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Sample records for alters molecular systems

  1. ENVIRONMENTAL AND MOLECULAR CHARACTERIZATION OF SYSTEMS WHICH ALTER GENOME STABILITY IN PSEUDOMONAS

    EPA Science Inventory

    Pseudomonas aeruginosa was used a model organism to study mechanisms that lead to genome alteration in freshwater microbial populations. ur studies demonstrated horizontal transmission by both transduction and conjugation in freshwater ecosystems and provided data that suggest th...

  2. Molecular cytogenetic characterization of cancer cell alterations.

    PubMed

    Popescu, N C; Zimonjic, D B

    1997-01-01

    Chromosomal abnormalities are the hallmark of cancer cells. Recurring and highly consistent structural and numerical alterations have been identified in a large number of leukemias, lymphomas, and solid tumors. The identification of recurrent genetic alterations and the isolation of molecular markers have clinical applications in the diagnosis and prognosis of neoplasia and in the detection of minimal residual disease that are essential for designing the most effective therapeutic approach. Polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) are powerful techniques for detection of genomic alterations. The battery of FISH methods and DNA probes that are available can resolve virtually any chromosomal alterations regardless of their complexity. Combined chromosome banding, multifluor or spectral karyotype, and comparative genomic hybridization (CGH) allow identification of structural and numerical alterations on a global basis, mapping of the DNA copy number on the entire tumor genome, complete derivation of complex rearrangements, and localization of the breakpoints of translocations and deletions. Regions of recurrent alterations can be microdisected, amplified, microclone libraries constructed and probes localized on extended chromosomes or chromatin fibers for construction of high resolution physical maps that are critical for positional cloning and gene identification. In this review we attempted to cover the current trends in cancer molecular cytogenetics, and to outline the importance of molecular chromosome analysis in the understanding of oncogenesis and its clinical applications. PMID:9062575

  3. Molecular multiproxy analysis of ancient root systems suggests strong alteration of deep subsoil organic matter by rhizomicrobial activity

    NASA Astrophysics Data System (ADS)

    Gocke, Martina; Huguet, Arnaud; Derenne, Sylvie; Kolb, Steffen; Wiesenberg, Guido L. B.

    2013-04-01

    Roots have a high potential capacity to store large amounts of CO2 in the subsoil. However, associated with rooting, microorganisms enter the subsoil and might contribute to priming effects of carbon mineralisation in the microbial hotspot rhizosphere. Although these processes are well known for recent surface soils, it remains questionable, if and how microorganisms contribute to priming effects in the subsoil and if these effects can be traced after the roots' lifetime. The current study implies several state-of-the-art techniques like DNA and lipid molecular proxies to trace remains of microbial biomass in ancient root systems. These can provide valuable information if parts of the root and rhizomicrobial biomass are preserved, e.g. by encrustation with secondary carbonate during the root's lifespan or shortly thereafter. At the Late Pleistocene loess-paleosol sequence near Nussloch (SW Germany), rhizoliths (calcified roots) occur highly abundant in the deep subsoil from 1 to 9 m depth and below. They were formed by Holocene woody vegetation. Their size can account for up to several cm in diameter and up to > 1 m length. Rhizoliths and surrounding sediment with increasing distances of up to 10 cm, as well as reference loess without visible root remains were collected at several depth intervals. Samples were analysed for n-fatty acids (FAs) and glycerol dialkyl glycerol tetraethers (GDGTs; membrane lipids from Archaea and some Bacteria), as well as structural diversity based on the RNA gene of the prokaryotic ribosome subunit 16S (16S rRNA). GDGT represent organic remains from microbial biomass, whereas FA comprise both microbial remains and degradation products. 16S rRNA indicates the presence of both living cells and/or cell fragments. Despite the general low RNA contents in the sample set, results pointed to a much higher abundance of bacterial compared to archaeal RNA. The latter occured in notable amounts only in some rhizoliths. This was in part enforced by

