culture conditions need to be chosen so that the cell population in culture best mimics tumor cells in vivo . Glioblastoma (GBM) is one of the most aggressive and heterogeneous tumor types and the GBM research field would certainly benefit from culture conditions that could maintain the original plethora of phenotype of the cells. Here, we review culture media and supplementation options for GBM cultures, the rationale behind their use, and how much those choices affect drug-screening outcomes. We provide an overview of 120 papers that use primary GBM cultures and discuss the current predominant conditions. We also show important primary research data indicating that "mis-cultured" glioma cells can acquire unnatural drug sensitivity, which would have devastating effects for clinical translations. Finally, we propose the concurrent test of four culture conditions to minimize the loss of cell coverage in culture.

Epidemiologic methods lessons learned from environmental public health disasters: Chernobyl, the World Trade Center, Bhopal, and Graniteville, South Carolina.

PubMed

Svendsen, Erik R; Runkle, Jennifer R; Dhara, Venkata Ramana; Lin, Shao; Naboka, Marina; Mousseau, Timothy A; Bennett, Charles

2012-08-01

Environmental public health disasters involving hazardous contaminants may have devastating effects. While much is known about their immediate devastation, far less is known about long-term impacts of these disasters. Extensive latent and chronic long-term public health effects may occur. Careful evaluation of contaminant exposures and long-term health outcomes within the constraints imposed by limited financial resources is essential. Here, we review epidemiologic methods lessons learned from conducting long-term evaluations of four environmental public health disasters involving hazardous contaminants at Chernobyl, the World Trade Center, Bhopal, and Graniteville (South Carolina, USA). We found several lessons learned which have direct implications for the on-going disaster recovery work following the Fukushima radiation disaster or for future disasters. These lessons should prove useful in understanding and mitigating latent health effects that may result from the nuclear reactor accident in Japan or future environmental public health disasters.

Knowledge discovery for pancreatic cancer using inductive logic programming.

PubMed

Qiu, Yushan; Shimada, Kazuaki; Hiraoka, Nobuyoshi; Maeshiro, Kensei; Ching, Wai-Ki; Aoki-Kinoshita, Kiyoko F; Furuta, Koh

2014-08-01

Pancreatic cancer is a devastating disease and predicting the status of the patients becomes an important and urgent issue. The authors explore the applicability of inductive logic programming (ILP) method in the disease and show that the accumulated clinical laboratory data can be used to predict disease characteristics, and this will contribute to the selection of therapeutic modalities of pancreatic cancer. The availability of a large amount of clinical laboratory data provides clues to aid in the knowledge discovery of diseases. In predicting the differentiation of tumour and the status of lymph node metastasis in pancreatic cancer, using the ILP model, three rules are developed that are consistent with descriptions in the literature. The rules that are identified are useful to detect the differentiation of tumour and the status of lymph node metastasis in pancreatic cancer and therefore contributed significantly to the decision of therapeutic strategies. In addition, the proposed method is compared with the other typical classification techniques and the results further confirm the superiority and merit of the proposed method.

Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta

DOE PAGES

Jiang, Lin; Liu, Cong; Leibly, David; ...

2013-07-16

Amyloid protein aggregates are associated with dozens of devastating diseases including Alzheimer’s, Parkinson’s, ALS, and diabetes type 2. While structure-based discovery of compounds has been effective in combating numerous infectious and metabolic diseases, ignorance of amyloid structure has hindered similar approaches to amyloid disease. Here we show that knowledge of the atomic structure of one of the adhesive, steric-zipper segments of the amyloid-beta (Aβ) protein of Alzheimer’s disease, when coupled with computational methods, identifies eight diverse but mainly flat compounds and three compound derivatives that reduce Aβ cytotoxicity against mammalian cells by up to 90%. Although these compounds bind tomore » Aβ fibers, they do not reduce fiber formation of Aβ. Structure-activity relationship studies of the fiber-binding compounds and their derivatives suggest that compound binding increases fiber stability and decreases fiber toxicity, perhaps by shifting the equilibrium of Aβ from oligomers to fibers.« less

The "Century of Biology" and the Evolving Role of Medicinal Chemists in Neuroscience.

PubMed

Doller, Dario

2017-01-18

Society expects that the wave of contemporary new discoveries in biological sciences will soon lead to novel treatments for human diseases, including many devastating brain disorders. Historically, medicinal chemists have contributed to drug discovery teams in ways that synergize with those from their partner sciences, and help transform new knowledge into the ultimate tangible asset: a new drug. The optimal balance of resources and the right strategy to minimize the risk of late clinical failure may differ for different therapeutic indications. Recent progress in the oncology and neuroscience therapeutic areas is compared and contrasted, in particular looking at the biological target space and functional attributes of recently FDA-approved drugs and those in the late clinical pipeline. Medicinal chemists are poised to have major influence in neuroscience drug research, and examples of areas of potential impact are presented, together with a discussion of the soft skills they bring to their project teams and why they have been so impactful.

Detection of Novel Sequences Related to African Swine Fever Virus in Human Serum and Sewage▿ †

PubMed Central

Loh, Joy; Zhao, Guoyan; Presti, Rachel M.; Holtz, Lori R.; Finkbeiner, Stacy R.; Droit, Lindsay; Villasana, Zoilmar; Todd, Collin; Pipas, James M.; Calgua, Byron; Girones, Rosina; Wang, David; Virgin, Herbert W.

2009-01-01

The family Asfarviridae contains only a single virus species, African swine fever virus (ASFV). ASFV is a viral agent with significant economic impact due to its devastating effects on populations of domesticated pigs during outbreaks but has not been reported to infect humans. We report here the discovery of novel viral sequences in human serum and sewage which are clearly related to the asfarvirus family but highly divergent from ASFV. Detection of these sequences suggests that greater genetic diversity may exist among asfarviruses than previously thought and raises the possibility that human infection by asfarviruses may occur. PMID:19812170

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.

Life-style transitions in plant pathogenic Colletotrichum fungi deciphered by genome and transcriptome analyses

USDA-ARS?s Scientific Manuscript database

Colletotrichum species are devastating fungal pathogens of major crop plants worldwide. Infection involves differentiation of specialized cell-types associated with host surface penetration, growth inside living host cells (biotrophy) and tissue destruction (necrotrophy). Here we report genome and t...

Epidemiologic Methods Lessons Learned from Environmental Public Health Disasters: Chernobyl, the World Trade Center, Bhopal, and Graniteville, South Carolina

PubMed Central

Svendsen, Erik R.; Runkle, Jennifer R.; Dhara, Venkata Ramana; Lin, Shao; Naboka, Marina; Mousseau, Timothy A.; Bennett, Charles

2012-01-01

Background: Environmental public health disasters involving hazardous contaminants may have devastating effects. While much is known about their immediate devastation, far less is known about long-term impacts of these disasters. Extensive latent and chronic long-term public health effects may occur. Careful evaluation of contaminant exposures and long-term health outcomes within the constraints imposed by limited financial resources is essential. Methods: Here, we review epidemiologic methods lessons learned from conducting long-term evaluations of four environmental public health disasters involving hazardous contaminants at Chernobyl, the World Trade Center, Bhopal, and Graniteville (South Carolina, USA). Findings: We found several lessons learned which have direct implications for the on-going disaster recovery work following the Fukushima radiation disaster or for future disasters. Interpretation: These lessons should prove useful in understanding and mitigating latent health effects that may result from the nuclear reactor accident in Japan or future environmental public health disasters. PMID:23066404

Advancing Partnerships Towards an Integrated Approach to Oil Spill Response

NASA Astrophysics Data System (ADS)

Green, D. S.; Stough, T.; Gallegos, S. C.; Leifer, I.; Murray, J. J.; Streett, D.

2015-12-01

Oil spills can cause enormous ecological and economic devastation, necessitating application of the best science and technology available, and remote sensing is playing a growing critical role in the detection and monitoring of oil spills, as well as facilitating validation of remote sensing oil spill products. The FOSTERRS (Federal Oil Science Team for Emergency Response Remote Sensing) interagency working group seeks to ensure that during an oil spill, remote sensing assets (satellite/aircraft/instruments) and analysis techniques are quickly, effectively, appropriately, and seamlessly available to oil spills responders. Yet significant challenges remain for addressing oils spanning a vast range of chemical properties that may be spilled from the Tropics to the Arctic, with algorithms and scientific understanding needing advances to keep up with technology. Thus, FOSTERRS promotes enabling scientific discovery to ensure robust utilization of available technology as well as identifying technologies moving up the TRL (Technology Readiness Level). A recent FOSTERRS facilitated support activity involved deployment of the AVIRIS NG (Airborne Visual Infrared Imaging Spectrometer- Next Generation) during the Santa Barbara Oil Spill to validate the potential of airborne hyperspectral imaging to real-time map beach tar coverage including surface validation data. Many developing airborne technologies have potential to transition to space-based platforms providing global readiness.

Sulfated Glycans and Related Digestive Enzymes in the Zika Virus Infectivity: Potential Mechanisms of Virus-Host Interaction and Perspectives in Drug Discovery.

PubMed

Pomin, Vitor H

2017-01-01

As broadly reported, there is an ongoing Zika virus (ZIKV) outbreak in countries of Latin America. Recent findings have demonstrated that ZIKV causes severe defects on the neural development in fetuses in utero and newborns. Very little is known about the molecular mechanisms involved in the ZIKV infectivity. Potential therapeutic agents are also under investigation. In this report, the possible mechanisms of action played by glycosaminoglycans (GAGs) displayed at the surface proteoglycans of host cells, and likely in charge of interactions with surface proteins of the ZIKV, are highlighted. As is common for the most viruses, these sulfated glycans serve as receptors for virus attachment onto the host cells and consequential entry during infection. The applications of (1) exogenous sulfated glycans of different origins and chemical structures capable of competing with the virus attachment receptors (supposedly GAGs) and (2) GAG-degrading enzymes able to digest the virus attachment receptors on the cells may be therapeutically beneficial as anti-ZIKV. This communication attempts, therefore, to offer some guidance for the future research programs aimed to unveil the molecular mechanisms underlying the ZIKV infectivity and to develop therapeutics capable of decreasing the devastating consequences caused by ZIKV outbreak in the Americas.

Did Zika Virus Mutate to Cause Severe Outbreaks?

PubMed

Rossi, Shannan L; Ebel, Gregory D; Shan, Chao; Shi, Pei-Yong; Vasilakis, Nikos

2018-06-11

Zika virus (ZIKV) has challenged the assumed knowledge regarding the pathobiology of flaviviruses. Despite causing sporadic and mild disease in the 50 years since its discovery, Zika virus has now caused multiple outbreaks in dozens of countries worldwide. Moreover, the disease severity in recent outbreaks, with neurological disease in adult and devastating congenital malformations in fetuses, was not previously seen. One hypothesis is that the virus has acquired mutations that have increased its virulence. Indeed, mutations in other arboviruses, such as West Nile virus (WNV), chikungunya virus (CHIKV), and Venezuelan equine encephalitis virus (VEEV), have enhanced outbreaks. This possibility, as well as alternative hypotheses, are explored here. Copyright © 2018 Elsevier Ltd. All rights reserved.

The past, present, and future of Leishmania genomics and transcriptomics

PubMed Central

Cantacessi, Cinzia; Dantas-Torres, Filipe; Nolan, Matthew J.; Otranto, Domenico

2015-01-01

It has been nearly 10 years since the completion of the first entire genome sequence of a Leishmania parasite. Genomic and transcriptomic analyses have advanced our understanding of the biology of Leishmania, and shed new light on the complex interactions occurring within the parasite–host–vector triangle. Here, we review these advances and examine potential avenues for translation of these discoveries into treatment and control programs. In addition, we argue for a strong need to explore how disease in dogs relates to that in humans, and how an improved understanding in line with the ‘One Health’ concept may open new avenues for the control of these devastating diseases. PMID:25638444

Laboratory experiments on dam-break flow of water-sediment mixtures

USDA-ARS?s Scientific Manuscript database

Dams induce sedimentation and store significant amounts of sediment as they age; therefore, dam failures often involve the release of sediment-laden water to the downstream floodplain. In particular, tailings dams, which are constructed to impound mining wastes, can cause devastating damage when the...

Real-Time Teaching: Lessons from Katrina

ERIC Educational Resources Information Center

Phillips, Antoinette S.; Phillips, Carl R.

2008-01-01

Professors strive constantly to find ways for students to apply what they are learning in the classroom, thereby reinforcing principles being taught and increasing student interest and involvement in the learning process. Hurricane Katrina's devastating impact on the Gulf Coast had wide-ranging consequences. As a result, many individuals…

A model for emergency department end-of-life communications after acute devastating events--part II: moving from resuscitative to end-of-life or palliative treatment.

PubMed

Limehouse, Walter E; Feeser, V Ramana; Bookman, Kelly J; Derse, Arthur

2012-11-01

The model for emergency department (ED) end-of-life communications after acute devastating events addresses decision-making capacity, surrogates, and advance directives, including legal definitions and application of these steps. Part II concerns communications moving from resuscitative to palliative and end-of-life treatments. After completing the steps involved in determining decision-making, emergency physicians (EPs) should consider starting palliative measures versus continuing resuscitative treatment. As communications related to these end-of-life decisions increasingly fall within the scope of emergency medicine (EM) practice, we need to become educated about and comfortable with them. © 2012 by the Society for Academic Emergency Medicine.

Emotional Reactions of Rescue Workers Following a Tornado.

ERIC Educational Resources Information Center

McCammon, Susan L.; And Others

Rescue and medical workers may be at risk for negative emotional experience following intervention efforts in disaster situations. To examine this possibility, 120 rescue and hospital personnel responded to a survey of their emotional reactions and coping behaviors 3 months after a devastating tornado. Twenty-eight subjects had been involved in…

Biofortification: How can we exploit plant science and biotechnology to reduce micronutrient deficiencies?

USDA-ARS?s Scientific Manuscript database

Throughout the developing world, the long-term consequences of insufficient amounts of essential micronutrients in the human diet can be more devastating than low energy intake. Micronutrients are involved in all aspects of development, growth, and physiology of the human body (including from early ...

Fear of Failure, Self-Handicapping, and Negative Emotions in Response to Failure

ERIC Educational Resources Information Center

Bartels, Jared M.; Herman, William E.

2011-01-01

Research suggests that students who fear failure are likely to utilize cognitive strategies such as self-handicapping that serve to perpetuate failure. Such devastating motivational dispositions clearly limit academic success. The present study examined negative emotional responses to scenarios involving academic failure among a sample of…

Genome-Wide Association Study of a Varroa-Specific Defense Behavior in Honeybees (Apis mellifera)

PubMed Central

Spötter, Andreas; Gupta, Pooja; Mayer, Manfred; Reinsch, Norbert

2016-01-01

Honey bees are exposed to many damaging pathogens and parasites. The most devastating is Varroa destructor, which mainly affects the brood. A promising approach for preventing its spread is to breed Varroa-resistant honey bees. One trait that has been shown to provide significant resistance against the Varroa mite is hygienic behavior, which is a behavioral response of honeybee workers to brood diseases in general. Here, we report the use of an Affymetrix 44K SNP array to analyze SNPs associated with detection and uncapping of Varroa-parasitized brood by individual worker bees (Apis mellifera). For this study, 22 000 individually labeled bees were video-monitored and a sample of 122 cases and 122 controls was collected and analyzed to determine the dependence/independence of SNP genotypes from hygienic and nonhygienic behavior on a genome-wide scale. After false-discovery rate correction of the P values, 6 SNP markers had highly significant associations with the trait investigated (α < 0.01). Inspection of the genomic regions around these SNPs led to the discovery of putative candidate genes. PMID:26774061

Hollow-organ perforation following thoracolumbar spinal injuries of fall from height

PubMed Central

Yudoyono, Farid; Dahlan, Rully Hanafi; Tjahjono, Firman Priguna; Imron, Akhmad; Arifin, Muhammad Zafrullah

2015-01-01

Introduction Spinal trauma is the cause of high mortality and morbidity, the fall from height as mechanism that can cause a wide variety of lesions, associated both with the direct impact on the ground and with the deceleration. In such fall cases greater heights and higher mortality are involved. Presentation of case We report the successful management of life-threatening hollow-organ perforation following thoracolumbar spinal injury. Discussion Perforation of the hollow-organ in the setting of thoracolumbar trauma may delay the diagnosis and can have devastating consequences. Conclusions This case supports the recommendation for neurosurgeon in the setting of thoracolumbar injury that perforation of the hollow-organ can have devastating consequences. It is vital to achieve an early diagnosis to improve survival rate. PMID:25967553

Question Number Two: How Many Factors?

ERIC Educational Resources Information Center

Goodwyn, Fara

2012-01-01

Exploratory factor analysis involves five key decisions. The second decision, how many factors to retain, is the focus of the current paper. Extracting too many or too few factors often leads to devastating effects on study results. The advantages and disadvantages of the most effective and/or most utilized strategies to determine the number of…

3 CFR 8967 - Proclamation 8967 of April 30, 2013. National Building Safety Month, 2013

Code of Federal Regulations, 2014 CFR

2014-01-01

... States of America A Proclamation When natural disasters and other hazards put American lives at risk... redevelopment. To get involved, visit www.Ready.gov. Time and again, devastating natural disasters have tested... stakeholders across our country to adopt disaster-resistant building codes and standards. We are collaborating...

The Space Between: Building Liberatory Capital in a School-Community Partnership

ERIC Educational Resources Information Center

Timm, Chad William

2014-01-01

Even before withstanding one of the most devastating economic crises in American history, families living in poverty have battled a dominant discourse that labels them as lacking personal responsibility, initiative, and the ability to make "good" choices. This discourse is reflected in the parent-involvement mandates of the No Child Left…

Toward The Identification Of Candidate Genes Involved In Black Pod Disease Resistance In Theobroma cacao L.

USDA-ARS?s Scientific Manuscript database

Black Pod (Phytophthora sp.) has a devastating effect on the worldwide cacao (Theobroma cacao) yield and incorporating resistance into production fields has been an ongoing effort of breeding programs. Previous meta-QTL analysis of genetic maps created with a variety of molecular markers identified...

Toward the identification of candidate genes involved In black pod disease resistance in Theobroma cacao L.

USDA-ARS?s Scientific Manuscript database

Black Pod (Phytophthora sp.) has a devastating effect on the worldwide cacao (Theobroma cacao) yield and incorporating resistance into production fields has been an ongoing effort of breeding programs. Previous meta-QTL analysis of genetic maps created with a variety of molecular markers identified...

Wheat transcription factor TaWRKY70 is positively involved in high-temperature seedling-plant resistance to Puccinia striiformis f. sp. tritici

USDA-ARS?s Scientific Manuscript database

Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a devastating disease of wheat (Triticum aestivum) worldwide. Wheat high-temperature seedling-plant (HTSP) resistance to Pst is non-race-specific and durable. WRKY transcription factors have proven to play important roles in ...

Ponytails & Death-Ray Looks: A Review of Research on Relational Aggression among Adolescent Girls

ERIC Educational Resources Information Center

Fisher, Glenn L.

2010-01-01

Relational aggression (RA) involves either indirect, verbal, or covert acts with the intent to humiliate, exclude peers from groups, and/or damage a peer's reputation and social status. RA is believed to be particularly devastating psychologically for adolescent girls, as they tend to form smaller and more intimate social groups. Unfortunately, RA…

Collaborative Research in a Post-Katrina Environment: The Facilitation, Communication, and Ethical Considerations of University Researchers

ERIC Educational Resources Information Center

Peters, Gary; McNeese, Rose M.

2008-01-01

The aftermath of Hurricane Katrina brought devastation and confusion to the Mississippi Gulf Coast region on August 29, 2005. A desperate need for leadership, collaboration, and coordination of relief and recovery efforts was revealed during a March 2007 strategic planning session involving 96 organizations, groups, agencies, and researchers…

Disaster nursing in the Oklahoma City bombing.

PubMed

Atkinson, R; Keylon, K; Odor, P S; Walker, G; Hunt, L

1995-10-01

The Oklahoma City Federal Building disaster quickly changed a routine day of eye surgical procedures into a chaotic trauma center for the victims with not only eye injuries, but multiple deep lacerations and other injuries. The devastating and disruptive effect of the bombing was stressful for the nursing staff who became disaster survivors of the emotional trauma involved.

Induction of humoral immune response to multiple recombinant rhipicephalus appendiculatus antigens and their effect on tick feeding success and pathogen transmission

USDA-ARS?s Scientific Manuscript database

Background: Rhipicephalus appendiculatus is the primary vector of Theileria parva, the etiologic agent of East Coast fever (ECF), a devastating disease of cattle in sub-Saharan Africa. We hypothesized that a vaccine targeting tick proteins that are involved in attachment and feeding might affect fee...

Peer Victimization among Adolescent Females: A Literature Review of the Significant Causes and Consequences Associated with Relational Aggression

ERIC Educational Resources Information Center

Tobin, Casey; Duncan, Jenny

2007-01-01

Peer victimization is an all too common occurrence in schools throughout the United States, affecting millions of adolescents every year. Involvement in peer victimization carries devastating consequences that can last a lifetime. Recent research indicates males and females engage in different forms of victimization, with males displaying more…

Mouse Models of Type 2 Diabetes Mellitus in Drug Discovery.

PubMed

Baribault, Helene

2016-01-01

Type 2 diabetes is a fast-growing epidemic in industrialized countries, associated with obesity, lack of physical exercise, aging, family history, and ethnic background. Diagnostic criteria are elevated fasting or postprandial blood glucose levels, a consequence of insulin resistance. Early intervention can help patients to revert the progression of the disease together with lifestyle changes or monotherapy. Systemic glucose toxicity can have devastating effects leading to pancreatic beta cell failure, blindness, nephropathy, and neuropathy, progressing to limb ulceration or even amputation. Existing treatments have numerous side effects and demonstrate variability in individual patient responsiveness. However, several emerging areas of discovery research are showing promises with the development of novel classes of antidiabetic drugs.The mouse has proven to be a reliable model for discovering and validating new treatments for type 2 diabetes mellitus. We review here commonly used methods to measure endpoints relevant to glucose metabolism which show good translatability to the diagnostic of type 2 diabetes in humans: baseline fasting glucose and insulin, glucose tolerance test, insulin sensitivity index, and body type composition. Improvements on these clinical values are essential for the progression of a novel potential therapeutic molecule through a preclinical and clinical pipeline.

Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies.

PubMed

Hellner, Karin; Miranda, Fabrizio; Fotso Chedom, Donatien; Herrero-Gonzalez, Sandra; Hayden, Daniel M; Tearle, Rick; Artibani, Mara; KaramiNejadRanjbar, Mohammad; Williams, Ruth; Gaitskell, Kezia; Elorbany, Samar; Xu, Ruoyan; Laios, Alex; Buiga, Petronela; Ahmed, Karim; Dhar, Sunanda; Zhang, Rebecca Yu; Campo, Leticia; Myers, Kevin A; Lozano, María; Ruiz-Miró, María; Gatius, Sónia; Mota, Alba; Moreno-Bueno, Gema; Matias-Guiu, Xavier; Benítez, Javier; Witty, Lorna; McVean, Gil; Leedham, Simon; Tomlinson, Ian; Drmanac, Radoje; Cazier, Jean-Baptiste; Klein, Robert; Dunne, Kevin; Bast, Robert C; Kennedy, Stephen H; Hassan, Bassim; Lise, Stefano; Garcia, María José; Peters, Brock A; Yau, Christopher; Sauka-Spengler, Tatjana; Ahmed, Ahmed Ashour

2016-08-01

Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells. We identified frequent mutations involving a 40kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p<2(-16)), which was not found in patients without cancer (n=108). Importantly, we show that SOX2 overexpression in FTE is nearly ubiquitous in patients with HGSOCs (n=100), and common in BRCA1-BRCA2 mutation carriers (n=71) who underwent prophylactic salpingo-oophorectomy. We propose that the finding of SOX2 overexpression in FTE could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease. Copyright © 2016 The Ohio State University Wexner Medical Center. Published by Elsevier B.V. All rights reserved.

Dysregulation of synaptic proteins, dendritic spine abnormalities and pathological plasticity of synapses as experience-dependent mediators of cognitive and psychiatric symptoms in Huntington's disease.

PubMed

Nithianantharajah, J; Hannan, A J

2013-10-22

Huntington's disease (HD) is an autosomal dominant tandem repeat expansion disorder involving cognitive, psychiatric and motor symptoms. The expanded trinucleotide (CAG) repeat leads to an extended polyglutamine tract in the huntingtin protein and a subsequent cascade of molecular and cellular pathogenesis. One of the key features of neuropathology, which has been shown to precede the eventual loss of neurons in the cerebral cortex, striatum and other areas, are changes to synapses, including the dendritic protrusions known as spines. In this review we will focus on synapse and spine pathology in HD, including molecular and experience-dependent aspects of pathogenesis. Dendritic spine pathology has been found in both the human HD brain at post mortem as well as various transgenic and knock-in animal models. These changes may help explain the symptoms in HD, and synaptopathy within the cerebral cortex may be particularly important in mediating the psychiatric and cognitive manifestations of this disease. The earliest stages of synaptic dysfunction in HD, as assayed in various mouse models, appears to involve changes in synaptic proteins and associated physiological abnormalities such as synaptic plasticity deficits. In mouse models, synaptic and cortical plasticity deficits have been directly correlated with the onset of cognitive deficits, implying a causal link. Furthermore, following the discovery that environmental enrichment can delay onset of affective, cognitive and motor deficits in HD transgenic mice, specific synaptic molecules shown to be dysregulated by the polyglutamine-induced toxicity were also found to be beneficially modulated by environmental stimulation. This identifies potential molecular targets for future therapeutic developments to treat this devastating disease. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options.

PubMed

Gerards, Mike; Sallevelt, Suzanne C E H; Smeets, Hubert J M

2016-03-01

Leigh syndrome is a progressive neurodegenerative disorder, affecting 1 in 40,000 live births. Most patients present with symptoms between the ages of three and twelve months, but adult onset Leigh syndrome has also been described. The disease course is characterized by a rapid deterioration of cognitive and motor functions, in most cases resulting in death due to respiratory failure. Despite the high genetic heterogeneity of Leigh syndrome, patients present with identical, symmetrical lesions in the basal ganglia or brainstem on MRI, while additional clinical manifestations and age of onset varies from case to case. To date, mutations in over 60 genes, both nuclear and mitochondrial DNA encoded, have been shown to cause Leigh syndrome, still explaining only half of all cases. In most patients, these mutations directly or indirectly affect the activity of the mitochondrial respiratory chain or pyruvate dehydrogenase complex. Exome sequencing has accelerated the discovery of new genes and pathways involved in Leigh syndrome, providing novel insights into the pathophysiological mechanisms. This is particularly important as no general curative treatment is available for this devastating disorder, although several recent studies imply that early treatment might be beneficial for some patients depending on the gene or process affected. Timely, gene-based personalized treatment may become an important strategy in rare, genetically heterogeneous disorders like Leigh syndrome, stressing the importance of early genetic diagnosis and identification of new genes/pathways. In this review, we provide a comprehensive overview of the most important clinical manifestations and genes/pathways involved in Leigh syndrome, and discuss the current state of therapeutic interventions in patients. Copyright © 2015 Elsevier Inc. All rights reserved.

47 CFR 1.729 - Discovery.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 1 2011-10-01 2011-10-01 false Discovery. 1.729 Section 1.729..., and Reports Involving Common Carriers Formal Complaints § 1.729 Discovery. (a) Subject to paragraph (i... seek discovery of any non-privileged matter that is relevant to the material facts in dispute in the...

47 CFR 1.729 - Discovery.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 47 Telecommunication 1 2012-10-01 2012-10-01 false Discovery. 1.729 Section 1.729..., and Reports Involving Common Carriers Formal Complaints § 1.729 Discovery. (a) Subject to paragraph (i... seek discovery of any non-privileged matter that is relevant to the material facts in dispute in the...

47 CFR 1.729 - Discovery.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 1 2013-10-01 2013-10-01 false Discovery. 1.729 Section 1.729..., and Reports Involving Common Carriers Formal Complaints § 1.729 Discovery. (a) Subject to paragraph (i... seek discovery of any non-privileged matter that is relevant to the material facts in dispute in the...

47 CFR 1.729 - Discovery.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 1 2014-10-01 2014-10-01 false Discovery. 1.729 Section 1.729..., and Reports Involving Common Carriers Formal Complaints § 1.729 Discovery. (a) Subject to paragraph (i... seek discovery of any non-privileged matter that is relevant to the material facts in dispute in the...

Bexsero® chronicle.

PubMed

Vernikos, George; Medini, Duccio

2014-10-01

Neisseria meningitidis causes globally 1·2 million invasive disease cases and 135,000 deaths per year, mostly in infants and adolescents. A century of traditional vaccinology had failed the fight against the serogroup B meningococcus (MenB), mostly prevalent in developed countries. Eighteen years after the publication of the first complete genome sequence from a living organism, thanks to an innovative genome-based approach named 'reverse vaccinology', the first broadly effective MenB vaccine was licensed for use by the European Medical Agency and other authorities, and is being implemented worldwide. Here we review this long and passionate journey, from the disease epidemiology to novel antigen discovery, from vaccine clinical development to public health impact: two decades of scientific and technological innovation to defeat one of the most sudden and devastating invasive diseases.

Discovery of Novel Isoforms of Huntingtin Reveals a New Hominid-Specific Exon

PubMed Central

Popowski, Melissa; Haremaki, Tomomi; Croft, Gist F.; Deglincerti, Alessia; Brivanlou, Ali H.

2015-01-01

Huntington’s disease (HD) is a devastating neurological disorder that is caused by an expansion of the poly-Q tract in exon 1 of the Huntingtin gene (HTT). HTT is an evolutionarily conserved and ubiquitously expressed protein that has been linked to a variety of functions including transcriptional regulation, mitochondrial function, and vesicle transport. This large protein has numerous caspase and calpain cleavage sites and can be decorated with several post-translational modifications such as phosphorylations, acetylations, sumoylations, and palmitoylations. However, the exact function of HTT and the role played by its modifications in the cell are still not well understood. Scrutiny of HTT function has been focused on a single, full length mRNA. In this study, we report the discovery of 5 novel HTT mRNA splice isoforms that are expressed in normal and HTT-expanded human embryonic stem cell (hESC) lines as well as in cortical neurons differentiated from hESCs. Interestingly, none of the novel isoforms generates a truncated protein. Instead, 4 of the 5 new isoforms specifically eliminate domains and modifications to generate smaller HTT proteins. The fifth novel isoform incorporates a previously unreported additional exon, dubbed 41b, which is hominid-specific and introduces a potential phosphorylation site in the protein. The discovery of this hominid-specific isoform may shed light on human-specific pathogenic mechanisms of HTT, which could not be investigated with current mouse models of the disease. PMID:26010866

Analysis and Characterization of Vitamin B Biosynthesis Pathways in the Phytoparasitic Nematode Heterodera Glycines

ERIC Educational Resources Information Center

Craig, James P.

2009-01-01

The soybean cyst nematode (SCN), "Heterodera glycines" is an obligate plant parasite that can cause devastating crop losses. To aide in the study of this pathogen, the SCN genome and the transcriptome of second stage juveniles and eggs were shotgun sequenced. A bioinformatic screen of the data revealed nine genes involved in the "de novo"…

Interferon alpha inhibits viral replication of a live-attenuated porcine reproductive and respiratory syndrome virus vaccine preventing development of an adaptive immune response in swine

USDA-ARS?s Scientific Manuscript database

Type I interferons, such as interferon alpha (IFNa), contribute to innate antiviral immunity by promoting production of antiviral mediators and are also involved in promoting an adaptive immune response. Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most devastating and c...

Draft genome of the most devastating insect pest of coffee worldwide: the coffee berry borer, Hypothenemus hampei

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

Vega, Fernando E.; Brown, Stuart M.; Chen, Hao

The coffee berry borer, Hypothenemus hampei, is the most economically important insect pest of coffee worldwide. We present an analysis of the draft genome of the coffee berry borer, the third genome for a Coleopteran species. The genome size is ca. 163 Mb with 19,222 predicted protein-coding genes. Analysis was focused on genes involved in primary digestion as well as gene families involved in detoxification of plant defense molecules and insecticides, such as carboxylesterases, cytochrome P450, gluthathione S-transferases, ATP-binding cassette transporters, and a gene that confers resistance to the insecticide dieldrin. A broad range of enzymes capable of degrading complexmore » polysaccharides were identified. We also evaluated the pathogen defense system and found homologs to antimicrobial genes reported in the Drosophila genome. Ten cases of horizontal gene transfer were identified with evidence for expression, integration into the H. hampei genome, and phylogenetic evidence that the sequences are more closely related to bacterial rather than eukaryotic genes. We find the draft genome analysis broadly expands our knowledge on the biology of a devastating tropical insect pest and suggests new pest management strategies.« less

Draft genome of the most devastating insect pest of coffee worldwide: the coffee berry borer, Hypothenemus hampei

PubMed Central

Vega, Fernando E.; Brown, Stuart M.; Chen, Hao; Shen, Eric; Nair, Mridul B.; Ceja-Navarro, Javier A.; Brodie, Eoin L.; Infante, Francisco; Dowd, Patrick F.; Pain, Arnab

2015-01-01

The coffee berry borer, Hypothenemus hampei, is the most economically important insect pest of coffee worldwide. We present an analysis of the draft genome of the coffee berry borer, the third genome for a Coleopteran species. The genome size is ca. 163 Mb with 19,222 predicted protein-coding genes. Analysis was focused on genes involved in primary digestion as well as gene families involved in detoxification of plant defense molecules and insecticides, such as carboxylesterases, cytochrome P450, gluthathione S-transferases, ATP-binding cassette transporters, and a gene that confers resistance to the insecticide dieldrin. A broad range of enzymes capable of degrading complex polysaccharides were identified. We also evaluated the pathogen defense system and found homologs to antimicrobial genes reported in the Drosophila genome. Ten cases of horizontal gene transfer were identified with evidence for expression, integration into the H. hampei genome, and phylogenetic evidence that the sequences are more closely related to bacterial rather than eukaryotic genes. The draft genome analysis broadly expands our knowledge on the biology of a devastating tropical insect pest and suggests new pest management strategies. PMID:26228545

Draft genome of the most devastating insect pest of coffee worldwide: the coffee berry borer, Hypothenemus hampei

DOE PAGES

Vega, Fernando E.; Brown, Stuart M.; Chen, Hao; ...

2015-07-31

The coffee berry borer, Hypothenemus hampei, is the most economically important insect pest of coffee worldwide. We present an analysis of the draft genome of the coffee berry borer, the third genome for a Coleopteran species. The genome size is ca. 163 Mb with 19,222 predicted protein-coding genes. Analysis was focused on genes involved in primary digestion as well as gene families involved in detoxification of plant defense molecules and insecticides, such as carboxylesterases, cytochrome P450, gluthathione S-transferases, ATP-binding cassette transporters, and a gene that confers resistance to the insecticide dieldrin. A broad range of enzymes capable of degrading complexmore » polysaccharides were identified. We also evaluated the pathogen defense system and found homologs to antimicrobial genes reported in the Drosophila genome. Ten cases of horizontal gene transfer were identified with evidence for expression, integration into the H. hampei genome, and phylogenetic evidence that the sequences are more closely related to bacterial rather than eukaryotic genes. We find the draft genome analysis broadly expands our knowledge on the biology of a devastating tropical insect pest and suggests new pest management strategies.« less

RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertension.

PubMed

Barman, Scott A; Zhu, Shu; White, Richard E

2009-01-01

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by progressive elevation of pulmonary arterial pressure and vascular resistance due to pulmonary vasoconstriction and vessel remodeling as well as inflammation. Rho-kinases (ROCKs) are one of the best-described effectors of the small G-protein RhoA, and ROCKs are involved in a variety of cellular functions including muscle cell contraction, proliferation and vascular inflammation through inhibition of myosin light chain phosphatase and activation of downstream mediators. A plethora of evidence in animal models suggests that heightened RhoA/ROCK signaling is important in the pathogenesis of pulmonary hypertension by causing enhanced constriction and remodeling of the pulmonary vasculature. Both animal and clinical studies suggest that ROCK inhibitors are effective for treatment of severe PAH with minimal risk, which supports the premise that ROCKs are important therapeutic targets in pulmonary hypertension and that ROCK inhibitors are a promising new class of drugs for this devastating disease.

A Journey of Self-Discovery: An Intervention Involving Massage, Yoga and Relaxation for Children with Emotional and Behavioural Difficulties Attending Primary Schools

ERIC Educational Resources Information Center

Powell, Lesley; Gilchrist, Mollie; Stapley, Jacqueline

2008-01-01

This study reports on an intervention involving massage, yoga and relaxation delivered to young children with identified emotional and behavioural difficulties, and at risk of exclusion. Children (n = 126) were invited by the head teacher to participate in the Self-discovery Programme (involving massage, yoga, breath work and relaxation) with…

Cerebellar degeneration following neuroleptic malignant syndrome.

PubMed Central

Lal, V.; Sardana, V.; Thussu, A.; Sawhney, I. M.; Prabhakar, S.

1997-01-01

A 55-year-old woman with a history of bipolar affective disorder developed hyperpyrexia, rigidity and depressed consciousness (neuroleptic malignant syndrome) after commencing neuroleptic therapy. On regaining consciousness, she was mute and had signs suggesting pancerebellar involvement. Hyperpyrexia, which is a cardinal feature of neuroleptic malignant syndrome, may have caused cerebellar damage. Neuroleptic malignant syndrome needs both early recognition and prompt treatment to obviate devastating complications. PMID:9519191

Pleiotropic effects of statins: new therapeutic targets in drug design.

PubMed

Bedi, Onkar; Dhawan, Veena; Sharma, P L; Kumar, Puneet

2016-07-01

The HMG Co-enzyme inhibitors and new lipid-modifying agents expand their new therapeutic target options in the field of medical profession. Statins have been described as the most effective class of drugs to reduce serum cholesterol levels. Since the discovery of the first statin nearly 30 years ago, these drugs have become the main therapeutic approach to lower cholesterol levels. The present scientific research demonstrates numerous non-lipid modifiable effects of statins termed as pleiotropic effects of statins, which could be beneficial for the treatment of various devastating disorders. The most important positive effects of statins are anti-inflammatory, anti-proliferative, antioxidant, immunomodulatory, neuroprotective, anti-diabetes, and antithrombotic, improving endothelial dysfunction and attenuating vascular remodeling besides many others which are discussed under the scope of this review. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil-containing protein kinase (ROCK), and their agonistic action on peroxisome proliferator-activated receptors (PPARs) can be viewed as the principle mechanisms underlying the pleiotropic effects of statins. With gradually increasing knowledge of new therapeutic targets of statins, their use has also been advocated in chronic inflammatory disorders for example rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE). In the scope of review, we highlight statins and their pleiotropic effects with reference to their harmful and beneficial effects as a novel approach for their use in the treatment of devastating disorders. Graphical abstract Pleiotropic effect of statins.

Crystal structure of Zika virus NS5 RNA-dependent RNA polymerase.

PubMed

Godoy, Andre S; Lima, Gustavo M A; Oliveira, Ketllyn I Z; Torres, Naiara U; Maluf, Fernando V; Guido, Rafael V C; Oliva, Glaucius

2017-03-27

The current Zika virus (ZIKV) outbreak became a global health threat of complex epidemiology and devastating neurological impacts, therefore requiring urgent efforts towards the development of novel efficacious and safe antiviral drugs. Due to its central role in RNA viral replication, the non-structural protein 5 (NS5) RNA-dependent RNA-polymerase (RdRp) is a prime target for drug discovery. Here we describe the crystal structure of the recombinant ZIKV NS5 RdRp domain at 1.9 Å resolution as a platform for structure-based drug design strategy. The overall structure is similar to other flaviviral homologues. However, the priming loop target site, which is suitable for non-nucleoside polymerase inhibitor design, shows significant differences in comparison with the dengue virus structures, including a tighter pocket and a modified local charge distribution.

Recommendations for the Critical Care Management of Devastating Brain Injury: Prognostication, Psychosocial, and Ethical Management : A Position Statement for Healthcare Professionals from the Neurocritical Care Society.

PubMed

Souter, Michael J; Blissitt, Patricia A; Blosser, Sandralee; Bonomo, Jordan; Greer, David; Jichici, Draga; Mahanes, Dea; Marcolini, Evie G; Miller, Charles; Sangha, Kiranpal; Yeager, Susan

2015-08-01

Devastating brain injuries (DBIs) profoundly damage cerebral function and frequently cause death. DBI survivors admitted to critical care will suffer both intracranial and extracranial effects from their brain injury. The indicators of quality care in DBI are not completely defined, and despite best efforts many patients will not survive, although others may have better outcomes than originally anticipated. Inaccuracies in prognostication can result in premature termination of life support, thereby biasing outcomes research and creating a self-fulfilling cycle where the predicted course is almost invariably dismal. Because of the potential complexities and controversies involved in the management of devastating brain injury, the Neurocritical Care Society organized a panel of expert clinicians from neurocritical care, neuroanesthesia, neurology, neurosurgery, emergency medicine, nursing, and pharmacy to develop an evidence-based guideline with practice recommendations. The panel intends for this guideline to be used by critical care physicians, neurologists, emergency physicians, and other health professionals, with specific emphasis on management during the first 72-h post-injury. Following an extensive literature review, the panel used the GRADE methodology to evaluate the robustness of the data. They made actionable recommendations based on the quality of evidence, as well as on considerations of risk: benefit ratios, cost, and user preference. The panel generated recommendations regarding prognostication, psychosocial issues, and ethical considerations.

Plasma membrane wounding and repair in pulmonary diseases.

PubMed

Cong, Xiaofei; Hubmayr, Rolf D; Li, Changgong; Zhao, Xiaoli

2017-03-01

Various pathophysiological conditions such as surfactant dysfunction, mechanical ventilation, inflammation, pathogen products, environmental exposures, and gastric acid aspiration stress lung cells, and the compromise of plasma membranes occurs as a result. The mechanisms necessary for cells to repair plasma membrane defects have been extensively investigated in the last two decades, and some of these key repair mechanisms are also shown to occur following lung cell injury. Because it was theorized that lung wounding and repair are involved in the pathogenesis of acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF), in this review, we summarized the experimental evidence of lung cell injury in these two devastating syndromes and discuss relevant genetic, physical, and biological injury mechanisms, as well as mechanisms used by lung cells for cell survival and membrane repair. Finally, we discuss relevant signaling pathways that may be activated by chronic or repeated lung cell injury as an extension of our cell injury and repair focus in this review. We hope that a holistic view of injurious stimuli relevant for ARDS and IPF could lead to updated experimental models. In addition, parallel discussion of membrane repair mechanisms in lung cells and injury-activated signaling pathways would encourage research to bridge gaps in current knowledge. Indeed, deep understanding of lung cell wounding and repair, and discovery of relevant repair moieties for lung cells, should inspire the development of new therapies that are likely preventive and broadly effective for targeting injurious pulmonary diseases. Copyright © 2017 the American Physiological Society.

Roles of proteolysis in regulation of GPCR function

PubMed Central

Cottrell, GS

2013-01-01

The enzymatic activity of peptidases must be tightly regulated to prevent uncontrolled hydrolysis of peptide bonds, which could have devastating effects on biological systems. Peptidases are often generated as inactive propeptidases, secreted with endogenous inhibitors, or they are compartmentalized. Propeptidases become active after proteolytic removal of N-terminal activation peptides by other peptidases. Some peptidases only become active towards substrates only at certain pHs, thus confining activity to specific compartments or conditions. This review discusses the different roles proteolysis plays in regulating GPCRs. At the cell-surface, certain GPCRs are regulated by the hydrolytic inactivation of bioactive peptides by membrane-anchored peptidases, which prevent signalling. Conversely, cell-surface peptidases can also generate bioactive peptides, which directly activate GPCRs. Alternatively, cell-surface peptidases activated by GPCRs, can generate bioactive peptides to cause transactivation of receptor tyrosine kinases, thereby promoting signalling. Certain peptidases can signal directly to cells, by cleaving GPCR to initiate intracellular signalling cascades. Intracellular peptidases also regulate GPCRs; lysosomal peptidases destroy GPCRs in lysosomes to permanently terminate signalling and mediate down-regulation; endosomal peptidases cleave internalized peptide agonists to regulate GPCR recycling, resensitization and signalling; and soluble intracellular peptidases also participate in GPCR function by regulating the ubiquitination state of GPCRs, thereby altering GPCR signalling and fate. Although the use of peptidase inhibitors has already brought success in the treatment of diseases such as hypertension, the discovery of new regulatory mechanisms involving proteolysis that control GPCRs may provide additional targets to modulate dysregulated GPCR signalling in disease. PMID:23043558

The transcriptional response to the olive fruit fly (Bactrocera oleae) reveals extended differences between tolerant and susceptible olive (Olea europaea L.) varieties

PubMed Central

Grasso, Filomena; Coppola, Mariangela; Carbone, Fabrizio; Baldoni, Luciana; Alagna, Fiammetta; Perrotta, Gaetano; Pérez-Pulido, Antonio J.; Garonna, Antonio; Facella, Paolo; Daddiego, Loretta; Lopez, Loredana; Vitiello, Alessia; Rao, Rosa

2017-01-01

The olive fruit fly Bactrocera oleae (Diptera: Tephritidae) is the most devastating pest of cultivated olive (Olea europaea L.). Intraspecific variation in plant resistance to B. oleae has been described only at phenotypic level. In this work, we used a transcriptomic approach to study the molecular response to the olive fruit fly in two olive cultivars with contrasting level of susceptibility. Using next-generation pyrosequencing, we first generated a catalogue of more than 80,000 sequences expressed in drupes from approximately 700k reads. The assembled sequences were used to develop a microarray layout with over 60,000 olive-specific probes. The differential gene expression analysis between infested (i.e. with II or III instar larvae) and control drupes indicated a significant intraspecific variation between the more tolerant and susceptible cultivar. Around 2500 genes were differentially regulated in infested drupes of the tolerant variety. The GO annotation of the differentially expressed genes implies that the inducible resistance to the olive fruit fly involves a number of biological functions, cellular processes and metabolic pathways, including those with a known role in defence, oxidative stress responses, cellular structure, hormone signalling, and primary and secondary metabolism. The difference in the induced transcriptional changes between the cultivars suggests a strong genetic role in the olive inducible defence, which can ultimately lead to the discovery of factors associated with a higher level of tolerance to B. oleae. PMID:28797083

The transcriptional response to the olive fruit fly (Bactrocera oleae) reveals extended differences between tolerant and susceptible olive (Olea europaea L.) varieties.

PubMed

Grasso, Filomena; Coppola, Mariangela; Carbone, Fabrizio; Baldoni, Luciana; Alagna, Fiammetta; Perrotta, Gaetano; Pérez-Pulido, Antonio J; Garonna, Antonio; Facella, Paolo; Daddiego, Loretta; Lopez, Loredana; Vitiello, Alessia; Rao, Rosa; Corrado, Giandomenico

2017-01-01

The olive fruit fly Bactrocera oleae (Diptera: Tephritidae) is the most devastating pest of cultivated olive (Olea europaea L.). Intraspecific variation in plant resistance to B. oleae has been described only at phenotypic level. In this work, we used a transcriptomic approach to study the molecular response to the olive fruit fly in two olive cultivars with contrasting level of susceptibility. Using next-generation pyrosequencing, we first generated a catalogue of more than 80,000 sequences expressed in drupes from approximately 700k reads. The assembled sequences were used to develop a microarray layout with over 60,000 olive-specific probes. The differential gene expression analysis between infested (i.e. with II or III instar larvae) and control drupes indicated a significant intraspecific variation between the more tolerant and susceptible cultivar. Around 2500 genes were differentially regulated in infested drupes of the tolerant variety. The GO annotation of the differentially expressed genes implies that the inducible resistance to the olive fruit fly involves a number of biological functions, cellular processes and metabolic pathways, including those with a known role in defence, oxidative stress responses, cellular structure, hormone signalling, and primary and secondary metabolism. The difference in the induced transcriptional changes between the cultivars suggests a strong genetic role in the olive inducible defence, which can ultimately lead to the discovery of factors associated with a higher level of tolerance to B. oleae.

77 FR 6820 - Proposed Information Collection; Comment Request: Creating Stewardship Through Biodiversity...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-09

... Information Collection; Comment Request: Creating Stewardship Through Biodiversity Discovery in National Parks... collection (IC) described below. This collection will survey participants of Biodiversity Discovery efforts... Biodiversity Discovery refers to a variety of efforts to discover living organisms through public involvement...