  4. Genetic and molecular alterations across medulloblastoma subgroups.

    PubMed

    Skowron, Patryk; Ramaswamy, Vijay; Taylor, Michael D

    2015-10-01

    Medulloblastoma is the most common malignant brain tumour diagnosed in children. Over the last few decades, advances in radiation and chemotherapy have significantly improved the odds of survival. Nevertheless, one third of all patients still succumb to their disease, and many long-term survivors are afflicted with neurocognitive sequelae. Large-scale multi-institutional efforts have provided insight into the transcriptional and genetic landscape of medulloblastoma. Four distinct subgroups of medulloblastoma have been identified, defined by distinct transcriptomes, genetics, demographics and outcomes. Integrated genomic profiling of each of these subgroups has revealed distinct genetic alterations, driving pathways and in some instances cells of origin. In this review, we highlight, in a subgroup-specific manner, our current knowledge of the genetic and molecular alterations in medulloblastoma and underscore the possible avenues for future therapeutic intervention. PMID:26350064

  5. [Molecular alterations in melanoma and targeted therapies].

    PubMed

    Mourah, Samia; Lebbé, Céleste

    2014-12-01

    Melanoma is a skin cancer whose incidence is increasing steadily. The recent discovery of frequent and recurrent genetic alterations in cutaneous melanoma allowed a molecular classification of tumors into distinct subgroups, and paved the way for targeted therapy. Several signaling pathways are involved in the progression of this disease with oncogenic mutations affecting signaling pathways: MAPK, PI3K, cAMP and cyclin D1/CDK4. In each of these pathways, several potential therapeutic targets have been identified and specific inhibitors have already been developed and have shown clinical efficacy. The use of these inhibitors is often conditioned by tumors genotyping. In France, melanomas genotyping is supported by the platforms of the National Cancer Institute (INCA), which implemented a national program ensuring access to innovation for personalized medicine. The identification of new targets in melanoma supplies a very active dynamic development of innovative molecules contributing to changing the therapeutic landscape of this pathology. PMID:25776766

  6. Genetic and molecular alterations in meningiomas.

    PubMed

    Alexiou, George A; Markoula, Sofia; Gogou, Pinelopi; Kyritsis, Athanasios P

    2011-05-01

    Meningiomas are the most common benign intracranial tumors in adults arising from the dura matter. The etiology of meningiomas is mostly unknown, although several risk factors have been described, such as ionizing radiation, head injury, hormones and genetic factors. According to WHO they are classified into 3 grades, grade I, grade II and grade III. Meningiomas express various hormonal and growth factor receptors, such as progesterone, estrogen, somatostatin, transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) receptors, which may be related to their biological behavior and response to treatment. Chromosomal abnormalities linked to meningiomas involve chromosomes 22, 1p, 9p, 10p, 11, 14q, 15, 17, and 18q. In addition, genes that may be involved in the formation of meningiomas include NF2, DAL-1, p14 (ARF), p53, MDM2, Rb, p16 and c-myc. It is likely that detailed molecular information will aid in establishing a molecular grading of these tumors and predict response to treatment and survival. PMID:21227570

  7. MOLECULAR ALTERATIONS IN GLIOBLASTOMA: POTENTIAL TARGETS FOR IMMUNOTHERAPY

    PubMed Central

    Haque, Azizul; Banik, Naren L.; Ray, Swapan K.

    2015-01-01

    Glioblastoma is the most common and deadly brain tumor, possibly arising from genetic and epigenetic alterations in normal astroglial cells. Multiple cytogenetic, chromosomal, and genetic alterations have been identified in glioblastoma, with distinct expression of antigens (Ags) and biomarkers that may alter therapeutic potential of this aggressive cancer. Current therapy consists of surgical resection, followed by radiation therapy and chemotherapy. In spite of these treatments, the prognosis for glioblastoma patients is poor. Although recent studies have focused on the development of novel immunotherapeutics against glioblastoma, little is known about glioblastoma specific immune responses. A better understanding of the molecular interactions among glioblastoma tumors, host immune cells, and the tumor microenvironment may give rise to novel integrated approaches for the simultaneous control of tumor escape pathways and the activation of antitumor immune responses. This review provides a detailed overview concerning genetic alterations in glioblastoma, their effects on Ag and biomarker expression and the future design of chemoimmunotherapeutics against glioblastoma. PMID:21199773

  8. Tumors of the Testis: Morphologic Features and Molecular Alterations.

    PubMed

    Howitt, Brooke E; Berney, Daniel M

    2015-12-01

    This article reviews the most frequently encountered tumor of the testis; pure and mixed malignant testicular germ cell tumors (TGCT), with emphasis on adult (postpubertal) TGCTs and their differential diagnoses. We additionally review TGCT in the postchemotherapy setting, and findings to be integrated into the surgical pathology report, including staging of testicular tumors and other problematic issues. The clinical features, gross pathologic findings, key histologic features, common differential diagnoses, the use of immunohistochemistry, and molecular alterations in TGCTs are discussed. PMID:26612222

  9. Glaucoma Alters the Circadian Timing System

    PubMed Central

    Drouyer, Elise; Dkhissi-Benyahya, Ouria; Chiquet, Christophe; WoldeMussie, Elizabeth; Ruiz, Guadalupe; Wheeler, Larry A.; Denis, Philippe; Cooper, Howard M.

    2008-01-01

    Glaucoma is a widespread ocular disease and major cause of blindness characterized by progressive, irreversible damage of the optic nerve. Although the degenerative loss of retinal ganglion cells (RGC) and visual deficits associated with glaucoma have been extensively studied, we hypothesize that glaucoma will also lead to alteration of the circadian timing system. Circadian and non-visual responses to light are mediated by a specialized subset of melanopsin expressing RGCs that provide photic input to mammalian endogenous clock in the suprachiasmatic nucleus (SCN). In order to explore the molecular, anatomical and functional consequences of glaucoma we used a rodent model of chronic ocular hypertension, a primary causal factor of the pathology. Quantitative analysis of retinal projections using sensitive anterograde tracing demonstrates a significant reduction (∼50–70%) of RGC axon terminals in all visual and non-visual structures and notably in the SCN. The capacity of glaucomatous rats to entrain to light was challenged by exposure to successive shifts of the light dark (LD) cycle associated with step-wise decreases in light intensity. Although glaucomatous rats are able to entrain their locomotor activity to the LD cycle at all light levels, they require more time to re-adjust to a shifted LD cycle and show significantly greater variability in activity onsets in comparison with normal rats. Quantitative PCR reveals the novel finding that melanopsin as well as rod and cone opsin mRNAs are significantly reduced in glaucomatous retinas. Our findings demonstrate that glaucoma impacts on all these aspects of the circadian timing system. In light of these results, the classical view of glaucoma as pathology unique to the visual system should be extended to include anatomical and functional alterations of the circadian timing system. PMID:19079596

  10. Sex speeds adaptation by altering the dynamics of molecular evolution.

    PubMed

    McDonald, Michael J; Rice, Daniel P; Desai, Michael M

    2016-03-10

    Sex and recombination are pervasive throughout nature despite their substantial costs. Understanding the evolutionary forces that maintain these phenomena is a central challenge in biology. One longstanding hypothesis argues that sex is beneficial because recombination speeds adaptation. Theory has proposed several distinct population genetic mechanisms that could underlie this advantage. For example, sex can promote the fixation of beneficial mutations either by alleviating interference competition (the Fisher-Muller effect) or by separating them from deleterious load (the ruby in the rubbish effect). Previous experiments confirm that sex can increase the rate of adaptation, but these studies did not observe the evolutionary dynamics that drive this effect at the genomic level. Here we present the first, to our knowledge, comparison between the sequence-level dynamics of adaptation in experimental sexual and asexual Saccharomyces cerevisiae populations, which allows us to identify the specific mechanisms by which sex speeds adaptation. We find that sex alters the molecular signatures of evolution by changing the spectrum of mutations that fix, and confirm theoretical predictions that it does so by alleviating clonal interference. We also show that substantially deleterious mutations hitchhike to fixation in adapting asexual populations. In contrast, recombination prevents such mutations from fixing. Our results demonstrate that sex both speeds adaptation and alters its molecular signature by allowing natural selection to more efficiently sort beneficial from deleterious mutations. PMID:26909573