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

A Combined Metabonomic and Proteomic Approach Identifies Frontal Cortex Changes in a Chronic Phencyclidine Rat Model in Relation to Human Schizophrenia Brain Pathology

PubMed Central

Wesseling, Hendrik; Chan, Man K; Tsang, T M; Ernst, Agnes; Peters, Fabian; Guest, Paul C; Holmes, Elaine; Bahn, Sabine

2013-01-01

Current schizophrenia (SCZ) treatments fail to treat the broad range of manifestations associated with this devastating disorder. Thus, new translational models that reproduce the core pathological features are urgently needed to facilitate novel drug discovery efforts. Here, we report findings from the first comprehensive label-free liquid-mass spectrometry proteomic- and proton nuclear magnetic resonance-based metabonomic profiling of the rat frontal cortex after chronic phencyclidine (PCP) intervention, which induces SCZ-like symptoms. The findings were compared with results from a proteomic profiling of post-mortem prefrontal cortex from SCZ patients and with relevant findings in the literature. Through this approach, we identified proteomic alterations in glutamate-mediated Ca2+ signaling (Ca2+/calmodulin-dependent protein kinase II, PPP3CA, and VISL1), mitochondrial function (GOT2 and PKLR), and cytoskeletal remodeling (ARP3). Metabonomic profiling revealed changes in the levels of glutamate, glutamine, glycine, pyruvate, and the Ca2+ regulator taurine. Effects on similar pathways were also identified in the prefrontal cortex tissue from human SCZ subjects. The discovery of similar but not identical proteomic and metabonomic alterations in the chronic PCP rat model and human brain indicates that this model recapitulates only some of the molecular alterations of the disease. This knowledge may be helpful in understanding mechanisms underlying psychosis, which, in turn, can facilitate improved therapy and drug discovery for SCZ and other psychiatric diseases. Most importantly, these molecular findings suggest that the combined use of multiple models may be required for more effective translation to studies of human SCZ. PMID:23942359

Biomarkers for kidney involvement in pediatric lupus

PubMed Central

Goilav, Beatrice; Putterman, Chaim; Rubinstein, Tamar B

2015-01-01

Lupus nephritis (LN), the renal involvement in systemic lupus erythematosus, is currently diagnosed by histopathology obtained by percutaneous renal biopsy and is associated with increased morbidity and mortality in both adults and children. LN is more prevalent and severe in children, requiring aggressive and prolonged immunosuppression. The consequences of the diagnosis and its treatment have devastating long-term effects on the growth, well-being and quality of life of affected children. The paucity of reliable clinical indicators of the presence and severity of renal involvement have contributed to a halt in the reduction of progression to end-stage renal disease in recent years. Here, we discuss the recent development of biomarkers in the management of LN and their role as therapeutic targets. PMID:26079958

The intricate mechanisms of neurodegeneration in prion diseases

PubMed Central

Soto, Claudio; Satani, Nikunj

2010-01-01

Prion diseases are a group of infectious neurodegenerative diseases with an entirely novel mechanism of transmission, involving a protein-only infectious agent that propagates the disease by transmitting protein conformational changes. The disease results from extensive and progressive brain degeneration. The molecular mechanisms involved in neurodegeneration are not entirely known but involve multiple processes operating simultaneously and synergistically in the brain, including spongiform degeneration, synaptic alterations, brain inflammation, neuronal death and the accumulation of protein aggregates. Here, we review the pathways implicated in prion-induced brain damage and put the pieces together into a possible model of neurodegeneration in prion disorders. A more comprehensive understanding of the molecular basis of brain degeneration is essential to develop a much needed therapy for these devastating diseases. PMID:20889378

Enabling the Discovery of Gravitational Radiation

NASA Astrophysics Data System (ADS)

Isaacson, Richard

2017-01-01

The discovery of gravitational radiation was announced with the publication of the results of a physics experiment involving over a thousand participants. This was preceded by a century of theoretical work, involving a similarly large group of physicists, mathematicians, and computer scientists. This huge effort was enabled by a substantial commitment of resources, both public and private, to develop the different strands of this complex research enterprise, and to build a community of scientists to carry it out. In the excitement following the discovery, the role of key enablers of this success has not always been adequately recognized in popular accounts. In this talk, I will try to call attention to a few of the key ingredients that proved crucial to enabling the successful discovery of gravitational waves, and the opening of a new field of science.

N-Myristoyltransferase inhibitors as new leads to treat sleeping sickness

PubMed Central

Frearson, Julie A.; Brand, Stephen; McElroy, Stuart P.; Cleghorn, Laura A.T.; Smid, Ondrej; Stojanovski, Laste; Price, Helen P.; Guther, M. Lucia S.; Torrie, Leah S.; Robinson, David A.; Hallyburton, Irene; Mpamhanga, Chidochangu P.; Brannigan, James A.; Wilkinson, Anthony J.; Hodgkinson, Michael; Hui, Raymond; Qiu, Wei; Raimi, Olawale G.; van Aalten, Daan M. F.; Brenk, Ruth; Gilbert, Ian H.; Read, Kevin D.; Fairlamb, Alan H.; Ferguson, Michael A. J.; Smith, Deborah F.; Wyatt, Paul G.

2010-01-01

African sleeping sickness or human African trypanosomiasis (HAT), caused by Trypanosoma brucei spp., is responsible for ~30,000 deaths each year. Available treatments for this neglected disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease, when the parasite has infected the central nervous system. Here, we report the validation of a molecular target and discovery of associated lead compounds with potential to address this unmet need. Inhibition of this target, T. brucei N-myristoyltransferase (TbNMT), leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have very promising pharmaceutical properties and represent an exciting opportunity to develop oral drugs to treat this devastating disease. Our studies validate TbNMT as a promising therapeutic target for HAT. PMID:20360736

Synthesis and evaluation of 1-amino-6-halo-β-carbolines as antimalarial and antiprion agents.

PubMed

Thompson, Mark J; Louth, Jennifer C; Little, Susan M; Jackson, Matthew P; Boursereau, Yohan; Chen, Beining; Coldham, Iain

2012-04-01

Malaria is one of the world's most devastating parasitic diseases, causing almost one million deaths each year. Growing resistance to classical antimalarial drugs, such as chloroquine, necessitates the discovery of new therapeutic agents for successful control of this global disease. Here, we report the synthesis of some 6-halo-β-carbolines as analogues of the potent antimalarial natural product, manzamine A, retaining its heteroaromatic core whilst providing compounds with much improved synthetic accessibility. Two compounds displayed superior activity to chloroquine itself against a resistant Plasmodium falciparum strain, identifying them as promising leads for future development. Furthermore, in line with previous reports of similarities in antimalarial and antiprion effects of aminoaryl-based antimalarial agents, the 1-amino-β-carboline libraries were also found to possess significant bioactivity against a prion-infected cell line. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Jiang, Lin; Liu, Cong; Leibly, David

Amyloid protein aggregates are associated with dozens of devastating diseases including Alzheimer’s, Parkinson’s, ALS, and diabetes type 2. While structure-based discovery of compounds has been effective in combating numerous infectious and metabolic diseases, ignorance of amyloid structure has hindered similar approaches to amyloid disease. Here we show that knowledge of the atomic structure of one of the adhesive, steric-zipper segments of the amyloid-beta (Aβ) protein of Alzheimer’s disease, when coupled with computational methods, identifies eight diverse but mainly flat compounds and three compound derivatives that reduce Aβ cytotoxicity against mammalian cells by up to 90%. Although these compounds bind tomore » Aβ fibers, they do not reduce fiber formation of Aβ. Structure-activity relationship studies of the fiber-binding compounds and their derivatives suggest that compound binding increases fiber stability and decreases fiber toxicity, perhaps by shifting the equilibrium of Aβ from oligomers to fibers.« less

Mosquito Vectors and the Globalization of Plasmodium falciparum Malaria.

PubMed

Molina-Cruz, Alvaro; Zilversmit, Martine M; Neafsey, Daniel E; Hartl, Daniel L; Barillas-Mury, Carolina

2016-11-23

Plasmodium falciparum malaria remains a devastating public health problem. Recent discoveries have shed light on the origin and evolution of Plasmodium parasites and their interactions with their vertebrate and mosquito hosts. P. falciparum malaria originated in Africa from a single horizontal transfer between an infected gorilla and a human, and became global as the result of human migration. Today, P. falciparum malaria is transmitted worldwide by more than 70 different anopheline mosquito species. Recent studies indicate that the mosquito immune system can be a barrier to malaria transmission and that the P. falciparum Pfs47 gene allows the parasite to evade mosquito immune detection. Here, we review the origin and globalization of P. falciparum and integrate this history with analysis of the biology, evolution, and dispersal of the main mosquito vectors. This new perspective broadens our understanding of P. falciparum population structure and the dispersal of important parasite genetic traits.

New discoveries in the pathogenesis and classification of vitiligo.

PubMed

Rodrigues, Michelle; Ezzedine, Khaled; Hamzavi, Iltefat; Pandya, Amit G; Harris, John E

2017-07-01

Vitiligo is a common autoimmune disease that progressively destroys melanocytes in the skin, resulting in the appearance of patchy depigmentation. This disfiguring condition frequently affects the face and other visible areas of the body, which can be psychologically devastating. The onset of vitiligo often occurs in younger individuals and progresses for life, resulting in a heavy burden of disease and decreased quality of life. Presentation patterns of vitiligo vary, and recognition of these patterns provides both diagnostic and prognostic clues. Recent insights into disease pathogenesis offer a better understanding of the natural history of the disease, its associations, and potential for future treatments. The first article in this continuing medical education series outlines typical and atypical presentations of vitiligo, how they reflect disease activity, prognosis, and response to treatment. Finally, we discuss disease associations, risk factors, and our current understanding of disease pathogenesis. Copyright © 2016 American Academy of Dermatology, Inc. All rights reserved.

The Discovery of Insulin: A Case Study of Scientific Methodology

ERIC Educational Resources Information Center

Stansfield, William D.

2012-01-01

The nature of scientific research sometimes involves a trial-and-error procedure. Popular reviews of successful results from this approach often sanitize the story by omitting unsuccessful trials, thus painting the rosy impression that research simply follows a direct route from hypothesis to experiment to scientific discovery. The discovery of…

Collaborative Core Research Program for Chemical-Biological Warfare Defense

DTIC Science & Technology

2015-01-04

Discovery through High Throughput Screening (HTS) and Fragment-Based Drug Design (FBDD...Discovery through High Throughput Screening (HTS) and Fragment-Based Drug Design (FBDD) Current pharmaceutical approaches involving drug discovery...structural analysis and docking program generally known as fragment based drug design (FBDD). The main advantage of using these approaches is that

Environmental factors influencing the risk of autism

PubMed Central

Karimi, Padideh; Kamali, Elahe; Mousavi, Seyyed Mohammad; Karahmadi, Mojgan

2017-01-01

Autism is a developmental disability with age of onset in childhood (under 3 years old), which is characterized by definite impairments in social interactions, abnormalities in speech, and stereotyped pattern of behaviors. Due to the progress of autism in recent decades, a wide range of studies have been done to identify the etiological factors of autism. It has been found that genetic and environmental factors are both involved in autism pathogenesis. Hence, in this review article, a set of environmental factors involved in the occurrence of autism has been collected, and finally, some practical recommendations for reduction of the risk of this devastating disease in children are represented. PMID:28413424

Facial transplants: current situation and ethical issues.

PubMed

Petrini, C

2015-01-01

The first transplantation of a face from a cadaver was performed in 2005, since when about thirty have been performed globally. The technique is now beginning to appear in Italy. Face transplants are performed exclusively on persons who have suffered devastating lesions to the face. The ethical problems involved are very considerable, particularly where personal identity is concerned. The case records reveal surprisingly positive outcomes regarding both clinical follow-up and functional recovery, as well as psychological aspects and social integration. Thus, while early documents addressing the ethical issues involved in facial transplants were somewhat cautious or even unfavourable on the subject of this technique, a positive approach is now more prevalent.

A Journey of Self-Discovery: An Intervention Involving Massage, Yoga and Relaxation for Children with Emotional and Behavioural Difficulties Attending Primary Schools

ERIC Educational Resources Information Center

Powell, Lesley; Gilchrist, Mollie; Stapley, Jacqueline

2008-01-01

This study reports on an intervention involving massage, yoga and relaxation delivered to young children with emotional and behavioural difficulties. Children (n = 126) were invited to participate in the Self-discovery Programme (SDP) with parental consent. A total of 107 children aged 8-11 years completed the SDP and all measures. Children were…

Nasal septal abscess in association with pediatric acute rhinosinusitis.

PubMed

Tien, Duc A; Krakovitz, Paul; Anne, Samantha

2016-12-01

Nasal septal abscess (NSA) in the pediatric population is rare and can result in devastating complications. Objective of this study is to review a case series of pediatric patients presenting with NSA in association with acute rhinosinusitis (ARS) for possible risk factors and predisposing conditions. This is a retrospective review of pediatric patients that presented to a tertiary care hospital with nasal septal abscess associated with ARS. Patient demographics, presence of ARS, sinuses involved, and other potential risk factors were recorded. In addition, a literature review was conducted to evaluate other reported cases of NSA in association with ARS. Cases of NSA associated with trauma or other causes were excluded from analysis. Five patients with NSA were treated by the pediatric otolaryngology department of a tertiary care center from 2003 to 2014. Three of these cases were associated with ARS. Of these cases, the average age at diagnosis was 9.7 years. Two were male and one was female. In these cases, the bilateral frontal, maxillary and ethmoid sinuses were involved. Sphenoid involvement occurred in two patients. One case was associated with ipsilateral middle turbinate concha bullosa. The cartilaginous septum was compromised in all three cases. All patients were treated with incision and drainage. This is the largest case series of NSA described in the pediatric population. NSA is exceedingly rare but may be associated with ARS. While the etiology of NSA is not always clear, identifying and treating nasal septal abscesses early is imperative to reduce potentially devastating complications. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Why Quantify Uncertainty in Ecosystem Studies: Obligation versus Discovery Tool?

NASA Astrophysics Data System (ADS)

Harmon, M. E.

2016-12-01

There are multiple motivations for quantifying uncertainty in ecosystem studies. One is as an obligation; the other is as a tool useful in moving ecosystem science toward discovery. While reporting uncertainty should become a routine expectation, a more convincing motivation involves discovery. By clarifying what is known and to what degree it is known, uncertainty analyses can point the way toward improvements in measurements, sampling designs, and models. While some of these improvements (e.g., better sampling designs) may lead to incremental gains, those involving models (particularly model selection) may require large gains in knowledge. To be fully harnessed as a discovery tool, attitudes toward uncertainty may have to change: rather than viewing uncertainty as a negative assessment of what was done, it should be viewed as positive, helpful assessment of what remains to be done.

Automated discovery of safety and efficacy concerns for joint & muscle pain relief treatments from online reviews.

PubMed

Adams, David Z; Gruss, Richard; Abrahams, Alan S

2017-04-01

Product issues can cost companies millions in lawsuits and have devastating effects on a firm's sales, image and goodwill, especially in the era of social media. The ability for a system to detect the presence of safety and efficacy (S&E) concerns early on could not only protect consumers from injuries due to safety hazards, but could also mitigate financial damage to the manufacturer. Prior studies in the field of automated defect discovery have found industry-specific techniques appropriate to the automotive, consumer electronics, home appliance, and toy industries, but have not investigated pain relief medicines and medical devices. In this study, we focus specifically on automated discovery of S&E concerns in over-the-counter (OTC) joint and muscle pain relief remedies and devices. We select a dataset of over 32,000 records for three categories of Joint & Muscle Pain Relief treatments from Amazon's online product reviews, and train "smoke word" dictionaries which we use to score holdout reviews, for the presence of safety and efficacy issues. We also score using conventional sentiment analysis techniques. Compared to traditional sentiment analysis techniques, we found that smoke term dictionaries were better suited to detect product concerns from online consumer reviews, and significantly outperformed the sentiment analysis techniques in uncovering both efficacy and safety concerns, across all product subcategories. Our research can be applied to the healthcare and pharmaceutical industry in order to detect safety and efficacy concerns, reducing risks that consumers face using these products. These findings can be highly beneficial to improving quality assurance and management in joint and muscle pain relief. Copyright © 2017 Elsevier B.V. All rights reserved.

Scenes of Devastation: Chasing Hawaii's Deadly Ohia Fungus | Hawaii Public

Science.gov Websites

Scenes of Devastation: Chasing Hawaii's Deadly Ohia Fungus By Molly Solomon * Mar 25, 2016 TweetShareGoogle+Email Molly Solomon Rapid Ohia Death has devastated native forests on Hawaii Island, especially in Lower Puna subdivisions like Leilani Estates. Credit Molly Solomon One of Hawai'i's oldest and most

Assessment of composite motif discovery methods.

PubMed

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

2008-02-26

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

The Pause That Refreshes: A Study of the Discovery Corners in the National Museum of History and Technology Smithsonian Institution.

ERIC Educational Resources Information Center

Wolf, Robert L.; Tymitz, Barbara L.

This report examines the impact and effectiveness of an educational program (Discovery Corners) offered by the National Museum of History and Technology. The main objective is to offer feedback to museum personnel regarding the impact of museum exhibits and programs. The Discovery Corners program involves on-site presentations and demonstrations…

Schizophrenia: an integrative approach to modelling a complex disorder

PubMed Central

Robertson, George S.; Hori, Sarah E.; Powell, Kelly J.

2006-01-01

The discovery of candidate susceptibility genes for schizophrenia and the generation of mice lacking proteins that reproduce biochemical processes that are disrupted in this mental illness offer unprecedented opportunities for improved modelling of this complex disorder. Several lines of evidence indicate that obstetrical complications, as well as fetal or neonatal exposure to viral infection, are predisposing events for some forms of schizophrenia. These environmental events can be modelled in animals, resulting in some of the characteristic features of schizophrenia; however, animal models have yet to be developed that encompass both environmental and genetic aspects of this mental illness. A large number of candidate schizophrenia susceptibility genes have been identified that encode proteins implicated in the regulation of synaptic plasticity, neurotransmission, neuronal migration, cell adherence, signal transduction, energy metabolism and neurite outgrowth. In support of the importance of these processes in schizophrenia, mice that have reduced levels or completely lack proteins that control glutamatergic neurotransmission, neuronal migration, cell adherence, signal transduction, neurite outgrowth and synaptic plasticity display many features reminiscent of schizophrenia. In the present review, we discuss strategies for modelling schizophrenia that involve treating mice that bear these mutations in a variety of ways to better model both environmental and genetic factors responsible for this complex mental illness according to a “two-hit hypothesis.” Because rodents are able to perform complex cognitive tasks using odour but not visual or auditory cues, we hypothesize that olfactory-based tests of cognitive performance should be used to search for novel therapeutics that ameliorate the cognitive deficits that are a feature of this devastating mental disorder. PMID:16699601

Structure and mechanism of the T-box riboswitches

PubMed Central

Zhang, Jinwei

2015-01-01

In most Gram-positive bacteria, including many clinically devastating pathogens from genera such as Bacillus, Clostridium, Listeria and Staphylococcus, T-box riboswitches sense and regulate intracellular availability of amino acids through a multipartite mRNA-tRNA interaction. The T-box mRNA leaders respond to nutrient starvation by specifically binding cognate tRNAs and sensing whether the bound tRNA is aminoacylated, as a proxy for amino acid availability. Based on this readout, T-boxes direct a transcriptional or translational switch to control the expression of downstream genes involved in various aspects of amino acid metabolism: biosynthesis, transport, aminoacylation, transamidation, etc. Two decades after its discovery, the structural and mechanistic underpinnings of the T-box riboswitch were recently elucidated, producing a wealth of insights into how two structured RNAs can recognize each other with robust affinity and exquisite selectivity. The T-box paradigm exemplifies how natural non-coding RNAs can interact not just through sequence complementarity, but can add molecular specificity by precisely juxtaposing RNA structural motifs, exploiting inherently flexible elements and the biophysical properties of post-transcriptional modifications, ultimately achieving a high degree of shape complementarity through mutually induced fit. The T-box also provides a proof-of-principle that compact RNA domains can recognize minute chemical changes (such as tRNA aminoacylation) on another RNA. The unveiling of the structure and mechanism of the T-box system thus expands our appreciation of the range of capabilities and modes of action of structured non-coding RNAs, and hints at the existence of networks of non-coding RNAs that communicate through both, structural and sequence specificity. PMID:25959893

Kynurenine–3–monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

PubMed Central

Mole, Damian J; Webster, Scott P; Uings, Iain; Zheng, Xiaozhong; Binnie, Margaret; Wilson, Kris; Hutchinson, Jonathan P; Mirguet, Olivier; Walker, Ann; Beaufils, Benjamin; Ancellin, Nicolas; Trottet, Lionel; Bénéton, Véronique; Mowat, Christopher G; Wilkinson, Martin; Rowland, Paul; Haslam, Carl; McBride, Andrew; Homer, Natalie ZM; Baily, James E; Sharp, Matthew GF; Garden, O James; Hughes, Jeremy; Howie, Sarah EM; Holmes, Duncan S; Liddle, John; Iredale, John P

2015-01-01

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death1,2 Acute mortality from AP-MODS exceeds 20%3 and for those who survive the initial episode, their lifespan is typically shorter than the general population4. There are no specific therapies available that protect individuals against AP-MODS. Here, we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism5, is central to the pathogenesis of AP-MODS. We created a mouse strain deficient for Kmo with a robust biochemical phenotype that protected against extrapancreatic tissue injury to lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in levels of kynurenine pathway metabolites in vivo and afforded therapeutic protection against AP-MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS and open up a new area for drug discovery in critical illness. PMID:26752518

Venoms, toxins and derivatives from the Brazilian fauna: valuable sources for drug discovery.

PubMed

De Marco Almeida, Flávia; de Castro Pimenta, Adriano Monteiro; Oliveira, Mônica Cristina; De Lima, Maria Elena

2015-06-25

Animal venoms have been widely investigated throughout the world. The great number of biotechnological articles as well as patent applications in the field of drug discovery based on these compounds indicates how important the source is. This review presents a list of the most studied Brazilian venomous animal species and shows the most recent patent applications filed from 2000 to 2013, which comprise Brazilian venoms, toxins and derivatives. We analyze the data according to the species, the type of products claimed and the nationality of the inventors. Fifty-five patent applications were found, involving 8 genera. Crotalus, Lachesis, Bothrops and Loxosceles represented 78% of the patent applications. The other 22% were represented by Phoneutria, Tityus, Acanthoscurria and Phyllomedusa. Most of the inventions (42%) involved anticancer, immunomodulator or antimicrobial drugs, while 13% involved anti-venoms and vaccines, 11% involved hypotensive compositions, 9% involved antinociceptive and/or anti-inflammatory compositions, and the other 25% involved methods, kits or compositions for various purposes. Brazilian inventors filed 49% of the patent applications, but other countries, mainly the United States of America, Germany, Russia and France, also filed patent applications claiming products comprising venoms, toxins and/or derivatives from the Brazilian fauna. Brazil holds an important number of patent applications which mostly belong to universities and research institutes, but the pharmaceutical industry in this field is still weak in Brazil. Although, Brazilian venomous animal species have been reported in drug discovery throughout the world, many species remain to be explored as valuable and promising tools for drug discovery and development.

Understanding bureaucracy in health science ethics: toward a better institutional review board.

PubMed

Bozeman, Barry; Slade, Catherine; Hirsch, Paul

2009-09-01

Research involving human participants continues to grow dramatically, fueled by advances in medical technology, globalization of research, and financial and professional incentives. This creates increasing opportunities for ethical errors with devastating effects. The typical professional and policy response to calamities involving human participants in research is to layer on more ethical guidelines or strictures. We used a recent case-the Johns Hopkins University/Kennedy Kreiger Institute Lead Paint Study-to examine lessons learned since the Tuskegee Syphilis Study about the role of institutionalized science ethics in the protection of human participants in research. We address the role of the institutional review board as the focal point for policy attention.

Understanding Bureaucracy in Health Science Ethics: Toward a Better Institutional Review Board

PubMed Central

Bozeman, Barry; Hirsch, Paul

2009-01-01

Research involving human participants continues to grow dramatically, fueled by advances in medical technology, globalization of research, and financial and professional incentives. This creates increasing opportunities for ethical errors with devastating effects. The typical professional and policy response to calamities involving human participants in research is to layer on more ethical guidelines or strictures. We used a recent case—the Johns Hopkins University/Kennedy Kreiger Institute Lead Paint Study—to examine lessons learned since the Tuskegee Syphilis Study about the role of institutionalized science ethics in the protection of human participants in research. We address the role of the institutional review board as the focal point for policy attention. PMID:19608947

Management of chemical dependence in pregnancy.

PubMed

Christensen, Carl

2008-06-01

Although the percentage of pregnant patients who use illicit drugs is relatively low, the effects can be devastating on both mother and fetus-loss of custody, growth restriction, placental abruption, and death. The practicing obstetrician may be unfamiliar with the various presentations of chemical dependency in pregnancy, including intoxication and withdrawal, and difficulty in making the diagnosis. The obstetrician is in the unique situation of being responsible for the safety of both mother and fetus, which may involve engaging the unwilling patient in treatment.

Penile Cancer

PubMed Central

Clark, Peter E.; Spiess, Philippe E.; Agarwal, Neeraj; Biagioli, Matthew C.; Eisenberger, Mario A.; Greenberg, Richard E.; Herr, Harry W.; Inman, Brant A.; Kuban, Deborah A.; Kuzel, Timothy M.; Lele, Subodh M.; Michalski, Jeff; Pagliaro, Lance; Pal, Sumanta K.; Patterson, Anthony; Plimack, Elizabeth R.; Pohar, Kamal S.; Porter, Michael P.; Richie, Jerome P.; Sexton, Wade J.; Shipley, William U.; Small, Eric J.; Trump, Donald L.; Wile, Geoffrey; Wilson, Timothy G.; Dwyer, Mary; Ho, Maria

2014-01-01

Squamous cell carcinoma of the penis represents approximately 0.5% of all cancers among men in the United States and other developed countries. Although rare, it is associated with significant disfigurement, and only half of the patients survive beyond 5 years. Proper evaluation of both the primary lesion and lymph nodes is critical, because nodal involvement is the most important factor of survival. The NCCN Clinical Practice Guidelines in Oncology for Penile Cancer provide recommendations on the diagnosis and management of this devastating disease based on evidence and expert consensus. PMID:23667209

Lawn mower injuries in children: a 30-year experience.

PubMed

Nguyen, Anh; Raymond, Simon; Morgan, Vanessa; Peters, Julian; Macgill, Kirstie; Johnstone, Bruce

2008-09-01

Lawn mowers cause severe injuries that are particularly devastating to children. This study analyses the patterns and trends in lawn mower injuries involving children referred to Victoria's principal children's hospital. A retrospective review of the patient medical records at the Royal Children's Hospital (Melbourne) Victoria, Australia was carried out. The series included all patients admitted for lawn mower injury during the 30-year period spanning 1975-2004. Lawn mower injuries treated at Royal Children's Hospital were severe and included partially amputated limbs. Overall, admissions for lawn mower injury generally decreased over time from n = 26 in the 1975-1979 interval to n = 14 in the 2000-2004 interval. However, the frequency of admission for injuries caused by ride-on mowers contradicted the overall trend and generally increased over time from n = 5 in the 1975-1979 interval to n = 11 in the 2000-2004 interval. This is of particular concern. Ride-on lawn mowers caused significantly more severe injuries requiring longer periods of admission and more operations during admission in comparison to standard mowers. Rural location at the time of injury was a risk factor associated with requiring longer periods of admission and more operations during admission. Children injured while operating mowers were generally older than children injured as bystanders. Lawn mower injuries are a significant cause of morbidity. These injuries are particularly devastating to children. The tragedy is keenly felt in the realization that these devastating injuries to children could all be prevented. Strategic preventative measures should be developed through partnership between the medical profession, the media, industry specialists and the wider community.

Scientific Prediction and Prophetic Patenting in Drug Discovery.

PubMed

Curry, Stephen H; Schneiderman, Anne M

2015-01-01

Pharmaceutical patenting involves writing claims based on both discoveries already made, and on prophesy of future developments in an ongoing project. This is necessitated by the very different timelines involved in the drug discovery and product development process on the one hand, and successful patenting on the other. If patents are sought too early there is a risk that patent examiners will disallow claims because of lack of enablement. If patenting is delayed, claims are at risk of being denied on the basis of existence of prior art, because the body of relevant known science will have developed significantly while the project was being pursued. This review examines the role of prophetic patenting in relation to the essential predictability of many aspects of drug discovery science, promoting the concepts of discipline-related and project-related prediction. This is especially directed towards patenting activities supporting commercialization of academia-based discoveries, where long project timelines occur, and where experience, and resources to pay for patenting, are limited. The need for improved collaborative understanding among project scientists, technology transfer professionals in, for example, universities, patent attorneys, and patent examiners is emphasized.

Fragment-Based Phenotypic Lead Discovery: Cell-Based Assay to Target Leishmaniasis.

PubMed

Ayotte, Yann; Bilodeau, François; Descoteaux, Albert; LaPlante, Steven R

2018-05-02

A rapid and practical approach for the discovery of new chemical matter for targeting pathogens and diseases is described. Fragment-based phenotypic lead discovery (FPLD) combines aspects of traditional fragment-based lead discovery (FBLD), which involves the screening of small-molecule fragment libraries to target specific proteins, with phenotypic lead discovery (PLD), which typically involves the screening of drug-like compounds in cell-based assays. To enable FPLD, a diverse library of fragments was first designed, assembled, and curated. This library of soluble, low-molecular-weight compounds was then pooled to expedite screening. Axenic cultures of Leishmania promastigotes were screened, and single hits were then tested for leishmanicidal activity against intracellular amastigote forms in infected murine bone-marrow-derived macrophages without evidence of toxicity toward mammalian cells. These studies demonstrate that FPLD can be a rapid and effective means to discover hits that can serve as leads for further medicinal chemistry purposes or as tool compounds for identifying known or novel targets. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Potential insight for drug discovery from high fidelity receptor-mediated transduction mechanisms in insects

PubMed Central

Raffa, Robert B.; Raffa, Kenneth F.

2011-01-01

Introduction There is a pervasive and growing concern about the small number of new pharmaceutical agents. There are many proposed explanations for this trend that do not involve the drug-discovery process per se, but the discovery process itself has also come under scrutiny. If the current paradigms are indeed not working, where are novel ideas to come from? Perhaps it is time to look to novel sources. Areas covered The receptor-signaling and 2nd-messenger transduction processes present in insects are quite similar to those in mammals (involving G proteins, ion channels, etc.). However, a review of these systems reveals an unprecedented degree of high potency and receptor selectivity to an extent greater than that modeled in most current drug-discovery approaches. Expert opinion A better understanding of insect receptor pharmacology could stimulate novel theoretical and practical ideas in mammalian pharmacology (drug discovery) and, conversely, the application of pharmacology and medicinal chemistry principles could stimulate novel advances in entomology (safer and more targeted control of pest species). PMID:21984882

A facial reconstruction and identification technique for seriously devastating head wounds.

PubMed

Joukal, Marek; Frišhons, Jan

2015-07-01

Many authors have focused on facial identification techniques, and facial reconstructions for cases when skulls have been found are especially well known. However, a standardized facial identification technique for an unknown body with seriously devastating head injuries has not yet been developed. A reconstruction and identification technique was used in 7 cases of accidents involving trains striking pedestrians. This identification technique is based on the removal of skull bone fragments, subsequent fixation of soft tissue onto a universal commercial polystyrene head model, precise suture of dermatomuscular flaps, and definitive adjustment using cosmetic treatments. After reconstruction, identifying marks such as scars, eyebrows, facial lines, facial hair and partly hairstyle become evident. It is then possible to present a modified picture of the reconstructed face to relatives. After comparing the results with photos of the person before death, this technique has proven to be very useful for identifying unknown bodies when other identification techniques are not available. This technique is useful for its being rather quick and especially for its results. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Neurodegenerative signaling factors and mechanisms in Parkinson's pathology.

PubMed

Goswami, Poonam; Joshi, Neeraj; Singh, Sarika

2017-09-01

Parkinson's disease (PD) is a chronic and progressive degenerative disorder of central nervous system which is mainly characterized by selective loss of dopaminergic neurons in the nigrostrial pathway. Clinical symptoms of this devastating disease comprise motor impairments such as resting tremor, bradykinesia, postural instability and rigidity. Current medications only provide symptomatic relief but fail to halt the dopaminergic neuronal death. While the etiology of dopaminergic neuronal death is not fully understood, combination of various molecular mechanisms seems to play a critical role. Studies from experimental animal models have provided crucial insights into the molecular mechanisms in disease pathogenesis and recognized possible targets for therapeutic interventions. Recent findings implicate the involvement of abnormal protein accumulation and phosphorylation, mitochondrial dysfunction, oxidative damage and deregulated kinase signaling as key molecular mechanisms affecting the normal function as well survival of dopaminergic neurons. Here we discuss the relevant findings on the PD pathology related mechanisms and recognition of the cell survival mechanisms which could be used as targets for neuroprotective strategies in preventing this devastating disorder. Copyright © 2017 Elsevier Ltd. All rights reserved.

The geomorphic impact of catastrophic glacier ice loss in mountain regions

NASA Astrophysics Data System (ADS)

Evans, S. G.

2006-12-01

Perhaps the most dramatic manifestation of global warming is catastrophic glacier ice loss in mountain regions. The geomorphic impact of this process was first outlined by Evans and Clague in 1994 and includes mountain slope instability, glacier avalanching, the formation and failure of moraine dammed lakes, and the formation and failure of ice dammed lakes. The present paper is an update of the 1994 publication and has three components. First, a global review of recent glacier-related geomorphic events is undertaken. Second, an analysis of two cases from the Coast Mountains of British Columbia - the 1975 Devastation Glacier landslide and the 1983 Nostetuko Lake outburst resulting from the failure of a moraine dam illustrates the interaction of glacier ice loss and related geomorphic events. At Devastation Glacier, approximately 13 M m3 of altered Quaternary volcanic rock and glacier ice was lost from the west flank of Pylon Peak in the Mount Meager volcanic complex. The events were initiated by a catastrophic rockslide, involving altered Quaternary pyroclastic rocks, which continued down Devastation Creek valley as a high velocity debris avalanche. The overall length of the slide path was 7 km and the vertical height of the path was 1220 m yielding a fahrboschung of 10°. Other large landslides occurred in Devastation Creek valley in 1931 and 1947. Stability analysis of the initial failure shows that the 1975 rockslide was the result of a complex history of glacial erosion, loading and unloading of the toe of the slide mass caused by the Little Ice Age advance and subsequent retreat of Devastation Glacier. The shearing resistance along the base of the rockslide mass was reduced prior to 1975 by substantial previous slope displacements related to glacial ice loss. Some of this displacement is likely to have occurred as subglacial slope deformation since ice fall and crevasse patterns suggest the presence of slide like shearing displacements below the base of adjacent glacier ice. In the Nostetuko case, the analysis of large-scale digital elevation models indicate that the outburst of 6.5 M m3 of water was initiated by a 1.5 M m3 glacier avalanche from Cumberland Glacier which initiated the breach. 1.6 M m3 of moraine was removed during the sudden breach and injected into the headwaters of the Nostetuko River. Thirdly, an attempt is made to quantify the increase in denudation and related sediment flux in mountain landscapes subject to catastrophic glacier-ice loss.

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.

In the Footsteps of Giants.

ERIC Educational Resources Information Center

McLure, John W.

1996-01-01

Explores three classic turning points in science and presents close-up views of the scientists involved and their discoveries. Discussions include William Herschel and light; Lavoisier, Priestley, Scheele and oxygen; and Faraday and electromagnetism. Presents suggestions for experiments to demonstrate these discoveries. (JRH)

Natural-product-based chromenes as a novel class of potential termiticides.

PubMed

Meepagala, Kumudini M; Osbrink, Weste; Burandt, Charles; Lax, Alan; Duke, Stephen O

2011-11-01

Among the termite infestations in the United States, the Formosan subterranean termite, Coptotermes formosanus Shiraki (Isoptera: Rhinotermitidae), is considered to be the most devastating termite pest. This pest most likely invaded North America as a result of the disembarkation of wooden military cargo at the port of New Orleans that arrived from Asia during and after World War II. It has now spread over other states, including Texas, Florida, South Carolina and California. Devastation caused by C. formosanus in North America has been estimated to cost $ US 1 billion a year. Over the past decades, organochlorines and organophosphates, the two prominent classes of termite control agents, have been banned owing to environmental and human health concerns. At the present time, phenylpyrazoles, pyrethroids, chloronicotinyls and pyrroles are being used as termite control agents. Mammalian toxicity and seeping of these compounds into groundwater are some of the drawbacks associated with these treatments. The instruction for the application of these termiticides indicate ground water advisory. Hence, with the increasing spread of termite infestation there is an increased need to discover effective, environmentally friendly and safe termite control agents with minimal mammalian toxicity. Chromene analogs derived from a natural-product-based chromene amide isolated from Amyris texana were tested in a collaborative discovery program for effective, environmentally friendly termite control agents. Several chromene derivatives were synthesized and characterized as a novel class of potential termiticides, followed by bioassays. These compounds exhibited significantly higher mortalities compared with untreated controls in laboratory bioassays. Chromene derivatives have been shown to be a potential novel class of termiticides against Formosan subterranean termites. Copyright © 2011 Society of Chemical Industry.

43 CFR 4.1132 - Scope of discovery.

Code of Federal Regulations, 2014 CFR

2014-10-01

..., the parties may obtain discovery regarding any matter, not privileged, which is relevant to the subject matter involved in the proceeding, including the existence, description, nature, custody... persons having knowledge of any discoverable matter. (b) It is not ground for objection that information...

43 CFR 4.1132 - Scope of discovery.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., the parties may obtain discovery regarding any matter, not privileged, which is relevant to the subject matter involved in the proceeding, including the existence, description, nature, custody... persons having knowledge of any discoverable matter. (b) It is not ground for objection that information...

43 CFR 4.1132 - Scope of discovery.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., the parties may obtain discovery regarding any matter, not privileged, which is relevant to the subject matter involved in the proceeding, including the existence, description, nature, custody... persons having knowledge of any discoverable matter. (b) It is not ground for objection that information...

43 CFR 4.1132 - Scope of discovery.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., the parties may obtain discovery regarding any matter, not privileged, which is relevant to the subject matter involved in the proceeding, including the existence, description, nature, custody... persons having knowledge of any discoverable matter. (b) It is not ground for objection that information...

Science of the science, drug discovery and artificial neural networks.

PubMed

Patel, Jigneshkumar

2013-03-01

Drug discovery process many times encounters complex problems, which may be difficult to solve by human intelligence. Artificial Neural Networks (ANNs) are one of the Artificial Intelligence (AI) technologies used for solving such complex problems. ANNs are widely used for primary virtual screening of compounds, quantitative structure activity relationship studies, receptor modeling, formulation development, pharmacokinetics and in all other processes involving complex mathematical modeling. Despite having such advanced technologies and enough understanding of biological systems, drug discovery is still a lengthy, expensive, difficult and inefficient process with low rate of new successful therapeutic discovery. In this paper, author has discussed the drug discovery science and ANN from very basic angle, which may be helpful to understand the application of ANN for drug discovery to improve efficiency.

16 CFR 1025.31 - General provisions governing discovery.

Code of Federal Regulations, 2012 CFR

2012-01-01

...: (1) In general. Parties may obtain discovery regarding any matter, not privileged, which is within the Commission's statutory authority and is relevant to the subject matter involved in the proceedings... any discoverable matter. It is not ground for objection that the information sought will be...

16 CFR 1025.31 - General provisions governing discovery.

Code of Federal Regulations, 2011 CFR

2011-01-01

...: (1) In general. Parties may obtain discovery regarding any matter, not privileged, which is within the Commission's statutory authority and is relevant to the subject matter involved in the proceedings... any discoverable matter. It is not ground for objection that the information sought will be...

16 CFR 1025.31 - General provisions governing discovery.

Code of Federal Regulations, 2014 CFR

2014-01-01

...: (1) In general. Parties may obtain discovery regarding any matter, not privileged, which is within the Commission's statutory authority and is relevant to the subject matter involved in the proceedings... any discoverable matter. It is not ground for objection that the information sought will be...

Insights into toxic Prymnesium parvum blooms: the role of sugars and algal viruses.

PubMed

Wagstaff, Ben A; Hems, Edward S; Rejzek, Martin; Pratscher, Jennifer; Brooks, Elliot; Kuhaudomlarp, Sakonwan; O'Neill, Ellis C; Donaldson, Matthew I; Lane, Steven; Currie, John; Hindes, Andrew M; Malin, Gill; Murrell, J Colin; Field, Robert A

2018-04-17

Prymnesium parvum is a toxin-producing microalga that causes harmful algal blooms globally, which often result in large-scale fish kills that have severe ecological and economic implications. Although many toxins have previously been isolated from P. parvum , ambiguity still surrounds the responsible ichthyotoxins in P. parvum blooms and the biotic and abiotic factors that promote bloom toxicity. A major fish kill attributed to P. parvum occurred in Spring 2015 on the Norfolk Broads, a low-lying set of channels and lakes (Broads) found on the East of England. Here, we discuss how water samples taken during this bloom have led to diverse scientific advances ranging from toxin analysis to discovery of a new lytic virus of P. parvum , P. parvum DNA virus (PpDNAV-BW1). Taking recent literature into account, we propose key roles for sialic acids in this type of viral infection. Finally, we discuss recent practical detection and management strategies for controlling these devastating blooms. © 2018 The Author(s).

Age-Related Macular Degeneration: Genetics and Biology Coming Together

PubMed Central

Fritsche, Lars G.; Fariss, Robert N.; Stambolian, Dwight; Abecasis, Gonçalo R.; Curcio, Christine A.

2014-01-01

Genetic and genomic studies have enhanced our understanding of complex neurodegenerative diseases that exert a devastating impact on individuals and society. One such disease, age-related macular degeneration (AMD), is a major cause of progressive and debilitating visual impairment. Since the pioneering discovery in 2005 of complement factor H (CFH) as a major AMD susceptibility gene, extensive investigations have confirmed 19 additional genetic risk loci, and more are anticipated. In addition to common variants identified by now-conventional genome-wide association studies, targeted genomic sequencing and exome-chip analyses are uncovering rare variant alleles of high impact. Here, we provide a critical review of the ongoing genetic studies and of common and rare risk variants at a total of 20 susceptibility loci, which together explain 40–60% of the disease heritability but provide limited power for diagnostic testing of disease risk. Identification of these susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment. PMID:24773320

Ebola and Marburg haemorrhagic fever viruses: major scientific advances, but a relatively minor public health threat for Africa.

PubMed

Leroy, E M; Gonzalez, J-P; Baize, S

2011-07-01

Ebola and Marburg viruses are the only members of the Filoviridae family (order Mononegavirales), a group of viruses characterized by a linear, non-segmented, single-strand negative RNA genome. They are among the most virulent pathogens for humans and great apes, causing acute haemorrhagic fever and death within a matter of days. Since their discovery 50 years ago, filoviruses have caused only a few outbreaks, with 2317 clinical cases and 1671 confirmed deaths, which is negligible compared with the devastation caused by malnutrition and other infectious diseases prevalent in Africa (malaria, cholera, AIDS, dengue, tuberculosis …). Yet considerable human and financial resourses have been devoted to research on these viruses during the past two decades, partly because of their potential use as bioweapons. As a result, our understanding of the ecology, host interactions, and control of these viruses has improved considerably. © 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.

Severe Cutaneous Adverse Reactions: The Pharmacogenomics from Research to Clinical Implementation

PubMed Central

Su, Shih-Chi; Hung, Shuen-Iu; Fan, Wen-Lang; Dao, Ro-Lan; Chung, Wen-Hung

2016-01-01

Severe cutaneous adverse reactions (SCARs), previously thought to be idiosyncratic or unpredictable, are a deadly form of adverse drug reactions with skin manifestations. Current pharmacogenomic studies of SCARs have made important strides, as the prevention of SCARs, to some extent, appears attainable with the identification of genetic variants for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). Despite the improvement of incidence, a treatment guideline for this devastating condition is still unavailable, highlighting the inadequacy of contemporary accepted therapeutic interventions. As such, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we discuss recent cutting-edge findings concerning the discovery of biomarkers for SCARs and their clinical utilities in the better prediction and early diagnosis of this disease. The knowledge compiled herein provides clues for future investigations on deciphering additional genetic markers for SCARs and the design of clinical trials for the prospective identification of subjects at genetic risk for this condition, ultimately personalizing the medicine. PMID:27854302

Quinoline hybrids and their antiplasmodial and antimalarial activities.

PubMed

Hu, Yuan-Qiang; Gao, Chuan; Zhang, Shu; Xu, Lei; Xu, Zhi; Feng, Lian-Shun; Wu, Xiang; Zhao, Feng

2017-10-20

Malaria, in particular infection with P. falciparum (the most lethal of the human malaria parasite species, responsible for nearly one million deaths every year), is one of the most devastating and common infectious disease throughout the world. Beginning with quinine, quinoline containing compounds have long been used in clinical treatment of malaria and remained the mainstays of chemotherapy against malaria. The emergence of P. falciparum strains resistant to almost all antimalarials prompted medicinal chemists and biologists to study their effective replacement with an alternative mechanism of action and new molecules. Combination with variety of quinolines and other active moieties may increase the antiplasmodial and antimalarial activities and reduce the side effects. Thus, hybridization is a very attractive strategy to develop novel antimalarials. This review aims to summarize the recent advances towards the discovery of antiplasmodial and antimalarial hybrids including quinoline skeleton to provide an insight for rational designs of more active and less toxic quinoline hybrids antimalarials. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

LGR5 and Nanog identify stem cell signature of pancreas beta cells which initiate pancreatic cancer.

PubMed

Amsterdam, Abraham; Raanan, Calanit; Schreiber, Letizia; Polin, Nava; Givol, David

2013-04-05

Pancreas cancer, is the fourth leading cause of cancer death but its cell of origin is controversial. We compared the localization of stem cells in normal and cancerous pancreas using antibodies to the stem cell markers Nanog and LGR5. Here we show, for the first time, that LGR5 is expressed in normal pancreas, exclusively in the islets of Langerhans and it is co-localized, surprisingly, with Nanog and insulin in clusters of beta cells. In cancerous pancreas Nanog and LGR5 are expressed in the remaining islets and in all ductal cancer cells. We observed insulin staining among the ductal cancer cells, but not in metastases. This indicates that the islet's beta cells, expressing LGR5 and Nanog markers are the initiating cells of pancreas cancer, which migrated from the islets to form the ductal cancerous tissue, probably after mutation and de-differentiation. This discovery may facilitate treatment of this devastating cancer. Copyright © 2013 Elsevier Inc. All rights reserved.

Basic science of anterior cruciate ligament injury and repair

PubMed Central

Kiapour, A. M.; Murray, M. M.

2014-01-01

Injury to the anterior cruciate ligament (ACL) is one of the most devastating and frequent injuries of the knee. Surgical reconstruction is the current standard of care for treatment of ACL injuries in active patients. The widespread adoption of ACL reconstruction over primary repair was based on early perception of the limited healing capacity of the ACL. Although the majority of ACL reconstruction surgeries successfully restore gross joint stability, post-traumatic osteoarthritis is commonplace following these injuries, even with ACL reconstruction. The development of new techniques to limit the long-term clinical sequelae associated with ACL reconstruction has been the main focus of research over the past decades. The improved knowledge of healing, along with recent advances in tissue engineering and regenerative medicine, has resulted in the discovery of novel biologically augmented ACL-repair techniques that have satisfactory outcomes in preclinical studies. This instructional review provides a summary of the latest advances made in ACL repair. Cite this article: Bone Joint Res 2014;3:20–31. PMID:24497504

N-myristoyltransferase inhibitors as new leads to treat sleeping sickness

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

Frearson, Julie A.; Brand, Stephen; McElroy, Stuart P.

2010-11-05

African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for {approx}30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target - T. brucei N-myristoyltransferase - leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis inmore » mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis.« less

Discovery of Bioactive Compounds by the UIC-ICBG Drug Discovery Program in the 18 Years Since 1998.

PubMed

Zhang, Hong-Jie; Li, Wan-Fei; Fong, Harry H S; Soejarto, Djaja Doel

2016-10-31

The International Cooperative Biodiversity Groups (ICBG) Program based at the University of Illinois at Chicago (UIC) is a program aimed to address the interdependent issues of inventory and conservation of biodiversity, drug discovery and sustained economic growth in both developing and developed countries. It is an interdisciplinary program involving the extensive synergies and collaborative efforts of botanists, chemists and biologists in the countries of Vietnam, Laos and the USA. The UIC-ICBG drug discovery efforts over the past 18 years have resulted in the collection of a cumulative total of more than 5500 plant samples (representing more than 2000 species), that were evaluated for their potential biological effects against cancer, HIV, bird flu, tuberculosis and malaria. The bioassay-guided fractionation and separation of the bioactive plant leads resulted in the isolation of approximately 300 compounds of varying degrees of structural complexity and/or biological activity. The present paper summarizes the significant drug discovery achievements made by the UIC-ICBG team of multidisciplinary collaborators in the project over the period of 1998-2012 and the projects carried on in the subsequent years by involving the researchers in Hong Kong.

Interoperability and information discovery

USGS Publications Warehouse

Christian, E.

2001-01-01

In the context of information systems, there is interoperability when the distinctions between separate information systems are not a barrier to accomplishing a task that spans those systems. Interoperability so defined implies that there are commonalities among the systems involved and that one can exploit such commonalities to achieve interoperability. The challenge of a particular interoperability task is to identify relevant commonalities among the systems involved and to devise mechanisms that exploit those commonalities. The present paper focuses on the particular interoperability task of information discovery. The Global Information Locator Service (GILS) is described as a policy, standards, and technology framework for addressing interoperable information discovery on a global and long-term basis. While there are many mechanisms for people to discover and use all manner of data and information resources, GILS initiatives exploit certain key commonalities that seem to be sufficient to realize useful information discovery interoperability at a global, long-term scale. This paper describes ten of the specific commonalities that are key to GILS initiatives. It presents some of the practical implications for organizations in various roles: content provider, system engineer, intermediary, and searcher. The paper also provides examples of interoperable information discovery as deployed using GILS in four types of information communities: bibliographic, geographic, environmental, and government.

The Greatest Mathematical Discovery?

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

Bailey, David H.; Borwein, Jonathan M.

2010-05-12

What mathematical discovery more than 1500 years ago: (1) Is one of the greatest, if not the greatest, single discovery in the field of mathematics? (2) Involved three subtle ideas that eluded the greatest minds of antiquity, even geniuses such as Archimedes? (3) Was fiercely resisted in Europe for hundreds of years after its discovery? (4) Even today, in historical treatments of mathematics, is often dismissed with scant mention, or else is ascribed to the wrong source? Answer: Our modern system of positional decimal notation with zero, together with the basic arithmetic computational schemes, which were discovered in India aboutmore » 500 CE.« less

Genetic approaches to interfere with malaria transmission by vector mosquitoes

PubMed Central

Wang, Sibao; Jacobs-Lorena, Marcelo

2013-01-01

Malaria remains one of the world’s most devastating diseases, causing over one million deaths every year. The most vulnerable stages of Plasmodium development in the vector mosquito occur in the midgut lumen, making the midgut a prime target for intervention. Mosquito transgenesis and paratransgenesis are two novel strategies that aim at rendering the vector incapable of sustaining Plasmodium development. Mosquito transgenesis involves direct genetic engineering of the mosquito itself for delivery of anti-Plasmodium effector molecules. Conversely, paratransgenesis involves the genetic modification of mosquito symbionts for expression of anti-pathogen effector molecules. Here we consider both genetic manipulation strategies for rendering mosquitoes refractory to Plasmodium infection, and discuss challenges for the translation of laboratory findings to field applications. PMID:23395485

Discovery and Nurturance of Giftedness in the Culturally Different.

ERIC Educational Resources Information Center

Torrance, E. Paul

Discussed in the monograph are methods for identifying and developing programs for culturally different gifted students. In an overview section, the important issues and trends associated with the discovery and nurturance of giftedness among the culturally different are considered; and screening methods which involve modified traditional…

29 CFR 18.14 - Scope of discovery.

Code of Federal Regulations, 2014 CFR

2014-07-01

... administrative law judge in accordance with these rules, the parties may obtain discovery regarding any matter, not privileged, which is relevant to the subject matter involved in the proceeding, including the... things and the identity and location of persons having knowledge of any discoverable matter. (b) It is...

49 CFR 386.38 - Scope of discovery.

Code of Federal Regulations, 2011 CFR

2011-10-01

... accordance with these rules, the parties may obtain discovery regarding any matter, not privileged, which is relevant to the subject matter involved in the proceeding, including the existence, description, nature... location of persons having knowledge of any discoverable matter. (b) It is not ground for objection that...

49 CFR 386.38 - Scope of discovery.

Code of Federal Regulations, 2012 CFR

2012-10-01

... accordance with these rules, the parties may obtain discovery regarding any matter, not privileged, which is relevant to the subject matter involved in the proceeding, including the existence, description, nature... location of persons having knowledge of any discoverable matter. (b) It is not ground for objection that...

29 CFR 18.14 - Scope of discovery.

Code of Federal Regulations, 2012 CFR

2012-07-01

... administrative law judge in accordance with these rules, the parties may obtain discovery regarding any matter, not privileged, which is relevant to the subject matter involved in the proceeding, including the... things and the identity and location of persons having knowledge of any discoverable matter. (b) It is...

16 CFR § 1025.31 - General provisions governing discovery.

Code of Federal Regulations, 2013 CFR

2013-01-01

...: (1) In general. Parties may obtain discovery regarding any matter, not privileged, which is within the Commission's statutory authority and is relevant to the subject matter involved in the proceedings... any discoverable matter. It is not ground for objection that the information sought will be...

49 CFR 386.38 - Scope of discovery.

Code of Federal Regulations, 2013 CFR

2013-10-01

... accordance with these rules, the parties may obtain discovery regarding any matter, not privileged, which is relevant to the subject matter involved in the proceeding, including the existence, description, nature... location of persons having knowledge of any discoverable matter. (b) It is not ground for objection that...

29 CFR 18.14 - Scope of discovery.

Code of Federal Regulations, 2011 CFR

2011-07-01

... administrative law judge in accordance with these rules, the parties may obtain discovery regarding any matter, not privileged, which is relevant to the subject matter involved in the proceeding, including the... things and the identity and location of persons having knowledge of any discoverable matter. (b) It is...

29 CFR 18.14 - Scope of discovery.

Code of Federal Regulations, 2013 CFR

2013-07-01

... administrative law judge in accordance with these rules, the parties may obtain discovery regarding any matter, not privileged, which is relevant to the subject matter involved in the proceeding, including the... things and the identity and location of persons having knowledge of any discoverable matter. (b) It is...

49 CFR 386.38 - Scope of discovery.

Code of Federal Regulations, 2014 CFR

2014-10-01

... accordance with these rules, the parties may obtain discovery regarding any matter, not privileged, which is relevant to the subject matter involved in the proceeding, including the existence, description, nature... location of persons having knowledge of any discoverable matter. (b) It is not ground for objection that...

Impacts of flood on health: epidemiologic evidence from Hanoi, Vietnam

PubMed Central

Bich, Tran Huu; Quang, La Ngoc; Thanh Ha, Le Thi; Duc Hanh, Tran Thi; Guha-Sapir, Debarati

2011-01-01

Background Vietnam is one of the most disaster-prone countries in the world. The country suffers from many kinds of natural disasters, of which the most common and serious one is flooding. Long and heavy rainfall during the last days of October and the first week of November 2008 resulted in a devastating flood unseen for over three decades in the capital city of Hanoi. It caused a substantial health impact on residents in and around the city and compromised the capacity of local health services. Objective The aim of this study is to ascertain the vulnerability and health impacts of the devastating flood in Hanoi by identifying the differences in mortality, injuries, and morbidity patterns (dengue, pink eye, dermatitis, psychological problems, and hypertension) between flood affected and non-affected households. Design A cross-sectional study was carried out involving 871 households in four selected communes (two heavily flood affected and two comparatively less affected) from two severely flooded districts of Hanoi. Participants were interviewed and information collected on the social, economic, and health impacts of the devastation within 1 month after the flood. Results The self-reported number of deaths and injuries reported in this study within 1 month after the heavy rainfall were a bit higher in severely affected communes as compared to that of the less affected communes of our study. The findings showed higher incidences of dengue fever, pink eye, dermatitis, and psychological problems in communes severely affected by flood as compared to that of the controlled communes. Conclusions For people in flood prone areas (at risk for flooding), flood prevention and mitigation strategies need to be seriously thought through and acted upon, as these people are exposed to greater health problems such as psychological issues and communicable diseases such as pink eye or dermatitis. PMID:21866222

Impacts of flood on health: epidemiologic evidence from Hanoi, Vietnam.

PubMed

Bich, Tran Huu; Quang, La Ngoc; Ha, Le Thi Thanh; Hanh, Tran Thi Duc; Guha-Sapir, Debarati

2011-01-01

Vietnam is one of the most disaster-prone countries in the world. The country suffers from many kinds of natural disasters, of which the most common and serious one is flooding. Long and heavy rainfall during the last days of October and the first week of November 2008 resulted in a devastating flood unseen for over three decades in the capital city of Hanoi. It caused a substantial health impact on residents in and around the city and compromised the capacity of local health services. The aim of this study is to ascertain the vulnerability and health impacts of the devastating flood in Hanoi by identifying the differences in mortality, injuries, and morbidity patterns (dengue, pink eye, dermatitis, psychological problems, and hypertension) between flood affected and non-affected households. A cross-sectional study was carried out involving 871 households in four selected communes (two heavily flood affected and two comparatively less affected) from two severely flooded districts of Hanoi. Participants were interviewed and information collected on the social, economic, and health impacts of the devastation within 1 month after the flood. The self-reported number of deaths and injuries reported in this study within 1 month after the heavy rainfall were a bit higher in severely affected communes as compared to that of the less affected communes of our study. The findings showed higher incidences of dengue fever, pink eye, dermatitis, and psychological problems in communes severely affected by flood as compared to that of the controlled communes. For people in flood prone areas (at risk for flooding), flood prevention and mitigation strategies need to be seriously thought through and acted upon, as these people are exposed to greater health problems such as psychological issues and communicable diseases such as pink eye or dermatitis.

Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis.

PubMed

Mole, Damian J; Webster, Scott P; Uings, Iain; Zheng, Xiaozhong; Binnie, Margaret; Wilson, Kris; Hutchinson, Jonathan P; Mirguet, Olivier; Walker, Ann; Beaufils, Benjamin; Ancellin, Nicolas; Trottet, Lionel; Bénéton, Véronique; Mowat, Christopher G; Wilkinson, Martin; Rowland, Paul; Haslam, Carl; McBride, Andrew; Homer, Natalie Z M; Baily, James E; Sharp, Matthew G F; Garden, O James; Hughes, Jeremy; Howie, Sarah E M; Holmes, Duncan S; Liddle, John; Iredale, John P

2016-02-01

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.

Osteoporosis treatment: recent developments and ongoing challenges

PubMed Central

Khosla, Sundeep; Hofbauer, Lorenz C

2018-01-01

Osteoporosis is an enormous and growing public health problem. Once considered an inevitable consequence of ageing, it is now eminently preventable and treatable. Ironically, despite tremendous therapeutic advances, there is an increasing treatment gap for patients at high fracture risk. In this Series paper, we trace the evolution of drug therapy for osteoporosis, which began in the 1940s with the demonstration by Fuller Albright that treatment with oestrogen could reverse the negative calcium balance that developed in women after menopause or oophorectomy. We note a watershed in osteoporosis drug discovery around the year 2000, when the approach to developing novel therapeutics shifted from one driven by discoveries in animal studies and clinical observations (eg, oestrogen, calcitonin, and teriparatide) or opportunistic repurposing of existing compounds (eg, bisphosphonates) to one driven by advances in fundamental bone biology (eg, denosumab) coupled with clues from patients with rare bone diseases (eg, romosozumab, odanacatib). Despite these remarkable advances, concerns about rare side-effects of anti-resorptive drugs, particularly bisphosphonates, and the absence of clear evidence in support of their long-term efficacy is leading many patients who could benefit from drug therapy to not take these drugs. As such, there remains an important clinical need to develop ways to enhance patient acceptance and compliance with these effective drugs, and to continue to develop new drugs that do not cause these side-effects and have prolonged anabolic effects on bone. Such changes could lead to a true reversal of this potentially devastating disease of ageing. PMID:28689769

Presidential address: distinction or extinction.

PubMed

Pressman, Barry D

2008-10-01

Despite its continuing scientific successes in imaging, radiology as a specialty is faced with a very difficult and competitive environment. Nonradiologists are more and more interested in vertically integrating imaging into their practices, while teleradiology and picture archiving and communication systems are resulting in the greater isolation of radiologists. Commoditization is a realistic and devastating threat to the survival and professionalism of the specialty. To remain viable as a specialty, radiologists must elevate their practice by subspecializing, becoming more involved with clinical care, and actively interacting with patients and referring clinicians. Distinction will prevent extinction.

Ocular alkali burn associated with automobile air-bag activation.

PubMed Central

White, J E; McClafferty, K; Orton, R B; Tokarewicz, A C; Nowak, E S

1995-01-01

Alkali burns of the eye can result in permanent visual impairment and are therefore potentially devastating. Immedicate diagnosis and treatment are essential to a good prognosis. The authors report the case of a 52-year-old woman who suffered alkali keratitis as the result of the activation of an automobile air bag. This type of injury will be seen more frequently as more cars are equipped with air bags and should be suspected in drivers and passengers involved in accidents in which air bags have been activated. PMID:7553495

Functional Magnetic Resonance Imaging (MRI) and MRI Tractography in Progressive Supranuclear Palsy-Like Syndrome

PubMed Central

Vaphiades, Michael S.; Visscher, Kristina; Rucker, Janet C.; Vattoth, Surjith; Roberson, Glenn H.

2015-01-01

ABSTRACT An 18-year-old woman underwent an uneventful ascending aortic aneurysm repair then developed progressive supranuclear palsy-like syndrome. Extensive neuroimaging including contrasted fat-suppressed cranial and orbital magnetic resonance imaging (MRI), MRI tractography, and functional MRI (fMRI) revealed no clear radiographic involvement except for a single tiny hypoechoic midbrain dot on the T2*-weighted gradient-echo imaging, which is not considered sufficient to account for the patient’s deficits. This case attests to the occult nature of this rare and devastating syndrome. PMID:27928334

In re K.I.

PubMed

1999-07-29

The District of Columbia Court of Appeals upheld a lower court decision that had issued a do-not-resuscitate order over the objection of an infant's biological mother. The Court of Appeals agreed that the trial court had jurisdiction to enter a DNR order for an adjudicated neglected child. The infant was "neurologically devastated," although able to feel pain. While a parent has a fundamental liberty interest in her child, this interest is outweighed by the "best interests of the child." The Court held the substituted judgment standard to be inapplicable to cases involving infants.

Host Factors in Ebola Infection.

PubMed

Rasmussen, Angela L

2016-08-31

Ebola virus (EBOV) emerged in West Africa in 2014 to devastating effect, and demonstrated that infection can cause a broad range of severe disease manifestations. As the virus itself was genetically similar to other Zaire ebolaviruses, the spectrum of pathology likely resulted from variable responses to infection in a large and genetically diverse population. This review comprehensively summarizes current knowledge of the host response to EBOV infection, including pathways hijacked by the virus to facilitate replication, host processes that contribute directly to pathogenesis, and host-pathogen interactions involved in subverting or antagonizing host antiviral immunity.

Hazard Potential of Volcanic Flank Collapses Raised by New Megatsunami Evidence

NASA Astrophysics Data System (ADS)

Ramalho, R. S.; Winckler, G.; Madeira, J.; Helffrich, G. R.; Hipólito, A.; Quartau, R.; Adena, K.; Schaefer, J. M.

2015-12-01

Large-scale gravitational flank collapses of steep volcanic islands are hypothetically capable of triggering megatsunamis with highly catastrophic effects. Yet evidence for the existence and impact of collapsed-triggered megatsunamis and their run-up heights remains scarce and/or is highly contentious. Therefore a considerable debate still exists over the potential magnitude of collapse-triggered tsunamis and their inherent hazard. In particular, doubts still remain whether or not large-scale flank failures typically generate enough volume flux to result in megatsunamis, or alternatively operate by slow-moving or multiple smaller episodic failures with much lower tsunamigenic potential. Here we show that one of the tallest and most active oceanic volcanoes on Earth - Fogo, in the Cape Verde Islands - collapsed catastrophically and triggered a megatsunami with devastating near-field effects ~73,000 years ago. Our deductions are based on the recent discovery and cosmogenic 3He dating of tsunamigenic deposits - comprising fields of stranded megaclasts, chaotic conglomerates, and sand sheets - found on the adjacent Santiago Island, which attest to the impact of this megatsunami and document wave run-up heights exceeding 270 m. The evidence reported here implies that Fogo's flank failure involved at least one sudden and voluminous event that resulted in a megatsunami, in contrast to what has been suggested before. Our work thus provides another line of evidence that large-scale flank failures at steep volcanic islands may indeed happen catastrophically and are capable of triggering tsunamis of enormous height and energy. This new line of evidence therefore reinforces the hazard potential of volcanic island collapses and stands as a warning that such hazard should not be underestimated, particularly in areas where volcanic island edifices are close to other islands or to highly populated continental margins.

An in vitro study of the antifungal activity of Trichoderma virens 7b and a profile of its non-polar antifungal components released against Ganoderma boninense.

PubMed

Angel, Lee Pei Lee; Yusof, Mohd Termizi; Ismail, Intan Safinar; Ping, Bonnie Tay Yen; Mohamed Azni, Intan Nur Ainni; Kamarudin, Norman Hj; Sundram, Shamala

2016-11-01

Ganoderma boninense is the causal agent of a devastating disease affecting oil palm in Southeast Asian countries. Basal stem rot (BSR) disease slowly rots the base of palms, which radically reduces productive lifespan of this lucrative crop. Previous reports have indicated the successful use of Trichoderma as biological control agent (BCA) against G. boninense and isolate T. virens 7b was selected based on its initial screening. This study attempts to decipher the mechanisms responsible for the inhibition of G. boninense by identifying and characterizing the chemical compounds as well as the physical mechanisms by T. virens 7b. Hexane extract of the isolate gave 62.60% ± 6.41 inhibition against G. boninense and observation under scanning electron microscope (SEM) detected severe mycelial deformation of the pathogen at the region of inhibition. Similar mycelia deformation of G. boninense was observed with a fungicide treatment, Benlate ® indicating comparable fungicidal effect by T. virens 7b. Fraction 4 and 5 of hexane active fractions through preparative thin layer chromatography (P-TLC) was identified giving the best inhibition of the pathogen. These fractions comprised of ketones, alcohols, aldehydes, lactones, sesquiterpenes, monoterpenes, sulphides, and free fatty acids profiled through gas chromatography mass spectrometry detector (GC/MSD). A novel antifungal compound discovery of phenylethyl alcohol (PEA) by T. virens 7b is reported through this study. T. virens 7b also proved to be an active siderophore producer through chrome azurol S (CAS) agar assay. The study demonstrated the possible mechanisms involved and responsible in the successful inhibition of G. boninense.

46 CFR 502.75 - Proceedings involving assessment agreements.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Shipping Act of 1984 (46 U.S.C. 40301(e), 40305), the Notice of Filing of Complaint and Assignment will... who desires to utilize the prehearing discovery procedures provided by subpart L of this part shall... to intervene. Discovery matters accompanying complaints shall be filed with the Secretary of the...

A Safer, Discovery-Based Nucleophilic Substitution Experiment

ERIC Educational Resources Information Center

Horowitz, Gail

2009-01-01

A discovery-based nucleophilic substitution experiment is described in which students compare the reactivity of chloride and iodide ions in an S[subscript N]2 reaction. This experiment improves upon the well-known "Competing Nucleophiles" experiment in that it does not involve the generation of hydrogen halide gas. The experiment also introduces…

Staff Workshop: Exploring Science with Young Children

ERIC Educational Resources Information Center

Seefeldt, Carol; Rillero, Peter

2005-01-01

This article begins with a section entitled, "Involving Parents in Science Discovery" written by Carol Seefeldt. This section discusses staff workshop for exploring discovery science. Here, the author provides the staff workshop instructions. This is followed by a section entitled, "Exploring Science with Young Children" written by Peter Rillero.…

Confronting Science: The Dilemma of Genetic Testing.

ERIC Educational Resources Information Center

Zallen, Doris T.

1997-01-01

Considers the opportunities and ethical issues involved in genetic testing. Reviews the history of genetics from the first discoveries of Gregor Mendel, through the spurious pseudo-science of eugenics, and up to the discovery of DNA by James Watson and Francis Crick. Explains how genetic tests are done. (MJP)

A role for ion channels in perivascular glioma invasion

PubMed Central

Thompson, Emily G.

2017-01-01

Malignant gliomas are devastating tumors, frequently killing those diagnosed in little over a year. The profuse infiltration of glioma cells into healthy tissue surrounding the main tumor mass is one of the major obstacles limiting the improvement of patient survival. Migration along the abluminal side of blood vessels is one of the salient features of glioma cell invasion. Invading glioma cells are attracted to the vascular network, in part by the neuro-peptide bradykinin, where glioma cells actively modify the gliovascular interface and undergo volumetric alterations to navigate the confined space. Critical to these volume modifications is a proposed hydrodynamic model that involves the flux of ions in and out of the cell, followed by osmotically obligated water. Ion and water channels expressed by the glioma cell are essential in this model of invasion and make opportune therapeutic targets. Lastly, there is growing evidence that vascular-associated glioma cells are able to control the vascular tone, presumably to free up space for invasion and growth. The unique mechanisms that enable perivascular glioma invasion may offer critical targets for therapeutic intervention in this devastating disease. Indeed, a chloride channel-blocking peptide has already been successfully tested in human clinical trials. PMID:27424110

Connecting the virtual world of computers to the real world of medicinal chemistry.

PubMed

Glen, Robert C

2011-03-01

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

The discovery of the structure of DNA

NASA Astrophysics Data System (ADS)

Squires, G. L.

2003-04-01

On 25 April 1953, Nature published a letter by Francis Crick and James Watson, at the Cavendish Laboratory, Cambridge, proposing a structure for DNA. This letter marked the beginning of a revolution in biology. Besides Crick and Watson, two other scientists, Rosalind Franklin and Maurice Wilkins, played key roles in the discovery. After sketching the early careers of the four scientists, the present article gives an account of the physics and chemistry involved in the discovery, and the events leading up to it.

The Discovery of the Higgs Boson: America's Role

ScienceCinema

None

2018-05-30

The discovery of the Higgs boson was an international endeavor, involving thousands of physicists from across the world. While the accelerator at which the experimental work was done is located on Europe, the US supplied more physicists than any other single country. America had a very large role in the discovery of the Higgs particle and continues to have a leading role in the ongoing studies of the boson's properties. This video describes some of the contributions of U.S. universities and laboratories.

Human prion diseases: surgical lessons learned from iatrogenic prion transmission.

PubMed

Bonda, David J; Manjila, Sunil; Mehndiratta, Prachi; Khan, Fahd; Miller, Benjamin R; Onwuzulike, Kaine; Puoti, Gianfranco; Cohen, Mark L; Schonberger, Lawrence B; Cali, Ignazio

2016-07-01

The human prion diseases, or transmissible spongiform encephalopathies, have captivated our imaginations since their discovery in the Fore linguistic group in Papua New Guinea in the 1950s. The mysterious and poorly understood "infectious protein" has become somewhat of a household name in many regions across the globe. From bovine spongiform encephalopathy (BSE), commonly identified as mad cow disease, to endocannibalism, media outlets have capitalized on these devastatingly fatal neurological conditions. Interestingly, since their discovery, there have been more than 492 incidents of iatrogenic transmission of prion diseases, largely resulting from prion-contaminated growth hormone and dura mater grafts. Although fewer than 9 cases of probable iatrogenic neurosurgical cases of Creutzfeldt-Jakob disease (CJD) have been reported worldwide, the likelihood of some missed cases and the potential for prion transmission by neurosurgery create considerable concern. Laboratory studies indicate that standard decontamination and sterilization procedures may be insufficient to completely remove infectivity from prion-contaminated instruments. In this unfortunate event, the instruments may transmit the prion disease to others. Much caution therefore should be taken in the absence of strong evidence against the presence of a prion disease in a neurosurgical patient. While the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have devised risk assessment and decontamination protocols for the prevention of iatrogenic transmission of the prion diseases, incidents of possible exposure to prions have unfortunately occurred in the United States. In this article, the authors outline the historical discoveries that led from kuru to the identification and isolation of the pathological prion proteins in addition to providing a brief description of human prion diseases and iatrogenic forms of CJD, a brief history of prion disease nosocomial transmission, and a summary of the CDC and WHO guidelines for prevention of prion disease transmission and decontamination of prion-contaminated neurosurgical instruments.

High-density genetic map using whole-genome resequencing for fine mapping and candidate gene discovery for disease resistance in peanut.

PubMed

Agarwal, Gaurav; Clevenger, Josh; Pandey, Manish K; Wang, Hui; Shasidhar, Yaduru; Chu, Ye; Fountain, Jake C; Choudhary, Divya; Culbreath, Albert K; Liu, Xin; Huang, Guodong; Wang, Xingjun; Deshmukh, Rupesh; Holbrook, C Corley; Bertioli, David J; Ozias-Akins, Peggy; Jackson, Scott A; Varshney, Rajeev K; Guo, Baozhu

2018-04-10

Whole-genome resequencing (WGRS) of mapping populations has facilitated development of high-density genetic maps essential for fine mapping and candidate gene discovery for traits of interest in crop species. Leaf spots, including early leaf spot (ELS) and late leaf spot (LLS), and Tomato spotted wilt virus (TSWV) are devastating diseases in peanut causing significant yield loss. We generated WGRS data on a recombinant inbred line population, developed a SNP-based high-density genetic map, and conducted fine mapping, candidate gene discovery and marker validation for ELS, LLS and TSWV. The first sequence-based high-density map was constructed with 8869 SNPs assigned to 20 linkage groups, representing 20 chromosomes, for the 'T' population (Tifrunner × GT-C20) with a map length of 3120 cM and an average distance of 1.45 cM. The quantitative trait locus (QTL) analysis using high-density genetic map and multiple season phenotyping data identified 35 main-effect QTLs with phenotypic variation explained (PVE) from 6.32% to 47.63%. Among major-effect QTLs mapped, there were two QTLs for ELS on B05 with 47.42% PVE and B03 with 47.38% PVE, two QTLs for LLS on A05 with 47.63% and B03 with 34.03% PVE and one QTL for TSWV on B09 with 40.71% PVE. The epistasis and environment interaction analyses identified significant environmental effects on these traits. The identified QTL regions had disease resistance genes including R-genes and transcription factors. KASP markers were developed for major QTLs and validated in the population and are ready for further deployment in genomics-assisted breeding in peanut. © 2018 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

Human prion diseases: surgical lessons learned from iatrogenic prion transmission

PubMed Central

Bonda, David J.; Manjila, Sunil; Mehndiratta, Prachi; Khan, Fahd; Miller, Benjamin R.; Onwuzulike, Kaine; Puoti, Gianfranco; Cohen, Mark L.; Schonberger, Lawrence B.; Cali, Ignazio

2016-01-01

The human prion diseases, or transmissible spongiform encephalopathies, have captivated our imaginations since their discovery in the Fore linguistic group in Papua New Guinea in the 1950s. The mysterious and poorly understood “infectious protein” has become somewhat of a household name in many regions across the globe. From bovine spongiform encephalopathy (BSE), commonly identified as mad cow disease, to endocannibalism, media outlets have capitalized on these devastatingly fatal neurological conditions. Interestingly, since their discovery, there have been more than 492 incidents of iatrogenic transmission of prion diseases, largely resulting from prion-contaminated growth hormone and dura mater grafts. Although fewer than 9 cases of probable iatrogenic neurosurgical cases of Creutzfeldt-Jakob disease (CJD) have been reported worldwide, the likelihood of some missed cases and the potential for prion transmission by neurosurgery create considerable concern. Laboratory studies indicate that standard decontamination and sterilization procedures may be insufficient to completely remove infectivity from prion-contaminated instruments. In this unfortunate event, the instruments may transmit the prion disease to others. Much caution therefore should be taken in the absence of strong evidence against the presence of a prion disease in a neurosurgical patient. While the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have devised risk assessment and decontamination protocols for the prevention of iatrogenic transmission of the prion diseases, incidents of possible exposure to prions have unfortunately occurred in the United States. In this article, the authors outline the historical discoveries that led from kuru to the identification and isolation of the pathological prion proteins in addition to providing a brief description of human prion diseases and iatrogenic forms of CJD, a brief history of prion disease nosocomial transmission, and a summary of the CDC and WHO guidelines for prevention of prion disease transmission and decontamination of prion-contaminated neurosurgical instruments. PMID:27364252

Get Involved in Planetary Discoveries through New Worlds, New Discoveries

NASA Astrophysics Data System (ADS)

Shupla, Christine; Shipp, S. S.; Halligan, E.; Dalton, H.; Boonstra, D.; Buxner, S.; SMD Planetary Forum, NASA

2013-01-01

"New Worlds, New Discoveries" is a synthesis of NASA’s 50-year exploration history which provides an integrated picture of our new understanding of our solar system. As NASA spacecraft head to and arrive at key locations in our solar system, "New Worlds, New Discoveries" provides an integrated picture of our new understanding of the solar system to educators and the general public! The site combines the amazing discoveries of past NASA planetary missions with the most recent findings of ongoing missions, and connects them to the related planetary science topics. "New Worlds, New Discoveries," which includes the "Year of the Solar System" and the ongoing celebration of the "50 Years of Exploration," includes 20 topics that share thematic solar system educational resources and activities, tied to the national science standards. This online site and ongoing event offers numerous opportunities for the science community - including researchers and education and public outreach professionals - to raise awareness, build excitement, and make connections with educators, students, and the public about planetary science. Visitors to the site will find valuable hands-on science activities, resources and educational materials, as well as the latest news, to engage audiences in planetary science topics and their related mission discoveries. The topics are tied to the big questions of planetary science: how did the Sun’s family of planets and bodies originate and how have they evolved? How did life begin and evolve on Earth, and has it evolved elsewhere in our solar system? Scientists and educators are encouraged to get involved either directly or by sharing "New Worlds, New Discoveries" and its resources with educators, by conducting presentations and events, sharing their resources and events to add to the site, and adding their own public events to the site’s event calendar! Visit to find quality resources and ideas. Connect with educators, students and the public to share the exciting planetary science discoveries as they’re uncovered during this unprecedented period of solar system exploration!

An Azulene-Based Discovery Experiment: Challenging Students to Watch for the "False Assumption"

ERIC Educational Resources Information Center

Garner, Charles M.

2005-01-01

A discovery-based experiment is developed depending on a "false assumption" that the students mistakenly assume they know the structure of a reaction product and are forced to reconcile observations that are inconsistent with this assumption. This experiment involves the chemistry of azulenes, an interesting class of intensely colored aromatic…

Triple Scheme of Learning Support Design for Scientific Discovery Learning Based on Computer Simulation: Experimental Research

ERIC Educational Resources Information Center

Zhang, Jianwei; Chen, Qi; Sun, Yanquing; Reid, David J.

2004-01-01

Learning support studies involving simulation-based scientific discovery learning have tended to adopt an ad hoc strategies-oriented approach in which the support strategies are typically pre-specified according to learners' difficulties in particular activities. This article proposes a more integrated approach, a triple scheme for learning…

2012 Division of Medicinal Chemistry Award Address: Trekking the Cannabinoid Road: A Personal Perspective

PubMed Central

Makriyannis, Alexandros

2014-01-01

My involvement with the field of cannabinoids spans close to three decades, and covers a major part of my scientific career. It also reflects the robust progress in this initially largely unexplored area of biology. During this period of time, I have witnessed the growth of modern cannabinoid biology, starting from the discovery of its two receptors and followed by the characterization of its endogenous ligands and the identification of the enzyme systems involved in their biosynthesis and biotransformation. I was fortunate enough to start at the beginning of this new era and participate in a number of the new discoveries. It has been a very exciting journey. By covering some key aspects of my work during this period of “modern cannabinoid research,” this perspective, in part historical, intends to give an account of how the field grew, the key discoveries, and the most promising directions for the future. PMID:24707904

Applications of chemogenomic library screening in drug discovery.

PubMed

Jones, Lyn H; Bunnage, Mark E

2017-04-01

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

Portfolio management in early stage drug discovery - a traveler's guide through uncharted territory.

PubMed

Betz, Ulrich A K

2011-07-01

Portfolio management in drug development has become a best practice in the pharmaceutical industry. By contrast, early on in the value chain - the discovery phase - portfolio management is still in its infancy. Nevertheless, owing to the attrition of R&D projects from phase to phase and the cost of capital involved, these early phases of drug discovery play a significant part for the overall cost of bringing new, innovative drugs to the market. This paper describes various approaches to manage a portfolio of projects in early-stage drug discovery and provides crucial factors that determine the success of such an approach. Copyright © 2011 Elsevier Ltd. All rights reserved.

Historical review of californium-252 discovery and development

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

Stoddard, D.H.

1985-01-01

This paper discusses the discovery and history of californium 252. This isotope may be synthesized by irradiating plutonium 239, plutonium 242, americium 243, or curium 244 with neutrons in a nuclear reactor. Various experiments and inventions involving /sup 252/Cf conducted at the Savannah River Plant are discussed. The evolution of radiotherapy using californium 252 is reviewed. (PLG)

The Relation of Learners' Motivation with the Process of Collaborative Scientific Discovery Learning

ERIC Educational Resources Information Center

Saab, Nadira; van Joolingen, Wouter R.; van Hout-Wolters, B. H. A. M.

2009-01-01

In this study, we investigated the influence of individual learners' motivation on the collaborative discovery learning process. In this we distinguished the motivation of the individual learners and had eye for the composition of groups, which could be homogeneous or heterogeneous in terms of motivation. The study involved 73 dyads of 10th-grade…

Historical Review of Californium-252 Discovery and Development

DOE R&D Accomplishments Database

Stoddard, D. H.

1985-01-01

This paper discusses the discovery and history of californium 252. This isotope may be synthesized by irradiating plutonium 239, plutonium 242, americium 243, or curium 244 with neutrons in a nuclear reactor. Various experiments and inventions involving Cf conducted at the Savannah River Plant are discussed. The evolution of radiotherapy using californium 252 is reviewed. (PLG)

Use of digital PCR to improve early detection of CLas infection

USDA-ARS?s Scientific Manuscript database

Huanglongbing is a devastating disease of citrus caused by the bacterium Candidatus Liberibacter asiaticus. Huanglongbing has devastated the Florida citrus industry and is threatening citrus in Texas and California. Detection of Candidatus Liberibacter asiaticus infections as early as possible is ...

Dismounted Complex Blast Injury.

PubMed

Andersen, Romney C; Fleming, Mark; Forsberg, Jonathan A; Gordon, Wade T; Nanos, George P; Charlton, Michael T; Ficke, James R

2012-01-01

The severe Dismounted Complex Blast Injury (DCBI) is characterized by high-energy injuries to the bilateral lower extremities (usually proximal transfemoral amputations) and/or upper extremity (usually involving the non-dominant side), in addition to open pelvic injuries, genitourinary, and abdominal trauma. Initial resuscitation and multidisciplinary surgical management appear to be the keys to survival. Definitive treatment follows general principals of open wound management and includes decontamination through aggressive and frequent debridement, hemorrhage control, viable tissue preservation, and appropriate timing of wound closure. These devastating injuries are associated with paradoxically favorable survival rates, but associated injuries and higher amputation levels lead to more difficult reconstructive challenges.

Mining large heterogeneous data sets in drug discovery.

PubMed

Wild, David J

2009-10-01

Increasingly, effective drug discovery involves the searching and data mining of large volumes of information from many sources covering the domains of chemistry, biology and pharmacology amongst others. This has led to a proliferation of databases and data sources relevant to drug discovery. This paper provides a review of the publicly-available large-scale databases relevant to drug discovery, describes the kinds of data mining approaches that can be applied to them and discusses recent work in integrative data mining that looks for associations that pan multiple sources, including the use of Semantic Web techniques. The future of mining large data sets for drug discovery requires intelligent, semantic aggregation of information from all of the data sources described in this review, along with the application of advanced methods such as intelligent agents and inference engines in client applications.

Intercultural Communication.

ERIC Educational Resources Information Center

Newmark, Eileen; Asante, Molefi K.

Human communication involves the interaction of selves, and an intercultural encounter permits the discovery of one's own cultural self. Participatory learning of intercultural communication provides students with an opportunity for involvement through analysis of their and others' perceptions, improvement of language fidelity, emphasis on…

A role for physicians in ethnopharmacology and drug discovery.

PubMed

Raza, Mohsin

2006-04-06

Ethnopharmacology investigations classically involved traditional healers, botanists, anthropologists, chemists and pharmacologists. The role of some groups of researchers but not of physician has been highlighted and well defined in ethnopharmacological investigations. Historical data shows that discovery of several important modern drugs of herbal origin owe to the medical knowledge and clinical expertise of physicians. Current trends indicate negligible role of physicians in ethnopharmacological studies. Rising cost of modern drug development is attributed to the lack of classical ethnopharmacological approach. Physicians can play multiple roles in the ethnopharmacological studies to facilitate drug discovery as well as to rescue authentic traditional knowledge of use of medicinal plants. These include: (1) Ethnopharmacological field work which involves interviewing healers, interpreting traditional terminologies into their modern counterparts, examining patients consuming herbal remedies and identifying the disease for which an herbal remedy is used. (2) Interpretation of signs and symptoms mentioned in ancient texts and suggesting proper use of old traditional remedies in the light of modern medicine. (3) Clinical studies on herbs and their interaction with modern medicines. (4) Advising pharmacologists to carryout laboratory studies on herbs observed during field studies. (5) Work in collaboration with local healers to strengthen traditional system of medicine in a community. In conclusion, physician's involvement in ethnopharmacological studies will lead to more reliable information on traditional use of medicinal plants both from field and ancient texts, more focused and cheaper natural product based drug discovery, as well as bridge the gap between traditional and modern medicine.

Using MALDI-IMS and MRM to stablish a pipeline for discovery and validation of tumor neovasculature biomarker candidates. — EDRN Public Portal

Cancer.gov

In an effort to circumvent the limitations associated with biomarker discovery workflows involving cell lines and cell cultures, histology-directed MALDI protein profiling and imaging mass spectrometry will be used for identification of vascular endothelial biomarkers suitable for early prostate cancer detection by CEUS targeted molecular imaging

STEM Progress in Katrina's Wake

ERIC Educational Resources Information Center

Gonzales, Dana

2008-01-01

When Hurricane Katrina hit New Orleans in 2005, it caused a devastating impact on the Crescent City's public education system. The devastating storm and its aftermath completely wiped out the educational infrastructure of the New Orleans Public Schools, making one of the country's largest metropolitan school districts virtually disappear. Two…

Early Probe and Drug Discovery in Academia: A Minireview.

PubMed

Roy, Anuradha

2018-02-09

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

Treating pediatric neuromuscular disorders: The future is now

PubMed Central

D. Gonorazky, Hernan; Cohn, Ronald D.; Campbell, Craig

2017-01-01

Pediatric neuromuscular diseases encompass all disorders with onset in childhood and where the primary area of pathology is in the peripheral nervous system. These conditions are largely genetic in etiology, and only those with a genetic underpinning will be presented in this review. This includes disorders of the anterior horn cell (e.g., spinal muscular atrophy), peripheral nerve (e.g., Charcot–Marie–Tooth disease), the neuromuscular junction (e.g., congenital myasthenic syndrome), and the muscle (myopathies and muscular dystrophies). Historically, pediatric neuromuscular disorders have uniformly been considered to be without treatment possibilities and to have dire prognoses. This perception has gradually changed, starting in part with the discovery and widespread application of corticosteroids for Duchenne muscular dystrophy. At present, several exciting therapeutic avenues are under investigation for a range of conditions, offering the potential for significant improvements in patient morbidities and mortality and, in some cases, curative intervention. In this review, we will present the current state of treatment for the most common pediatric neuromuscular conditions, and detail the treatment strategies with the greatest potential for helping with these devastating diseases. PMID:28889642

Batrachochytrium salamandrivorans and the risk of a second amphibian pandemic

USGS Publications Warehouse

Yap, Tiffany A.; Nguyen, Natalie T.; Serr, Megan; Shepak, Alex; Vredenburg, Vance

2017-01-01

Amphibians are experiencing devastating population declines globally. A major driver is chytridiomycosis, an emerging infectious disease caused by the fungal pathogens Batrachochytrium dendrobatidis (Bd) and Batrachochytrium salamandrivorans (Bsal). Bdwas described in 1999 and has been linked with declines since the 1970s, while Bsal is a more recently discovered pathogen that was described in 2013. It is hypothesized that Bsaloriginated in Asia and spread via international trade to Europe, where it has been linked to salamander die-offs. Trade in live amphibians thus represents a significant threat to global biodiversity in amphibians. We review the current state of knowledge regarding Bsal and describe the risk of Bsal spread. We discuss regional responses to Bsal and barriers that impede a rapid, coordinated global effort. The discovery of a second deadly emerging chytrid fungal pathogen in amphibians poses an opportunity for scientists, conservationists, and governments to improve global biosecurity and further protect humans and wildlife from a growing number of emerging infectious diseases.

Models for discovery of targeted therapy in genetic epileptic encephalopathies.

PubMed

Maljevic, Snezana; Reid, Christopher A; Petrou, Steven

2017-10-01

Epileptic encephalopathies are severe disorders emerging in the first days to years of life that commonly include refractory seizures, various types of movement disorders, and different levels of developmental delay. In recent years, many de novo occurring variants have been identified in individuals with these devastating disorders. To unravel disease mechanisms, the functional impact of detected variants associated with epileptic encephalopathies is investigated in a range of cellular and animal models. This review addresses efforts to advance and use such models to identify specific molecular and cellular targets for the development of novel therapies. We focus on ion channels as the best-studied group of epilepsy genes. Given the clinical and genetic heterogeneity of epileptic encephalopathy disorders, experimental models that can reflect this complexity are critical for the development of disease mechanisms-based targeted therapy. The convergence of technological advances in gene sequencing, stem cell biology, genome editing, and high throughput functional screening together with massive unmet clinical needs provides unprecedented opportunities and imperatives for precision medicine in epileptic encephalopathies. © 2017 International Society for Neurochemistry.

Sex and hibernaculum temperature predict survivorship in white-nose syndrome affected little brown myotis (Myotis lucifugus).

PubMed

Grieneisen, Laura E; Brownlee-Bouboulis, Sarah A; Johnson, Joseph S; Reeder, DeeAnn M

2015-02-01

White-nose syndrome (WNS), an emerging infectious disease caused by the novel fungus Pseudogymnoascus destructans, has devastated North American bat populations since its discovery in 2006. The little brown myotis, Myotis lucifugus, has been especially affected. The goal of this 2-year captive study was to determine the impact of hibernacula temperature and sex on WNS survivorship in little brown myotis that displayed visible fungal infection when collected from affected hibernacula. In study 1, we found that WNS-affected male bats had increased survival over females and that bats housed at a colder temperature survived longer than those housed at warmer temperatures. In study 2, we found that WNS-affected bats housed at a colder temperature fared worse than unaffected bats. Our results demonstrate that WNS mortality varies among individuals, and that colder hibernacula are more favourable for survival. They also suggest that female bats may be more negatively affected by WNS than male bats, which has important implications for the long-term survival of the little brown myotis in eastern North America.

[The possible causes of the tragedy of "Port Famine" in the Strait of Magellan].

PubMed

Espinoza G, Juan Pablo; Espinoza G, Ricardo

2010-11-01

The attempts to colonize the Strait of Magellan soon followed the discovery of this route. PeDro Sarmiento de Gamboa, a Spanish sailor, established human settlements to fortify those lands and control the transit of vessels, especially those of English corsairs, which devastated Chilean and Peruvian coasts. During the summer of 1584, approximately 500 soldiers, artisans, priests, women and children established two villages called "Nombre de Jesús" and "Rey Don Felipe". From the beginning, these settlers had leadership and communication problems and difficulties to obtain food. After three winters only 17 to 18 people survived according to the testimony of one of the survivors, that was rescued by an English sailor named Cavendish, which renamed the village "Rey Don Felipe" as "Port Famine". When he observed the scenes of abandonment and death, he supposed that the settlers died due to lack of food. Other factors that facilitated the desolation were hypothermia, execution, anthropophagy and lesions caused by natives. There is also a possibility that intoxication by red tide (harmful algal bloom) could explain in part the finding of unburied corpses in the strait beaches.

Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia.

PubMed

Lee, P H; Baker, J T; Holmes, A J; Jahanshad, N; Ge, T; Jung, J-Y; Cruz, Y; Manoach, D S; Hibar, D P; Faskowitz, J; McMahon, K L; de Zubicaray, G I; Martin, N H; Wright, M J; Öngür, D; Buckner, R; Roffman, J; Thompson, P M; Smoller, J W

2016-12-01

Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide single-nucleotide polymorphism (SNP) and neuroimaging data from 1750 healthy individuals. We find that schizophrenia-associated genetic variants explain a significantly enriched proportion of trait heritability in eight brain phenotypes (false discovery rate=10%). In particular, intracranial volume and left superior frontal gyrus thickness exhibit significant and robust associations with schizophrenia genetic risk under varying SNP selection conditions. Cross-disorder comparison suggests that the neurogenetic architecture of schizophrenia-associated brain regions is, at least in part, shared with other psychiatric disorders. Our study highlights key neuroanatomical correlates of schizophrenia genetic risk in the general population. These may provide fundamental insights into the complex pathophysiology of the illness, and a potential link to neurocognitive deficits shaping the disorder.

The relationship between stress and Alzheimer's disease.

PubMed

Justice, Nicholas J

2018-02-01

Stress is critically involved in the development and progression of disease. From the stress of undergoing treatments to facing your own mortality, the physiological processes that stress drives have a serious detrimental effect on the ability to heal, cope and maintain a positive quality of life. This is becoming increasingly clear in the case of neurodegenerative diseases. Neurodegenerative diseases involve the devastating loss of cognitive and motor function which is stressful in itself, but can also disrupt neural circuits that mediate stress responses. Disrupting these circuits produces aberrant emotional and aggressive behavior that causes long-term care to be especially difficult. In addition, added stress drives progression of the disease and can exacerbate symptoms. In this review, I describe how neural and endocrine pathways activated by stress interact with ongoing neurodegenerative disease from both a clinical and experimental perspective.

No evidence of deer mouse involvement in plague (Yersinia pestis) epizootics in prairie dogs.

PubMed

Salkeld, Daniel J; Stapp, Paul

2008-06-01

Plague, the disease caused by the bacterium Yersinia pestis, can have devastating impacts on black-tailed prairie dog (Cynomys ludovicianus) colonies. One suggested mechanism behind sporadic prairie dog die-offs involves an alternative mammal host, such as the deer mouse (Peromyscus maniculatus), which often inhabits prairie dog colonies. We examined the flea populations of deer mice to investigate the potential of flea-borne transmission of plague between deer mice and prairie dogs in northern Colorado, where plague is active in prairie dog colonies. Deer mice were predominantly infested with the flea Aetheca wagneri, and were rarely infested with prairie dog fleas, Oropsylla hirsuta. Likelihood of flea infestation increased with average monthly temperature, and flea loads were higher in reproductive animals. These results suggest that the deer mouse is an unlikely maintenance host of plague in this region.

Complex Virus-Host Interactions Involved in the Regulation of Classical Swine Fever Virus Replication: A Minireview.

PubMed

Li, Su; Wang, Jinghan; Yang, Qian; Naveed Anwar, Muhammad; Yu, Shaoxiong; Qiu, Hua-Ji

2017-07-05

Classical swine fever (CSF), caused by classical swine fever virus (CSFV), is one of the most devastating epizootic diseases of pigs in many countries. Viruses are small intracellular parasites and thus rely on the cellular factors for replication. Fundamental aspects of CSFV-host interactions have been well described, such as factors contributing to viral attachment, modulation of genomic replication and translation, antagonism of innate immunity, and inhibition of cell apoptosis. However, those host factors that participate in the viral entry, assembly, and release largely remain to be elucidated. In this review, we summarize recent progress in the virus-host interactions involved in the life cycle of CSFV and analyze the potential mechanisms of viral entry, assembly, and release. We conclude with future perspectives and highlight areas that require further understanding.

Complex Virus–Host Interactions Involved in the Regulation of Classical Swine Fever Virus Replication: A Minireview

PubMed Central

Li, Su; Wang, Jinghan; Yang, Qian; Naveed Anwar, Muhammad; Yu, Shaoxiong; Qiu, Hua-Ji

2017-01-01

Classical swine fever (CSF), caused by classical swine fever virus (CSFV), is one of the most devastating epizootic diseases of pigs in many countries. Viruses are small intracellular parasites and thus rely on the cellular factors for replication. Fundamental aspects of CSFV–host interactions have been well described, such as factors contributing to viral attachment, modulation of genomic replication and translation, antagonism of innate immunity, and inhibition of cell apoptosis. However, those host factors that participate in the viral entry, assembly, and release largely remain to be elucidated. In this review, we summarize recent progress in the virus–host interactions involved in the life cycle of CSFV and analyze the potential mechanisms of viral entry, assembly, and release. We conclude with future perspectives and highlight areas that require further understanding. PMID:28678154

Translational bioinformatics: linking the molecular world to the clinical world.

PubMed

Altman, R B

2012-06-01

Translational bioinformatics represents the union of translational medicine and bioinformatics. Translational medicine moves basic biological discoveries from the research bench into the patient-care setting and uses clinical observations to inform basic biology. It focuses on patient care, including the creation of new diagnostics, prognostics, prevention strategies, and therapies based on biological discoveries. Bioinformatics involves algorithms to represent, store, and analyze basic biological data, including DNA sequence, RNA expression, and protein and small-molecule abundance within cells. Translational bioinformatics spans these two fields; it involves the development of algorithms to analyze basic molecular and cellular data with an explicit goal of affecting clinical care.

The impact of prolonged disorders of consciousness on the occupational life of family members.

PubMed

Elliott, Karen; McVicar, Andrew

2016-10-27

The impact of vegetative state (VS) and minimally conscious states (MCSs) on an individual is devastating. VS and MCSs may be transitional towards recovery, but may become permanent. Although devastating for the individual the nature of these conditions also has a profound effect on the family. This study examined the impact on the family member and the changes in the individuals' occupation. Six participants (spouses, partners or parents) were recruited to the study. Mixed methods were adopted to meet the requirements of the research and participants. Data were collected at 6 and 12 months post-injury, using time diaries, a questionnaire and semi-structured interviews. At 6 months post-injury the greatest amount of carers' time was allocated to occupations involving the person in a Disorder of Consciousness and less time to social and leisure activities. Participants had difficulty viewing the future, lacked the desire or capacity to engage in previously enjoyed activities. At 12 months those impacts were still evident although changing. The transition to balanced occupational activity is slow, requiring a number of catalysts to change. A conceptual framework for a return to balance is provided, and guidance on advice from family members to families in a similar situation is given.

Postgenomic strategies in antibacterial drug discovery.

PubMed

Brötz-Oesterhelt, Heike; Sass, Peter

2010-10-01

During the last decade the field of antibacterial drug discovery has changed in many aspects including bacterial organisms of primary interest, discovery strategies applied and pharmaceutical companies involved. Target-based high-throughput screening had been disappointingly unsuccessful for antibiotic research. Understanding of this lack of success has increased substantially and the lessons learned refer to characteristics of targets, screening libraries and screening strategies. The 'genomics' approach was replaced by a diverse array of discovery strategies, for example, searching for new natural product leads among previously abandoned compounds or new microbial sources, screening for synthetic inhibitors by targeted approaches including structure-based design and analyses of focused libraries and designing resistance-breaking properties into antibiotics of established classes. Furthermore, alternative treatment options are being pursued including anti-virulence strategies and immunotherapeutic approaches. This article summarizes the lessons learned from the genomics era and describes discovery strategies resulting from that knowledge.

The Discovery of the Tau Lepton and the Changes in Elementary Particle Physics in 40 Years

DOE R&D Accomplishments Database

Perl, M.