  11. Genomic alterations and molecular subtypes of gastric cancers in Asians.

    PubMed

    Ye, Xiang S; Yu, Chunping; Aggarwal, Amit; Reinhard, Christoph

    2016-01-01

    Gastric cancer (GC) is a highly heterogenic disease, and it is the second leading cause of cancer death in the world. Common chemotherapies are not very effective for GC, which often presents as an advanced or metastatic disease at diagnosis. Treatment options are limited, and the prognosis for advanced GCs is poor. The landscape of genomic alterations in GCs has recently been characterized by several international cancer genome programs, including studies that focused exclusively on GCs in Asians. These studies identified major recurrent driver mutations and provided new insights into the mutational heterogeneity and genetic profiles of GCs. An analysis of gene expression data by the Asian Cancer Research Group (ACRG) further uncovered four distinct molecular subtypes with well-defined clinical features and their intersections with actionable genetic alterations to which targeted therapeutic agents are either already available or under clinical development. In this article, we review the ACRG GC project. We also discuss the implications of the genetic and molecular findings from various GC genomic studies with respect to developing more precise diagnoses and treatment approaches for GCs. PMID:27160712

  12. Molecular alteration of marine dissolved organic matter under experimental hydrothermal conditions

    NASA Astrophysics Data System (ADS)

    Hawkes, Jeffrey A.; Hansen, Christian T.; Goldhammer, Tobias; Bach, Wolfgang; Dittmar, Thorsten

    2016-02-01

    Marine dissolved organic matter (DOM) is a large (660 Pg) pool of reduced carbon that is subject to thermal alteration in hydrothermal systems and sedimentary basins. In natural high-temperature hydrothermal systems, DOM is almost completely removed, but the mechanism and temperature dependence of this removal have not been studied to date. We investigated molecular-level changes to DOM that was solid-phase extracted (SPE-DOM) from the deep ocean of the North Pacific Ocean. This complex molecular mixture was experimentally exposed to temperatures between 100 and 380 °C over the course of two weeks in artificial seawater, and was then characterised on a molecular level via ultrahigh-resolution Fourier-transform ion cyclotron mass spectrometry (FT-ICR-MS). Almost 93% of SPE-DOM was removed by the treatment at 380 °C, and this removal was accompanied by a consistent pattern of SPE-DOM alteration across the temperatures studied. Higher molecular weight and more oxygen rich compounds were preferentially removed, suggesting that decarboxylation and dehydration of carboxylic acid and alcohol groups are the most rapid degradation mechanisms. Nitrogen containing compounds followed the same overall trends as those containing just C, H and O up to 300 °C. Above this temperature, the most highly altered samples contained very little of the original character of marine DOM, instead being mainly composed of very low intensity N- and S- containing molecules with a high H/C ratio (>1.5). Our results suggest that abiotic hydrothermal alteration of SPE-DOM may already occur at temperatures above 68 °C. Our experiments were conducted without a sedimentary or mineral phase, and demonstrate that profound molecular alteration and almost complete removal of marine SPE-DOM requires nothing more than heating in a seawater matrix.