2003-10-22

This is a history of my discovery of the tau lepton in the 1970s for which I was awarded the Nobel Prize in Physics. I have previously described some aspects of the discovery. In 1996 in my collection of papers entitled, ''Reflections on Experimental Science,'' I gave a straightforward account of the experimental method and the physics involved in the discovery as an introduction to the collection. In a 2002 paper written with Mary A. Meyer published in the journal ''Theoria et Historia Scientiarum'' I used the story of the discovery to outline my thoughts on the practice of experimental science. That 2002 paper was written primarily for young women and men who are beginning their lives in science and it was based on a lecture given at Los Alamos National Laboratory. Some of the historical material in this paper has appeared in those two earlier papers.

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.

Perianal Crohn disease.

PubMed

Asma, Sioud Dhrif; Soumaya, Youssef; Kahena, Jaber; Raouf, Dhaoui Mohamed; Nejib, Doss

2006-12-10

Crohn disease is a chronic inflammatory disease characterized by sharply demarcated segments of gastrointestinal involvement from mouth to anus. Its perineal manifestations are among the most devastating and mutilating complications. They occur at any time and may precede the intestinal manifestations. Their most common presentations are perineal ulceration, fistula, and abscess. Proliferative and polypoid morphology of the cutaneous lesions mimicking warts and condyloma are rarely described. We report a 25-year-old woman with a 4-month history of confluent plaques of the perineal region with vegetant surfaces, suspected to be genital warts. The lesions progressed to fistulas, inducing deep ulcerations surrounded by pseudocondylomatous tumors. About 2 months prior to presentation she began to suffer from gastrointestinal symptoms and noted weight loss. Physical examination, endoscopic examination, and pathological interpretation led to the diagnosis of Crohn disease with perineal involvement being the initial presenting sign. Significant improvement was induced with prednisone (45 mg daily) and azathioprine. Our observation is notable for the pseudocondylomatous appearance and the dramatic response to medical treatment despite severe involvement.

Safe use of epidural corticosteroid injections: recommendations of the WIP Benelux workgroup.

PubMed

Van Boxem, Koen; Rijsdijk, Mienke; Hans, Guy; de Jong, Jasper; Kallewaard, Jan Willem; Vissers, Kris; van Kleef, Maarten; Rathmell, James P; Van Zundert, Jan

2018-05-14

Epidural corticosteroid injections are used frequently worldwide in the treatment of radicular pain. Concerns have risen involving rare major neurologic injuries after this treatment. Recommendations to prevent these complications have been published, but local implementation is not always feasible due to local circumstances and necessitating local recommendations based on literature review. A workgroup of 4 stakeholder pain societies in Belgium, The Netherlands and Luxembourg (Benelux) has reviewed the literature involving neurological complications after epidural corticosteroid injections and possible safety measures to prevent these major neurologic injuries. Twenty-six considerations and recommendations were selected by the workgroup. These involve the use of imaging, injection equipment particulate and non-particulate corticosteroids, epidural approach and maximal volume to be injected. Raising awareness about possible neurological complications and adoption of safety measures recommended by the work group aim at reducing the risks of these devastating events. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

KSC-07pd2825

NASA Image and Video Library

2007-10-09

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

KSC-07pd2824

NASA Image and Video Library

2007-10-09

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

KSC-07pd2820

NASA Image and Video Library

2007-10-09

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

KSC-07pd2823

NASA Image and Video Library

2007-10-09

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

KSC-07pd2822

NASA Image and Video Library

2007-10-09

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

KSC-07pd2821

NASA Image and Video Library

2007-10-09

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

Bacterial polyesters: biosynthesis, biodegradable plastics and biotechnology.

PubMed

Lenz, Robert W; Marchessault, Robert H

2005-01-01

The discovery and chemical identification, in the 1920s, of the aliphatic polyester: poly(3-hydroxybutyrate), PHB, as a granular component in bacterial cells proceeded without any of the controversies which marked the recognition of macromolecules by Staudinger. Some thirty years after its discovery, PHB was recognized as the prototypical biodegradable thermoplastic to solve the waste disposal challenge. The development effort led by Imperial Chemical Industries Ltd., encouraged interdisciplinary research from genetic engineering and biotechnology to the study of enzymes involved in biosynthesis and biodegradation. From the simple PHB homopolyester discovered by Maurice Lemoigne in the mid-twenties, a family of over 100 different aliphatic polyesters of the same general structure has been discovered. Depending on bacterial species and substrates, these high molecular weight stereoregular polyesters have emerged as a new family of natural polymers ranking with nucleic acids, polyamides, polyisoprenoids, polyphenols, polyphosphates, and polysaccharides. In this historical review, the chemical, biochemical and microbial highlights are linked to personalities and locations involved with the events covering a discovery timespan of 75 years.

Up from the Ruins

ERIC Educational Resources Information Center

Maxwell, Lesli A.

2007-01-01

More than 100 public schools in New Orleans were flooded in the hours after the hurricane struck. The roughly two dozen schools that did not fill up with water suffered wind and rain damage. It was a devastating blow to old, already battered school buildings that were among the most rundown in the country. The devastation created an unprecedented…

The Children's War: Their Reactions to Devastating Events.

ERIC Educational Resources Information Center

Atwood, Joan D.; Donnelly, Joseph W.

2002-01-01

A thorough review of the literature reveals that there is little or no information on children's psychological reactions to devastating events, such as the Oklahoma City bombing, the Gulf War, or the recent destruction of the World Trade Center and the Pentagon. This article explores children's psychological reactions in light of Piagetian theory.…

Vibrational duetting mimics to trap and disrupt mating of the devastating Asian citrus psyllid insect pest

USDA-ARS?s Scientific Manuscript database

The Asian citrus psyllid (ACP) is the primary vector of a bacterium that produces a devastating disease of citrus, huanglongbing. Efficient surveillance of ACP at low population densities is essential for timely pest management programs. ACP males search for mates on tree branches by producing vibra...

Modern drug discovery technologies: opportunities and challenges in lead discovery.

PubMed

Guido, Rafael V C; Oliva, Glaucius; Andricopulo, Adriano D

2011-12-01

The identification of promising hits and the generation of high quality leads are crucial steps in the early stages of drug discovery projects. The definition and assessment of both chemical and biological space have revitalized the screening process model and emphasized the importance of exploring the intrinsic complementary nature of classical and modern methods in drug research. In this context, the widespread use of combinatorial chemistry and sophisticated screening methods for the discovery of lead compounds has created a large demand for small organic molecules that act on specific drug targets. Modern drug discovery involves the employment of a wide variety of technologies and expertise in multidisciplinary research teams. The synergistic effects between experimental and computational approaches on the selection and optimization of bioactive compounds emphasize the importance of the integration of advanced technologies in drug discovery programs. These technologies (VS, HTS, SBDD, LBDD, QSAR, and so on) are complementary in the sense that they have mutual goals, thereby the combination of both empirical and in silico efforts is feasible at many different levels of lead optimization and new chemical entity (NCE) discovery. This paper provides a brief perspective on the evolution and use of key drug design technologies, highlighting opportunities and challenges.

Arterial Cannulation and Cerebral Perfusion Strategies for Aortic Arch Operations.

PubMed

Foley, Lisa S; Yamanaka, Katsuhiro; Reece, T Brett

2016-12-01

Neurologic injuries following aortic arch operations can be devastating, with stroke occurring in up to 12% of elective operations and significant cerebral dysfunction occurring in up to 25% of cases. The primary challenge unique to aortic arch operations involves interruption of direct perfusion of the brachiocephalic vessels during arch reconstruction. For this reason, neuroprotection is paramount. The 2 main modes of protection are (1) reducing metabolic demand through hypothermia and (2) limiting, or even eliminating, the ischemic period. Preoperative selection of the cerebral perfusion plan for each operation is imperative to maintain maximal diffuse cerebral protection and prevent focal neurologic events. © The Author(s) 2016.

Leo Szilard Lectureship Award: Fissile Materials: A Global Threat

NASA Astrophysics Data System (ADS)

Rajaraman, Ramamurti

2014-03-01

The world has built up a huge glut of Fissile Materials, posing a potentially devastating threat. While specialists in the field have been aware of this danger for a long time, it was only after President Obama organized the Nuclear Security Summit in 2010 that the attention of the world's political leadership was drawn to it. We will present here an introductory overview of Fissile materials - their definition, significance and their production facilities and stocks in different parts of the world. We will also mention some of the efforts being made to verifiably cap and reduce their stocks as well as the technical and political complications involved in the process.

Rib Fracture Fixation: Indications and Outcomes.

PubMed

Senekjian, Lara; Nirula, Raminder

2017-01-01

Rib fractures are a frequently identified injury in the trauma population. Not only are multiple rib fractures painful, but they are associated with an increased risk of adverse outcomes. Pneumonia in particular can be devastating, especially to an elderly patient, but other complications such as prolonged ventilation and increased intensive care and hospital durations of stay have a negative impact on the patient. Computed tomography scan is the best modality to diagnosis rib fractures but the treatment of fractures is still evolving. Currently patient care involves a multidisciplinary approach that includes pain control, aggressive pulmonary therapy, and possibly surgical fixation. Copyright © 2016 Elsevier Inc. All rights reserved.

Vacuum-assisted closure as a surgical assistant in life-threatening necrotizing fasciitis in children

PubMed Central

Al-Subhi, FS; Zuker, RM; Cole, WG

2010-01-01

Necrotizing fasciitis is a severe soft tissue infection that can involve skin, subcutaneous fat, fascia and muscle. It can result in devastating sequelae including tissue necrosis, sepsis, toxic shock syndrome, cardiopulmonary collapse and death. To control rapidly spreading necrosis, early diagnosis and aggressive surgical treatment with extensive radical debridement of the affected areas is necessary, as well as systemic administration of broad-spectrum antimicrobials and, very often, intensive care support. The subatmospheric negative pressure dressing has been previously used in acute and complex wounds management. The concept of using vacuum-assisted closure dressing as another management component is presented in the current article. PMID:22131841

Regenerating new heart with stem cells

PubMed Central

Anversa, Piero; Kajstura, Jan; Rota, Marcello; Leri, Annarosa

2013-01-01

This article discusses current understanding of myocardial biology, emphasizing the regeneration potential of the adult human heart and the mechanisms involved. In the last decade, a novel conceptual view has emerged. The heart is no longer considered a postmitotic organ, but is viewed as a self-renewing organ characterized by a resident stem cell compartment responsible for tissue homeostasis and cardiac repair following injury. Additionally, HSCs possess the ability to transdifferentiate and acquire the cardiomyocyte, vascular endothelial, and smooth muscle cell lineages. Both cardiac and hematopoietic stem cells may be used therapeutically in an attempt to reverse the devastating consequences of chronic heart failure of ischemic and nonischemic origin. PMID:23281411

Ferritin for the Clinician

PubMed Central

Knovich, Mary Ann; Storey, Jonathan A.; Coffman, Lan G.; Torti, Suzy V.

2009-01-01

Ferritin, a major iron storage protein, is essential to iron homeostasis and is involved in a wide range of physiologic and pathologic processes. In clinical medicine, ferritin is predominantly utilized as a serum marker of total body iron stores. In cases of iron deficiency and overload, serum ferritin serves a critical role in both diagnosis and management. Elevated serum and tissue ferritin are linked to coronary artery disease, malignancy, and poor outcomes following stem cell transplantation. Ferritin is directly implicated in less common but potentially devastating human diseases including sideroblastic anemias, neurodegenerative disorders, and hemophagocytic syndrome. Additionally, recent research describes novel functions of ferritin independent of iron storage. PMID:18835072

Hurricane Recovery Report 2004

NASA Technical Reports Server (NTRS)

Gordon, Joseph P.

2005-01-01

During August and September 2004, four hurricanes tested the mettle of Space Coast residents and the Kennedy Space Center (KSC) leadership and workforce. These threats underscored two important points: the very real vulnerability of KSC and its valuable space program assets to the devastating power of a hurricane, and the planning required to effectively deal with such threats. The damage was significant even though KSC did not experience sustained hurricane-force winds. To better understand and appreciate these points, this report provides an overview of the meteorological history of the Space Coast and what is involved in the planning, preparation, and recovery activities, as well as addressing the impacts of the 2004 hurricane season.

Third-degree burns caused by ignition of chlorhexidine: A case report and systematic review of the literature

PubMed Central

Vo, Anthony; Bengezi, Omar

2014-01-01

Ignition of chlorhexidine by an electrocautery unit is rare but can have devastating consequences for the patient and the surgeon. A case involving a 77-year-old man who underwent removal of an indwelling artificial urethral sphincter is presented. The chlorhexidine was ignited when the urologist activated the electrocautery unit, causing third-degree burns to the patient. A plastic surgeon treated the burns with surgical debridement and split-thickness skin grafting. A systematic review of the literature was performed with best practice recommendations. To the authors’ knowledge, the present case is the ninth such case reported. PMID:25535466

How Are Television Networks Involved in Distance Learning?

ERIC Educational Resources Information Center

Bucher, Katherine

1996-01-01

Reviews the involvement of various television networks in distance learning, including public broadcasting stations, Cable in the Classroom, Arts and Entertainment Network, Black Entertainment Television, C-SPAN, CNN (Cable News Network), The Discovery Channel, The Learning Channel, Mind Extension University, The Weather Channel, National Teacher…

[Role of myostatin in wasting syndrome associated with chronic diseases].

PubMed

Zamora, Elisabet; Galán, Amparo; Simó, Rafael

2008-11-01

Muscle wasting is a common process of numerous chronic diseases. Sarcopenia is associated with poor prognosis independently of the outcome of the disease. To date, the mechanisms by which sarcopenia induces these alterations are unknown, but the complexity of muscular metabolism anticipates that many factors can be involved. Myostatin, a new family member of transforming growth factor beta, was initially described from the observation of significant muscular growing in knock out mice for myostatin. Numerous experimental and clinical studies have provided insights in the physiologic knowledge of this protein and its implication in muscle wasting conditions. In recent years different substances have been described that counteract myostatin through numerous physiopathological mecanisms and, therefore, they might be novel therapeutic strategies against the wasting syndrome associated with chronic diseases. In spite of that, more studies are needed to improve the knowledge of all processes involved in muscle wasting in order to prevent its devastating consequences.

Preliminary Study of OCD and Health Disparities at the U.S.-Mexico Border

PubMed Central

Olson, Tom; Vera, Beatriz; Perez, Oriana

2007-01-01

The widespread and devastating nature of obsessive compulsive disorder (OCD) sharply contrasts with the paucity of research involving Mexican Americans and Mexicans who suffer from this condition. This mixed-methods preliminary study was intended to provide initial data and to pilot the procedures for a larger investigation of the cultural identification, symptomatology, health concerns, coping mechanisms, and quality of life of Mexican Americans and Mexicans with OCD living in the U.S.-Mexico border region of El Paso, Texas and Ciudad Juarez, Mexico. For the sample of six participants, whose symptoms ranged from moderate to extreme, OCD was associated with marked impairment in quality of life, particularly in terms of social functioning, an area of central importance for many Mexican Americans and Mexicans. Areas of further study were identified, with the aim of developing culturally sensitive interventions to decrease health disparities involving OCD. PMID:17917689

Nurses respond to Hurricane Hugo victims' disaster stress.

PubMed

Weinrich, S; Hardin, S B; Johnson, M

1990-06-01

Hugo, a class IV hurricane, hit South Carolina September 22, 1989, and left behind a wake of terror and destruction. Sixty-one nursing students and five faculty were involved in disaster relief with families devastated by the hurricane. A review of the literature led these authors to propose a formulation of the concept of disaster stress, a synthesis of theories that explains response to disaster as a crisis response, a stress response, or as posttraumatic stress. With the concept of disaster stress serving as a theoretical foundation, the nurses observed, assessed, and intervened with one population of hurricane Hugo victims, noting their immediate psychosocial reactions and coping mechanisms. Victims' reactions to disaster stress included confusion, irritability, lethargy, withdrawal, and crying. The most frequently observed coping strategy of these hurricane Hugo victims was talking about their experiences; other coping tactics involved humor, religion, and altruism.

New discoveries of sylvatic Triatoma infestans (Hemiptera: Reduviidae) throughout the Bolivian Chaco.

PubMed

Waleckx, Etienne; Depickère, Stéphanie; Salas, Renata; Aliaga, Claudia; Monje, Marcelo; Calle, Hiber; Buitrago, Rosio; Noireau, François; Brenière, Simone Frédérique

2012-03-01

Sylvatic populations of Triatoma infestans might be involved in the recolonization of human dwellings. We report here the discoveries of new T. infestans sylvatic foci in the Bolivian Chaco. Eighty-one triatomines were caught, 38 of which were identified as T. infestans. Triatoma sordida and Panstrongylus geniculatus were the other species collected. One T. infestans and one T. sordida were infected with Trypanosoma cruzi TcI; one T. infestans was infected with TcII. These discoveries add to the debate on the geographic distribution of sylvatic T. infestans populations, the geographic origin of the species, and the epidemiological role of these populations.

New Discoveries of Sylvatic Triatoma infestans (Hemiptera: Reduviidae) Throughout the Bolivian Chaco

PubMed Central

Waleckx, Etienne; Depickère, Stéphanie; Salas, Renata; Aliaga, Claudia; Monje, Marcelo; Calle, Hiber; Buitrago, Rosio; Noireau, François; Brenière, Simone Frédérique

2012-01-01

Sylvatic populations of Triatoma infestans might be involved in the recolonization of human dwellings. We report here the discoveries of new T. infestans sylvatic foci in the Bolivian Chaco. Eighty-one triatomines were caught, 38 of which were identified as T. infestans. Triatoma sordida and Panstrongylus geniculatus were the other species collected. One T. infestans and one T. sordida were infected with Trypanosoma cruzi TcI; one T. infestans was infected with TcII. These discoveries add to the debate on the geographic distribution of sylvatic T. infestans populations, the geographic origin of the species, and the epidemiological role of these populations. PMID:22403316

Cultural aspects of SETI

NASA Technical Reports Server (NTRS)

Billingham, John

1991-01-01

The paper presents a broad range of issues that raise important questions about the search for exterrestrial life forms or intelligence. The history of the concept of plurality of inhabited worlds is reviewed, and disciplinary areas are cited that are considered crucial for SETI. Such issues involve analogs of the discovery of ETI, immediate responses to such detections, and the significance of journalistic and media response. The responses of religion is also considered, and it is suggested that humankind respond to the discovery of ETI with a single voice and message. The issues discussed demonstrate the need for explicit protocols that would be followed after any discovery of the types discussed.

Neutrophil migration into the placenta: Good, bad or deadly?

PubMed Central

Giaglis, Stavros; Stoikou, Maria; Grimolizzi, Franco; Subramanian, Bibin Y.; van Breda, Shane V.; Hoesli, Irene; Lapaire, Olav; Hasler, Paul; Than, Nandor Gabor; Hahn, Sinuhe

2016-01-01

ABSTRACT Almost 2 decades have passed since the discovery that pregnancy is associated with a basal inflammatory state involving neutrophil activation, and that this is more overt in cases with preeclampsia, than in instances with sepsis. This pivotal observation paved the way for our report, made almost a decade ago, describing the first involvement of neutrophil extracellular traps (NETs) in a non-infectious human pathology, namely preeclampsia, where an abundance of these structures were detected directly in the placental intervillous space. Despite these remarkable findings, there remains a paucity of interest among reproductive biologists in further exploring the role or involvement of neutrophils in pregnancy and related pathologies. In this review we attempt to redress this deficit by highlighting novel recent findings including the discovery of a novel neutrophil subset in the decidua, the interaction of placental protein 13 (PP13) and neutrophils in modulating spiral artery modification, as well as the use of animal model systems to elucidate neutrophil function in implantation, gestation and parturition. These model systems have been particularly useful in identifying key components implicated in recurrent fetal loss, preeclampsia or new signaling molecules such as sphingolipids. Finally, the recent discovery that anti-phospolipid antibodies can trigger NETosis, supports our hypothesis that these structures may contribute to placental dysfunction in pertinent cases with recurrent fetal loss. PMID:26933824

Computational Tools for Allosteric Drug Discovery: Site Identification and Focus Library Design.

PubMed

Huang, Wenkang; Nussinov, Ruth; Zhang, Jian

2017-01-01

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

Exchange protein directly activated by cAMP (epac): a multidomain cAMP mediator in the regulation of diverse biological functions.

PubMed

Schmidt, Martina; Dekker, Frank J; Maarsingh, Harm

2013-04-01

Since the discovery nearly 60 years ago, cAMP is envisioned as one of the most universal and versatile second messengers. The tremendous feature of cAMP to tightly control highly diverse physiologic processes, including calcium homeostasis, metabolism, secretion, muscle contraction, cell fate, and gene transcription, is reflected by the award of five Nobel prizes. The discovery of Epac (exchange protein directly activated by cAMP) has ignited a new surge of cAMP-related research and has depicted novel cAMP properties independent of protein kinase A and cyclic nucleotide-gated channels. The multidomain architecture of Epac determines its activity state and allows cell-type specific protein-protein and protein-lipid interactions that control fine-tuning of pivotal biologic responses through the "old" second messenger cAMP. Compartmentalization of cAMP in space and time, maintained by A-kinase anchoring proteins, phosphodiesterases, and β-arrestins, contributes to the Epac signalosome of small GTPases, phospholipases, mitogen- and lipid-activated kinases, and transcription factors. These novel cAMP sensors seem to implement certain unexpected signaling properties of cAMP and thereby to permit delicate adaptations of biologic responses. Agonists and antagonists selective for Epac are developed and will support further studies on the biologic net outcome of the activation of Epac. This will increase our current knowledge on the pathophysiology of devastating diseases, such as diabetes, cognitive impairment, renal and heart failure, (pulmonary) hypertension, asthma, and chronic obstructive pulmonary disease. Further insights into the cAMP dynamics executed by the Epac signalosome will help to optimize the pharmacological treatment of these diseases.

Novel opportunities for computational biology and sociology in drug discovery

PubMed Central

Yao, Lixia

2009-01-01

Drug discovery today is impossible without sophisticated modeling and computation. In this review we touch on previous advances in computational biology and by tracing the steps involved in pharmaceutical development, we explore a range of novel, high value opportunities for computational innovation in modeling the biological process of disease and the social process of drug discovery. These opportunities include text mining for new drug leads, modeling molecular pathways and predicting the efficacy of drug cocktails, analyzing genetic overlap between diseases and predicting alternative drug use. Computation can also be used to model research teams and innovative regions and to estimate the value of academy-industry ties for scientific and human benefit. Attention to these opportunities could promise punctuated advance, and will complement the well-established computational work on which drug discovery currently relies. PMID:19674801

Component architecture in drug discovery informatics.

PubMed

Smith, Peter M

2002-05-01

This paper reviews the characteristics of a new model of computing that has been spurred on by the Internet, known as Netcentric computing. Developments in this model led to distributed component architectures, which, although not new ideas, are now realizable with modern tools such as Enterprise Java. The application of this approach to scientific computing, particularly in pharmaceutical discovery research, is discussed and highlighted by a particular case involving the management of biological assay data.

Responding to Hard Times in the "Big Easy": Meeting the Vocational Needs of Low-Income African American New Orleans Residents

ERIC Educational Resources Information Center

Lyons, Heather Z.

2011-01-01

The already limited vocational prospects of low-income African Americans in New Orleans were further devastated by Hurricane Katrina in 2005. The 2010 Deepwater Horizon oil spill added to the devastation, highlighting the continued vulnerability of New Orleanians seeking employment. As a result, opportunities persist for vocational practitioners…

Strategic Communication in Pursuit of National Interests

DTIC Science & Technology

2012-03-22

the tsunami-induced loss of electricity triggered a hydrogen explosion at Fukushima Daiichi Nuclear Power Plant, further compounding the disaster .38...assistance and disaster relief. Operation Tomodachi conducted in Japan after the devastating earthquake and tsunami in spring of 2011 provided an...humanitarian assistance and disaster relief. Operation Tomodachi conducted in Japan after the devastating earthquake and tsunami in spring of 2011 provided

Talking about Twisters: Relations between Mothers' and Children's Contributions to Conversations about a Devastating Tornado

ERIC Educational Resources Information Center

Bauer, Patricia J.; Burch, Melissa M.; Van Abbema, Dana L.; Ackil, Jennifer K.

2007-01-01

Mother-child dyads who experienced a devastating tornado talked about the storm and about two affectively more positive or neutral events at each of two time points: 4 months and 10 months after the storm. The conversations were analyzed to determine whether mothers and/or children's contributions differed as a function of event type and whether…

[Cooperation and support activities of infection control after the Great East Japan Earthquake].

PubMed

Hatta, Masumitsu; Kaku, Mitsuo

2013-12-01

On 11 March 2011, an earthquake measuring 9.0 on the Richter scale occurred off the northeast coast of Honshu Island, Japan, produced a devastating tsunami that destroyed many towns and villages near the coast in Iwate, Miyagi, and Fukushima prefectures. Miyagi Prefecture was the area most severely devastated by the tsunami, with extensive loss of life and property; hundreds of thousands of people lost their houses and were forced to move to evacuation areas. In the days and weeks following devastating natural disasters, the threat of infectious disease outbreak is high. We initiated cooperation and support activities in terms of infection control at evacuation centers in the aftermath of the disaster. For example, we assessed sanitary and infectious risk factors in evacuation centers, in collaboration with Miyagi Prefectural Government and public health centers in the devastated area, to prevent the transmission of infectious diseases among evacuees. We also supported the control of two outbreaks of influenza A, which occurred in different centers in Miyagi Prefecture in the early period after the disaster. Both outbreaks subsided without any complicated or fatal cases of influenza as a result of the prompt implementation of a systemic approach with a bundle of control measures.

Function-driven discovery of disease genes in zebrafish using an integrated genomics big data resource.

PubMed

Shim, Hongseok; Kim, Ji Hyun; Kim, Chan Yeong; Hwang, Sohyun; Kim, Hyojin; Yang, Sunmo; Lee, Ji Eun; Lee, Insuk

2016-11-16

Whole exome sequencing (WES) accelerates disease gene discovery using rare genetic variants, but further statistical and functional evidence is required to avoid false-discovery. To complement variant-driven disease gene discovery, here we present function-driven disease gene discovery in zebrafish (Danio rerio), a promising human disease model owing to its high anatomical and genomic similarity to humans. To facilitate zebrafish-based function-driven disease gene discovery, we developed a genome-scale co-functional network of zebrafish genes, DanioNet (www.inetbio.org/danionet), which was constructed by Bayesian integration of genomics big data. Rigorous statistical assessment confirmed the high prediction capacity of DanioNet for a wide variety of human diseases. To demonstrate the feasibility of the function-driven disease gene discovery using DanioNet, we predicted genes for ciliopathies and performed experimental validation for eight candidate genes. We also validated the existence of heterozygous rare variants in the candidate genes of individuals with ciliopathies yet not in controls derived from the UK10K consortium, suggesting that these variants are potentially involved in enhancing the risk of ciliopathies. These results showed that an integrated genomics big data for a model animal of diseases can expand our opportunity for harnessing WES data in disease gene discovery. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Devastating metabolic brain disorders of newborns and young infants.

PubMed

Yoon, Hyun Jung; Kim, Ji Hye; Jeon, Tae Yeon; Yoo, So-Young; Eo, Hong

2014-01-01

Metabolic disorders of the brain that manifest in the neonatal or early infantile period are usually associated with acute and severe illness and are thus referred to as devastating metabolic disorders. Most of these disorders may be classified as organic acid disorders, amino acid metabolism disorders, primary lactic acidosis, or fatty acid oxidation disorders. Each disorder has distinctive clinical, biochemical, and radiologic features. Early diagnosis is important both for prompt treatment to prevent death or serious sequelae and for genetic counseling. However, diagnosis is often challenging because many findings overlap and may mimic those of more common neonatal conditions, such as hypoxic-ischemic encephalopathy and infection. Ultrasonography (US) may be an initial screening method for the neonatal brain, and magnetic resonance (MR) imaging is the modality of choice for evaluating metabolic brain disorders. Although nonspecific imaging findings are common in early-onset metabolic disorders, characteristic patterns of brain involvement have been described for several disorders. In addition, diffusion-weighted images may be used to characterize edema during an acute episode of encephalopathy, and MR spectroscopy depicts changes in metabolites that may help diagnose metabolic disorders and assess response to treatment. Imaging findings, including those of advanced MR imaging techniques, must be closely reviewed. If one of these rare disorders is suspected, the appropriate biochemical test or analysis of the specific gene should be performed to confirm the diagnosis. ©RSNA, 2014.

Ethical controversies surrounding the management of potential organ donors in the emergency department.

PubMed

Venkat, Arvind; Baker, Eileen F; Schears, Raquel M

2014-08-01

On a daily basis, emergency physicians are confronted by patients with devastating neurological injuries and insults. Some of these patients, despite our best efforts, will not survive. However, from these tragedies, there may be benefit given to others who are awaiting organ transplantation. Steps taken in the emergency department (ED) can be critical to preserving the option of organ donation in patients whose neurologic insult places them on a potential path to declaration of brain death. Much of the literature on this subject has focused on the utilitarian value of clinical interventions in the potential organ donor to optimize the likelihood of effective organ procurement. In this article, we present an actual case that reveals additional ethical perspectives to consider in how emergency physicians manage patients in the ED who can be confidently predicted to progress to death, as attested by neurologic criteria, and become organ donors. The case involves a patient with a devastating, nonsurvivable intracerebral hemorrhage who rapidly progressed to hemodynamic instability. This case reveals how the current organ donor referral and maintenance system raises ethical tensions for emergency physicians and ED personnel. This process imposes limitations on communication with patient surrogate decision-makers while calling for interventions with the primary purpose of benefiting off-site patients awaiting transplantation. Copyright © 2014 Elsevier Inc. All rights reserved.

Acute intraoperative heparin-induced thrombocytopenia (HIT) and thrombosis during coronary artery bypass grafting: Two case reports providing evidence for the role of preoperative LMWH in triggering sensitization.

PubMed

Khoury, M; Pitsis, A; Poumpouridou-Kioura, H; Soufla, G; Kanthou, C; Matoula, N; Angelidis, A; Melissari, E

2016-10-01

Systemic anticoagulation is necessary during cardiac surgery. To date, the only well established anticoagulation protocol involves the use of heparin. However, heparin can cause heparin-induced thrombocytopenia (HIT) a potentially life threatening immune-mediated thromboembolic syndrome. Until now, devastating consequences of HIT syndrome in patients undergoing heart surgery have been described, but only postoperatively. Here we report the development of HIT syndrome during cardiac revascularization by intra-operative heparin administration in two patients previously exposed to LMWH. We report on two patients who developed rapid and profound intravascular coagulation with severe thrombocytopenia (platelet count decreased from ≥250×10 9 /L to 50×10 9 /L) due to HIT development caused by heparin administration during coronary artery bypass graft surgery. In addition we report that fondaparinux, given intra-operatively in association with antithrombin, may be a suitable alternative anticoagulant for successfully preventing the devastating consequences of intra-operative HIT development. To our knowledge, this is the first report describing the development of acute intra-operative HIT, secondary to high-dose UFH administered for coronary revascularization, in which the unexpected presence of platelet-activating anti-PF4/heparin antibodies at surgery was explained by preoperative administration of a one-week course of LMWH but without any preoperative evidence for HIT. Copyright © 2016 Elsevier Ltd. All rights reserved.

Causal discovery and inference: concepts and recent methodological advances.

PubMed

Spirtes, Peter; Zhang, Kun

This paper aims to give a broad coverage of central concepts and principles involved in automated causal inference and emerging approaches to causal discovery from i.i.d data and from time series. After reviewing concepts including manipulations, causal models, sample predictive modeling, causal predictive modeling, and structural equation models, we present the constraint-based approach to causal discovery, which relies on the conditional independence relationships in the data, and discuss the assumptions underlying its validity. We then focus on causal discovery based on structural equations models, in which a key issue is the identifiability of the causal structure implied by appropriately defined structural equation models: in the two-variable case, under what conditions (and why) is the causal direction between the two variables identifiable? We show that the independence between the error term and causes, together with appropriate structural constraints on the structural equation, makes it possible. Next, we report some recent advances in causal discovery from time series. Assuming that the causal relations are linear with nonGaussian noise, we mention two problems which are traditionally difficult to solve, namely causal discovery from subsampled data and that in the presence of confounding time series. Finally, we list a number of open questions in the field of causal discovery and inference.

RNA-based ovarian cancer research from 'a gene to systems biomedicine' perspective.

PubMed

Gov, Esra; Kori, Medi; Arga, Kazim Yalcin

2017-08-01

Ovarian cancer remains the leading cause of death from a gynecologic malignancy, and treatment of this disease is harder than any other type of female reproductive cancer. Improvements in the diagnosis and development of novel and effective treatment strategies for complex pathophysiologies, such as ovarian cancer, require a better understanding of disease emergence and mechanisms of progression through systems medicine approaches. RNA-level analyses generate new information that can help in understanding the mechanisms behind disease pathogenesis, to identify new biomarkers and therapeutic targets and in new drug discovery. Whole RNA sequencing and coding and non-coding RNA expression array datasets have shed light on the mechanisms underlying disease progression and have identified mRNAs, miRNAs, and lncRNAs involved in ovarian cancer progression. In addition, the results from these analyses indicate that various signalling pathways and biological processes are associated with ovarian cancer. Here, we present a comprehensive literature review on RNA-based ovarian cancer research and highlight the benefits of integrative approaches within the systems biomedicine concept for future ovarian cancer research. We invite the ovarian cancer and systems biomedicine research fields to join forces to achieve the interdisciplinary caliber and rigor required to find real-life solutions to common, devastating, and complex diseases such as ovarian cancer. CAF: cancer-associated fibroblasts; COG: Cluster of Orthologous Groups; DEA: disease enrichment analysis; EOC: epithelial ovarian carcinoma; ESCC: oesophageal squamous cell carcinoma; GSI: gamma secretase inhibitor; GO: Gene Ontology; GSEA: gene set enrichment analyzes; HAS: Hungarian Academy of Sciences; lncRNAs: long non-coding RNAs; MAPK/ERK: mitogen-activated protein kinase/extracellular signal-regulated kinases; NGS: next-generation sequencing; ncRNAs: non-coding RNAs; OvC: ovarian cancer; PI3K/Akt/mTOR: phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin; RT-PCR: real-time polymerase chain reaction; SNP: single nucleotide polymorphism; TF: transcription factor; TGF-β: transforming growth factor-β.

At the cross-roads of participatory research and biomarker discovery in autism: the need for empirical data.

PubMed

Yusuf, Afiqah; Elsabbagh, Mayada

2015-12-15

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

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.

Economic Dimensions of Civil Conflicts

DTIC Science & Technology

2012-09-01

international system after the Cold War , due to changes in the nature of war , and globalization. First , before the Cold War , insurgent movements were dependent...socialist and post-secession transitions.121 First , the civil war and NATO’s air bombardment devastated the country and an already crippled economic...Uncertainty The devastation of war , a volatile security environment and political uncertainty were the first major obstacles for post-conflict economic

In situ click chemistry: a powerful means for lead discovery.

PubMed

Sharpless, K Barry; Manetsch, Roman

2006-11-01

Combinatorial chemistry and parallel synthesis are important and regularly applied tools for lead identification and optimisation, although they are often accompanied by challenges related to the efficiency of library synthesis and the purity of the compound library. In the last decade, novel means of lead discovery approaches have been investigated where the biological target is actively involved in the synthesis of its own inhibitory compound. These fragment-based approaches, also termed target-guided synthesis (TGS), show great promise in lead discovery applications by combining the synthesis and screening of libraries of low molecular weight compounds in a single step. Of all the TGS methods, the kinetically controlled variant is the least well known, but it has the potential to emerge as a reliable lead discovery method. The kinetically controlled TGS approach, termed in situ click chemistry, is discussed in this article.

Classic fungal natural products in the genomic age: the molecular legacy of Harold Raistrick.

PubMed

Schor, Raissa; Cox, Russell

2018-03-01

Covering: 1893 to 2017Harold Raistrick was involved in the discovery of many of the most important classes of fungal metabolites during the 20th century. This review focusses on how these discoveries led to developments in isotopic labelling, biomimetic chemistry and the discovery, analysis and exploitation of biosynthetic gene clusters for major classes of fungal metabolites including: alternariol; geodin and metabolites of the emodin pathway; maleidrides; citrinin and the azaphilones; dehydrocurvularin; mycophenolic acid; and the tropolones. Key recent advances in the molecular understanding of these important pathways, including the discovery of biosynthetic gene clusters, the investigation of the molecular and chemical aspects of key biosynthetic steps, and the reengineering of key components of the pathways are reviewed and compared. Finally, discussion of key relationships between metabolites and pathways and the most important recent advances and opportunities for future research directions are given.

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

Perl, M.

This is a history of my discovery of the tau lepton in the 1970s for which I was awarded the Nobel Prize in Physics. I have previously described some aspects of the discovery. In 1996 in my collection of papers entitled, ''Reflections on Experimental Science,'' I gave a straightforward account of the experimental method and the physics involved in the discovery as an introduction to the collection. In a 2002 paper written with Mary A. Meyer published in the journal ''Theoria et Historia Scientiarum'' I used the story of the discovery to outline my thoughts on the practice of experimentalmore » science. That 2002 paper was written primarily for young women and men who are beginning their lives in science and it was based on a lecture given at Los Alamos National Laboratory. Some of the historical material in this paper has appeared in those two earlier papers.« less

Discovery of novel drug targets and their functions using phenotypic screening of natural products.

PubMed

Chang, Junghwa; Kwon, Ho Jeong

2016-03-01

Natural products are valuable resources that provide a variety of bioactive compounds and natural pharmacophores in modern drug discovery. Discovery of biologically active natural products and unraveling their target proteins to understand their mode of action have always been critical hurdles for their development into clinical drugs. For effective discovery and development of bioactive natural products into novel therapeutic drugs, comprehensive screening and identification of target proteins are indispensable. In this review, a systematic approach to understanding the mode of action of natural products isolated using phenotypic screening involving chemical proteomics-based target identification is introduced. This review highlights three natural products recently discovered via phenotypic screening, namely glucopiericidin A, ecumicin, and terpestacin, as representative case studies to revisit the pivotal role of natural products as powerful tools in discovering the novel functions and druggability of targets in biological systems and pathological diseases of interest.

A history of the DNA repair and mutagenesis field: The discovery of base excision repair.

PubMed

Friedberg, Errol C

2016-01-01

This article reviews the early history of the discovery of an DNA repair pathway designated as base excision repair (BER), since in contrast to the enzyme-catalyzed removal of damaged bases from DNA as nucleotides [called nucleotide excision repair (NER)], BER involves the removal of damaged or inappropriate bases, such as the presence of uracil instead of thymine, from DNA as free bases. Copyright © 2015. Published by Elsevier B.V.

Gene-Specific Demethylation as Targeted Therapy in MDS

DTIC Science & Technology

2016-07-01

methylation remain elusive. This proposal builds on our recent discovery of a novel class of RNAs , the DiRs or DNMT1-interacting RNAs , involved in...cell type-specific DNA methylation patterns. Based on these findings, we hypothesize that DNA methylation changes can be corrected by RNAs . We aim to...aberrant DNA methylation remain elusive. This proposal builds on our recent discovery of a novel class of RNAs , the DiRs or DNMT1-interacting RNAs

Paradigms: examples from the bacterium Xylella fastidiosa.

PubMed

Purcell, Alexander

2013-01-01

The history of advances in research on Xylella fastidiosa provides excellent examples of how paradigms both advance and limit our scientific understanding of plant pathogens and the plant diseases they cause. I describe this from a personal perspective, having been directly involved with many persons who made paradigm-changing discoveries, beginning with the discovery that a bacterium, not a virus, causes Pierce's disease of grape and other plant diseases in numerous plant species, including important crop and forest species.

One level up: abnormal proteolytic regulation of IGF activity plays a role in human pathophysiology.

PubMed

Argente, Jesús; Chowen, Julie A; Pérez-Jurado, Luis A; Frystyk, Jan; Oxvig, Claus

2017-10-01

The discovery of a mutation in a specific gene can be very important for determining the pathophysiology underlying the disease of a patient and may also help to decide the best treatment protocol on an individual basis. However, sometimes the discovery of mutations in new proteins advances our comprehension in a more widespread manner. The growth hormone (GH)/insulin-like growth factor (IGF)-1 axis is fundamental for systemic growth, but is also involved in many other important processes. Our understanding of this system in physiology and pathophysiology has advanced throughout the years with each discovery of mutations in members of this axis. This review focuses on the most recent discovery: mutations in the metalloproteinase pregnancy-associated plasma protein-A2 (PAPP-A2), one of the proteases involved in liberating IGF-1 from the complexes in which it circulates, in patients with delayed growth failure. We also discuss the advances in the stanniocalcins (STC1 and STC2), proteins that modulate PAPP-A2, as well as PAPP-A. These new advances not only bring us one step closer to understanding the strict spatial and temporal control of this axis in systemic growth and maturation, but also highlight possible therapeutic targets when this system goes awry. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Neurologic manifestations of chronic methamphetamine abuse

PubMed Central

Rusyniak, Daniel E.

2011-01-01

Summary Chronic methamphetamine abuse has devastating effects on the central nervous system. The degree to which addicts will tolerate the dysfunction in the way they think, feel, move, and even look, is a powerful testimony to the addictive properties of this drug. While the mechanisms behind these disorders are complex, at their heart they involve the recurring increase in the concentrations of central monoamines with subsequent dysfunction in dopaminergic neurotransmission. The mainstay of treatment for the problems associated with chronic methamphetamine abuse is abstinence. However, by recognizing the manifestations of chronic abuse, clinicians will be better able to help their patients get treatment for their addiction and to deal with the neurologic complications related to chronic abuse. PMID:21803215

Software support for Huntingtons disease research.

PubMed

Conneally, P M; Gersting, J M; Gray, J M; Beidleman, K; Wexler, N S; Smith, C L

1991-01-01

Huntingtons disease (HD) is a hereditary disorder involving the central nervous system. Its effects are devastating, to the affected person as well as his family. The Department of Medical and Molecular Genetics at Indiana University (IU) plays an integral part in Huntingtons research by providing computerized repositories of HD family information for researchers and families. The National Huntingtons Disease Research Roster, founded in 1979 at IU, and the Huntingtons Disease in Venezuela Project database contain information that has proven to be invaluable in the worldwide field of HD research. This paper addresses the types of information stored in each database, the pedigree database program (MEGADATS) used to manage the data, and significant findings that have resulted from access to the data.

Necrotizing Fasciitis of the lower extremity: a case report and current concept of diagnosis and management

PubMed Central

Naqvi, GA; Malik, SA; Jan, W

2009-01-01

Necrotizing fasciitis is a severe soft tissue infection characterized by rapidly progressing necrosis, involving subcutaneous tissues. This rare condition carries high mortality rate and require prompt diagnosis and urgent treatment with radical debridement and antibiotics. We describe a case of 21-year old man who presented with the history of trivial injury to the knee. Initially he was admitted and treated for septic arthritis but later was diagnosed as necrotizing fasciitis which was successfully treated with no ill effects what so ever from this devastating condition. This rare condition has been reported in literature but still early diagnosis, which is a key for successful treatment, remains a challenge. PMID:19527519

The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

NASA Astrophysics Data System (ADS)

Bürli, Roland W.; Thomas, Elizabeth; Beaumont, Vahri

Neurodegenerative disorders are devastating for patients and their social environment. Their etiology is poorly understood and complex. As a result, there is clearly an urgent need for therapeutic agents that slow down disease progress and alleviate symptoms. In this respect, interference with expression and function of multiple gene products at the epigenetic level has offered much promise, and histone deacetylases play a crucial role in these processes. This review presents an overview of the biological pathways in which these enzymes are involved and illustrates the complex network of proteins that governs their activity. An overview of small molecules that interfere with histone deacetylase function is provided.

Cancer cachexia: understanding the molecular basis.

PubMed

Argilés, Josep M; Busquets, Sílvia; Stemmler, Britta; López-Soriano, Francisco J

2014-11-01

Cancer cachexia is a devastating, multifactorial and often irreversible syndrome that affects around 50-80% of cancer patients, depending on the tumour type, and that leads to substantial weight loss, primarily from loss of skeletal muscle and body fat. Since cachexia may account for up to 20% of cancer deaths, understanding the underlying molecular mechanisms is essential. The occurrence of cachexia in cancer patients is dependent on the patient response to tumour progression, including the activation of the inflammatory response and energetic inefficiency involving the mitochondria. Interestingly, crosstalk between different cell types ultimately seems to result in muscle wasting. Some of the recent progress in understanding the molecular mechanisms of cachexia may lead to new therapeutic approaches.

The role of Epstein-Barr virus in systemic lupus erythematosus.

PubMed

McClain, M T; Harley, J B; James, J A

2001-10-01

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease with no known cure. Lupus patients suffer from a myriad of clinical symptoms which variably include arthritis, pleuritis, pericarditis, vasculitis, and nephritis. The underlying mechanisms behind these clinical findings and the etiologic events preceding and causing disease onset, however, remain largely unknown. For many years, investigators have suspected that Epstein-Barr virus might somehow be involved in the etiology and/or pathogenesis of systemic lupus. Numerous studies have examined this possibility from various angles and have arrived at different conclusions. This work reviews these historical papers in the context of new results and presents a hypothetical role for this virus as an etiological environmental trigger for SLE.

Pennies and Eggs: Initiation into Inquiry Learning for Preservice Elementary Education Teachers

ERIC Educational Resources Information Center

Wink, Donald J.; Hwang-Choe, Jeong Hye

2008-01-01

Two labs incorporating the Science Writing Heuristic are described that introduce scientific inquiry in a course for preservice students majoring in elementary education. One lab adapts a previously described discovery learning opportunity involving the change in composition and mass of pennies in 1982. The other involves the use of flotation…

Framing the Undergraduate Research Experience: Discovery Involvement in Retailing Undergraduate Education

ERIC Educational Resources Information Center

Sternquist, Brenda; Huddleston, Patricia; Fairhurst, Ann

2018-01-01

We provide an overview of ways to involve undergraduate business and retailing students in faculty research projects and discuss advantages of these student-faculty collaborations. We use Kolb's experiential learning cycle to provide a framework for creating an effective and engaging undergraduate research experience and use it to classify types…

The Immune System’s Role in the Biology of Autism

PubMed Central

Goines, Paula; Van de Water, Judy

2010-01-01

PURPOSE OF REVIEW The following is a review of the most recent research concerning the potential role of immune system dysfunction in autism. This body of literature has expanded dramatically over the past few years as researchers continue to identify immune anomalies in individuals with autism. RECENT FINDINGS The most exciting of these recent findings is the discovery of autoantibodies targeting brain proteins in both children with autism and their mothers. In particular, circulating maternal autoantibodies directed towards fetal brain proteins are highly specific for autism. This finding has great potential as a biomarker for disease risk, and may provide an avenue for future therapeutics and prevention. Additionally, data concerning the cellular immune system in children with autism suggest there may be a defect in signaling pathways that are shared by the immune and central nervous systems. While studies to explore this hypothesis are ongoing, there is great interest in the commonalities between the neural and immune systems and their extensive interactions. SUMMARY In summary, there is exciting research regarding the role of the immune system in autism spectrum disorders that may have profound implications for diagnosis and treatment of this devastating disease. PMID:20160651

Epigenetics, microbiota, and intraocular inflammation: New paradigms of immune regulation in the eye.

PubMed

Wen, Xiaofeng; Hu, Xiao; Miao, Li; Ge, Xiaofei; Deng, Yuhua; Bible, Paul W; Wei, Lai

2018-05-01

Sight threatening immune responses that damage the eye characterize intraocular inflammatory diseases. These diseases including uveitis and age-related macular degeneration are worryingly common and quality of life shattering. Genetic studies in past decades significantly advanced our understanding of the etiology of these devastating diseases. Unfortunately, patient genetics alone failed to adequately explain disease origin, susceptibility, and progression. Non-genetic factors such as the epigenetic regulation of ocular diseases and the environmental factors triggering intraocular inflammation offer new insight into intraocular inflammatory disorders. Importantly, mounting evidence is signaling that dysbiosis of human microbiota leads to rapid epigenomic reprograming of host cells and results in the onset of many diseases. In this review, we discuss how epigenetic mechanisms and microbiota may cooperate to initiate and perpetuate ocular inflammation. Lastly, we propose that the discovery of intraocular microbiota presents a significant shift in thought affecting current approaches to the diagnosis, treatment, and prevention of intraocular inflammatory diseases such as uveitis and age-related macular degeneration. The geographical and genetic background difference in both disease presentation and genetic association of intraocular inflammatory diseases may be due to the variation of intraocular microbiota. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Transfer of a cyanobacterial neurotoxin within a temperate aquatic ecosystem suggests pathways for human exposure

PubMed Central

Jonasson, Sara; Eriksson, Johan; Berntzon, Lotta; Spáčil, Zdenĕk; Ilag, Leopold L.; Ronnevi, Lars-Olof; Rasmussen, Ulla; Bergman, Birgitta

2010-01-01

β-methylamino-L-alanine (BMAA), a neurotoxic nonprotein amino acid produced by most cyanobacteria, has been proposed to be the causative agent of devastating neurodegenerative diseases on the island of Guam in the Pacific Ocean. Because cyanobacteria are widespread globally, we hypothesized that BMAA might occur and bioaccumulate in other ecosystems. Here we demonstrate, based on a recently developed extraction and HPLC-MS/MS method and long-term monitoring of BMAA in cyanobacterial populations of a temperate aquatic ecosystem (Baltic Sea, 2007–2008), that BMAA is biosynthesized by cyanobacterial genera dominating the massive surface blooms of this water body. BMAA also was found at higher concentrations in organisms of higher trophic levels that directly or indirectly feed on cyanobacteria, such as zooplankton and various vertebrates (fish) and invertebrates (mussels, oysters). Pelagic and benthic fish species used for human consumption were included. The highest BMAA levels were detected in the muscle and brain of bottom-dwelling fishes. The discovery of regular biosynthesis of the neurotoxin BMAA in a large temperate aquatic ecosystem combined with its possible transfer and bioaccumulation within major food webs, some ending in human consumption, is alarming and requires attention. PMID:20439734

Child dermoid cyst mimicking a craniopharyngioma: the benefit of MRI T2-weighted diffusion sequence.

PubMed

Amelot, Aymeric; Borha, Alin; Calmon, Raphael; Barbet, Patrick; Puget, Stephanie

2018-02-01

Brain dermoid cysts are very rare lesions. Although benign, these cysts may be associated with devastating complications due to mass effect or meningitis. The discovery of completely asymptomatic dermoid cysts in the pediatric population is exceedingly rare. Despite the advances in imaging modalities, it sometimes remains difficult to exclude the differential diagnosis of craniopharyngioma. We describe a 12-year-old boy addressed for suspicion of craniopharyngioma diagnosed by decreased visual acuity, bitemporal hemianopia and a CT scan showing a large hypodense suprasellar lesion with intralesional calcifications. Despite the unusual localization and size of this lesion, the absence of dermal sinus commonly found, and before visualizing a hyperintense mass on MRI-diffusion, the diagnosis of craniopharyngioma was ruled out in favor of a dermoid cyst. Radical excision was performed. In the suprasellar area, craniopharyngioma and dermoid cyst may have very similar radiological aspects: low density masses on CT scan and a hyperintense signal on T1-weighted MRI sequences with a variable signal on T2-weighted sequences. Hitherto, only two cases in literature have described suprasellar dermoid cyst. Their initial diagnosis was facilitated by the presence of a dermal sinus.

A Physicist’s Quest in Biology: Max Delbrück and “Complementarity”

PubMed Central

Strauss, Bernard S.

2017-01-01

Max Delbrück was trained as a physicist but made his major contribution in biology and ultimately shared a Nobel Prize in Physiology or Medicine. He was the acknowledged leader of the founders of molecular biology, yet he failed to achieve his key scientific goals. His ultimate scientific aim was to find evidence for physical laws unique to biology: so-called “complementarity.” He never did. The specific problem he initially wanted to solve was the nature of biological replication but the discovery of the mechanism of replication was made by others, in large part because of his disdain for the details of biochemistry. His later career was spent investigating the effect of light on the fungus Phycomyces, a topic that turned out to be of limited general interest. He was known both for his informality but also for his legendary displays of devastating criticism. His life and that of some of his closest colleagues was acted out against a background of a world in conflict. This essay describes the man and his career and searches for an explanation of his profound influence. PMID:28592501

A Physicist's Quest in Biology: Max Delbrück and "Complementarity".

PubMed

Strauss, Bernard S

2017-06-01

Max Delbrück was trained as a physicist but made his major contribution in biology and ultimately shared a Nobel Prize in Physiology or Medicine. He was the acknowledged leader of the founders of molecular biology, yet he failed to achieve his key scientific goals. His ultimate scientific aim was to find evidence for physical laws unique to biology: so-called "complementarity." He never did. The specific problem he initially wanted to solve was the nature of biological replication but the discovery of the mechanism of replication was made by others, in large part because of his disdain for the details of biochemistry. His later career was spent investigating the effect of light on the fungus Phycomyces , a topic that turned out to be of limited general interest. He was known both for his informality but also for his legendary displays of devastating criticism. His life and that of some of his closest colleagues was acted out against a background of a world in conflict. This essay describes the man and his career and searches for an explanation of his profound influence. Copyright © 2017 by the Genetics Society of America.

Patient-Specific Pluripotent Stem Cells in Neurological Diseases

PubMed Central

Durnaoglu, Serpen; Genc, Sermin; Genc, Kursad

2011-01-01

Many human neurological diseases are not currently curable and result in devastating neurologic sequelae. The increasing availability of induced pluripotent stem cells (iPSCs) derived from adult human somatic cells provides new prospects for cellreplacement strategies and disease-related basic research in a broad spectrum of human neurologic diseases. Patient-specific iPSC-based modeling of neurogenetic and neurodegenerative diseases is an emerging efficient tool for in vitro modeling to understand disease and to screen for genes and drugs that modify the disease process. With the exponential increase in iPSC research in recent years, human iPSCs have been successfully derived with different technologies and from various cell types. Although there remain a great deal to learn about patient-specific iPSC safety, the reprogramming mechanisms, better ways to direct a specific reprogramming, ideal cell source for cellular grafts, and the mechanisms by which transplanted stem cells lead to an enhanced functional recovery and structural reorganization, the discovery of the therapeutic potential of iPSCs offers new opportunities for the treatment of incurable neurologic diseases. However, iPSC-based therapeutic strategies need to be thoroughly evaluated in preclinical animal models of neurological diseases before they can be applied in a clinical setting. PMID:21776279

Effector proteins of rust fungi.

PubMed

Petre, Benjamin; Joly, David L; Duplessis, Sébastien

2014-01-01

Rust fungi include many species that are devastating crop pathogens. To develop resistant plants, a better understanding of rust virulence factors, or effector proteins, is needed. Thus far, only six rust effector proteins have been described: AvrP123, AvrP4, AvrL567, AvrM, RTP1, and PGTAUSPE-10-1. Although some are well established model proteins used to investigate mechanisms of immune receptor activation (avirulence activities) or entry into plant cells, how they work inside host tissues to promote fungal growth remains unknown. The genome sequences of four rust fungi (two Melampsoraceae and two Pucciniaceae) have been analyzed so far. Genome-wide analyses of these species, as well as transcriptomics performed on a broader range of rust fungi, revealed hundreds of small secreted proteins considered as rust candidate secreted effector proteins (CSEPs). The rust community now needs high-throughput approaches (effectoromics) to accelerate effector discovery/characterization and to better understand how they function in planta. However, this task is challenging due to the non-amenability of rust pathosystems (obligate biotrophs infecting crop plants) to traditional molecular genetic approaches mainly due to difficulties in culturing these species in vitro. The use of heterologous approaches should be promoted in the future.

The Genetics of Pulmonary Arterial Hypertension

PubMed Central

Austin, Eric D.; Loyd, James E.

2014-01-01

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease for which there is an ever-expanding body of genetic and related pathophysiological information on disease pathogenesis. A number of germline gene mutations have now been described, including mutations in the gene coding bone morphogenic protein receptor type 2 (BMPR2) and related genes. Recent advanced gene sequencing methods have facilitated the discovery of additional genes with mutations among those with and without familial forms of PAH (CAV1, KCNK3, EIF2AK4). The reduced penetrance, variable expressivity, and female predominance of PAH suggest that genetic, genomic and other factors modify disease expression. These multi-faceted variations are an active area of investigation in the field, including but not limited to common genetic variants and epigenetic processes, and may provide novel opportunities for pharmacologic intervention in the near future. They also highlight the need for a systems-oriented multi-level approach to incorporate the multitude of biologic variations now associated with PAH. Ultimately, improved understanding provides the opportunity for improved patient and family counseling about this devastating disease, but do require in depth understanding of the genetic factors relevant to PAH. PMID:24951767

Computational Biology Tools for Identifying Specific Ligand Binding Residues for Novel Agrochemical and Drug Design.

PubMed

Neshich, Izabella Agostinho Pena; Nishimura, Leticia; de Moraes, Fabio Rogerio; Salim, Jose Augusto; Villalta-Romero, Fabian; Borro, Luiz; Yano, Inacio Henrique; Mazoni, Ivan; Tasic, Ljubica; Jardine, Jose Gilberto; Neshich, Goran

2015-01-01

The term "agrochemicals" is used in its generic form to represent a spectrum of pesticides, such as insecticides, fungicides or bactericides. They contain active components designed for optimized pest management and control, therefore allowing for economically sound and labor efficient agricultural production. A "drug" on the other side is a term that is used for compounds designed for controlling human diseases. Although drugs are subjected to much more severe testing and regulation procedures before reaching the market, they might contain exactly the same active ingredient as certain agrochemicals, what is the case described in present work, showing how a small chemical compound might be used to control pathogenicity of Gram negative bacteria Xylella fastidiosa which devastates citrus plantations, as well as for control of, for example, meningitis in humans. It is also clear that so far the production of new agrochemicals is not benefiting as much from the in silico new chemical compound identification/discovery as pharmaceutical production. Rational drug design crucially depends on detailed knowledge of structural information about the receptor (target protein) and the ligand (drug/agrochemical). The interaction between the two molecules is the subject of analysis that aims to understand relationship between structure and function, mainly deciphering some fundamental elements of the nanoenvironment where the interaction occurs. In this work we will emphasize the role of understanding nanoenvironmental factors that guide recognition and interaction of target protein and its function modifier, an agrochemical or a drug. The repertoire of nanoenvironment descriptors is used for two selected and specific cases we have approached in order to offer a technological solution for some very important problems that needs special attention in agriculture: elimination of pathogenicity of a bacterium which is attacking citrus plants and formulation of a new fungicide. Finally, we also briefly describe a workflow which might be useful when research requires that model structures of target proteins are firstly generated (starting from genome sequences), followed by identification of ligand-target sites at the surface of those modeled structures, then application of procedures that adequately prepare both protein and ligand structures (the latter also involving filtration that satisfies acceptable adsorption/desorption/metabolism/excretion/toxicity [ADMET] parameters) for virtual high throughput screening (involving docking of ligands to indicated sites) and terminating by ranking of best pairs: target protein with selected ligand.

Personal discovery in diabetes self-management: Discovering cause and effect using self-monitoring data

PubMed Central

Mamykina, Lena; Heitkemper, Elizabeth M.; Smaldone, Arlene M.; Kukafka, Rita; Cole-Lewis, Heather J.; Davidson, Patricia G.; Mynatt, Elizabeth D.; Cassells, Andrea; Tobin, Jonathan N.; Hripcsak, George

2017-01-01

Objective To outline new design directions for informatics solutions that facilitate personal discovery with self-monitoring data. We investigate this question in the context of chronic disease self-management with the focus on type 2 diabetes. Materials and methods We conducted an observational qualitative study of discovery with personal data among adults attending a diabetes self-management education (DSME) program that utilized a discovery-based curriculum. The study included observations of class sessions, and interviews and focus groups with the educator and attendees of the program (n = 14). Results The main discovery in diabetes self-management evolved around discovering patterns of association between characteristics of individuals’ activities and changes in their blood glucose levels that the participants referred to as “cause and effect”. This discovery empowered individuals to actively engage in self-management and provided a desired flexibility in selection of personalized self-management strategies. We show that discovery of cause and effect involves four essential phases: (1) feature selection, (2) hypothesis generation, (3) feature evaluation, and (4) goal specification. Further, we identify opportunities to support discovery at each stage with informatics and data visualization solutions by providing assistance with: (1) active manipulation of collected data (e.g., grouping, filtering and side-by-side inspection), (2) hypotheses formulation (e.g., using natural language statements or constructing visual queries), (3) inference evaluation (e.g., through aggregation and visual comparison, and statistical analysis of associations), and (4) translation of discoveries into actionable goals (e.g., tailored selection from computable knowledge sources of effective diabetes self-management behaviors). Discussion The study suggests that discovery of cause and effect in diabetes can be a powerful approach to helping individuals to improve their self-management strategies, and that self-monitoring data can serve as a driving engine for personal discovery that may lead to sustainable behavior changes. Conclusions Enabling personal discovery is a promising new approach to enhancing chronic disease self-management with informatics interventions. PMID:28974460

Personal discovery in diabetes self-management: Discovering cause and effect using self-monitoring data.

PubMed

Mamykina, Lena; Heitkemper, Elizabeth M; Smaldone, Arlene M; Kukafka, Rita; Cole-Lewis, Heather J; Davidson, Patricia G; Mynatt, Elizabeth D; Cassells, Andrea; Tobin, Jonathan N; Hripcsak, George

2017-12-01

To outline new design directions for informatics solutions that facilitate personal discovery with self-monitoring data. We investigate this question in the context of chronic disease self-management with the focus on type 2 diabetes. We conducted an observational qualitative study of discovery with personal data among adults attending a diabetes self-management education (DSME) program that utilized a discovery-based curriculum. The study included observations of class sessions, and interviews and focus groups with the educator and attendees of the program (n = 14). The main discovery in diabetes self-management evolved around discovering patterns of association between characteristics of individuals' activities and changes in their blood glucose levels that the participants referred to as "cause and effect". This discovery empowered individuals to actively engage in self-management and provided a desired flexibility in selection of personalized self-management strategies. We show that discovery of cause and effect involves four essential phases: (1) feature selection, (2) hypothesis generation, (3) feature evaluation, and (4) goal specification. Further, we identify opportunities to support discovery at each stage with informatics and data visualization solutions by providing assistance with: (1) active manipulation of collected data (e.g., grouping, filtering and side-by-side inspection), (2) hypotheses formulation (e.g., using natural language statements or constructing visual queries), (3) inference evaluation (e.g., through aggregation and visual comparison, and statistical analysis of associations), and (4) translation of discoveries into actionable goals (e.g., tailored selection from computable knowledge sources of effective diabetes self-management behaviors). The study suggests that discovery of cause and effect in diabetes can be a powerful approach to helping individuals to improve their self-management strategies, and that self-monitoring data can serve as a driving engine for personal discovery that may lead to sustainable behavior changes. Enabling personal discovery is a promising new approach to enhancing chronic disease self-management with informatics interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

Open Access High Throughput Drug Discovery in the Public Domain: A Mount Everest in the Making

PubMed Central

Roy, Anuradha; McDonald, Peter R.; Sittampalam, Sitta; Chaguturu, Rathnam

2013-01-01

High throughput screening (HTS) facilitates screening large numbers of compounds against a biochemical target of interest using validated biological or biophysical assays. In recent years, a significant number of drugs in clinical trails originated from HTS campaigns, validating HTS as a bona fide mechanism for hit finding. In the current drug discovery landscape, the pharmaceutical industry is embracing open innovation strategies with academia to maximize their research capabilities and to feed their drug discovery pipeline. The goals of academic research have therefore expanded from target identification and validation to probe discovery, chemical genomics, and compound library screening. This trend is reflected in the emergence of HTS centers in the public domain over the past decade, ranging in size from modestly equipped academic screening centers to well endowed Molecular Libraries Probe Centers Network (MLPCN) centers funded by the NIH Roadmap initiative. These centers facilitate a comprehensive approach to probe discovery in academia and utilize both classical and cutting-edge assay technologies for executing primary and secondary screening campaigns. The various facets of academic HTS centers as well as their implications on technology transfer and drug discovery are discussed, and a roadmap for successful drug discovery in the public domain is presented. New lead discovery against therapeutic targets, especially those involving the rare and neglected diseases, is indeed a Mount Everestonian size task, and requires diligent implementation of pharmaceutical industry’s best practices for a successful outcome. PMID:20809896

JPRS Report, West Europe

DTIC Science & Technology

1987-06-05

Economy Through 1989 (Jan Magnus Fahlstrom; DAGENS NYHETER, 9 Apr 87) 98 SOCIAL SWEDEN Lapps Weigh Emigration Following Chernobyl Devastation...after Chernobyl the Soviet state is a bogeyman for the rest of the world—in human terms, economically and in the area of envir- onmental technology...election year." 11798 , CS0: 3650/102 99 „«„■P»T SWEDEN SOCIAL LAPPS WEIGH EMIGRATION FOLLOWING CHERNOBYL DEVASTATION Stockholm DAGENS NYHETER

Tiered analytics for purity assessment of macrocyclic peptides in drug discovery: Analytical consideration and method development.

PubMed

Qian Cutrone, Jingfang Jenny; Huang, Xiaohua Stella; Kozlowski, Edward S; Bao, Ye; Wang, Yingzi; Poronsky, Christopher S; Drexler, Dieter M; Tymiak, Adrienne A

2017-05-10

Synthetic macrocyclic peptides with natural and unnatural amino acids have gained considerable attention from a number of pharmaceutical/biopharmaceutical companies in recent years as a promising approach to drug discovery, particularly for targets involving protein-protein or protein-peptide interactions. Analytical scientists charged with characterizing these leads face multiple challenges including dealing with a class of complex molecules with the potential for multiple isomers and variable charge states and no established standards for acceptable analytical characterization of materials used in drug discovery. In addition, due to the lack of intermediate purification during solid phase peptide synthesis, the final products usually contain a complex profile of impurities. In this paper, practical analytical strategies and methodologies were developed to address these challenges, including a tiered approach to assessing the purity of macrocyclic peptides at different stages of drug discovery. Our results also showed that successful progression and characterization of a new drug discovery modality benefited from active analytical engagement, focusing on fit-for-purpose analyses and leveraging a broad palette of analytical technologies and resources. Copyright © 2017. Published by Elsevier B.V.

DPS Discovery Slide Sets for the Introductory Astronomy Instructor

NASA Astrophysics Data System (ADS)

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

2016-10-01

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

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

A Discovery-Based Experiment Involving Rearrangement in the Conversion of Alcohols to Alkyl Halides: Permanent Magnet [to the thirteenth power]C NMR in the First-Semester Organic Chemistry Lab

ERIC Educational Resources Information Center

Kjonaas, Richard A.; Tucker, Ryand J. F.

2008-01-01

The use of permanent magnet [to the thirteenth power]C NMR in large-section first-semester organic chemistry lab courses is limited by the availability of experiments that not only hinge on first-semester lecture topics, but which also produce at least 0.5 mL of neat liquid sample. This article reports a discovery-based experiment that meets both…

Discovery of a diazo-forming enzyme in cremeomycin biosynthesis.

PubMed

Waldman, Abraham J; Balskus, Emily P

2018-05-17

The molecular architectures and potent bioactivities of diazo-containing natural products have attracted the interest of synthetic and biological chemists. Despite this attention, the biosynthetic enzymes involved in diazo group construction have not been identified. Here, we show the ATP-dependent enzyme CreM installs the diazo group in cremeomycin via late-stage N-N bond formation using nitrite. This finding should inspire efforts to use diazo-forming enzymes in biocatalysis and synthetic biology and enable genome-based discovery of new diazo-containing metabolites.

Insecticide discovery: an evaluation and analysis.

PubMed

Sparks, Thomas C

2013-09-01

There is an on-going need for the discovery and development of new insecticides due to the loss of existing products through the development of resistance, the desire for products with more favorable environmental and toxicological profiles, shifting pest spectrums, and changing agricultural practices. Since 1960, the number of research-based companies in the US and Europe involved in the discovery of new insecticidal chemistries has been declining. In part this is a reflection of the increasing costs of the discovery and development of new pesticides. Likewise, the number of compounds that need to be screened for every product developed has, until recently, been climbing. In the past two decades the agrochemical industry has been able to develop a range of new products that have more favorable mammalian vs. insect selectivity. This review provides an analysis of the time required for the discovery, or more correctly the building process, for a wide range of insecticides developed during the last 60 years. An examination of the data around the time requirements for the discovery of products based on external patents, prior internal products, or entirely new chemistry provides some unexpected observations. In light of the increasing costs of discovery and development, coupled with fewer companies willing or able to make the investment, insecticide resistance management takes on greater importance as a means to preserve existing and new insecticides. Copyright © 2013 Elsevier Inc. All rights reserved.

Computational methods for a three-dimensional model of the petroleum-discovery process

USGS Publications Warehouse

Schuenemeyer, J.H.; Bawiec, W.J.; Drew, L.J.

1980-01-01

A discovery-process model devised by Drew, Schuenemeyer, and Root can be used to predict the amount of petroleum to be discovered in a basin from some future level of exploratory effort: the predictions are based on historical drilling and discovery data. Because marginal costs of discovery and production are a function of field size, the model can be used to make estimates of future discoveries within deposit size classes. The modeling approach is a geometric one in which the area searched is a function of the size and shape of the targets being sought. A high correlation is assumed between the surface-projection area of the fields and the volume of petroleum. To predict how much oil remains to be found, the area searched must be computed, and the basin size and discovery efficiency must be estimated. The basin is assumed to be explored randomly rather than by pattern drilling. The model may be used to compute independent estimates of future oil at different depth intervals for a play involving multiple producing horizons. We have written FORTRAN computer programs that are used with Drew, Schuenemeyer, and Root's model to merge the discovery and drilling information and perform the necessary computations to estimate undiscovered petroleum. These program may be modified easily for the estimation of remaining quantities of commodities other than petroleum. ?? 1980.

The future of discovery chemistry: quo vadis? Academic to industrial--the maturation of medicinal chemistry to chemical biology.

PubMed

Hoffmann, Torsten; Bishop, Cheryl

2010-04-01

At Roche, we set out to think about the future role of medicinal chemistry in drug discovery in a project involving both Roche internal stakeholders and external experts in drug discovery chemistry. To derive a coherent strategy, selected scientists were asked to take extreme positions and to derive two orthogonal strategic options: chemistry as the traditional mainstream science and chemistry as the central entrepreneurial science. We believe today's role of medicinal chemistry in industry has remained too narrow. To provide the innovation that industry requires, medicinal chemistry must play its part and diversify at pace with our increasing understanding of chemical biology and network pharmacology. 2010 Elsevier Ltd. All rights reserved.

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.

Integrated Computational Analysis of Genes Associated with Human Hereditary Insensitivity to Pain. A Drug Repurposing Perspective

PubMed Central

Lötsch, Jörn; Lippmann, Catharina; Kringel, Dario; Ultsch, Alfred

2017-01-01

Genes causally involved in human insensitivity to pain provide a unique molecular source of studying the pathophysiology of pain and the development of novel analgesic drugs. The increasing availability of “big data” enables novel research approaches to chronic pain while also requiring novel techniques for data mining and knowledge discovery. We used machine learning to combine the knowledge about n = 20 genes causally involved in human hereditary insensitivity to pain with the knowledge about the functions of thousands of genes. An integrated computational analysis proposed that among the functions of this set of genes, the processes related to nervous system development and to ceramide and sphingosine signaling pathways are particularly important. This is in line with earlier suggestions to use these pathways as therapeutic target in pain. Following identification of the biological processes characterizing hereditary insensitivity to pain, the biological processes were used for a similarity analysis with the functions of n = 4,834 database-queried drugs. Using emergent self-organizing maps, a cluster of n = 22 drugs was identified sharing important functional features with hereditary insensitivity to pain. Several members of this cluster had been implicated in pain in preclinical experiments. Thus, the present concept of machine-learned knowledge discovery for pain research provides biologically plausible results and seems to be suitable for drug discovery by identifying a narrow choice of repurposing candidates, demonstrating that contemporary machine-learned methods offer innovative approaches to knowledge discovery from available evidence. PMID:28848388

Finding the Real You

PubMed Central

Crowcroft, Andrew

1972-01-01

Everyone has to sift through influences and affectations before settling into their enduring 'identity, but is there really a single 'Crisis' involved or is it a gradual process of discovery and self-acceptance? PMID:27671130

Giant axonal neuropathy–associated gigaxonin mutations impair intermediate filament protein degradation

PubMed Central

Mahammad, Saleemulla; Murthy, S.N. Prasanna; Didonna, Alessandro; Grin, Boris; Israeli, Eitan; Perrot, Rodolphe; Bomont, Pascale; Julien, Jean-Pierre; Kuczmarski, Edward; Opal, Puneet; Goldman, Robert D.

2013-01-01

Giant axonal neuropathy (GAN) is an early-onset neurological disorder caused by mutations in the GAN gene (encoding for gigaxonin), which is predicted to be an E3 ligase adaptor. In GAN, aggregates of intermediate filaments (IFs) represent the main pathological feature detected in neurons and other cell types, including patients’ dermal fibroblasts. The molecular mechanism by which these mutations cause IFs to aggregate is unknown. Using fibroblasts from patients and normal individuals, as well as Gan–/– mice, we demonstrated that gigaxonin was responsible for the degradation of vimentin IFs. Gigaxonin was similarly involved in the degradation of peripherin and neurofilament IF proteins in neurons. Furthermore, proteasome inhibition by MG-132 reversed the clearance of IF proteins in cells overexpressing gigaxonin, demonstrating the involvement of the proteasomal degradation pathway. Together, these findings identify gigaxonin as a major factor in the degradation of cytoskeletal IFs and provide an explanation for IF aggregate accumulation, the subcellular hallmark of this devastating human disease. PMID:23585478

Recent advances in genes involved in secondary metabolite synthesis, hyphal development, energy metabolism and pathogenicity in Fusarium graminearum (teleomorph Gibberella zeae).

PubMed

Geng, Zongyi; Zhu, Wei; Su, Hao; Zhao, Yong; Zhang, Ke-Qin; Yang, Jinkui

2014-01-01

The ascomycete fungus, Fusarium graminearum (teleomorph Gibberella zeae), is the most common causal agent of Fusarium head blight (FHB), a devastating disease for cereal crops worldwide. F. graminearum produces ascospores (sexual spores) and conidia (asexual spores), which can serve as disease inocula of FHB. Meanwhile, Fusarium-infected grains are often contaminated with mycotoxins such as trichothecenes (TRIs), fumonisins, and zearalenones, among which TRIs are related to the pathogenicity of F. graminearum, and these toxins are hazardous to humans and livestock. In recent years, with the complete genome sequencing of F. graminearum, an increasing number of functional genes involved in the production of secondary metabolites, hyphal differentiation, sexual and asexual reproduction, virulence and pathogenicity have been identified from F. graminearum. In this review, the secondary metabolite synthesis, hyphal development and pathogenicity related genes in F. graminearum were thoroughly summarized, and the genes associated with secondary metabolites, sexual reproduction, energy metabolism, and pathogenicity were highlighted. Copyright © 2013 Elsevier Inc. All rights reserved.

Host-pathogen interaction in Fusarium oxysporum infections: where do we stand?

PubMed

Husaini, Amjad M; Sakina, Aafreen; Cambay, Souliha R

2018-03-16

Fusarium oxysporum, a ubiquitous soil-borne pathogen causes devastating vascular wilt in more than 100 plant species and ranks fifth among top ten fungal plant pathogens. It has emerged as a human pathogen too, causing infections in immune-compromised patients. It is, therefore, important to gain insight into the molecular processes involved in the pathogenesis of this trans-kingdom pathogen. A complex network comprising of interconnected and over lapping signal pathways; mitogen-activated protein kinase (MAPK) signaling pathways, Ras proteins, G-protein signaling components and their downstream pathways, components of the velvet (LaeA/VeA/VelB) complex and cAMP pathways, is involved in perceiving the host. This network regulates the expression of various pathogenicity genes. Plants have however evolved an elaborate protection system to combat this attack. They too possess intricate mechanisms at molecular level, which once triggered by pathogen attack transduce signals to activate defense response. This review focuses on understanding and presenting a wholistic picture of the molecular mechanisms of F. oxysporum-host interactions in plant immunity.

Multifocal lymphangioendotheliomatosis with devastating intracranial hemorrhage.

PubMed

Huang, Christina; Rizk, Elias; Iantosca, Mark; Zaenglein, Andrea L; Helm, Klaus F; Choudhary, Arabinda K; Dias, Mark S

2013-11-01

An in utero female was found to have a small hemorrhage at the foramen of Monro, hydrocephalus, and what was originally interpreted as a Dandy-Walker variant. At birth she had macrocephaly and numerous cutaneous, multifocal, red-pink blanchable macules. Postnatal MRI demonstrated a hemorrhagic soft-tissue mass involving the upper brainstem, thalamus, and basal ganglia most consistent with in utero complex multifocal intracranial hemorrhage. The skin lesions were thought to be consistent with multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT). The size and location of the hemorrhage precluded operative intervention, although the hydrocephalus was treated with a ventricular shunt. The child continues to have severe developmental delays. Multifocal lymphangioendotheliomatosis with thrombocytopenia is a multifocal vascular disorder most commonly involving the skin and gastrointestinal tract. Intracranial hemorrhages are rare in this context. This case is the third reported instance of MLT with associated intracranial hemorrhage and the only case described in the neurosurgical literature. The authors review the presenting features and pathophysiology of this condition.

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity.

PubMed

Sorrentino, Vincenzo; Romani, Mario; Mouchiroud, Laurent; Beck, John S; Zhang, Hongbo; D'Amico, Davide; Moullan, Norman; Potenza, Francesca; Schmid, Adrien W; Rietsch, Solène; Counts, Scott E; Auwerx, Johan

2017-12-14

Alzheimer's disease is a common and devastating disease characterized by aggregation of the amyloid-β peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer's disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-β proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-β proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer's disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-β proteotoxic diseases, such as Alzheimer's disease.

The Use of Stem Cells in Burn Wound Healing: A Review

PubMed Central

Ghieh, Fadi; Jurjus, Rosalyn; Ibrahim, Amir; Geagea, Alice Gerges; El Baba, Bassel; Chams, Sana; Matar, Michel; Zein, Wadih

2015-01-01

Burn wound healing involves a series of complex processes which are subject to intensive investigations to improve the outcomes, in particular, the healing time and the quality of the scar. Burn injuries, especially severe ones, are proving to have devastating effects on the affected patients. Stem cells have been recently applied in the field to promote superior healing of the wounds. Not only have stem cells been shown to promote better and faster healing of the burn wounds, but also they have decreased the inflammation levels with less scar progression and fibrosis. This review aims to highlight the beneficial therapeutic effect of stem cells in burn wound healing and to discuss the involved pathways and signaling molecules. The review covers various types of burn wound healing like skin and corneal burns, along with the alternative recent therapies being studied in the field of burn wound healing. The current reflection of the attitudes of people regarding the use of stem cells in burn wound healing is also stated. PMID:26236731

Hepatitis C virus in Arab world: a state of concern.

PubMed

Daw, Mohamed A; Dau, Aghnaya A

2012-01-01

Hepatitis C virus has been considered to be one of the most important devastating causes of chronic hepatitis, cirrhosis, and hepatic cellular carcinoma. The prevalence of such virus varies greatly over the world. Arab world has a unique geography and consists over nineteen countries who share the same heritage and customs and do speak the same language. In this area, the epidemiology of hepatitis C is not well understandable. Hepatitis C virus was found to be endemic in Arabia. The serostatus of such virus was found to be variable among these countries with uniform patterns of genotypes. Such prevalence varies tremendously according to the risk factors involved. Blood and blood products, haemodialysis, intravenous, and percutaneous drug users, and occupational, habitual, and social behavior were found to be the important factors involved. Hepatitis C will have major social, economic, and even political burdens on such young and dynamic societies. Thus, strategies and clear policy of intervention are urgently needed to combat the consequences of HCV both regionally and at state level of each country.

Children acquire the later-greater principle after the cardinal principle

PubMed Central

Le Corre, Mathieu

2014-01-01

Many have proposed that the acquisition of the cardinal principle is a result of the discovery of the numerical significance of the order of the number words in the count list. However, this need not be the case. Indeed, the cardinal principle does not state anything about the numerical significance of the order of the number words. It only states that the last word of a correct count denotes the numerosity of the counted set. Here we test whether the acquisition of the cardinal principle involves the discovery of the later-greater principle – i.e., that the order of the number words corresponds to the relative size of the numerosities they denote. Specifically, we tested knowledge of verbal numerical comparisons (e.g., Is “ten” more than “six”?) in children who had recently learned the cardinal principle. We find that these children can compare number words between “six” and “ten” only if they have mapped them onto non-verbal representations of numerosity. We suggest that this means that the acquisition of the cardinal principle does not involve the discovery of the correspondence between the order of the number words and the relative size of the numerosities they denote. PMID:24372336

Children acquire the later-greater principle after the cardinal principle.

PubMed

Le Corre, Mathieu

2014-06-01

Many have proposed that the acquisition of the cardinal principle (CP) is a result of the discovery of the numerical significance of the order of the number words in the count list. However, this need not be the case. Indeed, the CP does not state anything about the numerical significance of the order of the number words. It only states that the last word of a correct count denotes the numerosity of the counted set. Here, we test whether the acquisition of the CP involves the discovery of the later-greater principle - that is, that the order of the number words corresponds to the relative size of the numerosities they denote. Specifically, we tested knowledge of verbal numerical comparisons (e.g., Is 'ten' more than 'six'?) in children who had recently learned the CP. We find that these children can compare number words between 'six' and 'ten' only if they have mapped them onto non-verbal representations of numerosity. We suggest that this means that the acquisition of the CP does not involve the discovery of the correspondence between the order of the number words and the relative size of the numerosities they denote. © 2013 The British Psychological Society.

Levee Safety: Army Corps and FEMA Have Made Little Progress in Carrying Out Required Activities

DTIC Science & Technology

2016-07-01

risk of flooding. Their failure can contribute to loss of lives or property, as shown by the devastation of Hurricane Katrina in 2005. It is...loss of lives or property. The impact of levee failures was brought to national attention in 2005, when waves from Hurricane Katrina resulted in...communities with levees may not be carried out. Since the devastation of Hurricane Katrina in 2005, Congress has enacted legislation, including the Water

Antibiotic discovery throughout the Small World Initiative: A molecular strategy to identify biosynthetic gene clusters involved in antagonistic activity.

PubMed

Davis, Elizabeth; Sloan, Tyler; Aurelius, Krista; Barbour, Angela; Bodey, Elijah; Clark, Brigette; Dennis, Celeste; Drown, Rachel; Fleming, Megan; Humbert, Allison; Glasgo, Elizabeth; Kerns, Trent; Lingro, Kelly; McMillin, MacKenzie; Meyer, Aaron; Pope, Breanna; Stalevicz, April; Steffen, Brittney; Steindl, Austin; Williams, Carolyn; Wimberley, Carmen; Zenas, Robert; Butela, Kristen; Wildschutte, Hans

2017-06-01

The emergence of bacterial pathogens resistant to all known antibiotics is a global health crisis. Adding to this problem is that major pharmaceutical companies have shifted away from antibiotic discovery due to low profitability. As a result, the pipeline of new antibiotics is essentially dry and many bacteria now resist the effects of most commonly used drugs. To address this global health concern, citizen science through the Small World Initiative (SWI) was formed in 2012. As part of SWI, students isolate bacteria from their local environments, characterize the strains, and assay for antibiotic production. During the 2015 fall semester at Bowling Green State University, students isolated 77 soil-derived bacteria and genetically characterized strains using the 16S rRNA gene, identified strains exhibiting antagonistic activity, and performed an expanded SWI workflow using transposon mutagenesis to identify a biosynthetic gene cluster involved in toxigenic compound production. We identified one mutant with loss of antagonistic activity and through subsequent whole-genome sequencing and linker-mediated PCR identified a 24.9 kb biosynthetic gene locus likely involved in inhibitory activity in that mutant. Further assessment against human pathogens demonstrated the inhibition of Bacillus cereus, Listeria monocytogenes, and methicillin-resistant Staphylococcus aureus in the presence of this compound, thus supporting our molecular strategy as an effective research pipeline for SWI antibiotic discovery and genetic characterization. © 2017 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

Assessing Hurricane Katrina Vegetation Damage at Stennis Space Center using IKONOS Image Classification Techniques

NASA Technical Reports Server (NTRS)

Spruce, Joseph P.; Ross, Kenton W.; Graham, William D.

2007-01-01

Hurricane Katrina hit southwestern Mississippi on August 29, 2005, at 9:45 a.m. CDT as a category 3 storm with surges up to approx. 9 m and sustained winds of approx. 120 mph. The hurricane's wind, rain, and flooding devastated several coastal towns, from New Orleans through Mobile. The storm also caused significant damage to infrastructure and vegetation of NASA's SSC (Stennis Space Center). Storm recovery at SSC involved not only repairs of critical infrastructure but also forest damage mitigation (via timber harvests and control burns to reduce fire risk). This presentation discusses an effort to use commercially available high spatial resolution multispectral IKONOS data for vegetation damage assessment, based on data collected over SSC on September 2, 2005.

Transformative experiences for Hurricanes Katrina and Rita disaster volunteers.

PubMed

Clukey, Lory

2010-07-01

The massive destruction caused by Hurricanes Katrina and Rita in 2005 provided an opportunity for many volunteers to be involved with disaster relief work. Exposure to devastation and personal trauma can have long-lasting and sometimes detrimental effects on people providing help. This qualitative study explored the experience of volunteer relief workers who provided disaster relief services after the hurricanes. Three major themes emerged: emotional reactions that included feelings of shock, fatigue, anger and grief as well as sleep disturbances; frustration with leadership; and life-changing personal transformation. Stress reactions were noted but appeared to be mitigated by feelings of compassion for the victims and personal satisfaction in being able to provide assistance. Suggestions are provided for further research.

The World Health Organization's safe abortion guidance document.

PubMed

Van Look, Paul F A; Cottingham, Jane

2013-04-01

We discuss the history of the World Health Organization's (WHO's) development of guidelines for governments on providing safe abortion services, which WHO published as Safe Abortion: Technical and Policy Guidance for Health Systems in 2003 and updated in 2012. We show how the recognition of the devastating impact of unsafe abortion on women's health and survival, the impetus of the International Conference on Population and Development and its five-year follow-up, and WHO's progressive leadership at the end of the century enabled the organization to elaborate guidance on providing safe abortion services. Guideline formulation involved extensive review of published evidence, an international technical expert meeting to review the draft document, and a protracted in-house review by senior WHO management.

Software support for Huntingtons disease research.

PubMed Central

Conneally, P. M.; Gersting, J. M.; Gray, J. M.; Beidleman, K.; Wexler, N. S.; Smith, C. L.

1991-01-01

Huntingtons disease (HD) is a hereditary disorder involving the central nervous system. Its effects are devastating, to the affected person as well as his family. The Department of Medical and Molecular Genetics at Indiana University (IU) plays an integral part in Huntingtons research by providing computerized repositories of HD family information for researchers and families. The National Huntingtons Disease Research Roster, founded in 1979 at IU, and the Huntingtons Disease in Venezuela Project database contain information that has proven to be invaluable in the worldwide field of HD research. This paper addresses the types of information stored in each database, the pedigree database program (MEGADATS) used to manage the data, and significant findings that have resulted from access to the data. PMID:1839672

Sudden cardiac death in athletes: a guide for emergency physicians.

PubMed

Germann, Carl A; Perron, Andrew D

2005-07-01

A conditioned athlete is usually regarded as a member of the healthiest segment of society, and exercise itself is looked upon as a means to improve health. Although extremely uncommon, sudden cardiac death (SCD) in young athletes is a devastating medical event to all involved (patient, family, community, team, and caregivers). Most etiologies of SCD in athletes result in the same final common denominator (cardiac arrest) on presentation to an emergency physician. There are, however, certain historic, physical examination, and electrocardiographic features of many of these disease processes that emergency physicians should have a working knowledge of to try to identify them before they result in SCD. This review examines the clinical presentation, diagnostic techniques, and management options applicable to emergency practitioners.

Genotyping of presenilin-1 polymorphism in amyotrophic lateral sclerosis.

PubMed

Panas, M; Karadima, G; Kalfakis, N; Psarrou, O; Floroskoufi, P; Kladi, A; Petersen, M B; Vassilopoulos, D

2000-12-01

The mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis are not fully understood. Recent studies suggest that apoptosis is involved in the abnormal neural death that occurs in this devastating disease. Presenilin-1, a transmembrane protein, seems to be implicated in apoptosis. To determine whether presenilin-1 intron 8 polymorphism has an influence in the course of amyotrophic lateral sclerosis, we examined this polymorphism genotypes in a large group of patients (n = 72) with amyotrophic lateral sclerosis and in a random sample of 213 healthy individuals. The results showed a significant difference in genotype (P < 0.04) and allele (P < 0.03) distribution between patients controls. These results suggest a possible intervention of presenilin-1 in the pathogenesis of amyotrophic lateral sclerosis.

A meta-analysis of platelet gel for prevention of sternal wound infections following cardiac surgery

PubMed Central

Kirmani, Bilal H.; Jones, Siôn G.; Datta, Subir; McLaughlin, Edward K.; Hoschtitzky, Andreas J.

2017-01-01

Deep sternal wound infection and bleeding are devastating complications following cardiac surgery, which may be reduced by topical application of autologous platelet gel. Systematic review identified seven comparative studies involving 4,692 patients. Meta-analysis showed significant reductions in all sternal wound infections (odds ratio 3.48 [1.08–11.23], p=0.04) and mediastinitis (odds ratio 2.69 [1.20–6.06], p=0.02) but not bleeding. No adverse events relating to the use of topical platelet-rich plasma were reported. The use of autologous platelet gel in cardiac surgery appears to provide significant reductions in serious sternal wound infections, and its use is unlikely to be associated with significant risk. PMID:27177403

Comprehensive management of pressure ulcers in spinal cord injury: Current concepts and future trends

PubMed Central

Kruger, Erwin A.; Pires, Marilyn; Ngann, Yvette; Sterling, Michelle; Rubayi, Salah

2013-01-01

Pressure ulcers in spinal cord injury represent a challenging problem for patients, their caregivers, and their physicians. They often lead to recurrent hospitalizations, multiple surgeries, and potentially devastating complications. They present a significant cost to the healthcare system, they require a multidisciplinary team approach to manage well, and outcomes directly depend on patients' education, prevention, and compliance with conservative and surgical protocols. With so many factors involved in the successful treatment of pressure ulcers, an update on their comprehensive management in spinal cord injury is warranted. Current concepts of local wound care, surgical options, as well as future trends from the latest wound healing research are reviewed to aid medical professionals in treating patients with this difficult problem. PMID:24090179

Reconstruction and rehabilitation of short-range gunshot injury to lower part of face: A systematic approach of three cases.

PubMed

Vatsyayan, Ashutosh; Adhyapok, Apurba-Kumar; Debnath, Subhas-Chandra; Malik, Kapil

2016-08-01

Gunshot injuries are always known to cause severe morbidity and mortality when head and neck are involved. They vary in morbidity, which can occur in civilian surroundings. The wound largely depends on the type of weapon, mass and velocity of the bullet, and the distance from where it has been shot. Close-range gunshot wounds in the head and neck region can result in devastating aesthetic and functional impairment. The complexity in facial skeletal anatomy cause multiple medical and surgical challenges to an operating surgeon, demanding elaborate soft and hard tissue reconstruction. Here we presented the successful management of three patients shot by short-range pistol with basic life support measures, wound management, reconstruction and rehabilitation.

Anaerobic orbital cellulitis: a clinical and experimental study.

PubMed Central

Jedrzynski, M S; Bullock, J D; McGuire, T W; Elder, B L; Bullock, J D

1991-01-01

In this article we have reviewed the clinical and bacteriologic aspects of anaerobic orbital cellulitis and have presented six patients to illustrate these points. Physicians who treat patients with orbital cellulitis should have a high index of suspicion for possible instances involving anaerobes, so that appropriate management can be started early. To investigate this problem further, we created an animal model of anaerobic orbital cellulitis. This model may be useful in future studies of the pathogenesis and treatment of this serious and often devastating disease. Images FIGURE 1 FIGURE 2 FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 6 FIGURE 7 FIGURE 8 FIGURE 9 FIGURE 10 FIGURE 11 FIGURE 12 FIGURE 13 FIGURE 14 FIGURE 15 FIGURE 16 FIGURE 17 FIGURE 18 FIGURE 19 PMID:1808813

The use of bioabsorbable staple line reinforcement for circular stapler (BSG "Seamguard") in colorectal surgery: initial experience.

PubMed

Franklin, Morris E; Ramila, Guillermo Portillo; Treviño, Jorge M; González, John J; Russek, Karla; Glass, Jeffrey L; Kim, Greg

2006-12-01

Of all the complications associated with colorectal surgery, the most devastating and constant, despite all techniques being performed properly is anastomotic leakage, especially in left colon and rectal resections with rates as high as 50% when the rectum is involved. In 2005, our center published the preliminary experience with the use of linear staple line reinforcement for colon surgery. The purpose of this paper is to present a series of cases using a new conformation of bioabsorbable reinforcement for circular staplers in 5 patients, 2 patients with rectal cancer, 2 patients with diverticular disease, and 1 patient with sigmoid cancer. These initial data are very promising and has encouraged us to continue using this device on further patients.

The Arm is Not the Leg: Pathophysiology, Diagnosis, and Management of Upper Extremity Deep Vein Thrombosis.

PubMed

Noyes, Adam M; Dickey, John

2017-05-01

Upper extremity deep venous thrombosis (UEDVT) involves thrombosis of the deep veins of the arm as they enter the thorax. They are increasing in frequency, largely due to the rising use of central venous catheters and implantable cardiac devices, and represent more than 10% of all DVT cases, Upper extremity deep venous thrombosis has been historically misunderstood when compared to lower extremity deep vein thrombosis (LEDVT). Their associated disease states may carry devastating complications, with mortality rates often higher than that of LEDVT. Thus, education on recognition, classification and management is critical to avoid long-term sequelae and mortality from UEDVT. [Full article available at http://rimed.org/rimedicaljournal-2017-05.asp].

Educational opportunities: a nursing school model for medical special-needs sheltering.

PubMed

Deal, Belinda; Alfred, Danita; Fountain, Rebecca; Ford, Terri; Chilton, Jennifer

2010-01-01

The devastation of New Orleans after Hurricane Katrina increased the awareness of persons who were unable to self-evacuate because of physical and/or mental disabilities. From that awareness, plans emerged to provide a safe haven for those who had special needs. In this article, we describe our efforts as a school of nursing to shelter medical special needs (MSN) evacuees in the wake of a hurricane. After the shelter closed, faculty and students involved in the shelter answered a short survey that included both open- and close-ended questions. The responses are summarized to encourage other schools of nursing to consider caring for MSN evacuees and to share our successes, our failures, and our plans for the future.

Overcoming hERG affinity in the discovery of maraviroc; a CCR5 antagonist for the treatment of HIV.

PubMed

Price, David A; Armour, Duncan; de Groot, Marcel; Leishman, Derek; Napier, Carolyn; Perros, Manos; Stammen, Blanda L; Wood, Anthony

2008-01-01

Avoiding cardiac liability associated with blockade of hERG (human ether a go-go) is key for successful drug discovery and development. This paper describes the work undertaken in the discovery of a potent CCR5 antagonist, maraviroc 34, for the treatment of HIV. In particular the use of a pharmacophore model of the hERG channel and a high throughput binding assay for the hERG channel are described that were critical to elucidate SAR to overcome hERG liabilities. The key SAR involves the introduction of polar substituents into regions of the molecule where it is postulated to undergo hydrophobic interactions with the ion channel. Within the CCR5 project there appeared to be no strong correlation between hERG affinity and physiochemical parameters such as pKa or lipophilicity. It is believed that chemists could apply these same strategies early in drug discovery to remove hERG interactions associated with lead compounds while retaining potency at the primary target.

Discovery and characterization of heme enzymes from unsequenced bacteria: application to microbial lignin degradation.

PubMed

Brown, Margaret E; Walker, Mark C; Nakashige, Toshiki G; Iavarone, Anthony T; Chang, Michelle C Y

2011-11-16

Bacteria and other living organisms offer a potentially unlimited resource for the discovery of new chemical catalysts, but many interesting reaction phenotypes observed at the whole organism level remain difficult to elucidate down to the molecular level. A key challenge in the discovery process is the identification of discrete molecular players involved in complex biological transformations because multiple cryptic genetic components often work in concert to elicit an overall chemical phenotype. We now report a rapid pipeline for the discovery of new enzymes of interest from unsequenced bacterial hosts based on laboratory-scale methods for the de novo assembly of bacterial genome sequences using short reads. We have applied this approach to the biomass-degrading soil bacterium Amycolatopsis sp. 75iv2 ATCC 39116 (formerly Streptomyces setonii and S. griseus 75vi2) to discover and biochemically characterize two new heme proteins comprising the most abundant members of the extracellular oxidative system under lignin-reactive growth conditions.

COMPUTER-AIDED DRUG DISCOVERY AND DEVELOPMENT (CADDD): in silico-chemico-biological approach

PubMed Central

Kapetanovic, I.M.

2008-01-01

It is generally recognized that drug discovery and development are very time and resources consuming processes. There is an ever growing effort to apply computational power to the combined chemical and biological space in order to streamline drug discovery, design, development and optimization. In biomedical arena, computer-aided or in silico design is being utilized to expedite and facilitate hit identification, hit-to-lead selection, optimize the absorption, distribution, metabolism, excretion and toxicity profile and avoid safety issues. Commonly used computational approaches include ligand-based drug design (pharmacophore, a 3-D spatial arrangement of chemical features essential for biological activity), structure-based drug design (drug-target docking), and quantitative structure-activity and quantitative structure-property relationships. Regulatory agencies as well as pharmaceutical industry are actively involved in development of computational tools that will improve effectiveness and efficiency of drug discovery and development process, decrease use of animals, and increase predictability. It is expected that the power of CADDD will grow as the technology continues to evolve. PMID:17229415

The history of aerobic ammonia oxidizers: from the first discoveries to today.

PubMed

Monteiro, Maria; Séneca, Joana; Magalhães, Catarina

2014-07-01

Nitrification, the oxidation of ammonia to nitrite and nitrate, has long been considered a central biological process in the global nitrogen cycle, with its first description dated 133 years ago. Until 2005, bacteria were considered the only organisms capable of nitrification. However, the recent discovery of a chemoautotrophic ammonia-oxidizing archaeon, Nitrosopumilus maritimus, changed our concept of the range of organisms involved in nitrification, highlighting the importance of ammonia-oxidizing archaea (AOA) as potential players in global biogeochemical nitrogen transformations. The uniqueness of these archaea justified the creation of a novel archaeal phylum, Thaumarchaeota. These recent discoveries increased the global scientific interest within the microbial ecology society and have triggered an analysis of the importance of bacterial vs archaeal ammonia oxidation in a wide range of natural ecosystems. In this mini review we provide a chronological perspective of the current knowledge on the ammonia oxidation pathway of nitrification, based on the main physiological, ecological and genomic discoveries.