  13. Genetic/molecular alterations of meningiomas and the signaling pathways targeted

    PubMed Central

    Domingues, Patrícia; González-Tablas, María; Otero, Álvaro; Pascual, Daniel; Ruiz, Laura; Miranda, David; Sousa, Pablo; Gonçalves, Jesús María; Lopes, María Celeste; Orfao, Alberto; Tabernero, María Dolores

    2015-01-01

    Meningiomas are usually considered to be benign central nervous system tumors; however, they show heterogenous clinical, histolopathological and cytogenetic features associated with a variable outcome. In recent years important advances have been achieved in the identification of the genetic/molecular alterations of meningiomas and the signaling pathways involved. Thus, monosomy 22, which is often associated with mutations of the NF2 gene, has emerged as the most frequent alteration of meningiomas; in addition, several other genes (e.g. AKT1, KLF4, TRAF7, SMO) and chromosomes have been found to be recurrently altered often in association with more complex karyotypes and involvement of multiple signaling pathways. Here we review the current knowledge about the most relevant genes involved and the signaling pathways targeted by such alterations. In addition, we summarize those proposals that have been made so far for classification and prognostic stratification of meningiomas based on their genetic/genomic features. PMID:25965831

  14. Prognostic Significance of the European LeukemiaNet Standardized System for Reporting Cytogenetic and Molecular Alterations in Adults With Acute Myeloid Leukemia

    PubMed Central

    Mrózek, Krzysztof; Marcucci, Guido; Nicolet, Deedra; Maharry, Kati S.; Becker, Heiko; Whitman, Susan P.; Metzeler, Klaus H.; Schwind, Sebastian; Wu, Yue-Zhong; Kohlschmidt, Jessica; Pettenati, Mark J.; Heerema, Nyla A.; Block, AnneMarie W.; Patil, Shivanand R.; Baer, Maria R.; Kolitz, Jonathan E.; Moore, Joseph O.; Carroll, Andrew J.; Stone, Richard M.; Larson, Richard A.; Bloomfield, Clara D.

    2012-01-01

    Purpose To evaluate the prognostic significance of the international European LeukemiaNet (ELN) guidelines for reporting genetic alterations in acute myeloid leukemia (AML). Patients and Methods We analyzed 1,550 adults with primary AML, treated on Cancer and Leukemia Group B first-line trials, who had pretreatment cytogenetics and, for cytogenetically normal patients, mutational status of NPM1, CEBPA, and FLT3 available. We compared complete remission (CR) rates, disease-free survival (DFS), and overall survival (OS) among patients classified into the four ELN genetic groups (favorable, intermediate-I, intermediate-II, adverse) separately for 818 younger (age < 60 years) and 732 older (age ≥ 60 years) patients. Results The percentages of younger versus older patients in the favorable (41% v 20%; P < .001), intermediate-II (19% v 30%; P < .001), and adverse (22% v 31%; P < .001) genetic groups differed. The favorable group had the best and the adverse group the worst CR rates, DFS, and OS in both age groups. Both intermediate groups had significantly worse outcomes than the favorable but better than the adverse group. Intermediate-I and intermediate-II groups in older patients had similar outcomes, whereas the intermediate-II group in younger patients had better OS but not better CR rates or DFS than the intermediate-I group. The prognostic significance of ELN classification was confirmed by multivariable analyses. For each ELN group, older patients had worse outcomes than younger patients. Conclusion The ELN classification clearly separates the genetic groups by outcome, supporting its use for risk stratification in clinical trials. Because they have different proportions of genetic alterations and outcomes, younger and older patients should be reported separately when using the ELN classification. PMID:22987078

  15. Expression alterations define unique molecular characteristics of spinal ependymomas

    PubMed Central

    Lourdusamy, Anbarasu; Rahman, Ruman; Grundy, Richard G.

    2015-01-01

    Ependymomas are glial tumors that originate in either intracranial or spinal regions. Although tumors from different regions are histologically similar, they are biologically distinct. We therefore sought to identify molecular characteristics of spinal ependymomas (SEPN) in order to better understand the disease biology of these tumors. Using gene expression profiles of 256 tumor samples, we identified increased expression of 1,866 genes in SEPN when compared to intracranial ependymomas. These genes are mainly related to anterior/posterior pattern specification, response to oxidative stress, glial cell differentiation, DNA repair, and PPAR signalling, and also significantly enriched with cellular senescence genes (P = 5.5 × 10−03). In addition, a high number of significantly down-regulated genes in SEPN are localized to chromosome 22 (81 genes from chr22: 43,325,255 – 135,720,974; FDR = 1.77 × 10−23 and 22 genes from chr22: 324,739 – 32,822,302; FDR = 2.07 × 10−09) including BRD1, EP300, HDAC10, HIRA, HIC2, MKL1, and NF2. Evaluation of NF2 co-expressed genes further confirms the enrichment of chromosome 22 regions. Finally, systematic integration of chromosome 22 genes with interactome and NF2 co-expression data identifies key candidate genes. Our results reveal unique molecular characteristics of SEPN such as altered expression of cellular senescence and chromosome 22 genes. PMID:25909290