Evolution of the NASA/IPAC Extragalactic Database (NED) into a Data Mining Discovery Engine

NASA Astrophysics Data System (ADS)

Mazzarella, Joseph M.; NED Team

2017-06-01

We review recent advances and ongoing work in evolving the NASA/IPAC Extragalactic Database (NED) beyond an object reference database into a data mining discovery engine. Updates to the infrastructure and data integration techniques are enabling more than a 10-fold expansion; NED will soon contain over a billion objects with their fundamental attributes fused across the spectrum via cross-identifications among the largest sky surveys (e.g., GALEX, SDSS, 2MASS, AllWISE, EMU), and over 100,000 smaller but scientifically important catalogs and journal articles. The recent discovery of super-luminous spiral galaxies exemplifies the opportunities for data mining and science discovery directly from NED's rich data synthesis. Enhancements to the user interface, including new APIs, VO protocols, and queries involving derived physical quantities, are opening new pathways for panchromatic studies of large galaxy samples. Examples are shown of graphics characterizing the content of NED, as well as initial steps in exploring the database via interactive statistical visualizations.

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

PubMed Central

Ansari, Morad; Balasubramanian, Meena; Blyth, Moira; Brady, Angela F.; Clayton, Stephen; Cole, Trevor; Deshpande, Charu; Fitzgerald, Tomas W.; Foulds, Nicola; Francis, Richard; Gabriel, George; Gerety, Sebastian S.; Goodship, Judith; Hobson, Emma; Jones, Wendy D.; Joss, Shelagh; King, Daniel; Klena, Nikolai; Kumar, Ajith; Lees, Melissa; Lelliott, Chris; Lord, Jenny; McMullan, Dominic; O'Regan, Mary; Osio, Deborah; Piombo, Virginia; Prigmore, Elena; Rajan, Diana; Rosser, Elisabeth; Sifrim, Alejandro; Smith, Audrey; Swaminathan, Ganesh J.; Turnpenny, Peter; Whitworth, James; Wright, Caroline F.; Firth, Helen V.; Barrett, Jeffrey C.; Lo, Cecilia W.; FitzPatrick, David R.; Hurles, Matthew E.

2018-01-01

Discovery of most autosomal recessive disease genes has involved analysis of large, often consanguineous, multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of novel dominant causes of rare, genetically heterogenous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios 1,2. Here we analysed 4,125 families with diverse, rare, genetically heterogeneous developmental disorders and identified four novel autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (identifying probands with rare biallelic putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population, and (ii) the phenotypic similarity of patients with the same recessive candidate gene. This new paradigm promises to catalyse discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations, and those caused predominantly by compound heterozygous genotypes. PMID:26437029

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

PubMed

Akawi, Nadia; McRae, Jeremy; Ansari, Morad; Balasubramanian, Meena; Blyth, Moira; Brady, Angela F; Clayton, Stephen; Cole, Trevor; Deshpande, Charu; Fitzgerald, Tomas W; Foulds, Nicola; Francis, Richard; Gabriel, George; Gerety, Sebastian S; Goodship, Judith; Hobson, Emma; Jones, Wendy D; Joss, Shelagh; King, Daniel; Klena, Nikolai; Kumar, Ajith; Lees, Melissa; Lelliott, Chris; Lord, Jenny; McMullan, Dominic; O'Regan, Mary; Osio, Deborah; Piombo, Virginia; Prigmore, Elena; Rajan, Diana; Rosser, Elisabeth; Sifrim, Alejandro; Smith, Audrey; Swaminathan, Ganesh J; Turnpenny, Peter; Whitworth, James; Wright, Caroline F; Firth, Helen V; Barrett, Jeffrey C; Lo, Cecilia W; FitzPatrick, David R; Hurles, Matthew E

2015-11-01

Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.

Low Cost Entry, Descent, and Landing (EDL) Instrumentation for Planetary Missions

NASA Technical Reports Server (NTRS)

Hwang, H. H.; Munk, M. M.; Dillman, R. A.; Mahzari, M.; Swanson, G. T.; White, T. R.

2016-01-01

Missions that involve traversing through a planetary atmosphere are unique opportunities that require elements of entry, descent, and landing (EDL). Many aspects of the EDL sequence are qualified using analysis and simulation due to the inability to conduct appropriate ground tests, however validating flight data are often lacking, especially for missions not involving Earth re-entry. NASA has made strategic decisions to collect EDL flight data in order to improve future mission designs. For example, MEDLI1 and EFT-1 gathered hypersonic pressure and in-depth temperature data in the thermal protection system (TPS). However, the ability to collect EDL flight data from the smaller competed missions, such as Discovery and New Frontiers, has been limited in part due to the Principal Investigator-managed cost-caps (PIMCC). The recent NASA decision to consider EDL instrumentation earlier in the mission design cycle led to the inclusion of a requirement in the Discovery 2014 Announcement of Opportunity which requires all missions that involve EDL to include an Engineering Science Investigation (ESI).2 The ESI would involve sensors for aerothermal environment and TPS; atmosphere, aerodynamics, and flight dynamics; atmospheric decelerator; and/or vehicle structure.3 The ESI activity would be funded outside of the PIMCC.

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

Knott, D.

Floating production system (FPS) technology has come of age in the North Sea. That's apparent in plans to use FPSs to tap two of Northwest Europe's largest offshore oil discoveries in the last 10 years. First North Sea oil production with a floater involved a converted semisubmersible drilling rig. Floaters have been in use for small field development projects ever since. Now, industry's rising interest in FPSs reflects two trends: As the North Sea matures, discoveries are likely to be in deeper, more remote locations; and Operators increasingly are under pressure to slash costs. The paper discusses UK trends, Norway'smore » needs, the Norne field, Norne contract, discovery of oil west of the Shetland Islands, Shell-Esso plans, the UK Machar field test, the UK Fife field, and prospects for other potential floater developments.« less

Compound scale-up at the discovery-development interface.

PubMed

Nikitenko, Antonia A

2006-11-01

As a result of an economically challenging environment within the pharmaceutical industry, pharmaceutical companies and their departments must increase productivity and cut costs to stay in line with the market. Discovery-led departments such as the medicinal chemistry and lead optimization groups focus on synthesizing large varieties of compounds in minimal amounts, while the chemical development groups must then deliver a few chosen leads employing an optimized synthesis method and using multi-kilogram quantities of material. A research group at the discovery-development interface has the task of medium-scale synthesis which is important in the lead selection stage. The primary objective of this group is the initial scale-up of promising leads for extensive physicochemical and biological testing. The challenge of the interface group involves overcoming synthetic issues within the rigid, accelerated timelines.

Novel opportunities for computational biology and sociology in drug discovery☆

PubMed Central

Yao, Lixia; Evans, James A.; Rzhetsky, Andrey

2013-01-01

Current drug discovery is impossible without sophisticated modeling and computation. In this review we outline previous advances in computational biology and, by tracing the steps involved in pharmaceutical development, explore a range of novel, high-value opportunities for computational innovation in modeling the biological process of disease and the social process of drug discovery. These opportunities include text mining for new drug leads, modeling molecular pathways and predicting the efficacy of drug cocktails, analyzing genetic overlap between diseases and predicting alternative drug use. Computation can also be used to model research teams and innovative regions and to estimate the value of academy–industry links for scientific and human benefit. Attention to these opportunities could promise punctuated advance and will complement the well-established computational work on which drug discovery currently relies. PMID:20349528

Alaskan North Slope Geology

NASA Astrophysics Data System (ADS)

Hamilton, Warren

The discovery well for the Prudhoe Bay field, the largest oil accumulatn yet found in the United States, was drilled on the Arctic coast of Alaska by ARCO and Exxon in 1968. A decade of exploratory geology and increasingly detailed geophysical surveys, mostly by Sinclair and British Petroleum in the early years, but then by a number of companies, preceded the discovery. Systematic U.S. Geological Survey (USGS) reconnaissance of the Brooks Range—the great mountain system of northern Alaska—had begun in the 1940s and was accelerated after the discovery, as was industry work. In the last decade, scientists from the Alaska Division of Geology and Geophysics and from various universities have become increasingly involved. This modestly priced two-volume work presents hitherto unavailable summaries of much of this modern work.

Automated Discovery of Elementary Chemical Reaction Steps Using Freezing String and Berny Optimization Methods.

PubMed

Suleimanov, Yury V; Green, William H

2015-09-08

We present a simple protocol which allows fully automated discovery of elementary chemical reaction steps using in cooperation double- and single-ended transition-state optimization algorithms--the freezing string and Berny optimization methods, respectively. To demonstrate the utility of the proposed approach, the reactivity of several single-molecule systems of combustion and atmospheric chemistry importance is investigated. The proposed algorithm allowed us to detect without any human intervention not only "known" reaction pathways, manually detected in the previous studies, but also new, previously "unknown", reaction pathways which involve significant atom rearrangements. We believe that applying such a systematic approach to elementary reaction path finding will greatly accelerate the discovery of new chemistry and will lead to more accurate computer simulations of various chemical processes.

Discovery and Development of Natural Products and their Derivatives as Photosensitizers for Photodynamic Therapy.

PubMed

Xiao, Qicai; Wu, Juan; Pang, Xin; Jiang, Yue; Wang, Pan; Leung, Albert W; Gao, Liqian; Jiang, Sheng; Xu, Chuanshan

2018-01-01

Photodynamic therapy (PDT) has been developed as an alternative modality for the management of neoplastic and nonneoplastic diseases. It is a minimally invasive treatment that involves the interaction of a non-toxic photosensitizer (PS), light and molecular oxygen to generate reactive oxygen species (ROS), resulting in the destruction of unwanted cells and tissues. Discovery and development of new PSs with optimized properties are much crucial for achieving a desirable therapeutic efficacy. This review describes the photochemical and photobiological mechanisms of PDT, and outlines the recent progress in discovery and development of natural products and their derivatives as phototherapeutic drugs. The potential limitations and future perspectives of PDT in clinical application are also presented and discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

From the Old to the New World of Nuclear Physics

NASA Astrophysics Data System (ADS)

Stuewer, Roger H.

Physicists passed from the Old to the New World of Nuclear Physics in the two decades between the first and second world wars. The transition occurred against the background of the Great War, the postwar hyperinflation in Germany and Austria, and the greatest intellection migrations in history after the Nazi Civil Service law of 1933, the Anschlussof Austria in March 1938, and the Fascist anti-Semitic laws that fall. It involved Rutherford's discovery of artificial disintegration, Pettersson and Kirsch's challenge of it, and the concomitant rise and fall of Rutherford's satellite model of the nucleus; Gamow's quantum-mechanical theory of alpha decay and his liquid-drop model of the nucleus; the discoveries of deuterium and the deuteron, neutron, and positron, and the inventions of the Cockcroft-Walton accelerator and the cyclotron; the influence of the seventh Solvay Conference; Joliot and Curie's discovery of artificial radioactivity; Pauli's neutrino hypothesis, Fermi's theory of beta decay, and his discovery of the efficacy of slow neutrons in producing nuclear reactions; Bohr's theory of the compound nucleus and Breit and Wigner's theory of neutron-nucleus resonances; and the discovery of nuclear fission, Meitner and Frisch's interpretation of it, and Bohr and Fermi revelation of both in America.

Citation Discovery Tools for Conducting Adaptive Meta-analyses to Update Systematic Reviews.

PubMed

Bae, Jong-Myon; Kim, Eun Hee

2016-03-01

The systematic review (SR) is a research methodology that aims to synthesize related evidence. Updating previously conducted SRs is necessary when new evidence has been produced, but no consensus has yet emerged on the appropriate update methodology. The authors have developed a new SR update method called 'adaptive meta-analysis' (AMA) using the 'cited by', 'similar articles', and 'related articles' citation discovery tools in the PubMed and Scopus databases. This study evaluates the usefulness of these citation discovery tools for updating SRs. Lists were constructed by applying the citation discovery tools in the two databases to the articles analyzed by a published SR. The degree of overlap between the lists and distribution of excluded results were evaluated. The articles ultimately selected for the SR update meta-analysis were found in the lists obtained from the 'cited by' and 'similar' tools in PubMed. Most of the selected articles appeared in both the 'cited by' lists in Scopus and PubMed. The Scopus 'related' tool did not identify the appropriate articles. The AMA, which involves using both citation discovery tools in PubMed, and optionally, the 'related' tool in Scopus, was found to be useful for updating an SR.

Stabilization of protein-protein interactions in drug discovery.

PubMed

Andrei, Sebastian A; Sijbesma, Eline; Hann, Michael; Davis, Jeremy; O'Mahony, Gavin; Perry, Matthew W D; Karawajczyk, Anna; Eickhoff, Jan; Brunsveld, Luc; Doveston, Richard G; Milroy, Lech-Gustav; Ottmann, Christian

2017-09-01

PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.

Microbial Efflux Systems and Inhibitors: Approaches to Drug Discovery and the Challenge of Clinical Implementation

PubMed Central

Kourtesi, Christina; Ball, Anthony R; Huang, Ying-Ying; Jachak, Sanjay M; Vera, D Mariano A; Khondkar, Proma; Gibbons, Simon; Hamblin, Michael R; Tegos, George P

2013-01-01

Conventional antimicrobials are increasingly ineffective due to the emergence of multidrug-resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered exploration for novel and unconventional approaches to controlling microbial infections. Multidrug efflux systems (MES) have been a profound obstacle in the successful deployment of antimicrobials. The discovery of small molecule efflux system blockers has been an active and rapidly expanding research discipline. A major theme in this platform involves efflux pump inhibitors (EPIs) from natural sources. The discovery methodologies and the available number of natural EPI-chemotypes are increasing. Advances in our understanding of microbial physiology have shed light on a series of pathways and phenotypes where the role of efflux systems is pivotal. Complementing existing antimicrobial discovery platforms such as photodynamic therapy (PDT) with efflux inhibition is a subject under investigation. This core information is a stepping stone in the challenge of highlighting an effective drug development path for EPIs since the puzzle of clinical implementation remains unsolved. This review summarizes advances in the path of EPI discovery, discusses potential avenues of EPI implementation and development, and underlines the need for highly informative and comprehensive translational approaches. PMID:23569468

Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer | Office of Cancer Genomics

Cancer.gov

Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets. Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding.

Chemical screening method for the rapid identification of microbial sources of marine invertebrate-associated metabolites.

PubMed

Berrue, Fabrice; Withers, Sydnor T; Haltli, Brad; Withers, Jo; Kerr, Russell G

2011-03-21

Marine invertebrates have proven to be a rich source of secondary metabolites. The growing recognition that marine microorganisms associated with invertebrate hosts are involved in the biosynthesis of secondary metabolites offers new alternatives for the discovery and development of marine natural products. However, the discovery of microorganisms producing secondary metabolites previously attributed to an invertebrate host poses a significant challenge. This study describes an efficient chemical screening method utilizing a 96-well plate-based bacterial cultivation strategy to identify and isolate microbial producers of marine invertebrate-associated metabolites.

A Metadata based Knowledge Discovery Methodology for Seeding Translational Research.

PubMed

Kothari, Cartik R; Payne, Philip R O

2015-01-01

In this paper, we present a semantic, metadata based knowledge discovery methodology for identifying teams of researchers from diverse backgrounds who can collaborate on interdisciplinary research projects: projects in areas that have been identified as high-impact areas at The Ohio State University. This methodology involves the semantic annotation of keywords and the postulation of semantic metrics to improve the efficiency of the path exploration algorithm as well as to rank the results. Results indicate that our methodology can discover groups of experts from diverse areas who can collaborate on translational research projects.

Microcomputer-Assisted Mathematics: From Simple Interest to e.

ERIC Educational Resources Information Center

Kimberling, Clark

1985-01-01

The progression from simple interest to compound interest leads naturally and quickly to the number e, involving mathematical discovery learning through writing programs. Several programs are given, with suggestions for a teaching sequence. (MNS)

Metabolic Interplay between the Asian Citrus Psyllid and Its Profftella Symbiont: An Achilles’ Heel of the Citrus Greening Insect Vector

PubMed Central

Ramsey, John S.; Johnson, Richard S.; Hoki, Jason S.; Kruse, Angela; Mahoney, Jaclyn; Hilf, Mark E.; Hunter, Wayne B.; Hall, David G.; Schroeder, Frank C.; MacCoss, Michael J.; Cilia, Michelle

2015-01-01

‘Candidatus Liberibacter asiaticus’ (CLas), the bacterial pathogen associated with citrus greening disease, is transmitted by Diaphorina citri, the Asian citrus psyllid. Interactions among D. citri and its microbial endosymbionts, including ‘Candidatus Profftella armatura’, are likely to impact transmission of CLas. We used quantitative mass spectrometry to compare the proteomes of CLas(+) and CLas(-) populations of D. citri, and found that proteins involved in polyketide biosynthesis by the endosymbiont Profftella were up-regulated in CLas(+) insects. Mass spectrometry analysis of the Profftella polyketide diaphorin in D. citri metabolite extracts revealed the presence of a novel diaphorin-related polyketide and the ratio of these two polyketides was changed in CLas(+) insects. Insect proteins differentially expressed between CLas(+) and CLas(-) D. citri included defense and immunity proteins, proteins involved in energy storage and utilization, and proteins involved in endocytosis, cellular adhesion, and cytoskeletal remodeling which are associated with microbial invasion of host cells. Insight into the metabolic interdependence between the insect vector, its endosymbionts, and the citrus greening pathogen reveals novel opportunities for control of this disease, which is currently having a devastating impact on citrus production worldwide. PMID:26580079

Ten years of a multidisciplinary diabetic foot team approach in Sao Paulo, Brazil

PubMed Central

Batista, Fábio; Augusto Magalhães, Antonio; Gamba, Mônica; Nery, Caio; Cardoso, Cristina

2010-01-01

Diabetes mellitus can cause devastating foot problems including loss of protective sensation with subsequent ulcerations and amputations. The natural history and pathophysiology of diabetic foot ulcers is best understood and managed by a multiprofessional team approach. The main factors for prevention and treatment of these devastating diabetic foot conditions are shown, with special attention to education of the patient. This approach decreases the morbidity of the disease, besides its economical and social feasibility. PMID:22396805

Interdisciplinary Laboratory Course Facilitating Knowledge Integration, Mutualistic Teaming, and Original Discovery.

PubMed

Full, Robert J; Dudley, Robert; Koehl, M A R; Libby, Thomas; Schwab, Cheryl

2015-11-01

Experiencing the thrill of an original scientific discovery can be transformative to students unsure about becoming a scientist, yet few courses offer authentic research experiences. Increasingly, cutting-edge discoveries require an interdisciplinary approach not offered in current departmental-based courses. Here, we describe a one-semester, learning laboratory course on organismal biomechanics offered at our large research university that enables interdisciplinary teams of students from biology and engineering to grow intellectually, collaborate effectively, and make original discoveries. To attain this goal, we avoid traditional "cookbook" laboratories by training 20 students to use a dozen research stations. Teams of five students rotate to a new station each week where a professor, graduate student, and/or team member assists in the use of equipment, guides students through stages of critical thinking, encourages interdisciplinary collaboration, and moves them toward authentic discovery. Weekly discussion sections that involve the entire class offer exchange of discipline-specific knowledge, advice on experimental design, methods of collecting and analyzing data, a statistics primer, and best practices for writing and presenting scientific papers. The building of skills in concert with weekly guided inquiry facilitates original discovery via a final research project that can be presented at a national meeting or published in a scientific journal. © The Author 2015. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

[Contribution of the rapid diagnostic tests for infectious diseases to the patient management in the Great East Japan earthquake].

PubMed

Hatta, Masumitsu; Kaku, Mitsuo

2012-01-01

On 11 March 2011, an earthquake measuring 9.0 on the Richter scale off the northeast coast of Honshu Island, Japan, produced a devastating tsunami that destroyed many towns and villages near the coast in Iwate, Miyagi, and Fukushima prefectures. Miyagi Prefecture was the area most severely devastated by the tsunami, with extensive loss of life and property; hundreds of thousands of people lost their houses and were forced to move to evacuation areas. In the days and weeks following devastating natural disasters, the threat of infectious disease outbreak is high. Rapid diagnostic tests can be performed at or near the site of patient care and the tests were very useful in this disaster, because they enabled us to manage patients appropriately in the settings where medical resources were limited. Here we report actual cases where the rapid diagnostic tests for infectious diseases were useful in the patient management.

Theoretical physics: Quarks fuse to release energy

NASA Astrophysics Data System (ADS)

Miller, Gerald A.

2017-11-01

In nuclear fusion, energy is produced by the rearrangement of protons and neutrons. The discovery of an analogue of this process involving particles called quarks has implications for both nuclear and particle physics. See Letter p.89

Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer's Disease Therapeutic Agents.

PubMed

Llorach-Pares, Laura; Nonell-Canals, Alfons; Sanchez-Martinez, Melchor; Avila, Conxita

2017-11-27

Computer-aided drug discovery/design (CADD) techniques allow the identification of natural products that are capable of modulating protein functions in pathogenesis-related pathways, constituting one of the most promising lines followed in drug discovery. In this paper, we computationally evaluated and reported the inhibitory activity found in meridianins A-G, a group of marine indole alkaloids isolated from the marine tunicate Aplidium , against various protein kinases involved in Alzheimer's disease (AD), a neurodegenerative pathology characterized by the presence of neurofibrillary tangles (NFT). Balance splitting between tau kinase and phosphate activities caused tau hyperphosphorylation and, thereby, its aggregation and NTF formation. Inhibition of specific kinases involved in its phosphorylation pathway could be one of the key strategies to reverse tau hyperphosphorylation and would represent an approach to develop drugs to palliate AD symptoms. Meridianins bind to the adenosine triphosphate (ATP) binding site of certain protein kinases, acting as ATP competitive inhibitors. These compounds show very promising scaffolds to design new drugs against AD, which could act over tau protein kinases Glycogen synthetase kinase-3 Beta (GSK3β) and Casein kinase 1 delta (CK1δ, CK1D or KC1D), and dual specificity kinases as dual specificity tyrosine phosphorylation regulated kinase 1 (DYRK1A) and cdc2-like kinases (CLK1). This work is aimed to highlight the role of CADD techniques in marine drug discovery and to provide precise information regarding the binding mode and strength of meridianins against several protein kinases that could help in the future development of anti-AD drugs.

Generic antibiotic industries: Challenges and implied strategies with regulatory perspectives

PubMed Central

Venkatesh, M.; Bairavi, V. G.; Sasikumar, K. C.

2011-01-01

Ever since the discovery of antibiotics, the quality of human life greatly improved in the 20th century. The discovery of penicillin transformed the medicine industry and initiated a search for a better antibiotic every time resulting in several synthetic and semi-synthetic antibiotics. Beginning with the 1937 sulfa drug tragedy, the drug regulations had a parallel growth along with the antibiotics and the antibiotic-based generic Pharma industries. This review article is focused on the scenario depicting current global Pharma industries based on generic antibiotics. Several regulatory aspects involved with these industries have been discussed along with the complexity of the market, issues that could affect their growth, their struggle for quality, and their compliance with the tightened regulations. With the skyrocketing commercialization of antibiotics through generics and the leveraging technologic renaissance, generic industries are involved in providing maximum safer benefits for the welfare of the people, highlighting its need today.. PMID:21430959

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.

Recurring errors among recent history of psychology textbooks.

PubMed

Thomas, Roger K

2007-01-01

Five recurring errors in history of psychology textbooks are discussed. One involves an identical misquotation. The remaining examples involve factual and interpretational errors that more than one and usually several textbook authors made. In at least 2 cases some facts were fabricated, namely, so-called facts associated with Pavlov's mugging and Descartes's reasons for choosing the pineal gland as the locus for mind-body interaction. A fourth example involves Broca's so-called discovery of the speech center, and the fifth example involves misinterpretations of Lloyd Morgan's intentions regarding his famous canon. When an error involves misinterpretation and thus misrepresentation, I will show why the misinterpretation is untenable.

Metabolomics studies in brain tissue: A review.

PubMed

Gonzalez-Riano, Carolina; Garcia, Antonia; Barbas, Coral

2016-10-25

Brain is still an organ with a composition to be discovered but beyond that, mental disorders and especially all diseases that curse with dementia are devastating for the patient, the family and the society. Metabolomics can offer an alternative tool for unveiling new insights in the discovery of new treatments and biomarkers of mental disorders. Until now, most of metabolomic studies have been based on biofluids: serum/plasma or urine, because brain tissue accessibility is limited to animal models or post mortem studies, but even so it is crucial for understanding the pathological processes. Metabolomics studies of brain tissue imply several challenges due to sample extraction, along with brain heterogeneity, sample storage, and sample treatment for a wide coverage of metabolites with a wide range of concentrations of many lipophilic and some polar compounds. In this review, the current analytical practices for target and non-targeted metabolomics are described and discussed with emphasis on critical aspects: sample treatment (quenching, homogenization, filtration, centrifugation and extraction), analytical methods, as well as findings considering the used strategies. Besides that, the altered analytes in the different brain regions have been associated with their corresponding pathways to obtain a global overview of their dysregulation, trying to establish the link between altered biological pathways and pathophysiological conditions. Copyright © 2016 Elsevier B.V. All rights reserved.

In Vitro Trypanocidal Activity of Antibodies to Bacterially Expressed Trypanosoma brucei Tubulin

PubMed Central

Kateete, DP; Alezuyo, C; Nanteza, A; Asiimwe, C; Lubega, GW

2012-01-01

Background There are only four drugs for treating African trypanosomiasis, a devastating disease in sub-Saharan Africa. With slow discovery of better drugs, vaccination is viewed as the best method of control. We previously showed that antibodies to native Trypanosoma brucei brucei tubulin inhibit the growth of trypanosomes in culture. Here, we aimed to determine the effect of antibodies to bacterially expressed trypanosome tubulin on T. brucei brucei growth. Methods T. brucei brucei alpha and beta tubulin genes were individually expressed in Escherichia coli under the tryptophan promoter. Monoclonal tubulin antibodies reacted specifically with the expressed tubulins with no cross-reaction with the opposite tubulin. Rabbits were immunized with 450µg each of the concentrated recombinant tubulin, and production of antibodies assessed by ELISA and Western blotting. The effect of polyclonal antibodies on trypanosome growth was determined by culturing bloodstream T. brucei brucei in up to 25% of antisera. Results Low antisera dilutions (25%) from the immunized rabbits inhibited trypanosome growth. The most cytotoxic antisera were from one rabbit immunized with a mixture of both alpha and beta tubulins. However, the result was not reproduced in other rabbits and there was no apparent effect on growth at higher antisera dilutions. Conclusion Antibodies to bacterially expressed trypanosome tubulin are not effective at killing cultured bloodstream trypanosomes. PMID:23109963

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

PubMed Central

McGurk, Leeanne; Berson, Amit; Bonini, Nancy M.

2015-01-01

With the increase in the ageing population, neurodegenerative disease is devastating to families and poses a huge burden on society. The brain and spinal cord are extraordinarily complex: they consist of a highly organized network of neuronal and support cells that communicate in a highly specialized manner. One approach to tackling problems of such complexity is to address the scientific questions in simpler, yet analogous, systems. The fruit fly, Drosophila melanogaster, has been proven tremendously valuable as a model organism, enabling many major discoveries in neuroscientific disease research. The plethora of genetic tools available in Drosophila allows for exquisite targeted manipulation of the genome. Due to its relatively short lifespan, complex questions of brain function can be addressed more rapidly than in other model organisms, such as the mouse. Here we discuss features of the fly as a model for human neurodegenerative disease. There are many distinct fly models for a range of neurodegenerative diseases; we focus on select studies from models of polyglutamine disease and amyotrophic lateral sclerosis that illustrate the type and range of insights that can be gleaned. In discussion of these models, we underscore strengths of the fly in providing understanding into mechanisms and pathways, as a foundation for translational and therapeutic research. PMID:26447127

Drosophila as an In Vivo Model for Human Neurodegenerative Disease.

PubMed

McGurk, Leeanne; Berson, Amit; Bonini, Nancy M

2015-10-01

With the increase in the ageing population, neurodegenerative disease is devastating to families and poses a huge burden on society. The brain and spinal cord are extraordinarily complex: they consist of a highly organized network of neuronal and support cells that communicate in a highly specialized manner. One approach to tackling problems of such complexity is to address the scientific questions in simpler, yet analogous, systems. The fruit fly, Drosophila melanogaster, has been proven tremendously valuable as a model organism, enabling many major discoveries in neuroscientific disease research. The plethora of genetic tools available in Drosophila allows for exquisite targeted manipulation of the genome. Due to its relatively short lifespan, complex questions of brain function can be addressed more rapidly than in other model organisms, such as the mouse. Here we discuss features of the fly as a model for human neurodegenerative disease. There are many distinct fly models for a range of neurodegenerative diseases; we focus on select studies from models of polyglutamine disease and amyotrophic lateral sclerosis that illustrate the type and range of insights that can be gleaned. In discussion of these models, we underscore strengths of the fly in providing understanding into mechanisms and pathways, as a foundation for translational and therapeutic research. Copyright © 2015 by the Genetics Society of America.

Genome Editing: A New Approach to Human Therapeutics.

PubMed

Porteus, Matthew

2016-01-01

The ability to manipulate the genome with precise spatial and nucleotide resolution (genome editing) has been a powerful research tool. In the past decade, the tools and expertise for using genome editing in human somatic cells and pluripotent cells have increased to such an extent that the approach is now being developed widely as a strategy to treat human disease. The fundamental process depends on creating a site-specific DNA double-strand break (DSB) in the genome and then allowing the cell's endogenous DSB repair machinery to fix the break such that precise nucleotide changes are made to the DNA sequence. With the development and discovery of several different nuclease platforms and increasing knowledge of the parameters affecting different genome editing outcomes, genome editing frequencies now reach therapeutic relevance for a wide variety of diseases. Moreover, there is a series of complementary approaches to assessing the safety and toxicity of any genome editing process, irrespective of the underlying nuclease used. Finally, the development of genome editing has raised the issue of whether it should be used to engineer the human germline. Although such an approach could clearly prevent the birth of people with devastating and destructive genetic diseases, questions remain about whether human society is morally responsible enough to use this tool.

Scientometric Analysis and Mapping of Scientific Articles on Diabetic Retinopathy.

PubMed

Ramin, Shahrokh; Gharebaghi, Reza; Heidary, Fatemeh

2015-01-01

Diabetic retinopathy (DR) is the major cause of blindness among the working-age population globally. No systematic research has been previously performed to analyze the research published on DR, despite the need for it. This study aimed to analyze the scientific production on DR to draw overall roadmap of future research strategic planning in this field. A bibliometric method was used to obtain a view on the scientific production about DR by the data extracted from the Institute for Scientific Information (ISI). Articles about DR published in 1993-2013 were analyzed to obtain a view of the topic's structure, history, and to document relationships. The trends in the most influential publications and authors were analyzed. Most highly cited articles addressed epidemiologic and translational research topics in this field. During the past 3 years, there has been a trend toward biomarker discovery and more molecular translational research. Areas such as gene therapy and micro-RNAs are also among the recent hot topics. Through analyzing the characteristics of papers and the trends in scientific production, we performed the first scientometric report on DR. Most influential articles have addressed epidemiology and translational research subjects in this field, which reflects that globally, the earlier diagnosis and treatment of this devastating disease still has the highest global priority.

The pathophysiology of Peyronie's disease.

PubMed

El-Sakka, Ahmed I; Salabas, Emre; Dinçer, Murat; Kadioglu, Ates

2013-09-01

To review the contemporary knowledge of the pathophysiology of Peyronie's disease (PD). Medline was searched for papers published in English from 2000 to March 2013, using the keywords 'Peyronie's disease' and 'pathophysiology'. More than 300 relevant articles were identified for the purpose of this review. Unfortunately only a few studies had a high level of evidence, and the remaining studies were not controlled in their design. Many theories have been proposed to explain the cause of PD, but the true pathogenesis of PD remains an enigma. Identifying particular growth factors and the specific genes responsible for the induction of PD have been the ultimate goal of research over the past several decades. This would provide the means to devise a possible gene therapy for this devastating condition. We discuss present controversies and new discoveries related to the pathophysiology of this condition. PD is one of the most puzzling diseases in urology. The pathogenesis remains uncertain and there is still controversy about the best management. The pathogenesis of PD has been explored in animal models, cell cultures and clinical trials, but the results have led to further questions. New research on the aetiology and pathogenesis of PD is needed, and which will hopefully improve the understanding and management for patients with this frustrating disease.

HISTORY OF THE ORIGIN OF THE CHEMICAL ELEMENTS AND THEIR DISCOVERIES.

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

HOLDEN,N.E.

The origin of the chemical elements show a wide diversity with some of these elements having their origin in antiquity. Still other elements have been synthesized within the past fifty years via nuclear reactions on heavy elements, because these other elements are unstable and radioactive and do not exist in nature. The names of the elements come from many sources including mythological concepts or characters; places, areas or countries; properties of the element or its compounds, such as color, smell or its inability to combine; and the names of scientists. There are also some miscellaneous names as well as somemore » obscure names for particular elements. The claim of discovery of an element has varied over the centuries. Many claims, e.g., the discovery of certain rare earth elements of the lanthanide series, involved the discovery of a mineral ore from which an element was later extracted. The honor of discovery has often been accorded not to the person who first isolated the element but to the person who discovered the original mineral itself, even when the ore was impure and contained many elements. The reason for this is that in the case of these rare earth elements, the ''earth'' now refers to oxides of a metal not to the metal itself. This fact was not realized at the time of their discovery, until the English chemist Humphry Davy showed that earths were compounds of oxygen and metals in 1808. In the early discoveries, the atomic weight of an element and spectral analysis of the element were not available. Later both of these elemental properties would be required before discovery of the element would be accepted. In general, the requirements for discovery claims have tightened through the years and claims that were previously accepted would no longer meet the minimum constraints now imposed. There are cases where the honor of discovery is not given to the first person to actually discover the element but to the first person to claim the discovery in print. If a publication was delayed, the discoverer has often historically been ''scooped'' by another scientist.« less

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

Discovery of potent HIV-1 non-nucleoside reverse transcriptase inhibitors from arylthioacetanilide structural motif.

PubMed

Li, Wenxin; Li, Xiao; De Clercq, Erik; Zhan, Peng; Liu, Xinyong

2015-09-18

The poor pharmacokinetics, side effects and particularly the rapid emergence of drug resistance compromise the efficiency of the clinically used anti-HIV drugs. Therefore, the discovery of novel and effective NNRTIs is still an extremely primary mission. Arylthioacetanilide family is one of the highly active HIV-1 NNRTIs against wide-type (WT) HIV-1 and a wide range of drug-resistant mutant strains. Especially, VRX-480773 and RDEA806 have been chosen as candidates for further clinical studies. In this article, we review the discovery and development of the arylthioacetanilides, and, especially, pay much attention to the structural modifications, SARs conclusions and molecular modeling. Moreover, several medicinal chemistry strategies to overcome drug resistance involved in the optimization process of arylthioacetanilides are highlighted, providing valuable clues for further investigations. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Drug discovery management, small is still beautiful: Why a number of companies get it wrong.

PubMed

Knutsen, Lars J S

2011-06-01

This review provides an account of why more companies involved in drug discovery fail than succeed at releasing the creative energy of gifted scientists, whose invention of new drugs they rely upon to remain at the forefront of the biopharma industry. Initiatives aimed at improving output of new chemical entities often have the opposite effect from that intended and scientists become demotivated. Those with drive, vision and enthusiasm may move to smaller companies to rediscover the spirit of discovery. Some executives fail to understand the psyche of researchers; an applied understanding of the intrinsic motivation of scientists would improve research performance. Entities that focus on smaller autonomous units and sound ethical values will discover the most innovative and successful new drugs. Copyright © 2011 Elsevier Ltd. All rights reserved.

An Inconvenient History: the Nuclear-Fission Display in the Deutsches Museum

NASA Astrophysics Data System (ADS)

Sime, Ruth Lewin

2010-06-01

One of the longstanding attractions of the Deutsches Museum in Munich, Germany, has been its display of the apparatus associated with the discovery of nuclear fission. Although the discovery involved three scientists, Otto Hahn, Lise Meitner, and Fritz Strassmann, the fission display was designated for over 30 years as the Arbeitstisch von Otto Hahn (Otto Hahn’s Worktable), with Strassmann mentioned peripherally and Meitner not at all, and it was not until the early 1990s that the display was revised to include all three codiscoverers more equitably. I examine the creation of the fission display in the context of the postwar German culture of silencing the National Socialist past, and trace the eventual transformation of the display into a contemporary exhibit that more accurately represents the scientific history of the fission discovery.

Tutorial on the Role of Cyclopentadienyl Ligands in the Discovery of Molecular Complexes of the Rare-Earth and Actinide Metals in New Oxidation States

DOE PAGES

Evans, William J.

2016-09-15

A fundamental aspect of any element is the range of oxidation states accessible for useful chemistry. This tutorial describes the recent expansion of the number of oxidation states available to the rare-earth and actinide metals in molecular complexes that has resulted through organometallic chemistry involving the cyclopentadienyl ligand. These discoveries demonstrate that the cyclopentadienyl ligand, which has been a key component in the development of organometallic chemistry since the seminal discovery of ferrocene in the 1950s, continues to contribute to the advancement of science. Lastly, we present background information on the rare-earth and actinide elements, as well as the sequencemore » of events that led to these unexpected developments in the oxidation state chemistry of these metals.« less

Tutorial on the Role of Cyclopentadienyl Ligands in the Discovery of Molecular Complexes of the Rare-Earth and Actinide Metals in New Oxidation States

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

Evans, William J.

A fundamental aspect of any element is the range of oxidation states accessible for useful chemistry. This tutorial describes the recent expansion of the number of oxidation states available to the rare-earth and actinide metals in molecular complexes that has resulted through organometallic chemistry involving the cyclopentadienyl ligand. These discoveries demonstrate that the cyclopentadienyl ligand, which has been a key component in the development of organometallic chemistry since the seminal discovery of ferrocene in the 1950s, continues to contribute to the advancement of science. Lastly, we present background information on the rare-earth and actinide elements, as well as the sequencemore » of events that led to these unexpected developments in the oxidation state chemistry of these metals.« less

Brief Report: Single-nucleotide polymorphisms in VKORC1 are risk factors for systemic lupus erythematosus in Asians.

PubMed

Kaiser, Rachel; Taylor, Kimberly E; Deng, Yun; Zhao, Jian; Li, Yonghong; Nititham, Joanne; Chang, Monica; Catanese, Joseph; Begovich, Ann B; Brown, Elizabeth E; Edberg, Jeffrey C; McGwin, Gerald; Alarcón, Graciela S; Ramsey-Goldman, Rosalind; Reveille, John D; Vila, Luis M; Petri, Michelle; Kimberly, Robert P; Feng, Xuebing; Sun, Lingyun; Shen, Nan; Li, Wei; Lu, Jian-Xin; Wakeland, Edward K; Li, Quan-Zhen; Yang, Wanling; Lau, Yu-Lung; Liu, Fei-Lan; Chang, Deh-Ming; Yu, Chack-Yung; Song, Yeong W; Tsao, Betty P; Criswell, Lindsey A

2013-01-01

The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. The present study was undertaken to investigate whether 33 established and novel single-nucleotide polymorphisms (SNPs) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis (DVT) in the general population are risk factors for SLE among Asian subjects. Patients in the discovery cohort were enrolled in 1 of 2 North American SLE cohorts. Patients in the replication cohort were enrolled in 1 of 4 Asian or 2 North American cohorts. We first genotyped 263 Asian patients with SLE and 357 healthy Asian control subjects for 33 SNPs in the discovery phase, and then genotyped 5 SNPs in up to an additional 1,496 patients and 993 controls in the replication phase. Patients were compared to controls for bivariate association with minor alleles. Principal components analysis was used to control for intra-Asian ancestry in the replication cohort. Two genetic variants in the gene VKORC1 were highly significant in both the discovery and replication cohorts: rs9934438 (in the discovery cohort, odds ratio [OR] 2.45, P=2×10(-9); in the replication cohort, OR 1.54, P=4×10(-6)) and rs9923231 (in the discovery cohort, OR 2.40, P=6×10(-9); in the replication cohort, OR 1.53, P=5×10(-6)). These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: for rs9934438, OR 1.34, P=0.0029; for rs9923231, OR 1.34, P=0.0032. Genetic variants in VKORC1, which are involved in vitamin K reduction and associated with DVT, correlate with SLE development in Asian subjects. These results suggest that there may be intersecting genetic pathways for the development of SLE and thrombosis. Copyright © 2013 by the American College of Rheumatology.

Neptune's Discovery: Le Verrier, Adams, and the Assignment of Credit

NASA Astrophysics Data System (ADS)

Sheehan, William

2011-01-01

As one of the most significant achievements of 19th century astronomy, the discovery of Neptune has been the subject of a vast literature. A large part of this literature--beginning with the period immediately after the optical discovery in Berlin--has been the obsession with assigning credit to the two men who attempted to calculate the planet's position (and initially this played out against the international rivalry between France and England). Le Verrier and Adams occupied much different positions in the Scientific Establishments of their respective countries; had markedly different personalities; and approached the investigation using different methods. A psychiatrist and historian of astronomy tries to provide some new contexts to the familiar story of the discovery of Neptune, and argues that the personalities of these two men played crucial roles in their approaches to the problem they set themselves and the way others reacted to their stimuli. Adams had features of high-functioning autism, while Le Verrier's domineering, obsessive, orderly personality--though it allowed him to be immensely productive--eventually led to serious difficulties with his peers (and an outright revolt). Though it took extraordinary smarts to calculate the position of Neptune, the discovery required social skills that these men lacked--and thus the process to discovery was more bumbling and adventitious than it might have been. The discovery of Neptune occurred at a moment when astronomy was changing from that of heroic individuals to team collaborations involving multiple experts, and remains an object lesson in the sociological aspects of scientific endeavor.

A historical reflection on the discovery of human retroviruses.

PubMed

Vahlne, Anders

2009-05-01

The discovery of HIV-1 as the cause of AIDS was one of the major scientific achievements during the last century. Here the events leading to this discovery are reviewed with particular attention to priority and actual contributions by those involved. Since I would argue that discovering HIV was dependent on the previous discovery of the first human retrovirus HTLV-I, the history of this discovery is also re-examined. The first human retroviruses (HTLV-I) was first reported by Robert C. Gallo and coworkers in 1980 and reconfirmed by Yorio Hinuma and coworkers in 1981. These discoveries were in turn dependent on the previous discovery by Gallo and coworkers in 1976 of interleukin 2 or T-cell growth factor as it was called then. HTLV-II was described by Gallo's group in 1982. A human retrovirus distinct from HTLV-I and HTLV-II in that it was shown to have the morphology of a lentivirus was in my mind described for the first time by Luc Montagnier in an oral presentation at Cold Spring Harbor in September of 1983. This virus was isolated from a patient with lymphadenopathy using the protocol previously described for HTLV by Gallo. The first peer reviewed paper by Montagnier's group of such a retrovirus, isolated from two siblings of whom one with AIDS, appeared in Lancet in April of 1984. However, the proof that a new human retrovirus (HIV-1) was the cause of AIDS was first established in four publications by Gallo's group in the May 4th issue of Science in 1984.

Anticoagulant factor V: factors affecting the integration of novel scientific discoveries into the broader framework.

PubMed

LaBonte, Michelle L

2014-09-01

Since its initial discovery in the 1940s, factor V has long been viewed as an important procoagulant protein in the coagulation cascade. However, in the later part of the 20th century, two different scientists proposed novel anticoagulant roles for factor V. Philip Majerus proposed the first anticoagulant function for factor V in 1983, yet ultimately it was not widely accepted by the broader scientific community. In contrast, Björn Dahlbäck proposed a different anticoagulant role for factor V in 1994. While this role was initially contested, it was ultimately accepted and integrated into the scientific framework. In this paper, I present a detailed historical account of these two anticoagulant discoveries and propose three key reasons why Dahlbäck's anticoagulant role for factor V was accepted whereas Majerus' proposed role was largely overlooked. Perhaps most importantly, Dahlbäck's proposed anticoagulant role was of great clinical interest because the discovery involved the study of an important subset of patients with thrombophilia. Soon after Dahlbäck's 1994 work, this patient population was shown to possess the factor V Leiden mutation. Also key in the ultimate acceptance of the second proposed anticoagulant role was the persistence of the scientist who made the discovery and the interest in and ability of others to replicate and reinforce this work. This analysis of two different yet similar discoveries sheds light on factors that play an important role in how new discoveries are incorporated into the existing scientific framework. Copyright © 2014 The Author. Published by Elsevier Ltd.. All rights reserved.

Three New Teosintes (Zea spp., Poaceae) From Mexico

USDA-ARS?s Scientific Manuscript database

The discovery of new species of teosinte from México motivated the comparative study of populations from México, Guatemala and Nicaragua through detailed ecogeographic, morphologic, cytogenetic and molecular characterization. The study involved a comparative analysis of morphological, ecogeographic,...

cDNA microarray analysis of esophageal cancer: discoveries and prospects.

PubMed

Shimada, Yutaka; Sato, Fumiaki; Shimizu, Kazuharu; Tsujimoto, Gozoh; Tsukada, Kazuhiro

2009-07-01

Recent progress in molecular biology has revealed many genetic and epigenetic alterations that are involved in the development and progression of esophageal cancer. Microarray analysis has also revealed several genetic networks that are involved in esophageal cancer. However, clinical application of microarray techniques and use of microarray data have not yet occurred. In this review, we focus on the recent developments and problems with microarray analysis of esophageal cancer.

Creating Geoscience Leaders

NASA Astrophysics Data System (ADS)

Buskop, J.; Buskop, W.

2013-12-01

The United Nations Educational, Scientific, and Cultural Organization recognizes 21 World Heritage in the United States, ten of which have astounding geological features: Wrangell St. Elias National Park, Olympic National Park, Mesa Verde National Park, Chaco Canyon, Glacier National Park, Carlsbad National Park, Mammoth Cave, Great Smokey Mountains National Park, Hawaii Volcanoes National Park, and Everglades National Park. Created by a student frustrated with fellow students addicted to smart phones with an extreme lack of interest in the geosciences, one student visited each World Heritage site in the United States and created one e-book chapter per park. Each chapter was created with original photographs, and a geological discovery hunt to encourage teen involvement in preserving remarkable geological sites. Each chapter describes at least one way young adults can get involved with the geosciences, such a cave geology, glaciology, hydrology, and volcanology. The e-book describes one park per chapter, each chapter providing a geological discovery hunt, information on how to get involved with conservation of the parks, geological maps of the parks, parallels between archaeological and geological sites, and how to talk to a ranger. The young author is approaching UNESCO to publish the work as a free e-book to encourage involvement in UNESCO sites and to prove that the geosciences are fun.

Why Is It Difficult to Predict Language Impairment and Outcome in Patients with Aphasia after Stroke?

PubMed Central

Kasselimis, Dimitrios; Varkanitsa, Maria; Selai, Caroline; Potagas, Constantin; Evdokimidis, Ioannis

2014-01-01

One of the most devastating consequences of stroke is aphasia. Communication problems after stroke can severely impair the patient's quality of life and make even simple everyday tasks challenging. Despite intense research in the field of aphasiology, the type of language impairment has not yet been localized and correlated with brain damage, making it difficult to predict the language outcome for stroke patients with aphasia. Our primary objective is to present the available evidence that highlights the difficulties of predicting language impairment after stroke. The different levels of complexity involved in predicting the lesion site from language impairment and ultimately predicting the long-term outcome in stroke patients with aphasia were explored. Future directions and potential implications for research and clinical practice are highlighted. PMID:24829592

The World Health Organization’s Safe Abortion Guidance Document

PubMed Central

Van Look, Paul F. A.; Cottingham, Jane

2013-01-01

We discuss the history of the World Health Organization’s (WHO’s) development of guidelines for governments on providing safe abortion services, which WHO published as Safe Abortion: Technical and Policy Guidance for Health Systems in 2003 and updated in 2012. We show how the recognition of the devastating impact of unsafe abortion on women’s health and survival, the impetus of the International Conference on Population and Development and its five-year follow-up, and WHO’s progressive leadership at the end of the century enabled the organization to elaborate guidance on providing safe abortion services. Guideline formulation involved extensive review of published evidence, an international technical expert meeting to review the draft document, and a protracted in-house review by senior WHO management. PMID:23409886

DVI missions in the Carribean-the practical aspects of disaster victim identification.

PubMed

Winskog, Calle

2012-06-01

Human trafficking of young men from Africa to Europe is a crime with often devastating consequences. The African continent loses members of the younger generation and many die during the attempt to reach their destinations. The identification of these victims is often difficult, however the structured and by now well-established procedures utilizing standard disaster victim identification protocols provide a reliable and functional approach. The logistics involved are straightforward, and one of the many functions of the team leader is to monitor and control the flow of cases through the system. The importance of ante mortem data for the purposes of identification is clear-no ante mortem data means no identification. Two different missions conducted in the Caribbean are described to illustrate particular difficulties that may occur.

Pathophysiology and Treatment of Memory Dysfunction after Traumatic Brain Injury

PubMed Central

Paterno, Rosalia; Folweiler, Kaitlin A.; Cohen, Akiva S.

2018-01-01

Memory is fundamental to everyday life, and cognitive impairments resulting from traumatic brain injury (TBI) have devastating effects on TBI survivors. A contributing component to memory impairments caused by TBI are alterations in the neural circuits associated with memory function. In this review, we aim to bring together experimental findings that characterize behavioral memory deficits and the underlying pathophysiology of memory-involved circuits after TBI. While there is little doubt that TBI causes memory and cognitive dysfunction, it is difficult to conclude which memory phase i.e., encoding, maintenance or retrieval is specifically altered by TBI. This is most likely due to variation in behavioral protocols and experimental models. Additionally we review a selection of experimental treatments that hold translational potential to mitigate memory dysfunction following injury. PMID:28500417

NMR-Fragment Based Virtual Screening: A Brief Overview.