  16. Multiphotochromic molecular systems.

    PubMed

    Fihey, Arnaud; Perrier, Aurélie; Browne, Wesley R; Jacquemin, Denis

    2015-06-01

    Molecular systems encompassing more than one photochromic entity can be used to build highly functional materials, thanks to their potential multi-addressability and/or multi-response properties. Over the last decade, the synthesis and spectroscopic and kinetic characterisation as well as the modeling of a wide range of multiphotochromes have been achieved in a field that is emerging as a distinct branch of photochemistry. In this review, we provide an overview of the available multiphotochromic compounds which use a variety of photoactive building blocks, e.g., diarylethene, azobenzene, spiropyran, naphthopyran or fulgimide derivatives. Their efficiency in terms of multi-responsiveness is discussed and several strategies to circumvent the most common limitation (i.e., the loss of photochromism of one part) are described. PMID:25921433

  17. Molecular Alterations in Primary Prostate Cancer After Androgen Ablation Therapy

    PubMed Central

    Best, Carolyn J. M.; Gillespie, John W.; Yi, Yajun; Chandramouli, G.V. R.; Perlmutter, Mark A.; Gathright, Yvonne; Erickson, Heidi S.; Georgevich, Lauren; Tangrea, Michael A.; Duray, Paul H.; González, Sergio; Velasco, Alfredo; Linehan, W. Marston; Matusik, Robert J.; Price, Douglas K.; Figg, William D.; Emmert-Buck, Michael R.; Chuaqui, Rodrigo F.

    2005-01-01

    PURPOSE After an initial response to androgen ablation, most prostate tumors recur, ultimately progressing to highly aggressive androgen independent (AI) cancer. The molecular mechanisms underlying progression are not well known, in part due to the rarity of AI samples from primary and metastatic sites. EXPERIMENTAL DESIGN We compared the gene expression profiles of ten AI primary prostate tumor biopsies with ten primary, untreated androgen-dependent (AD) tumors. Samples were laser capture microdissected, the RNA was amplified, and gene expression was assessed using Affymetrix Human Genome U133A Gene Chips. Differential expression was examined with principle component analysis (PCA) and Student t testing. Analysis of gene ontology was performed with Expression Analysis Systematic Explorer (EASE) and gene expression data were integrated with genomic alterations with DIfferential Gene locus MAPping (DIGMAP). RESULTS Unsupervised PCA showed that the AD and AI tumors segregated from one another. After filtering the data, 239 differentially expressed genes were identified. Two main gene ontologies were found discordant between AI and AD tumors: macromolecule biosynthesis was down-regulated and cell adhesion up-regulated in AI tumors. Other differentially expressed genes were related to IL-6 signaling, as well as angiogenesis, cell adhesion, apoptosis, oxidative stress, and hormone response. The DIGMAP analysis identified nine regions of potential chromosomal deletion in the AI tumors including 1p36, 3p21, 6p21, 8p21, 11p15, 11q12, 12q23, 16q12, and 16q21. CONCLUSIONS Taken together, these data identify several unique characteristics of AI prostate cancer that may hold potential for the development of targeted therapeutic intervention. PMID:16203770