PubMed

Singh, Meenakshi; Tam, Benjamin; Akabayov, Barak

2018-01-25

Fragment-based drug discovery (FBDD) using NMR has become a central approach over the last twenty years for development of small molecule inhibitors against biological macromolecules, to control a variety of cellular processes. Yet, several considerations should be taken into account for obtaining a therapeutically relevant agent. In this review, we aim to list the considerations that make NMR fragment screening a successful process for yielding potent inhibitors. Factors that may govern the competence of NMR in fragment based drug discovery are discussed, as well as later steps that involve optimization of hits obtained by NMR-FBDD.

Perspective: Interactive material property databases through aggregation of literature data

NASA Astrophysics Data System (ADS)

Seshadri, Ram; Sparks, Taylor D.

2016-05-01

Searchable, interactive, databases of material properties, particularly those relating to functional materials (magnetics, thermoelectrics, photovoltaics, etc.) are curiously missing from discussions of machine-learning and other data-driven methods for advancing new materials discovery. Here we discuss the manual aggregation of experimental data from the published literature for the creation of interactive databases that allow the original experimental data as well additional metadata to be visualized in an interactive manner. The databases described involve materials for thermoelectric energy conversion, and for the electrodes of Li-ion batteries. The data can be subject to machine-learning, accelerating the discovery of new materials.

Perspective: Proteomic approach to detect biomarkers of human growth hormone

PubMed Central

Ding, Juan; List, Edward O.; Okada, Shigeru; Kopchick, John J.

2009-01-01

Several serum biomarkers for recombinant human growth hormone (rhGH) have been established, however, none alone or in combination have generate a specific, sensitive, and reproducible ‘kit’ for the detection of rhGH abuse. Thus, the search for additional GH specific biomarkers continues. In this review, we focus on the use of proteomics in general and 2-dimensional electrophoresis (2-DE) in particular for the discovery of new GH induced serum biomarkers. Also, we review some of the protocols involved in 2DE. Finally, the possibility of tissues other than blood for biomarker discovery is discussed. PMID:19501004

The Study of “big data” to support internal business strategists

NASA Astrophysics Data System (ADS)

Ge, Mei

2018-01-01

How is big data different from previous data analysis systems? The primary purpose behind traditional small data analytics that all managers are more or less familiar with is to support internal business strategies. But big data also offers a promising new dimension: to discover new opportunities to offer customers high-value products and services. The study focus to introduce some strategists which big data support to. Business decisions using big data can also involve some areas for analytics. They include customer satisfaction, customer journeys, supply chains, risk management, competitive intelligence, pricing, discovery and experimentation or facilitating big data discovery.

New strategies in drug discovery.

PubMed

Ohlstein, Eliot H; Johnson, Anthony G; Elliott, John D; Romanic, Anne M

2006-01-01

Gene identification followed by determination of the expression of genes in a given disease and understanding of the function of the gene products is central to the drug discovery process. The ability to associate a specific gene with a disease can be attributed primarily to the extraordinary progress that has been made in the areas of gene sequencing and information technologies. Selection and validation of novel molecular targets have become of great importance in light of the abundance of new potential therapeutic drug targets that have emerged from human gene sequencing. In response to this revolution within the pharmaceutical industry, the development of high-throughput methods in both biology and chemistry has been necessitated. Further, the successful translation of basic scientific discoveries into clinical experimental medicine and novel therapeutics is an increasing challenge. As such, a new paradigm for drug discovery has emerged. This process involves the integration of clinical, genetic, genomic, and molecular phenotype data partnered with cheminformatics. Central to this process, the data generated are managed, collated, and interpreted with the use of informatics. This review addresses the use of new technologies that have arisen to deal with this new paradigm.

Simulation with quantum mechanics/molecular mechanics for drug discovery.

PubMed

Barbault, Florent; Maurel, François

2015-10-01

Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process. In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery. QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.

Simulation with quantum mechanics/molecular mechanics for drug discovery.

PubMed

Barbault, Florent; Maurel, François

2015-08-08

Biological macromolecules, such as proteins or nucleic acids, are (still) molecules and thus they follow the same chemical rules that any simple molecule follows, even if their size generally renders accurate studies unhelpful. However, in the context of drug discovery, a detailed analysis of ligand association is required for understanding or predicting their interactions and hybrid quantum mechanics/molecular mechanics (QM/MM) computations are relevant tools to help elucidate this process. Areas covered: In this review, the authors explore the use of QM/MM for drug discovery. After a brief description of the molecular mechanics (MM) technique, the authors describe the subtractive and additive techniques for QM/MM computations. The authors then present several application cases in topics involved in drug discovery. Expert opinion: QM/MM have been widely employed during the last decades to study chemical processes such as enzyme-inhibitor interactions. However, despite the enthusiasm around this area, plain MM simulations may be more meaningful than QM/MM. To obtain reliable results, the authors suggest fixing several keystone parameters according to the underlying chemistry of each studied system.

Workshop on Discovery Lessons-Learned

NASA Technical Reports Server (NTRS)

Saunders, M. (Editor)

1995-01-01

As part of the Discovery Program's continuous improvement effort, a Discovery Program Lessons-Learned workshop was designed to review how well the Discovery Program is moving toward its goal of providing low-cost research opportunities to the planetary science community while ensuring continued U.S. leadership in solar system exploration. The principal focus of the workshop was on the recently completed Announcement of Opportunity (AO) cycle, but the program direction and program management were also open to comment. The objective of the workshop was to identify both the strengths and weaknesses of the process up to this point, with the goal of improving the process for the next AO cycle. The process for initializing the workshop was to solicit comments from the communities involved in the program and to use the feedback as the basis for establishing the workshop agenda. The following four sessions were developed after reviewing and synthesizing both the formal feedback received and informal feedback obtained during discussions with various participants: (1) Science and Return on Investment; (2) Technology vs. Risk; Mission Success and Other Factors; (3) Cost; and (4) AO.AO Process Changes and Program Management.

Novel Directions for Diabetes Mellitus Drug Discovery

PubMed Central

Maiese, Kenneth; Chong, Zhao Zhong; Shang, Yan Chen; Wang, Shaohui

2012-01-01

Introduction Diabetes mellitus impacts almost 200 million individuals worldwide and leads to debilitating complications. New avenues of drug discovery must target the underlying cellular processes of oxidative stress, apoptosis, autophagy, and inflammation that can mediate multi-system pathology during diabetes mellitus. Areas Covered We examine novel directions for drug discovery that involve the β-nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide, the cytokine erythropoietin, the NAD+-dependent protein histone deacetylase SIRT1, the serine/threonine-protein kinase mammalian target of rapamycin (mTOR), and the wingless pathway. Implications for the targeting of these pathways that oversee gluconeogenic genes, insulin signaling and resistance, fatty acid beta-oxidation, inflammation, and cellular survival are presented. Expert Opinion Nicotinamide, erythropoietin, and the downstram pathways of SIRT1, mTOR, forkhead transcription factors, and wingless signaling offer exciting prospects for novel directions of drug discovery for the treatment of metabolic disorders. Future investigations must dissect the complex relationship and fine modulation of these pathways for the successful translation of robust reparative and regenerative strategies against diabetes mellitus and the complications of this disorder. PMID:23092114

Second impact syndrome in football: new imaging and insights into a rare and devastating condition.

PubMed

Weinstein, Elizabeth; Turner, Michael; Kuzma, Benjamin B; Feuer, Henry

2013-03-01

Premature return to play for the concussed pediatric athlete may result in devastating neurological injury. Identification of at-risk patients and ideal management of the concussed athlete remain challenging for the pediatrician. The authors review a case of second impact syndrome in which neuroimaging was obtained between the first and second impacts, a circumstance which to their knowledge has not been previously reported. This case offers new insights into the underlying pathophysiology of this disease process and potential risk factors for its development.

Drug discovery for alopecia: gone today, hair tomorrow.

PubMed

Santos, Zenildo; Avci, Pinar; Hamblin, Michael R

2015-03-01

Hair loss or alopecia affects the majority of the population at some time in their life, and increasingly, sufferers are demanding treatment. Three main types of alopecia (androgenic [AGA], areata [AA] and chemotherapy-induced [CIA]) are very different, and have their own laboratory models and separate drug-discovery efforts. In this article, the authors review the biology of hair, hair follicle (HF) cycling, stem cells and signaling pathways. AGA, due to dihydrotesterone, is treated by 5-α reductase inhibitors, androgen receptor blockers and ATP-sensitive potassium channel-openers. AA, which involves attack by CD8(+)NK group 2D-positive (NKG2D(+)) T cells, is treated with immunosuppressives, biologics and JAK inhibitors. Meanwhile, CIA is treated by apoptosis inhibitors, cytokines and topical immunotherapy. The desire to treat alopecia with an easy topical preparation is expected to grow with time, particularly with an increasing aging population. The discovery of epidermal stem cells in the HF has given new life to the search for a cure for baldness. Drug discovery efforts are being increasingly centered on these stem cells, boosting the hair cycle and reversing miniaturization of HF. Better understanding of the molecular mechanisms underlying the immune attack in AA will yield new drugs. New discoveries in HF neogenesis and low-level light therapy will undoubtedly have a role to play.

Fragment-based drug discovery and its application to challenging drug targets.

PubMed

Price, Amanda J; Howard, Steven; Cons, Benjamin D

2017-11-08

Fragment-based drug discovery (FBDD) is a technique for identifying low molecular weight chemical starting points for drug discovery. Since its inception 20 years ago, FBDD has grown in popularity to the point where it is now an established technique in industry and academia. The approach involves the biophysical screening of proteins against collections of low molecular weight compounds (fragments). Although fragments bind to proteins with relatively low affinity, they form efficient, high quality binding interactions with the protein architecture as they have to overcome a significant entropy barrier to bind. Of the biophysical methods available for fragment screening, X-ray protein crystallography is one of the most sensitive and least prone to false positives. It also provides detailed structural information of the protein-fragment complex at the atomic level. Fragment-based screening using X-ray crystallography is therefore an efficient method for identifying binding hotspots on proteins, which can then be exploited by chemists and biologists for the discovery of new drugs. The use of FBDD is illustrated here with a recently published case study of a drug discovery programme targeting the challenging protein-protein interaction Kelch-like ECH-associated protein 1:nuclear factor erythroid 2-related factor 2. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Devastating consequences of sex trafficking on women's health.

PubMed

McTavish, Fr James

2017-11-01

Sex trafficking has devastating consequences on the physical and mental well-being of millions of women around the world. These trafficking victims often come in contact with medical personnel, and these encounters with suitably prepared staff can be a step toward healing of the victims. The Catholic Church, especially through Pope Francis, is making strenuous efforts to curb the spread of sex trafficking. Same-sex feelings and behavior may arise post-trafficking in individuals, although this does not appear to be mentioned thus far in the literature. Here, we are most likely dealing with a type of "pseudo-lesbianism" post-trauma. The trafficking survivor can be helped to understand some of the likely roots of her feelings such as anti-male sentiments following abuse. She needs to be patiently, and expertly, accompanied to process the trauma she has experienced, and learn how to meet her genuine needs for female affection and affirmation in healthy, chaste, and non-erotic ways. Around the world, millions of female victims of human trafficking are forced into sex "work," often resulting in serious physical and mental-health problems. Healthcare staff should be alert to spot victims of sex trafficking and be ready to assist them. The Catholic Church, especially through Pope Francis, has been vocal in denouncing this form of modern slavery. Some female victims of sex trafficking may experience same-sex feelings afterward. Healing for such young women involves helping them to process their traumatic experiences, as well as patiently accompanying them as they seek to develop healthy, chaste friendships with other females and males.

Freezing of gait: Promising avenues for future treatment.

PubMed

Gilat, Moran; Lígia Silva de Lima, Ana; Bloem, Bastiaan R; Shine, James M; Nonnekes, Jorik; Lewis, Simon J G

2018-03-12

Freezing of gait is a devastating symptom of Parkinson's disease and other forms of parkinsonism. It poses a major burden on both patients and their families, as freezing often leads to falls, fall-related injuries and a loss of independence. Treating freezing of gait is difficult for a variety of reasons: it has a paroxysmal and unpredictable nature; a multifaceted pathophysiology, with an interplay between motor elements (disturbed stepping mechanisms) and non-motor elements (cognitive decline, anxiety); and a complex (and likely heterogeneous) underlying neural substrate, involving multiple failing neural networks. In recent years, advances in translational neuroscience have offered new insights into the pathophysiology underlying freezing. Furthermore, the mechanisms behind the effectiveness of available treatments (or lack thereof) are better understood. Driven by these concepts, researchers and clinicians have begun to improve currently available treatment options, and develop new and better treatment methods. Here, we evaluate the range of pharmacological (i.e. closed-looped approaches), surgical (i.e. multi-target and adaptive deep brain and spinal cord stimulation) and behavioural (i.e. biofeedback and cueing on demand) treatment options that are under development, and propose novel avenues that are likely to play a crucial role in the clinical management of freezing of gait in the near future. The outcomes of this review suggest that the successful future management of freezing of gait will require individualized treatments that can be implemented in an on-demand manner in response to imminent freezing. With this review we hope to guide much-needed advances in treating this devastating symptom of Parkinson's disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

Pregnancy discovery and acceptance among low-income primiparous women: a multicultural exploration.

PubMed

Peacock, N R; Kelley, M A; Carpenter, C; Davis, M; Burnett, G; Chavez, N; Aranda, V

2001-06-01

As part of a larger study exploring psychosocial factors that influence self-care and use of health care services during pregnancy, we investigated the process of pregnancy discovery and acceptance among a culturally diverse group of women who had given birth to their first child in the year preceding data collection. Eighty-seven low-income women from four cultural groups (African American, Mexican, Puerto Rican, and white) participated in eight focus groups held in their communities. The focus groups were ethnically homogenous and stratified by early and late entry into prenatal care. A social influence model guided the development of focus group questions, and the study followed a participatory action research model, with community members involved in all phases of the research. Issues that emerged from the focus groups as possible influences on timing of pregnancy recognition include the role of pregnancy signs and symptoms and pregnancy risk perception in the discovery process, the role of social network members in labeling and affirming the pregnancy, concerns about disclosure, "planning" status of the pregnancy, and perceived availability of choices for resolving an unintended pregnancy. The pregnancy discovery process is complex, and when protracted, can potentially result in delayed initiation of both prenatal care and healthful pregnancy behaviors. Enhancing our understanding of pregnancy discovery and acceptance has clear implications for primary and secondary prevention. Future research is needed to further explain the trajectory of pregnancy discovery and acceptance and its influence on health behaviors and pregnancy outcome.

[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.

Conceptual biology, hypothesis discovery, and text mining: Swanson's legacy.

PubMed

Bekhuis, Tanja

2006-04-03

Innovative biomedical librarians and information specialists who want to expand their roles as expert searchers need to know about profound changes in biology and parallel trends in text mining. In recent years, conceptual biology has emerged as a complement to empirical biology. This is partly in response to the availability of massive digital resources such as the network of databases for molecular biologists at the National Center for Biotechnology Information. Developments in text mining and hypothesis discovery systems based on the early work of Swanson, a mathematician and information scientist, are coincident with the emergence of conceptual biology. Very little has been written to introduce biomedical digital librarians to these new trends. In this paper, background for data and text mining, as well as for knowledge discovery in databases (KDD) and in text (KDT) is presented, then a brief review of Swanson's ideas, followed by a discussion of recent approaches to hypothesis discovery and testing. 'Testing' in the context of text mining involves partially automated methods for finding evidence in the literature to support hypothetical relationships. Concluding remarks follow regarding (a) the limits of current strategies for evaluation of hypothesis discovery systems and (b) the role of literature-based discovery in concert with empirical research. Report of an informatics-driven literature review for biomarkers of systemic lupus erythematosus is mentioned. Swanson's vision of the hidden value in the literature of science and, by extension, in biomedical digital databases, is still remarkably generative for information scientists, biologists, and physicians.

Zbrowse: An interactive GWAS results browser

USDA-ARS?s Scientific Manuscript database

The growing number of genotyped populations, the advent of high-throughput phenotyping techniques and the development of GWAS analysis software has rapidly accelerated the number of GWAS experimental results. Candidate gene discovery from these results files is often tedious, involving many manual s...

Teaching Quantum Mechanics on an Introductory Level.

ERIC Educational Resources Information Center

Muller, Rainer; Wiesner, Hartmut

2002-01-01

Presents a new research-based course on quantum mechanics in which the conceptual issues of quantum mechanics are taught at an introductory level. Involves students in the discovery of how quantum phenomena deviate from classical everyday experiences. (Contains 31 references.) (Author/YDS)

Discovering Steiner Triple Systems through Problem Solving

ERIC Educational Resources Information Center

Sriraman, Bharath

2004-01-01

An attempt to implement problem solving as a teacher of ninth grade algebra is described. The problems selected were not general ones, they involved combinations and represented various situations and were more complex which lead to the discovery of Steiner triple systems.

From Fibonacci Numbers To Geometric Sequences and the Binet Formula by Way of the Golden Ratio!

ERIC Educational Resources Information Center

DiDomenico, Angelo S.

1997-01-01

Provides activities that deal with Fibonacci-like sequences and guide students' thinking as they explore mathematical induction. Investigation leads to a discovery of an interesting relation that involves all Fibonacci-like sequences. (DDR)

Visual Compositions and Language Development.

ERIC Educational Resources Information Center

Sinatra, Richard

1981-01-01

Presents an approach for improving verbal development by using organized slide shows to produce visual/verbal interaction in classroom. Suggests strength of visual involvement is that it provides a procedure for language discovery while achieving cooperation between right and left brain processing. (Author/BK)

Organometallic Chemistry and Catalysis in Industry.

ERIC Educational Resources Information Center

Parshall, George W.; Putscher, Richard E.

1986-01-01

Traces the growth in the industrial usage of organometallic chemistry from 1950 to 1977, pointing out that this growth involved the production of commodity chemicals. Indicates that one of the early successes of organometallic chemistry was the discovery of ethylene polymerization catalysts. (JN)

Recent Discoveries and the Ultimate Fate of Organic Contaminants

EPA Science Inventory

With very few exceptions, the common organic contaminants in soils, sediments, and ground water can be transformed or entirely degraded by oxidation or reduction reactions that are either carried through direct involvement with microorganisms, or indirectly through abiotic reacti...

International Space Station (ISS) Low Pressure Intramodule Quick Disconnect Failures

NASA Technical Reports Server (NTRS)

Lewis, John F.; Harris, Danny; Link, Dwight; Morrison, Russel

2004-01-01

A failure of an ISS intermodule Quick Disconnect (QD) during protoflight vibration testing of ISS regenerative Environmental Control and Life Support (ECLS) hardware led to the discovery of QD design, manufacturing, and test flaws which can yield the male QD susceptible to failure of the secondary housing seal and inadequate housing assembly locking mechanisms. Discovery of this failure had large implications when considering that currently there are 399 similar units on orbit and approximately 1100 units on the ground integrated into flight hardware. Discovery of the nature of the failure required testing and analysis and implementation of a recovery plan requiring part screening and review of element level and project hazard analysis to determine if secondary seals are required. Implementation also involves coordination with the Nodes and MPLM project offices, Regenerative ECLS Project, ISS Payloads, JAXA, ESA, and ISS Logistics and Maintenance.

Towards novel therapeutics for HIV through fragment-based screening and drug design.

PubMed

Tiefendbrunn, Theresa; Stout, C David

2014-01-01

Fragment-based drug discovery has been applied with varying levels of success to a number of proteins involved in the HIV (Human Immunodeficiency Virus) life cycle. Fragment-based approaches have led to the discovery of novel binding sites within protease, reverse transcriptase, integrase, and gp41. Novel compounds that bind to known pockets within CCR5 have also been identified via fragment screening, and a fragment-based approach to target the TAR-Tat interaction was explored. In the context of HIV-1 reverse transcriptase (RT), fragment-based approaches have yielded fragment hits with mid-μM activity in an in vitro activity assay, as well as fragment hits that are active against drug-resistant variants of RT. Fragment-based drug discovery is a powerful method to elucidate novel binding sites within proteins, and the method has had significant success in the context of HIV proteins.

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 trajectory of scientific discovery: concept co-occurrence and converging semantic distance.

PubMed

Cohen, Trevor; Schvaneveldt, Roger W

2010-01-01

The paradigm of literature-based knowledge discovery originated by Swanson involves finding meaningful associations between terms or concepts that have not occurred together in any previously published document. While several automated approaches have been applied to this problem, these generally evaluate the literature at a point in time, and do not evaluate the role of change over time in distributional statistics as an indicator of meaningful implicit associations. To address this issue, we develop and evaluate Symmetric Random Indexing (SRI), a novel variant of the Random Indexing (RI) approach that is able to measure implicit association over time. SRI is found to compare favorably to existing RI variants in the prediction of future direct co-occurrence. Summary statistics over several experiments suggest a trend of converging semantic distance prior to the co-occurrence of key terms for two seminal historical literature-based discoveries.

Directional Bias and Pheromone for Discovery and Coverage on Networks

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

Fink, Glenn A.; Berenhaut, Kenneth S.; Oehmen, Christopher S.

2012-09-11

Natural multi-agent systems often rely on “correlated random walks” (random walks that are biased toward a current heading) to distribute their agents over a space (e.g., for foraging, search, etc.). Our contribution involves creation of a new movement and pheromone model that applies the concept of heading bias in random walks to a multi-agent, digital-ants system designed for cyber-security monitoring. We examine the relative performance effects of both pheromone and heading bias on speed of discovery of a target and search-area coverage in a two-dimensional network layout. We found that heading bias was unexpectedly helpful in reducing search time andmore » that it was more influential than pheromone for improving coverage. We conclude that while pheromone is very important for rapid discovery, heading bias can also greatly improve both performance metrics.« less

Reconstructive Management of Devastating Electrical Injuries to the Face.

PubMed

Janis, Jeffrey E; Khansa, Ibrahim; Lehrman, Craig R; Orgill, Dennis P; Pomahac, Bohdan

2015-10-01

Devastating fourth-degree electrical injuries to the face and head pose significant reconstructive challenges. To date, there have been few peer-reviewed articles in the literature that describe those reconstructive challenges. The authors present the largest case series to date that describes the management of these injuries, including the incorporation of face transplantation. A retrospective case series was conducted of patients with devastating electrical injuries to the face who were managed at two level-1 trauma centers between 2007 and 2011. Data describing patient injuries, initial management, and reconstructive procedures were collected. Five patients with devastating electrical injuries to the face were reviewed. After initial stabilization and treatment of life-threatening injuries, all five underwent burn excision and microsurgical reconstruction using distant flaps. Two of the patients eventually underwent face transplantation. The authors describe differences in management between the two trauma centers, one of which had the availability for composite tissue allotransplantation; the other did not. Also described is how initial attempts at traditional reconstruction affected the eventual face transplantation. The care of patients with complex electrical burns must be conducted in a multidisciplinary fashion. As with all other trauma, the initial priority should be management of the airway, breathing, and circulation. Additional considerations include cardiac arrhythmias and renal impairment attributable to myoglobinuria. Before embarking on aggressive reconstruction attempts, it is advisable to determine early whether the patient is a candidate for face transplantation in order to avoid antigen sensitization, loss of a reconstructive "lifeboat," surgical plane disruption, and sacrifice of potential recipient vessels. Therapeutic, V.

Lassa hemorrhagic fever in a late term pregnancy from northern sierra leone with a positive maternal outcome: case report

PubMed Central

2011-01-01

Lassa fever (LF) is a devastating viral disease prevalent in West Africa. Efforts to take on this public health crisis have been hindered by lack of infrastructure and rapid field deployable diagnosis in areas where the disease is prevalent. Recent capacity building at the Kenema Government Hospital Lassa Fever Ward (KGH LFW) in Sierra Leone has lead to a major turning point in the diagnosis, treatment and study of LF. Herein we present the first comprehensive rapid diagnosis and real time characterization of an acute hemorrhagic LF case at KGH LFW. This case report focuses on a third trimester pregnant Sierra Leonean woman from the historically non-endemic Northern district of Tonkolili who survived the illness despite fetal demise. Employed in this study were newly developed recombinant LASV Antigen Rapid Test cassettes and dipstick lateral flow immunoassays (LFI) that enabled the diagnosis of LF within twenty minutes of sample collection. Deregulation of overall homeostasis, significant hepatic and renal system involvement, and immunity profiles were extensively characterized during the course of hospitalization. Rapid diagnosis, prompt treatment with a full course of intravenous (IV) ribavirin, IV fluids management, and real time monitoring of clinical parameters resulted in a positive maternal outcome despite admission to the LFW seven days post onset of symptoms, fetal demise, and a natural still birth delivery. These studies solidify the growing rapid diagnostic, treatment, and surveillance capabilities at the KGH LF Laboratory, and the potential to significantly improve the current high mortality rate caused by LF. As a result of the growing capacity, we were also able to isolate Lassa virus (LASV) RNA from the patient and perform Sanger sequencing where we found significant genetic divergence from commonly circulating Sierra Leonean strains, showing potential for the discovery of a newly emerged LASV strain with expanded geographic distribution. Furthermore, recent emergence of LF cases in Northern Sierra Leone highlights the need for superior diagnostics to aid in the monitoring of LASV strain divergence with potentially increased geographic expansion. PMID:21843352

The Alveolate Perkinsus marinus: Biological Insights from EST Gene Discovery

PubMed Central

2010-01-01

Background Perkinsus marinus, a protozoan parasite of the eastern oyster Crassostrea virginica, has devastated natural and farmed oyster populations along the Atlantic and Gulf coasts of the United States. It is classified as a member of the Perkinsozoa, a recently established phylum considered close to the ancestor of ciliates, dinoflagellates, and apicomplexans, and a key taxon for understanding unique adaptations (e.g. parasitism) within the Alveolata. Despite intense parasite pressure, no disease-resistant oysters have been identified and no effective therapies have been developed to date. Results To gain insight into the biological basis of the parasite's virulence and pathogenesis mechanisms, and to identify genes encoding potential targets for intervention, we generated >31,000 5' expressed sequence tags (ESTs) derived from four trophozoite libraries generated from two P. marinus strains. Trimming and clustering of the sequence tags yielded 7,863 unique sequences, some of which carry a spliced leader. Similarity searches revealed that 55% of these had hits in protein sequence databases, of which 1,729 had their best hit with proteins from the chromalveolates (E-value ≤ 1e-5). Some sequences are similar to those proven to be targets for effective intervention in other protozoan parasites, and include not only proteases, antioxidant enzymes, and heat shock proteins, but also those associated with relict plastids, such as acetyl-CoA carboxylase and methyl erythrithol phosphate pathway components, and those involved in glycan assembly, protein folding/secretion, and parasite-host interactions. Conclusions Our transcriptome analysis of P. marinus, the first for any member of the Perkinsozoa, contributes new insight into its biology and taxonomic position. It provides a very informative, albeit preliminary, glimpse into the expression of genes encoding functionally relevant proteins as potential targets for chemotherapy, and evidence for the presence of a relict plastid. Further, although P. marinus sequences display significant similarity to those from both apicomplexans and dinoflagellates, the presence of trans-spliced transcripts confirms the previously established affinities with the latter. The EST analysis reported herein, together with the recently completed sequence of the P. marinus genome and the development of transfection methodology, should result in improved intervention strategies against dermo disease. PMID:20374649

Lassa hemorrhagic fever in a late term pregnancy from northern Sierra Leone with a positive maternal outcome: case report.

PubMed

Branco, Luis M; Boisen, Matt L; Andersen, Kristian G; Grove, Jessica N; Moses, Lina M; Muncy, Ivana J; Henderson, Lee A; Schieffellin, John S; Robinson, James E; Bangura, James J; Grant, Donald S; Raabe, Vanessa N; Fonnie, Mbalu; Zaitsev, Eleina M; Sabeti, Pardis C; Garry, Robert F

2011-08-15

Lassa fever (LF) is a devastating viral disease prevalent in West Africa. Efforts to take on this public health crisis have been hindered by lack of infrastructure and rapid field deployable diagnosis in areas where the disease is prevalent. Recent capacity building at the Kenema Government Hospital Lassa Fever Ward (KGH LFW) in Sierra Leone has lead to a major turning point in the diagnosis, treatment and study of LF. Herein we present the first comprehensive rapid diagnosis and real time characterization of an acute hemorrhagic LF case at KGH LFW. This case report focuses on a third trimester pregnant Sierra Leonean woman from the historically non-endemic Northern district of Tonkolili who survived the illness despite fetal demise. Employed in this study were newly developed recombinant LASV Antigen Rapid Test cassettes and dipstick lateral flow immunoassays (LFI) that enabled the diagnosis of LF within twenty minutes of sample collection. Deregulation of overall homeostasis, significant hepatic and renal system involvement, and immunity profiles were extensively characterized during the course of hospitalization. Rapid diagnosis, prompt treatment with a full course of intravenous (IV) ribavirin, IV fluids management, and real time monitoring of clinical parameters resulted in a positive maternal outcome despite admission to the LFW seven days post onset of symptoms, fetal demise, and a natural still birth delivery. These studies solidify the growing rapid diagnostic, treatment, and surveillance capabilities at the KGH LF Laboratory, and the potential to significantly improve the current high mortality rate caused by LF. As a result of the growing capacity, we were also able to isolate Lassa virus (LASV) RNA from the patient and perform Sanger sequencing where we found significant genetic divergence from commonly circulating Sierra Leonean strains, showing potential for the discovery of a newly emerged LASV strain with expanded geographic distribution. Furthermore, recent emergence of LF cases in Northern Sierra Leone highlights the need for superior diagnostics to aid in the monitoring of LASV strain divergence with potentially increased geographic expansion.

Ethics of the electrified mind: Defining issues and perspectives on the principled use of brain stimulation in medical research and clinical care

PubMed Central

Cabrera, Laura Y.; Evans, Emily L.; Hamilton, Roy H.

2013-01-01

In recent years, non-pharmacologic approaches to modifying human neural activity have gained increasing attention. One of these approaches is brain stimulation, which involves either the direct application of electrical current to structures in the nervous system or the indirect application of current by means of electromagnetic induction. Interventions that manipulate the brain have generally been regarded as having both the potential to alleviate devastating brain-related conditions and the capacity to create unforeseen and unwanted consequences. Hence, although brain stimulation techniques offer considerable benefits to society, they also raise a number of ethical concerns. In this paper we will address various dilemmas related to brain stimulation in the context of clinical practice and biomedical research. We will survey current work involving deep brain stimulation (DBS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). We will reflect upon relevant similarities and differences between them, and consider some potentially problematic issues that may arise within the framework of established principles of medical ethics: nonmaleficence and beneficence, autonomy, and justice. PMID:23733209

Exploring Anti-Prion Glyco-Based and Aromatic Scaffolds: A Chemical Strategy for the Quality of Life.

PubMed

Blázquez-Sánchez, María Teresa; de Matos, Ana M; Rauter, Amélia P

2017-05-24

Prion diseases are fatal neurodegenerative disorders caused by protein misfolding and aggregation, affecting the brain progressively and consequently the quality of life. Alzheimer's is also a protein misfolding disease, causing dementia in over 40 million people worldwide. There are no therapeutics able to cure these diseases. Cellular prion protein is a high-affinity binding partner of amyloid β (Aβ) oligomers, the most toxic species in Alzheimer's pathology. These findings motivate the development of new chemicals for a better understanding of the events involved. Disease control is far from being reached by the presently known therapeutics. In this review we describe the synthesis and mode of action of molecular entities with intervention in prion diseases' biological processes and, if known, their role in Alzheimer's. A diversity of structures is covered, based on glycans, steroids and terpenes, heterocycles, polyphenols, most of them embodying aromatics and a structural complexity. These molecules may be regarded as chemical tools to foster the understanding of the complex mechanisms involved, and to encourage the scientific community towards further developments for the cure of these devastating diseases.

Family structure and dynamics in DePalma's horror films.

PubMed

Gordon, N G

1983-01-01

An analysis of the familial relationships in Brian DePalma's five major horror films reveals a persistent unconscious fantasy formation involving the nuclear family. These single-parent, only-child families are all tragically destroyed because of an inability to adequately mourn the absent parent. Although the asexual young adults in the films are spared the completely disastrous effects of madness and violence, they are still psychologically traumatized. This hidden subtextual theme involving the family parallels DePalma's bleak view of authority figures outside the home, as well as American society in general. Adequate identity formation requires that people both inside and outside the family accept the adolescent as a separate person. The grim psychological truth threading its way throughout DePalma's horror films is that these young adults are psychically devastated by the effects of a primitive, fused symbiotic relationship in interaction with a society that does not provide an adequate role for the developing person. Consequently, their attempt to psychologically move outside the family, which includes the maturation of their sexuality, results in the destruction of the family itself.

Temporal Representation in Semantic Graphs

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

Levandoski, J J; Abdulla, G M

2007-08-07

A wide range of knowledge discovery and analysis applications, ranging from business to biological, make use of semantic graphs when modeling relationships and concepts. Most of the semantic graphs used in these applications are assumed to be static pieces of information, meaning temporal evolution of concepts and relationships are not taken into account. Guided by the need for more advanced semantic graph queries involving temporal concepts, this paper surveys the existing work involving temporal representations in semantic graphs.

The Discovery Dome: A Tool for Increasing Student Engagement

NASA Astrophysics Data System (ADS)

Brevik, Corinne

2015-04-01

The Discovery Dome is a portable full-dome theater that plays professionally-created science films. Developed by the Houston Museum of Natural Science and Rice University, this inflatable planetarium offers a state-of-the-art visual learning experience that can address many different fields of science for any grade level. It surrounds students with roaring dinosaurs, fascinating planets, and explosive storms - all immersive, engaging, and realistic. Dickinson State University has chosen to utilize its Discovery Dome to address Earth Science education at two levels. University courses across the science disciplines can use the Discovery Dome as part of their curriculum. The digital shows immerse the students in various topics ranging from astronomy to geology to weather and climate. The dome has proven to be a valuable tool for introducing new material to students as well as for reinforcing concepts previously covered in lectures or laboratory settings. The Discovery Dome also serves as an amazing science public-outreach tool. University students are trained to run the dome, and they travel with it to schools and libraries around the region. During the 2013-14 school year, our Discovery Dome visited over 30 locations. Many of the schools visited are in rural settings which offer students few opportunities to experience state-of-the-art science technology. The school kids are extremely excited when the Discovery Dome visits their community, and they will talk about the experience for many weeks. Traveling with the dome is also very valuable for the university students who get involved in the program. They become very familiar with the science content, and they gain experience working with teachers as well as the general public. They get to share their love of science, and they get to help inspire a new generation of scientists.

What age-related factors may be involved with infertility in females and males?

MedlinePlus

... NICHD News Videos OUTREACH Safe to Sleep® National Child & Maternal Health Education Program RELATED WEBSITES NIH.gov HHS.gov USA.gov ClinicalTrials.gov WEBSITE POLICIES Disclaimer FOIA Privacy Policy Accessibility NIH...Turning Discovery Into Health ®

A proteomic approach to understanding the pathogenesis of idiopathic macular hole formation.

PubMed

Zhang, Pingbo; Zhu, Min; Zhao, Yuming; Qian, Jiang; Dufresne, Craig; Turner, Randi; Semba, Richard D; Solomon, Sharon D

2017-01-01

Idiopathic macular holes (IMH) are full-thickness defects of retinal tissue that cause severe vision loss due to disruption of the anatomic fovea. Abnormal vitreous traction is involved in the formation of macular holes. Both glial cells and hyalocytes contribute to epiretinal membrane formation in IMH. In order to gain further insight into the pathophysiology of IMH, we conducted a discovery phase investigation of the vitreous proteome in four patients with macular holes and six controls using one-dimensional gel fractionation and liquid chromatography-tandem mass spectrometry analyses on an Orbitrap Elite mass spectrometer. Of a total of 5912 vitreous proteins, 32 proteins had increased and 39 proteins had decreased expression in IMH compared with controls, using a false discovery rate approach with p value < 0.001 and q value < 0.05. IMH was associated with increased expression of proteins in the complement pathway, α-2-macroglobulin, a major inducer of Müller glial cell migration, fibrinogen, and extracellular matrix proteins, and decreased expression of proteins involved in protein folding and actin filament binding. A proteomic approach revealed proteins and biological pathways that may be involved in the pathogenesis of IMH and could be targeted for future studies.

Commercial opportunities in bioseparations and physiological testing aboard Space Station Freedom

NASA Technical Reports Server (NTRS)

Hymer, W. C.

1992-01-01

The Center for Cell Research (CCR) is a NASA Center for the Commercial Development of Space which has as its main goal encouraging industry-driven biomedical/biotechnology space projects. Space Station Freedom (SSF) will provide long duration, crew-tended microgravity environments which will enhance the opportunities for commercial biomedical/biotechnology projects in bioseparations and physiological testing. The CCR bioseparations program, known as USCEPS (for United States Commercial Electrophoresis Program in Space), is developing access for American industry to continuous-flow electrophoresis aboard SSF. In space, considerable scale-up of continuous free-flow electrophoresis is possible for cells, sub cellular particles, proteins, growth factors, and other biological products. The lack of sedemination and buoyancy-driven convection flow enhances purity of separations and the amount of material processed/time. Through the CCR's physiological testing program, commercial organizations will have access aboard SSF to physiological systems experiments (PSE's); the Penn State Biomodule; and telemicroscopy. Physiological systems experiments involve the use of live animals for pharmaceutical product testing and discovery research. The Penn State Biomodule is a computer-controlled mini lab useful for projects involving live cells or tissues and macro molecular assembly studies, including protein crystallization. Telemicroscopy will enable staff on Earth to manipulate and monitor microscopic specimens on SSF for product development and discovery research or for medical diagnosis of astronaut health problems. Space-based product processing, testing, development, and discovery research using USCEPS and CCR's physiological testing program offer new routes to improved health on Earth. Direct crew involvement-in biomedical/biotechnology projects aboard SSF will enable better experimental outcomes. The current data base shows that there is reason for considerable optimism regarding what the CCDS program and the biomedical/biotechnology industry can expect to gain from a permanent manned presence in space.

Molecular genetics of Erwinia amylovora involved in the development of fire blight.

PubMed

Oh, Chang-Sik; Beer, Steven V

2005-12-15

The bacterial plant pathogen, Erwinia amylovora, causes the devastating disease known as fire blight in some Rosaceous plants like apple, pear, quince, raspberry and several ornamentals. Knowledge of the factors affecting the development of fire blight has mushroomed in the last quarter century. On the molecular level, genes encoding a Hrp type III secretion system, genes encoding enzymes involved in synthesis of extracellular polysaccharides and genes facilitating the growth of E. amylovora in its host plants have been characterized. The Hrp pathogenicity island, delimited by genes suggesting horizontal gene transfer, is composed of four distinct regions, the hrp/hrc region, the HEE (Hrp effectors and elicitors) region, the HAE (Hrp-associated enzymes) region, and the IT (Island transfer) region. The Hrp pathogenicity island encodes a Hrp type III secretion system (TTSS), which delivers several proteins from bacteria to plant apoplasts or cytoplasm. E. amylovora produces two exopolysaccharides, amylovoran and levan, which cause the characteristic fire blight wilting symptom in host plants. In addition, other genes, and their encoded proteins, have been characterized as virulence factors of E. amylovora that encode enzymes facilitating sorbitol metabolism, proteolytic activity and iron harvesting. This review summarizes our understanding of the genes and gene products of E. amylovora that are involved in the development of the fire blight disease.

Craniofacial neurofibromatosis: treatment of the midface deformity.

PubMed

Singhal, Dhruv; Chen, Yi-Chieh; Tsai, Yueh-Ju; Yu, Chung-Chih; Chen, Hung Chang; Chen, Yu-Ray; Chen, Philip Kuo-Ting

2014-07-01

Craniofacial Neurofibromatosis is a benign but devastating disease. While the most common location of facial involvement is the orbito-temporal region, patients often present with significant mid-face deformities. We reviewed our experience with Craniofacial Neurofibromatosis from June 1981 to June 2011 and included patients with midface soft tissue deformities defined as gross alteration of nasal or upper lip symmetry. Data reviewed included the medical records and photobank. Over 30 years, 52 patients presented to and underwent surgical management for Craniofacial Neurofibromatosis at the Chang Gung Craniofacial Center. 23 patients (43%) demonstrated gross mid-facial deformities at initial evaluation. 55% of patients with lip deformities and 28% of patients with nasal deformities demonstrated no direct tumour involvement. The respective deformity was solely due to secondary gravitational effects from neurofibromas of the cheek subunit. Primary tumour infiltration of the nasal and/or labial subunits was treated with excision followed by various methods of reconstruction including lower lateral cartilage repositioning, forehead flaps, free flaps, and/or oral commissure suspension. Soft tissue deformities of the midface are very common in patients with Craniofacial Neurofibromatosis and profoundly affect overall aesthetic outcomes. Distinguishing primary from secondary involvement of the midface assists in surgical decision making. Copyright © 2013 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

miRNAs regulated overexpression of ryanodine receptor is involved in chlorantraniliprole resistance in Plutella xylostella (L.)

PubMed Central

Li, Xiuxia; Guo, Lei; Zhou, Xuguo; Gao, Xiwu; Liang, Pei

2015-01-01

The amino acid mutations in ryanodine receptor (RyR) and elevated activity of detoxification enzymes have been associated with the diamide insecticide resistance in the diamondback moth, Plutella xylostella (L.). The up-regulation of P. xylostella RyR mRNA (PxRyR) expression has also been reported in field populations of different graphical origin. However, whether the up-regulation of PxRyR is involved in diamide resistance remains unknown. In this paper, 2.28- to 4.14-fold higher expression of PxRyR was detected in five field collected resistant populations, compared to that in a susceptible population. The expression of PxRyR was up-regulated 5.0- and 7.2-fold, respectively, after P. xylostella was treated with LC50 and LC75 of chlorantraniliprole for 12 h. Suppression of PxRyR using RNA interference restored the toxicity of chlorantraniliprole against the fourth instar larvae from the resistant population. More importantly, the expression of PxRyR is regulated by two miRNAs, miR-7a and miR-8519. These findings provide an empirical evidence of the involvement of miRNAs in the regulation of insecticide resistance, and shed light on the novel targets for the sustainable management of this devastating insect pest. PMID:26370154

The role of nailfold capillaroscopy in the assessment of internal organ involvement in systemic sclerosis: A critical review.

PubMed

Soulaidopoulos, Stergios; Triantafyllidou, Eva; Garyfallos, Alexandros; Kitas, George D; Dimitroulas, Theodoros

2017-08-01

Endothelial dysfunction and microvascular damage constitute the hallmarks of systemic sclerosis (SSc), explaining much of the pathophysiology and clinical manifestations of the disease. Nailfold videocapillaroscopy (NVC) is an established method for the assessment of the microvasculature, aiding in distinguishing different types of structural vascular abnormalities. Until recently, NVC was used in the diagnosis of SSc as well as in the assessment and follow-up of peripheral digital vasculopathy. On the top of digital ulcers, internal organ involvement such as myocardial dysfunction, pulmonary vascular and/or parenchymal lung disease characterizes severe SSc imparting a high risk of mortality. There is growing evidence suggesting that the extent of peripheral microvascular changes reflects the severity of the disease, especially in terms of life-threatening cardiopulmonary complications. The possible use of nailfold videocapillaroscopy as a useful, non-invasive modality to improve the ability to identify patients at higher risk for these devastating complications of the disease remains to be established. The aim of this review is to critically summarize and discuss current literature regarding the relationship between morphological alterations of nailfold dermal papillary vessels and several manifestations of SSc, focusing on visceral organ involvement, as well as their association with surrogate markers of macrovascular disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Worldwide Emerging Environmental Issues Affecting the U.S. Military. June 2010 Report

DTIC Science & Technology

2010-06-01

Increasing Advocacy for BPA Restrictions…………………………….……………8 6.9 Toxic Substances Control Act Up for Revision…………………………..………….8 6.10 Climate Change ...arrangements against EMPs in the light of this forecast. Source: NASA warns solar flares from ’huge space storm’ will cause devastation http...www.telegraph.co.uk/science/space/7819201/Nasa-warns-solar-flares-from-huge-space-sto rm-will- cause -devastation.html Item 2. OSCE is Enhancing Environmental

The concept of skin bleaching in Africa and its devastating health implications.

PubMed

de Souza, Melanie Miyanji

2008-01-01

Africa is considered a continent of mystery and intrigue with absurd concepts and beliefs. Cosmetic dermatology is no less intriguing than other issues. While quick judgement may be passed condemning attitudes and misconceptions in this field, we need to analyze factors that contribute to such ideas. Acquiring a lighter skin forms the basis of Skin Care and Cosmetology in dark skinned people. This regrettably has far reaching devastating effects on health and individual finances. This in return has enriched unscrupulous stake holders. Help from the international medical fraternity and the pharmaceutical/cosmetology industry is required to end this evil.

Examining the causes of a devastating debris flow

NASA Astrophysics Data System (ADS)

Balcerak, Ernie

2014-08-01

Storm-triggered landslides cause loss of life, property damage, and landscape alterations. For instance, the remnants of Hurricane Camille in 1969 caused 109 deaths in central Virginia, after 600 millimeters of rain fell in mountainous terrain in 6 hours. More recently, on 8 August 2010, a rainstorm-induced landslide devastated the Chinese county of Zhouqu, causing more than 1000 deaths. A new modeling study by Ren examines the multiple factors, natural and human caused, that came together to produce this event. Three things contribute to storm-triggered landslides: geological condition, surface loading and vegetation roots, and extreme precipitation.

Don't forget about the Christchurch earthquake: Lessons learned from this disaster

USGS Publications Warehouse

Hamburger, Michael W.; Mooney, Walter D.

2011-01-01

In the aftermath of the devastating magnitude-9.0 earthquake and tsunami that struck the Tohoku region of Japan on March 11, attention quickly turned away from a much smaller, but also highly destructive earthquake that struck the city of Christchurch, New Zealand, just a few weeks earlier, on Feb. 22. Both events are stark reminders of human vulnerability to natural disasters and provide a harsh reality check: Even technologically advanced countries with modern building codes are not immune from earthquake disasters. The Christchurch earthquake carried an additional message: Urban devastation can be triggered even by moderate-sized earthquakes.

Rational discovery of dengue type 2 non-competitive inhibitors.

PubMed

Heh, Choon H; Othman, Rozana; Buckle, Michael J C; Sharifuddin, Yusrizam; Yusof, Rohana; Rahman, Noorsaadah A

2013-07-01

Various works have been carried out in developing therapeutics against dengue. However, to date, no effective vaccine or anti-dengue agent has yet been discovered. The development of protease inhibitors is considered as a promising option, but most previous works have involved competitive inhibition. In this study, we focused on rational discovery of potential anti-dengue agents based on non-competitive inhibition of DEN-2 NS2B/NS3 protease. A homology model of the DEN-2 NS2B/NS3 protease (using West Nile Virus NS2B/NS3 protease complex, 2FP7, as the template) was used as the target, and pinostrobin, a flavanone, was used as the standard ligand. Virtual screening was performed involving a total of 13 341 small compounds, with the backbone structures of chalcone, flavanone, and flavone, available in the ZINC database. Ranking of the resulting compounds yielded compounds with higher binding affinities compared with the standard ligand. Inhibition assay of the selected top-ranking compounds against DEN-2 NS2B/NS3 proteolytic activity resulted in significantly better inhibition compared with the standard and correlated well with in silico results. In conclusion, via this rational discovery technique, better inhibitors were identified. This method can be used in further work to discover lead compounds for anti-dengue agents. © 2013 John Wiley & Sons A/S.

Combining knowledge discovery from databases (KDD) and case-based reasoning (CBR) to support diagnosis of medical images

NASA Astrophysics Data System (ADS)

Stranieri, Andrew; Yearwood, John; Pham, Binh

1999-07-01

The development of data warehouses for the storage and analysis of very large corpora of medical image data represents a significant trend in health care and research. Amongst other benefits, the trend toward warehousing enables the use of techniques for automatically discovering knowledge from large and distributed databases. In this paper, we present an application design for knowledge discovery from databases (KDD) techniques that enhance the performance of the problem solving strategy known as case- based reasoning (CBR) for the diagnosis of radiological images. The problem of diagnosing the abnormality of the cervical spine is used to illustrate the method. The design of a case-based medical image diagnostic support system has three essential characteristics. The first is a case representation that comprises textual descriptions of the image, visual features that are known to be useful for indexing images, and additional visual features to be discovered by data mining many existing images. The second characteristic of the approach presented here involves the development of a case base that comprises an optimal number and distribution of cases. The third characteristic involves the automatic discovery, using KDD techniques, of adaptation knowledge to enhance the performance of the case based reasoner. Together, the three characteristics of our approach can overcome real time efficiency obstacles that otherwise mitigate against the use of CBR to the domain of medical image analysis.

Ribosome profiling reveals the what, when, where and how of protein synthesis.

PubMed

Brar, Gloria A; Weissman, Jonathan S

2015-11-01

Ribosome profiling, which involves the deep sequencing of ribosome-protected mRNA fragments, is a powerful tool for globally monitoring translation in vivo. The method has facilitated discovery of the regulation of gene expression underlying diverse and complex biological processes, of important aspects of the mechanism of protein synthesis, and even of new proteins, by providing a systematic approach for experimental annotation of coding regions. Here, we introduce the methodology of ribosome profiling and discuss examples in which this approach has been a key factor in guiding biological discovery, including its prominent role in identifying thousands of novel translated short open reading frames and alternative translation products.