  18. Immune system alterations in amyotrophic lateral sclerosis.

    PubMed

    Hovden, H; Frederiksen, J L; Pedersen, S W

    2013-11-01

    Amyotrophic lateral sclerosis is a disease of which the underlying cause and pathogenesis are unknown. Cumulatative data clearly indicates an active participation by the immune system in the disease. An increasingly recognized theory suggests a non-cell autonomous mechanism, meaning that multiple cells working together are necessary for the pathogenesis of the disease. Observed immune system alterations could indicate an active participation in this mechanism. Damaged motor neurons are able to activate microglia, astrocytes and the complement system, which further can influence each other and contribute to neurodegeneration. Infiltrating peripheral immune cells appears to correlate with disease progression, but their significance and composition is unclear. The deleterious effects of this collaborating system of cells appear to outweigh the protective aspects, and revealing this interplay might give more insight into the disease. Markers from the classical complement pathway are elevated where its initiator C1q appears to derive primarily from motor neurons. Activated microglia and astrocytes are found in close proximity to dying motor neurons. Their activation status and proliferation seemingly increases with disease progression. Infiltrating monocytes, macrophages and T cells are associated with these areas, although with mixed reports regarding T cell composition. This literature review will provide evidence supporting the immune system as an important part of ALS disease mechanism and present a hypothesis to direct the way for further studies. PMID:23550891

  19. 32 CFR 310.33 - New and altered record systems.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... alterations. (ii) Increases in numbers of individuals due to normal growth are not considered alterations... significantly the scope of population covered (for example, expansion of a system of records covering a...

  20. 32 CFR 310.33 - New and altered record systems.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... alterations. (ii) Increases in numbers of individuals due to normal growth are not considered alterations... significantly the scope of population covered (for example, expansion of a system of records covering a...

  1. Molecular Sieve Regeneration System (MSRS)

    SciTech Connect

    Nasise, J.E.; Anderson, J.L. ); Naruse, Y. )

    1992-01-01

    A Molecular Sieve Regeneration System (MSRS) was added to the existing Tritium Waste Treatment system (TWT) within the Tritium Systems Test Assembly (TSTA) at Los Alamos National Laboratory. The Department of Energy (DOE) no longer allows inventory by difference'' for radioactive wastes that are to be buried. The MSRS was designed and built to comply with this requirement. Within the TWT, water is generated by the catalytic conversion of hydrogen isotopes and removed by molecular sieve trapping prior to release to the environment. Molecular sieve regeneration is required to remove the trapped water and to rejuvenate the beds. The MSRS permits the collection and direct tritium assay of regenerated tritiated water from molecular sieve beds. This paper describes the MSRS in detail and how it is interfaced with the TWT.

  2. Molecular Sieve Regeneration System (MSRS)

    SciTech Connect

    Nasise, J.E.; Anderson, J.L.; Naruse, Y.

    1992-03-01

    A Molecular Sieve Regeneration System (MSRS) was added to the existing Tritium Waste Treatment system (TWT) within the Tritium Systems Test Assembly (TSTA) at Los Alamos National Laboratory. The Department of Energy (DOE) no longer allows ``inventory by difference`` for radioactive wastes that are to be buried. The MSRS was designed and built to comply with this requirement. Within the TWT, water is generated by the catalytic conversion of hydrogen isotopes and removed by molecular sieve trapping prior to release to the environment. Molecular sieve regeneration is required to remove the trapped water and to rejuvenate the beds. The MSRS permits the collection and direct tritium assay of regenerated tritiated water from molecular sieve beds. This paper describes the MSRS in detail and how it is interfaced with the TWT.

  3. Common Somatic Alterations Identified in Maffucci Syndrome by Molecular Karyotyping

    PubMed Central

    Amyere, Mustapha; Dompmartin, Anne; Wouters, Vinciane; Enjolras, Odile; Kaitila, Ilkka; Docquier, Pierre-Louis; Godfraind, Catherine; Mulliken, John Butler; Boon, Laurence Myriam; Vikkula, Miikka