Federal Immunity Law in Higher Education: A Review of the 1997 Judicial Decisions.

ERIC Educational Resources Information Center

Johnsen, Christopher

1998-01-01

Monitors developments in 1997 in federal immunity law applicable to higher education, generally public institutions. Cases touched on Eleventh Amendment immunity (abrogation, waiver, removal, entities, interlocutory appeals, discovery), qualified immunity (claims involving motivation, interlocutory appeals), and absolute immunity. (EV)

Genomic Copy Number Variation in Disorders of Cognitive Development

ERIC Educational Resources Information Center

Morrow, Eric M.

2010-01-01

Objective: To highlight recent discoveries in the area of genomic copy number variation in neuropsychiatric disorders including intellectual disability, autism, and schizophrenia. To emphasize new principles emerging from this area, involving the genetic architecture of disease, pathophysiology, and diagnosis. Method: Review of studies published…

Constructivism in Reading Education.

ERIC Educational Resources Information Center

Stanovich, Keith

1994-01-01

In the development of word recognition skills, self-discovery may not be the most efficacious mode of learning, and it may be useful to isolate or fractionate cognitive components. Successful intervention directed at word recognition involves exogenous constructivism, in which explicit instruction and teacher-directed strategy teaching are not…

16 CFR 5.61 - Prehearing procedures; motions; interlocutory appeals; summary decision; discovery; compulsory...

Code of Federal Regulations, 2010 CFR

2010-01-01

... Actions Concerning Postemployment Conflict of Interest § 5.61 Prehearing procedures; motions... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Prehearing procedures; motions... involved in proceedings under this part, the Commission anticipates that extensive motions, prehearing...

16 CFR 5.61 - Prehearing procedures; motions; interlocutory appeals; summary decision; discovery; compulsory...

Code of Federal Regulations, 2011 CFR

2011-01-01

... Actions Concerning Postemployment Conflict of Interest § 5.61 Prehearing procedures; motions... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Prehearing procedures; motions... involved in proceedings under this part, the Commission anticipates that extensive motions, prehearing...

Information Science Research: The Search for the Nature of Information.

ERIC Educational Resources Information Center

Kochen, Manfred

1984-01-01

High-level scientific research in the information sciences is illustrated by sampling of recent discoveries involving adaptive information processing strategies, computer and information systems, centroid scaling, economic growth of computer and communication industries, and information flow in biological systems. Relationship of information…

University Technology Transfer Factors as Predictors of Entrepreneurial Orientation

ERIC Educational Resources Information Center

Kirkman, Dorothy M.

2011-01-01

University technology transfer is a collaborative effort between academia and industry involving knowledge sharing and learning. Working closely with their university partners affords biotechnology firms the opportunity to successfully develop licensed inventions and gain access to novel scientific and technological discoveries. These factors may…

Acetogenesis and the Wood-Ljungdahl Pathway of CO2 Fixation

PubMed Central

Ragsdale, Stephen W.; Pierce, Elizabeth

2008-01-01

I. Summary Conceptually, the simplest way to synthesize an organic molecule is to construct it one carbon at a time. The Wood-Ljungdahl pathway of CO2 fixation involves this type of stepwise process. The biochemical events that underlie the condensation of two one-carbon units to form the two-carbon compound, acetate, have intrigued chemists, biochemists, and microbiologists for many decades. We begin this review with a description of the biology of acetogenesis. Then, we provide a short history of the important discoveries that have led to the identification of the key components and steps of this usual mechanism of CO and CO2 fixation. In this historical perspective, we have included reflections that hopefully will sketch the landscape of the controversies, hypotheses, and opinions that led to the key experiments and discoveries. We then describe the properties of the genes and enzymes involved in the pathway and conclude with a section describing some major questions that remain unanswered. PMID:18801467

NASA Discovery Program Workshop

NASA Technical Reports Server (NTRS)

1992-01-01

The purpose of the workshop was to review concepts for Discover-class missions that would follow the first two missions (MESUR-Pathfinder and NEAR) of this new program. The concepts had been generated by scientists involved in NASA's Solar System Exploration Program to carry out scientifically important investigations within strict guidelines -- $150 million cap on development cost and 3 year cap on development schedule. Like the Astrophysics Small Explorers (SMEX), such 'faster and cheaper' missions could provide vitality to solar system exploration research by returning high quality data more frequently and regularly and by involving many more young researchers than normally participate directly in larger missions. An announcement of opportunity (AO) to propose a Discovery mission to NASA is expected to be released in about two years time. One purpose of the workshop was to assist Code SL in deciding how to allocate its advanced programs resources. A second, complimentary purpose was to provide the concept proposers with feedback to allow them to better prepare for the AO.

Biotin in microbes, the genes involved in its biosynthesis, its biochemical role and perspectives for biotechnological production.

PubMed

Streit, W R; Entcheva, P

2003-03-01

Biotin (vitamin H) is one of the most fascinating cofactors involved in central pathways in pro- and eukaryotic cell metabolism. Since its original discovery in 1901, research has led to the discovery of the complete biotin biosynthesis pathways in many different microbes and much work has been done on the highly intriguing and complex biochemistry of biotin biosynthesis. While humans and animals require several hundred micrograms of biotin per day, most microbes, plants and fungi appear to be able to synthesize the cofactor themselves. Biotin is added to many food, feed and cosmetic products, creating a world market of 10-30 t/year. However, the majority of the biotin sold is synthesized in a chemical process. Since the chemical synthesis is linked with a high environmental burden, much effort has been put into the development of biotin-overproducing microbes. A summary of biotin biosynthesis and its biological role is presented; and current strategies for the improvement of microbial biotin production using modern biotechnological techniques are discussed.

The path forward: 2015 International Children's Tumor Foundation conference on neurofibromatosis type 1, type 2, and schwannomatosis.

PubMed

Blakeley, Jaishri O; Bakker, Annette; Barker, Anne; Clapp, Wade; Ferner, Rosalie; Fisher, Michael J; Giovannini, Marco; Gutmann, David H; Karajannis, Matthias A; Kissil, Joseph L; Legius, Eric; Lloyd, Alison C; Packer, Roger J; Ramesh, Vijaya; Riccardi, Vincent M; Stevenson, David A; Ullrich, Nicole J; Upadhyaya, Meena; Stemmer-Rachamimov, Anat

2017-06-01

The Annual Children's Tumor Foundation International Neurofibromatosis Meeting is the premier venue for connecting discovery, translational and clinical scientists who are focused on neurofibromatosis types 1 and 2 (NF1 and NF2) and schwannomatosis (SWN). The meeting also features rare tumors such as glioma, meningioma, sarcoma, and neuroblastoma that occur both within these syndromes and spontaneously; associated with somatic mutations in NF1, NF2, and SWN. The meeting addresses both state of the field for current clinical care as well as emerging preclinical models fueling discovery of new therapeutic targets and discovery science initiatives investigating mechanisms of tumorigenesis. Importantly, this conference is a forum for presenting work in progress and bringing together all stakeholders in the scientific community. A highlight of the conference was the involvement of scientists from the pharmaceutical industry who presented growing efforts for rare disease therapeutic development in general and specifically, in pediatric patients with rare tumor syndromes. Another highlight was the focus on new investigators who presented new data about biomarker discovery, tumor pathogenesis, and diagnostic tools for NF1, NF2, and SWN. This report summarizes the themes of the meeting and a synthesis of the scientific discoveries presented at the conference in order to make the larger research community aware of progress in the neurofibromatoses. © 2017 Wiley Periodicals, Inc.

Drug discovery for alopecia: gone today, hair tomorrow

PubMed Central

Santos, Zenildo; Avci, Pinar; Hamblin, Michael R

2015-01-01

Introduction Hair loss or alopecia affects the majority of the population at some time in their life, and increasingly, sufferers are demanding treatment. Three main types of alopecia (androgenic [AGA], areata [AA] and chemotherapy-induced [CIA]) are very different, and have their own laboratory models and separate drug-discovery efforts. Areas covered In this article, the authors review the biology of hair, hair follicle (HF) cycling, stem cells and signaling pathways. AGA, due to dihydrotesterone, is treated by 5-α reductase inhibitors, androgen receptor blockers and ATP-sensitive potassium channel-openers. AA, which involves attack by CD8+NK group 2D-positive (NKG2D+) T cells, is treated with immunosuppressives, biologics and JAK inhibitors. Meanwhile, CIA is treated by apoptosis inhibitors, cytokines and topical immunotherapy. Expert opinion The desire to treat alopecia with an easy topical preparation is expected to grow with time, particularly with an increasing aging population. The discovery of epidermal stem cells in the HF has given new life to the search for a cure for baldness. Drug discovery efforts are being increasingly centered on these stem cells, boosting the hair cycle and reversing miniaturization of HF. Better understanding of the molecular mechanisms underlying the immune attack in AA will yield new drugs. New discoveries in HF neogenesis and low-level light therapy will undoubtedly have a role to play. PMID:25662177

POLAR/CEPPAD Data Analysis

NASA Technical Reports Server (NTRS)

Baker, D. N.; Hoffman, R. (Technical Monitor)

2001-01-01

This final report provides a final report on a NASA sponsored project involving data reduction and scientific analysis related to the Comprehensive Energetic Particle Pitch Angle Distribution (CEPPAD) experiment of POLAR. Dr. D.N. Baker, the chief scientist, has focused primarily on the calibration of CEPPAD sensors and the interpretation of data from the sensors which has led to discoveries regarding storm-substorm relationships in the earth's magnetosphere. The report contains approximately 190 bibliographic references to the activities of Baker and others involved.

From basic to clinical neuropharmacology: targetophilia or pharmacodynamics?

PubMed

Green, A Richard; Aronson, Jeffrey K

2012-06-01

Historically, much drug discovery and development in psychopharmacology tended to be empirical. However, over the last 20 years it has primarily been target oriented, with synthesis and selection of compounds designed to act at a specific neurochemical site. Such compounds are then examined in functional animal models of disease. There is little evidence that this approach (which we call 'targetophilia') has enhanced the discovery process and some indications that it may have retarded it. A major problem is the weakness of many animal models in mimicking the disease and the lack of appropriate biochemical markers of drug action in animals and patients. In this review we argue that preclinical studies should be conducted as if they were clinical studies in design, analysis, and reporting, and that clinical pharmacologists should be involved at the earliest stages, to help ensure that animal models reflect as closely as possible the clinical disease. In addition, their familiarity with pharmacokinetic-pharmacodynamic integration (PK-PD) would help ensure that appropriate dosing and drug measurement techniques are applied to the discovery process, thereby producing results with relevance to therapeutics. Better integration of experimental and clinical pharmacologists early in the discovery process would allow observations in animals and patients to be quickly exchanged between the two disciplines. This non-linear approach to discovery used to be the way research proceeded, and it resulted in productivity that has never been bettered. It also follows that occasionally 'look-see' studies, a proven technique for drug discovery, deserve to be reintroduced. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Pathophysiology and biology of peritoneal carcinomatosis.

PubMed

Kusamura, Shigeki; Baratti, Dario; Zaffaroni, Nadia; Villa, Raffaella; Laterza, Barbara; Balestra, Maria Rosaria; Deraco, Marcello

2010-01-15

Peritoneal carcinomatosis represents a devastating form of cancer progression with a very poor prognosis. Its complex pathogenesis is represented by a dynamic process comprising several steps. To the best of our knowledge pathogenesis can be partly explained by 3 major molecular pathways: (1) dissemination from the primary tumor; (2) primary tumor of peritoneum; and (3) independent origins of the primary tumor and peritoneal implants. These are not mutually exclusive and combinations of different mechanisms could occur inside a single case. There are still several aspects which need explanation by future studies. A comprehensive understanding of molecular events involved in peritoneal carcinomatosis is of paramount importance and should be systematically pursued not only to identify novel strategies for the prevention of the condition, but also to obtain therapeutic advances, through the identification of surrogate markers of prognosis and development of future molecular targeted therapies.

The Cretaceous-Tertiary extinction: A lethal mechanism involving anhydrite target rocks

USGS Publications Warehouse

Brett, R.

1992-01-01

The Chicxulub Crater, Yucatan, Mexico, is a leading contender as the site for the impact event that caused the Cretaceous-Tertiary (K-T) extinctions. A considerable thickness of anhydrite (CaSO4) forms part of the target rock. High temperatures resulting from impact would drive SO2 off from the anhydrite. Hundreds of billions of tonnes of sulfuric acid aerosol would thus enter the stratosphere and cause considerable cooling of the Earth's surface, decrease photosynthesis by orders of magnitude, deplete the ozone layer, and permit increased UV radiation to reach the Earth's surface. Finally, the aerosol would fall back to Earth as acid rain and devastate land and some lacustrine biota and near-surface marine creatures. The presence of anhydrite in the Chicxulub target rock may thus help explain the many extinctions observed at the K-T boundary. ?? 1992.

Cerebral candidiasis in a 4-year-old boy after intestinal surgery.

PubMed

Zhang, Shu-Cheng

2015-03-01

Cerebral candidiasis is a devastating disease which contributes to a high mortality. Most of the cerebral candidiasis are never microbiologically or radiologically confirmed. In this case, a 4-year-old boy who developed cerebral candidiasis was successfully rescued and presented. The diagnosis of cerebral candidiasis was established based on both microbiologic and radiologic examinations. The pathogen was revealed to be Candida albicans by cerebrospinal fluid and central venous catheter cultures, and the cerebral involvement was recorded by series head magnetic resonance imaging (MRI) with an appearance of special encephalitis demonstrated. The imaging studies played a critical role throughout the diagnosis and treatment. Familiarity with the imaging findings in the appropriate clinical setting may result in a heightened level of awareness of this infection and, consequently, in earlier diagnosis and treatment. © The Author(s) 2014.

Renal endoplasmic reticulum stress is coupled to impaired autophagy in a mouse model of GSD Ia.

PubMed

Farah, Benjamin L; Landau, Dustin J; Wu, Yajun; Sinha, Rohit A; Loh, Alwin; Bay, Boon-Huat; Koeberl, Dwight D; Yen, Paul M

2017-11-01

GSD Ia (von Gierke Disease, Glycogen Storage Disease Type Ia) is a devastating genetic disorder with long-term sequelae, such as non-alcoholic fatty liver disease and renal failure. Down-regulated autophagy is involved in the development of hepatic metabolic dysfunction in GSD Ia; however, the role of autophagy in the renal pathology is unknown. Here we show that autophagy is impaired and endoplasmic reticulum (ER) stress is increased in the kidneys of a mouse model of GSD Ia. Induction of autophagy by rapamycin also reduces this ER stress. Taken together, these results show an additional role for autophagy down-regulation in the pathogenesis of GSD Ia, and provide further justification for the use of autophagy modulators in GSD Ia. Copyright © 2017 Elsevier Inc. All rights reserved.

Pathophysiology and biology of peritoneal carcinomatosis

PubMed Central

Kusamura, Shigeki; Baratti, Dario; Zaffaroni, Nadia; Villa, Raffaella; Laterza, Barbara; Balestra, Maria Rosaria; Deraco, Marcello

2010-01-01

Peritoneal carcinomatosis represents a devastating form of cancer progression with a very poor prognosis. Its complex pathogenesis is represented by a dynamic process comprising several steps. To the best of our knowledge pathogenesis can be partly explained by 3 major molecular pathways: (1) dissemination from the primary tumor; (2) primary tumor of peritoneum; and (3) independent origins of the primary tumor and peritoneal implants. These are not mutually exclusive and combinations of different mechanisms could occur inside a single case. There are still several aspects which need explanation by future studies. A comprehensive understanding of molecular events involved in peritoneal carcinomatosis is of paramount importance and should be systematically pursued not only to identify novel strategies for the prevention of the condition, but also to obtain therapeutic advances, through the identification of surrogate markers of prognosis and development of future molecular targeted therapies. PMID:21160812

History of Smallpox and Its Spread in Human Populations.

PubMed

Thèves, Catherine; Crubézy, Eric; Biagini, Philippe

2016-08-01

Smallpox is considered among the most devastating of human diseases. Its spread in populations, initiated for thousands of years following a probable transmission from an animal host, was concomitant with movements of people across regions and continents, trade and wars. Literature permitted to retrace the occurrence of epidemics from ancient times to recent human history, smallpox having affected all levels of past society including famous monarchs. The disease was officially declared eradicated in 1979 following intensive vaccination campaigns.Paleomicrobiology dedicated to variola virus is restricted to few studies, most unsuccessful, involving ancient material. Only one recent approach allowed the identification of viral DNA fragments from lung tissue of a 300-year-old body excavated from permafrost in Eastern Siberia; phylogenetic analysis revealed that this ancient strain was distinct from those described during the 20th century.

Paravascular pathways contribute to vasculitis and neuroinflammation after subarachnoid hemorrhage independently of glymphatic control.

PubMed

Luo, C; Yao, X; Li, J; He, B; Liu, Q; Ren, H; Liang, F; Li, M; Lin, H; Peng, J; Yuan, T F; Pei, Z; Su, H

2016-03-31

Subarachnoid hemorrhage (SAH) is a devastating disease with high mortality. The mechanisms underlying its pathological complications have not been fully identified. Here, we investigate the potential involvement of the glymphatic system in the neuropathology of SAH. We demonstrate that blood components rapidly enter the paravascular space following SAH and penetrate into the perivascular parenchyma throughout the brain, causing disastrous events such as cerebral vasospasm, delayed cerebral ischemia, microcirculation dysfunction and widespread perivascular neuroinflammation. Clearance of the paravascular pathway with tissue-type plasminogen activator ameliorates the behavioral deficits and alleviates histological injury of SAH. Interestingly, AQP4(-/-) mice showed no improvements in neurological deficits and neuroinflammation at day 7 after SAH compared with WT control mice. In conclusion, our study proves that the paravascular pathway dynamically mediates the pathological complications following acute SAH independently of glymphatic control.

Diagnosis and Management of Systemic Sclerosis: A Practical Approach.

PubMed

Lee, Jason J; Pope, Janet E

2016-02-01

Systemic sclerosis is a devastating multisystem rheumatologic condition that is characterized by autoimmunity, tissue fibrosis, obliterative vasculopathy and inflammation. Clinical presentation and course of the condition vary greatly, which complicates both diagnosis and corresponding treatment. In this regard, recent advances in disease understanding, both clinically and biochemically, have led to newer classification criteria for systemic sclerosis that are more inclusive than ever before. Still, significant disease modifying therapies do not yet exist for most patients. Therefore, organ-based management strategies are employed and research has been directed within this paradigm focusing on either the most debilitating symptoms, such as Raynaud's phenomenon, digital ulcers and cutaneous sclerosis, or life-threatening organ involvement such as interstitial lung disease and pulmonary arterial hypertension. The current trends in systemic sclerosis diagnosis, evidence-based treatment recommendations and potential future directions in systemic sclerosis treatment are discussed.

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

PubMed

Cirulli, Elizabeth T; Lasseigne, Brittany N; Petrovski, Slavé; Sapp, Peter C; Dion, Patrick A; Leblond, Claire S; Couthouis, Julien; Lu, Yi-Fan; Wang, Quanli; Krueger, Brian J; Ren, Zhong; Keebler, Jonathan; Han, Yujun; Levy, Shawn E; Boone, Braden E; Wimbish, Jack R; Waite, Lindsay L; Jones, Angela L; Carulli, John P; Day-Williams, Aaron G; Staropoli, John F; Xin, Winnie W; Chesi, Alessandra; Raphael, Alya R; McKenna-Yasek, Diane; Cady, Janet; Vianney de Jong, J M B; Kenna, Kevin P; Smith, Bradley N; Topp, Simon; Miller, Jack; Gkazi, Athina; Al-Chalabi, Ammar; van den Berg, Leonard H; Veldink, Jan; Silani, Vincenzo; Ticozzi, Nicola; Shaw, Christopher E; Baloh, Robert H; Appel, Stanley; Simpson, Ericka; Lagier-Tourenne, Clotilde; Pulst, Stefan M; Gibson, Summer; Trojanowski, John Q; Elman, Lauren; McCluskey, Leo; Grossman, Murray; Shneider, Neil A; Chung, Wendy K; Ravits, John M; Glass, Jonathan D; Sims, Katherine B; Van Deerlin, Vivianna M; Maniatis, Tom; Hayes, Sebastian D; Ordureau, Alban; Swarup, Sharan; Landers, John; Baas, Frank; Allen, Andrew S; Bedlack, Richard S; Harper, J Wade; Gitler, Aaron D; Rouleau, Guy A; Brown, Robert; Harms, Matthew B; Cooper, Gregory M; Harris, Tim; Myers, Richard M; Goldstein, David B

2015-03-27

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention. Copyright © 2015, American Association for the Advancement of Science.

Emergence of artistic talent in frontotemporal dementia.

PubMed

Miller, B L; Cummings, J; Mishkin, F; Boone, K; Prince, F; Ponton, M; Cotman, C

1998-10-01

To describe the clinical, neuropsychological, and imaging features of five patients with frontotemporal dementia (FTD) who acquired new artistic skills in the setting of dementia. Creativity in the setting of dementia has recently been reported. We describe five patients who became visual artists in the setting of FTD. Sixty-nine FTD patients were interviewed regarding visual abilities. Five became artists in the early stages of FTD. Their history, artistic process, neuropsychology, and anatomy are described. On SPECT or pathology, four of the five patients had the temporal variant of FTD in which anterior temporal lobes are involved but the dorsolateral frontal cortex is spared. Visual skills were spared but language and social skills were devastated. Loss of function in the anterior temporal lobes may lead to the "facilitation" of artistic skills. Patients with the temporal lobe variant of FTD offer a window into creativity.

[Fragment-based drug discovery: concept and aim].

PubMed

Tanaka, Daisuke

2010-03-01

Fragment-Based Drug Discovery (FBDD) has been recognized as a newly emerging lead discovery methodology that involves biophysical fragment screening and chemistry-driven fragment-to-lead stages. Although fragments, defined as structurally simple and small compounds (typically <300 Da), have not been employed in conventional high-throughput screening (HTS), the recent significant progress in the biophysical screening methods enables fragment screening at a practical level. The intention of FBDD primarily turns our attention to weakly but specifically binding fragments (hit fragments) as the starting point of medicinal chemistry. Hit fragments are then promoted to more potent lead compounds through linking or merging with another hit fragment and/or attaching functional groups. Another positive aspect of FBDD is ligand efficiency. Ligand efficiency is a useful guide in screening hit selection and hit-to-lead phases to achieve lead-likeness. Owing to these features, a number of successful applications of FBDD to "undruggable targets" (where HTS and other lead identification methods failed to identify useful lead compounds) have been reported. As a result, FBDD is now expected to complement more conventional methodologies. This review, as an introduction of the following articles, will summarize the fundamental concepts of FBDD and will discuss its advantages over other conventional drug discovery approaches.

John Woolman and Ethical Progress in Kitcher's Pragmatic Naturalism.

PubMed

Barresi, John

2017-01-01

The development of John Woolman’s views on slavery plays an important evidentiary role in Philip Kitcher’s recent book, The ethical project (Kitcher 2011). In this work Kitcher takes what he calls a “pragmatic naturalist” approach to ethics and claims that the discovery of ethical truth plays no role in the emergence of ethical progress. To support his view, he argues that Woolman’s contribution was not due to his discovery of an ethical truth about slavery, not previously known, but due to his sensitivity to slavery and his influence on others, which contributed to collective progressive change in moral norms involving slavery. While not disputing Kitcher’s ethical theory, I argue that personal discoveries of a moral psychological nature made by Woolman served both as insights and motivations for his contribution. Thus, even if there are no such things as independent ethical truths that can be discovered by individuals, a fully naturalistic approach to ethical progress requires that we make room not only for group-level progressive evolution of norms, but also for individual discoveries of a moral psychological nature that can sometimes cause an individual to play a significant initiating role in progressive ethical transitions that occur at a group level.

A Fully Automated High-Throughput Flow Cytometry Screening System Enabling Phenotypic Drug Discovery.

PubMed

Joslin, John; Gilligan, James; Anderson, Paul; Garcia, Catherine; Sharif, Orzala; Hampton, Janice; Cohen, Steven; King, Miranda; Zhou, Bin; Jiang, Shumei; Trussell, Christopher; Dunn, Robert; Fathman, John W; Snead, Jennifer L; Boitano, Anthony E; Nguyen, Tommy; Conner, Michael; Cooke, Mike; Harris, Jennifer; Ainscow, Ed; Zhou, Yingyao; Shaw, Chris; Sipes, Dan; Mainquist, James; Lesley, Scott

2018-05-01

The goal of high-throughput screening is to enable screening of compound libraries in an automated manner to identify quality starting points for optimization. This often involves screening a large diversity of compounds in an assay that preserves a connection to the disease pathology. Phenotypic screening is a powerful tool for drug identification, in that assays can be run without prior understanding of the target and with primary cells that closely mimic the therapeutic setting. Advanced automation and high-content imaging have enabled many complex assays, but these are still relatively slow and low throughput. To address this limitation, we have developed an automated workflow that is dedicated to processing complex phenotypic assays for flow cytometry. The system can achieve a throughput of 50,000 wells per day, resulting in a fully automated platform that enables robust phenotypic drug discovery. Over the past 5 years, this screening system has been used for a variety of drug discovery programs, across many disease areas, with many molecules advancing quickly into preclinical development and into the clinic. This report will highlight a diversity of approaches that automated flow cytometry has enabled for phenotypic drug discovery.

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

Simple prediction scores predict good and devastating outcomes after stroke more accurately than physicians.

PubMed

Reid, John Michael; Dai, Dingwei; Delmonte, Susanna; Counsell, Carl; Phillips, Stephen J; MacLeod, Mary Joan

2017-05-01

physicians are often asked to prognosticate soon after a patient presents with stroke. This study aimed to compare two outcome prediction scores (Five Simple Variables [FSV] score and the PLAN [Preadmission comorbidities, Level of consciousness, Age, and focal Neurologic deficit]) with informal prediction by physicians. demographic and clinical variables were prospectively collected from consecutive patients hospitalised with acute ischaemic or haemorrhagic stroke (2012-13). In-person or telephone follow-up at 6 months established vital and functional status (modified Rankin score [mRS]). Area under the receiver operating curves (AUC) was used to establish prediction score performance. five hundred and seventy-five patients were included; 46% female, median age 76 years, 88% ischaemic stroke. Six months after stroke, 47% of patients had a good outcome (alive and independent, mRS 0-2) and 26% a devastating outcome (dead or severely dependent, mRS 5-6). The FSV and PLAN scores were superior to physician prediction (AUCs of 0.823-0.863 versus 0.773-0.805, P < 0.0001) for good and devastating outcomes. The FSV score was superior to the PLAN score for predicting good outcomes and vice versa for devastating outcomes (P < 0.001). Outcome prediction was more accurate for those with later presentations (>24 hours from onset). the FSV and PLAN scores are validated in this population for outcome prediction after both ischaemic and haemorrhagic stroke. The FSV score is the least complex of all developed scores and can assist outcome prediction by physicians. © The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com

Screening of sorghum lines for resistance against sugarcane aphid, Melanaphis sacchari (Zehnter)

USDA-ARS?s Scientific Manuscript database

The sugarcane aphid Melanaphis sacchari (Zehnter) has emerged as the most significant threat to sorghum (Sorghum bicolor (L.) Moench) production in the United States. Since 2013, discovery of aphid resistant germplasm has been a priority all stakeholders involved. We screened twenty three differen...

Mozambique Country Analysis Brief

EIA Publications

2016-01-01

There have been prolific natural gas discoveries in Mozambique's northern offshore Rovuma basin since 2010 that have the ability to transform Mozambique into a substantial exporter of liquefied natural gas (LNG). However, international companies involved have not made a final investment decision and LNG exports are unlikely to start before 2020.

Cattails or Concrete?

ERIC Educational Resources Information Center

Heal, Fred A.; And Others

Developed for elementary science studies, this unit on man and environment requires student involvement in discovery, observation, gathering and recording data, and problem solving. A series of 19 booklets, each designed as an activity which can be completed out-of-doors, comprise this student packet of materials. Topics studied in the activities…

Career Activity File K-12: School-Based Enterprise.

ERIC Educational Resources Information Center

2000

School-Based Enterprises or SBEs provide work-based learning opportunities to students in communities lacking business and industry involvement. SBEs promote discovery learning and student responsibility in the learning process. They expose students to creative thinking, problem solving, planning and organizational skills, and teamwork. SBEs help…

Space Science 2001: Some Problems with Artificial Gravity.

ERIC Educational Resources Information Center

Fisher, Nick

2001-01-01

Many pupils will be familiar with the ideas in "2001: A Space Odyssey" but few will have considered the physics involved. Simple calculations show that some of the effects depicted in the Space Station and on the Discovery are plausible but others would be impractical. (Author/ASK)

RCRA, Superfund and EPCRA hotline training module. Introduction to: the Superfund response program (updated February 1998); Directive

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

NONE

1998-06-01

This module includes the following: Regulatory Summary (Definitions; National Contingency Plan; Notification or Discovery; Response Process; Removal Process; Remedial Process; Community Involvement; State Role; Natural Resource Damage Assessments; Federal Facility Response; and Contractor Support); and Module Summary.

Beyond Discourse to Emancipatory Action: Lessons from an Undergraduate

ERIC Educational Resources Information Center

Pasque, Penny A.; Neubauer, Hailey

2013-01-01

One undergraduate's transformational story of self-discovery and personal development frames this discussion of the importance of undergraduate involvement in social justice research. In this article, the authors first share a bit about the national landscape regarding community-university engagement initiatives. They also share research findings…

Resituating the ethical gaze: government morality and the local worlds of impoverished Indigenous women.

PubMed

Tait, Caroline L

2013-01-01

Over generations, government policies have impacted upon the lives of Indigenous peoples of Canada in unique and often devastating ways. In this context, Indigenous women who struggle with poverty, mental illness, trauma and substance abuse are among the most vulnerable, as are Indigenous children involved in child welfare systems. By examining the life history of Wanda, a First Nations woman, this article examines the intergenerational role that government policies play in the lives of impoverished Indigenous women and their families. Questions of moral governance and responsibility and the need for ethical policies are raised. The life narrative presented in this article is part of a larger qualitative research programme that has collected over 100 life histories of Indigenous women with addictions and who have involvement with the child welfare system, as children or adults. Wanda's life story exemplifies the impact of government policies that is characteristic of vulnerable Indigenous women and draws attention to the lack of ethical standards in government policymaking in child welfare, public health and mental health/addictions. The path to recovery for Canadian Indigenous women in need of treatment for co-occurring mental disorders and substance addiction is too frequently characterized by an inadequate and ever shifting continuum of care. For those who feel intimidated, suspicious or have simply given up on seeking supports, a profound invisibility or forgetting of their struggle exists in areas of government policy and programming provision. Living outside the scope of mental health and addiction priorities, they become visible to the human service sector only if they become pregnant, their parenting draws the attention of child and family services (CFS), they need emergency health care, or are in trouble with the law. The intergenerational cycle of substance abuse, mental illness and poverty is commonly associated with child welfare involvement, specifically practices that place the health and well-being of Indigenous children at risk. In order to break this cycle, close attention to implementation of ethically based policies and best practice interventions is required. From an ethical policy perspective, the focus of government policies and the practices they generate must be first and foremost to ensure that individuals, families and groups are not left worse off than prior to a government policy impacting upon their life. Furthermore, the impact of living a life determined by multiple government policies should not be a story of individual and family devastation, and government policies should not be the most significant determinant of health for any group of people.

Resituating the ethical gaze: government morality and the local worlds of impoverished Indigenous women

PubMed Central

Tait, Caroline L.

2013-01-01

Background Over generations, government policies have impacted upon the lives of Indigenous peoples of Canada in unique and often devastating ways. In this context, Indigenous women who struggle with poverty, mental illness, trauma and substance abuse are among the most vulnerable, as are Indigenous children involved in child welfare systems. Objective By examining the life history of Wanda, a First Nations woman, this article examines the intergenerational role that government policies play in the lives of impoverished Indigenous women and their families. Questions of moral governance and responsibility and the need for ethical policies are raised. Design The life narrative presented in this article is part of a larger qualitative research programme that has collected over 100 life histories of Indigenous women with addictions and who have involvement with the child welfare system, as children or adults. Wanda's life story exemplifies the impact of government policies that is characteristic of vulnerable Indigenous women and draws attention to the lack of ethical standards in government policymaking in child welfare, public health and mental health/addictions. Results The path to recovery for Canadian Indigenous women in need of treatment for co-occurring mental disorders and substance addiction is too frequently characterized by an inadequate and ever shifting continuum of care. For those who feel intimidated, suspicious or have simply given up on seeking supports, a profound invisibility or forgetting of their struggle exists in areas of government policy and programming provision. Living outside the scope of mental health and addiction priorities, they become visible to the human service sector only if they become pregnant, their parenting draws the attention of child and family services (CFS), they need emergency health care, or are in trouble with the law. The intergenerational cycle of substance abuse, mental illness and poverty is commonly associated with child welfare involvement, specifically practices that place the health and well-being of Indigenous children at risk. In order to break this cycle, close attention to implementation of ethically based policies and best practice interventions is required. Conclusions From an ethical policy perspective, the focus of government policies and the practices they generate must be first and foremost to ensure that individuals, families and groups are not left worse off than prior to a government policy impacting upon their life. Furthermore, the impact of living a life determined by multiple government policies should not be a story of individual and family devastation, and government policies should not be the most significant determinant of health for any group of people. PMID:23986898

Predator crown-of-thorns starfish (Acanthaster planci) outbreak, mass mortality of corals, and cascading effects on reef fish and benthic communities.

PubMed

Kayal, Mohsen; Vercelloni, Julie; Lison de Loma, Thierry; Bosserelle, Pauline; Chancerelle, Yannick; Geoffroy, Sylvie; Stievenart, Céline; Michonneau, François; Penin, Lucie; Planes, Serge; Adjeroud, Mehdi

2012-01-01

Outbreaks of the coral-killing seastar Acanthaster planci are intense disturbances that can decimate coral reefs. These events consist of the emergence of large swarms of the predatory seastar that feed on reef-building corals, often leading to widespread devastation of coral populations. While cyclic occurrences of such outbreaks are reported from many tropical reefs throughout the Indo-Pacific, their causes are hotly debated, and the spatio-temporal dynamics of the outbreaks and impacts to reef communities remain unclear. Based on observations of a recent event around the island of Moorea, French Polynesia, we show that Acanthaster outbreaks are methodic, slow-paced, and diffusive biological disturbances. Acanthaster outbreaks on insular reef systems like Moorea's appear to originate from restricted areas confined to the ocean-exposed base of reefs. Elevated Acanthaster densities then progressively spread to adjacent and shallower locations by migrations of seastars in aggregative waves that eventually affect the entire reef system. The directional migration across reefs appears to be a search for prey as reef portions affected by dense seastar aggregations are rapidly depleted of living corals and subsequently left behind. Coral decline on impacted reefs occurs by the sequential consumption of species in the order of Acanthaster feeding preferences. Acanthaster outbreaks thus result in predictable alteration of the coral community structure. The outbreak we report here is among the most intense and devastating ever reported. Using a hierarchical, multi-scale approach, we also show how sessile benthic communities and resident coral-feeding fish assemblages were subsequently affected by the decline of corals. By elucidating the processes involved in an Acanthaster outbreak, our study contributes to comprehending this widespread disturbance and should thus benefit targeted management actions for coral reef ecosystems.

Discoveries far from the lamppost with matrix elements and ranking

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

Debnath, Dipsikha; Gainer, James S.; Matchev, Konstantin T.

2015-04-01

The prevalence of null results in searches for new physics at the LHC motivates the effort to make these searches as model-independent as possible. We describe procedures for adapting the Matrix Element Method for situations where the signal hypothesis is not known a priori. We also present general and intuitive approaches for performing analyses and presenting results, which involve the flattening of background distributions using likelihood information. The first flattening method involves ranking events by background matrix element, the second involves quantile binning with respect to likelihood (and other) variables, and the third method involves reweighting histograms by the inversemore » of the background distribution.« less

Inherited and acquired immunodeficiencies underlying tuberculosis in childhood

PubMed Central

Boisson-Dupuis, Stéphanie; Bustamante, Jacinta; El-Baghdadi, Jamila; Camcioglu, Yildiz; Parvaneh, Nima; Azbaoui, Safaa El; Agader, Aomar; Hassani, Amal; Hafidi, Naima El; Mrani, Nidal Alaoui; Jouhadi, Zineb; Ailal, Fatima; Najib, Jilali; Reisli, Ismail; Zamani, Adil; Yosunkaya, Sebnem; Gulle-Girit, Saniye; Yildiran, Alisan; Cipe, Funda Erol; Torun, Selda Hancerli; Metin, Ayse; Atikan, Basak Yildiz; Hatipoglu, Nevin; Aydogmus, Cigdem; Kilic, Sara Sebnem; Dogu, Figen; Karaca, Neslihan; Aksu, Guzide; Kutukculer, Necil; Keser-Emiroglu, Melike; Somer, Ayper; Tanir, Gonul; Aytekin, Caner; Adimi, Parisa; Mahdaviani, Seyed Alireza; Mamishi, Setareh; Bousfiha, Aziz; Sanal, Ozden; Mansouri, Davood; Casanova, Jean-Laurent; Abel, Laurent

2015-01-01

Summary Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey. PMID:25703555

Notch1 is a prognostic factor that is distinctly activated in the classical and proneural subtype of glioblastoma and that promotes glioma cell survival via the NF-κB(p65) pathway.

PubMed

Hai, Long; Zhang, Chen; Li, Tao; Zhou, Xingchen; Liu, Bo; Li, Shuai; Zhu, Meng; Lin, Yu; Yu, Shengping; Zhang, Kai; Ren, Bingcheng; Ming, Haolang; Huang, Yubao; Chen, Lei; Zhao, Pengfei; Zhou, Hua; Jiang, Tao; Yang, Xuejun

2018-02-06

Glioblastomas (GBMs) are the most prevalent and devastating primary intracranial malignancies and have extensive heterogeneity. Notch1 signaling is a more complex process in the development of numerous cell and tissue types, including gliomagenesis and progression, and is upregulated in glioma-initiating cells. However, the contradictory expression of Notch1 among lower grade gliomas and GBMs confounds our understanding of GBM biology and has made identifying effective therapies difficult. In this study, we validated that Notch1 and NF-κB(p65) are highly expressed in the classical and proneural subtypes of GBM using the data set from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). DAPT and shRNA targeting Notch1 decreased NF-κB(p65) expression, suppressed cell proliferation, and induced apoptosis of GBM cells in vitro and in vivo. Furthermore, we illustrated that the intracellular Notch could bind with NF-κB(p65) in GBM cells. These findings suggest that the cross-talk between Notch1 signaling and NF-κB(p65) could contribute to the proliferation and apoptosis of glioma, and this discovery could help drive the design of more effective therapies in Notch1-targeted clinical trials.

A yeast functional screen predicts new candidate ALS disease genes

PubMed Central

Couthouis, Julien; Hart, Michael P.; Shorter, James; DeJesus-Hernandez, Mariely; Erion, Renske; Oristano, Rachel; Liu, Annie X.; Ramos, Daniel; Jethava, Niti; Hosangadi, Divya; Epstein, James; Chiang, Ashley; Diaz, Zamia; Nakaya, Tadashi; Ibrahim, Fadia; Kim, Hyung-Jun; Solski, Jennifer A.; Williams, Kelly L.; Mojsilovic-Petrovic, Jelena; Ingre, Caroline; Boylan, Kevin; Graff-Radford, Neill R.; Dickson, Dennis W.; Clay-Falcone, Dana; Elman, Lauren; McCluskey, Leo; Greene, Robert; Kalb, Robert G.; Lee, Virginia M.-Y.; Trojanowski, John Q.; Ludolph, Albert; Robberecht, Wim; Andersen, Peter M.; Nicholson, Garth A.; Blair, Ian P.; King, Oliver D.; Bonini, Nancy M.; Van Deerlin, Vivianna; Rademakers, Rosa; Mourelatos, Zissimos; Gitler, Aaron D.

2011-01-01

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery. PMID:22065782

The flagellum of Trypanosoma brucei: new tricks from an old dog

PubMed Central

Ralston, Katherine S.; Hill, Kent L.

2010-01-01

African trypanosomes, i.e. Trypanosoma brucei and related sub-species, are devastating human and animal pathogens that cause significant human mortality and limit sustained economic development in sub-Saharan Africa. Trypanosoma brucei is a highly motile protozoan parasite and coordinated motility is central to both disease pathogenesis in the mammalian host and parasite development in the tsetse fly vector. Since motility is critical for parasite development and pathogenesis, understanding unique aspects of the T. brucei flagellum may uncover novel targets for therapeutic intervention in African sleeping sickness. Moreover, studies of conserved features of the T. brucei flagellum are directly relevant to understanding fundamental aspects of flagellum and cilium function in other eukaryotes, making T. brucei an important model system. The T. brucei flagellum contains a canonical 9 + 2 axoneme, together with additional features that are unique to kinetoplastids and a few closely-related organisms. Until recently, much of our knowledge of the structure and function of the trypanosome flagellum was based on analogy and inference from other organisms. There has been an explosion in functional studies in T. brucei in recent years, revealing conserved as well as novel and unexpected structural and functional features of the flagellum. Most notably, the flagellum has been found to be an essential organelle, with critical roles in parasite motility, morphogenesis, cell division and immune evasion. This review highlights recent discoveries on the T. brucei flagellum. PMID:18472102

The historical significance of anaesthesia events at Pearl Harbor.

PubMed

Crowhurst, Ja

2014-07-01

Up to the end of World War II, less than 10% of the general anaesthetics administered was with intravenous barbiturates. The remaining 90% of anaesthetics given in the USA were with diethyl ether. In the United Kingdom and elsewhere, chloroform was also popular. Diethyl ether administration was a relatively safe and simple procedure, often delegated to nurses or junior doctors with little or no specific training in anaesthesia. During the Japanese attack on the US bases at Pearl Harbor, with reduced stocks of diethyl ether available, intravenous Sodium Pentothal(®), a most 'sophisticated and complex' drug, was used with devastating effects in many of those hypovolaemic, anaemic and septic patients. The hazards of spinal anaesthesia too were realised very quickly. These effects were compounded by the dearth of trained anaesthetists. This paper presents the significance of the anaesthesia tragedies at Pearl Harbor, and the discovery in the next few years of many other superior drugs that caused medical and other health professionals to realise that anaesthesia needed to be a specialist medical discipline in its own right. Specialist recognition, aided by the foundation of the National Health Service in the UK, the establishment of Faculties of Anaesthesia and appropriate training in pharmacology, physiology and other sciences soon followed. Modern anaesthesiology, as we understand it today, was born and a century or more of ether anaesthesia finally ceased.

The processing and transmission of EEG data

NASA Technical Reports Server (NTRS)

Schulze, A. E.

1974-01-01

Interest in sleep research was stimulated by the discovery of a number of physiological changes that occur during sleep and by the observed effects of sleep on physical and mental performance and status. The use of the relatively new methods of EEG measurement, transmission, and automatic scoring makes sleep analysis and categorization feasible. Sleep research involving the use of the EEG as a fundamental input has the potential of answering many unanswered questions involving physical and mental behavior, drug effects, circadian rhythm, and anesthesia.

The Elusive Neutrino, Understanding the Atom Series.

ERIC Educational Resources Information Center

Bernstein, Jeremy

This booklet is one of the booklets in the "Understanding the Atom Series" published by the U. S. Atomic Energy Commission for high school science teachers and their students. The discovery of the neutrino and the research involving this important elementary particle of matter is discussed. The introductory section reviews topics basic…

40 CFR 164.70 - Subpoenas.

Code of Federal Regulations, 2010 CFR

2010-07-01

... witnesses or the production of documentary evidence may, by subpoena, be required at any designated place of... involved in the hearing or that the sought discovery pursuant to § 164.51 meets the standards set forth...) Motion for subpoena duces tecum. Subpoenas for the production of documentary evidence, unless issued by...

Fishing for Features

ScienceCinema

Heredia-Langner, Alejandro; Cort, John; Bailey, Vanessa

2018-01-16

The Fishing for Features Signature Discovery project developed a framework for discovering signature features in challenging environments involving large and complex data sets or where phenomena may be poorly characterized or understood. Researchers at PNNL have applied the framework to the optimization of biofuels blending and to discover signatures of climate change on microbial soil communities.

Teaching Practice: A Perspective on Inter-Text and Prior Knowledge

ERIC Educational Resources Information Center

Costley, Kevin C.; West, Howard G.

2012-01-01

The use of teaching practices that involve intertextual relationship discovery in today's elementary classrooms is increasingly essential to the success of young learners of reading. Teachers must constantly strive to expand their perspective of how to incorporate the dialogue included in prior knowledge assessment. Teachers must also consider how…

Jupiter Quest: A Path to Scientific Discovery.

ERIC Educational Resources Information Center

Bollman, Kelly A.; Rodgers, Mark H.; Mauller, Robert L.

2001-01-01

To experience the world of professional science, students must have access to the scientific community and be allowed to become real scientists. A partnership involving the National Aeronautics and Space Administration, the Jet Propulsion Laboratory, and the Lewis Center for Educational Research has produced Jupiter Quest, an engaging curriculum…

Using Relational Reasoning to Learn about Scientific Phenomena at Unfamiliar Scales

ERIC Educational Resources Information Center

Resnick, Ilyse; Davatzes, Alexandra; Newcombe, Nora S.; Shipley, Thomas F.

2016-01-01

Many scientific theories and discoveries involve reasoning about extreme scales, removed from human experience, such as time in geology, size in nanoscience. Thus, understanding scale is central to science, technology, engineering, and mathematics. Unfortunately, novices have trouble understanding and comparing sizes of unfamiliar large and small…

Rote or Raft? Science and Adventure at a Summer Camp.

ERIC Educational Resources Information Center

Martin, Jenni

1997-01-01

Describes the group dynamics, science discovery processes, and activities involved in building a raft at camp. The project used recycled products and required group cooperation; critical thinking about density, buoyancy, and balance; use of familiar resources in creative ways; and application of previously learned facts. (SAS)

Teacher-Student Communication Games: Some Experiments on Instruction.

ERIC Educational Resources Information Center

Olson, David R.; And Others

This inquiry began with the observation that learning from instruction is radically more efficient for obtaining information than learning by discovery. A series of seven experiments was conducted to determine some of the factors involved in learning from verbal instruction. The perspective adopted was that of communication theory, in which the…

Prospects: the tomato genome as a cornerstone for gene discovery

USDA-ARS?s Scientific Manuscript database

Those involved in the international tomato genome sequencing effort contributed to not only the development of an important genome sequence relevant to a major economic and nutritional crop, but also to the tomato experimental system as a model for plant biology. Without question, prior seminal work...

Fishing for Features

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

Heredia-Langner, Alejandro; Cort, John; Bailey, Vanessa

2016-07-21

The Fishing for Features Signature Discovery project developed a framework for discovering signature features in challenging environments involving large and complex data sets or where phenomena may be poorly characterized or understood. Researchers at PNNL have applied the framework to the optimization of biofuels blending and to discover signatures of climate change on microbial soil communities.

Open Classes to Local Communities: A Reflection Analysis of a School Environmental Project

ERIC Educational Resources Information Center

Kalathaki, Maria

2017-01-01

School projects of environmental education promote discovery learning, through teamwork, by involving local communities, scientists, organizations, authorities, and bodies and are carried out largely online in virtual environments. This research aimed to identify and highlight those characteristics of local communities that can be exploited by…

The Rewards of Qualitative Assessment Appropriate to Study Abroad

ERIC Educational Resources Information Center

Engle, Lilli

2013-01-01

With the interconnectedness of the peoples and nations of our world every year more patently apparent, the international education community has responded with heightened urgency to the challenge of integrating the discovery and understanding of other countries, cultures, and realities into the university curriculum. Even as all involved still…

Paintbrush of Discovery: Using Java Applets to Enhance Mathematics Education

ERIC Educational Resources Information Center

Eason, Ray; Heath, Garrett

2004-01-01

This article addresses the enhancement of the learning environment by using Java applets in the mathematics classroom. Currently, the first year mathematics program at the United States Military Academy involves one semester of modeling with discrete dynamical systems (DDS). Several faculty members from the Academy have integrated Java applets…

Monitoring Financial Conflict of Interest

ERIC Educational Resources Information Center

Hickson, Lorraine

2016-01-01

Conflict of interest is heavily intertwined with research. The purpose of this study was to examine the literature and regulations in order to describe efforts required to properly monitor and disclose conflict of interest as researchers become steadily involved in innovation and discovery. The public assumes that when a conflict is disclosed, it…

45 CFR 164.408 - Notification to the Secretary.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Notification to the Secretary. 164.408 Section 164... § 164.408 Notification to the Secretary. (a) Standard. A covered entity shall, following the discovery... Secretary. (b) Implementation specifications: Breaches involving 500 or more individuals. For breaches of...

45 CFR 164.408 - Notification to the Secretary.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 45 Public Welfare 1 2014-10-01 2014-10-01 false Notification to the Secretary. 164.408 Section 164... § 164.408 Notification to the Secretary. (a) Standard. A covered entity shall, following the discovery... Secretary. (b) Implementation specifications: Breaches involving 500 or more individuals. For breaches of...

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…

A Practice-Oriented Review of Learning Objects

ERIC Educational Resources Information Center

Sinclair, J.; Joy, M.; Yau, J. Y.-K.; Hagan, S.

2013-01-01

Reusable learning objects support packaging of educational materials allowing their discovery and reuse. Open educational resources emphasize the need for open licensing and promote sharing and community involvement. For both teachers and learners, finding appropriate tried and tested resources on a topic of interest and being able to incorporate…