    2014-01-01

    Maffucci syndrome (MS) is a rare congenital disorder characterized by multiple central cartilaginous tumors (enchondromas) in association with cutaneous spindle cell hemangiomas. These patients have a high incidence of malignant transformation. No familial case is known and the etiopathogenic cause remains unknown. In enchondromatosis (Ollier disease, OD), which is comprised of enchondromas only, 4 mutations in the PTHR1 gene have been identified in 4 patients; 3 were somatic and 1 was germline. No PTHR1 mutations have been detected in MS, whereas somatic IDH1 and, more rarely, IDH2 mutations have been observed in 77% of patients with MS and 81% of patients with OD. These genetic alterations are shared with other tumors, including glioma, leukemia and carcinoma. To search for underlying somatic genomic causes, we screened MS tissues using Affymetrix SNP-chips. We looked for CNVs, LOH and uniparental isodisomy (UPID) by performing pairwise analyses between allelic intensities in tumoral DNA versus the corresponding blood-extracted DNA. While common chromosomal anomalies were absent in constitutional DNA, several shared CNVs were identified in MS-associated tumors. The most frequently encountered somatic alterations were localized in 2p22.3, 2q24.3 and 14q11.2, implicating these chromosomal rearrangements in the formation of enchondromas and spindle cell hemangiomas in MS. In one chondrosarcoma specimen, large amplifications and/or deletions were observed in chromosomes 3, 6, 9, 10, 12, 13, and 19. Some of these genetic changes have been reported in other chondrosarcomas suggesting an etiopathogenic role. No LOH/UPID was observed in any Maffucci tissue. Our findings identify frequent somatic chromosomal rearrangements on 2p22.3, 2q24.3 and 14q11.2, which may unmask mutations leading to the lesions pathognomonic of MS. PMID:25565925

  4. Conformational Transitions in Molecular Systems

    NASA Astrophysics Data System (ADS)

    Bachmann, M.; Janke, W.

    2008-11-01

    Proteins are the "work horses" in biological systems. In almost all functions specific proteins are involved. They control molecular transport processes, stabilize the cell structure, enzymatically catalyze chemical reactions; others act as molecular motors in the complex machinery of molecular synthetization processes. Due to their significance, misfolds and malfunctions of proteins typically entail disastrous diseases, such as Alzheimer's disease and bovine spongiform encephalopathy (BSE). Therefore, the understanding of the trinity of amino acid composition, geometric structure, and biological function is one of the most essential challenges for the natural sciences. Here, we glance at conformational transitions accompanying the structure formation in protein folding processes.

  5. Molecular links between early energy metabolism alterations and Alzheimer's disease.

    PubMed

    Pedros, Ignacio; Patraca, Ivan; Martinez, Nohora; Petrov, Dmitry; Sureda, Francesc X; Auladell, Carme; Beas-Zarate, Carlos; Folch, Jaume

    2016-01-01

    Recent studies suggest that the neurobiology of Alzheimer's disease (AD) pathology could not be explained solely by an increase in beta-amyloid levels. In fact, success with potential therapeutic drugs that inhibit the generation of beta amyloid has been low. Therefore, due to therapeutic failure in recent years, the scientists are looking for alternative hypotheses to explain the causes of the disease and the cognitive loss. Accordingly, alternative hypothesis propose a link between AD and peripheral metabolic alteration. Then, we review in depth changes related to insulin signalling and energy metabolism in the context of the APPSwe/PS1dE9 (APP/PS1) mice model of AD. We show an integrated view of the changes that occur in the early stages of the amyloidogenic process in the APP/PS1 double transgenic mice model. These early changes affect several key metabolic processes related to glucose uptake and insulin signalling, cellular energy homeostasis, mitochondrial biogenesis and increased Tau phosphorylation by kinase molecules like mTOR and Cdk5. PMID:26709757

  6. TRIETHYLTIN: AMBIENT TEMPERATURE ALTERS VISUAL SYSTEM TOXICITY

    EPA Science Inventory

    Previous studies have indicated that acute exposure to triethyltin (TET) increases latencies of the flash evoked response (VER) recorded from the rat cortex. TET also produces hypothermia, which may be modified by altering environmental (ambient) temperature. In this study, the r...

  7. Molecular pathways associated with transcriptional alterations in hyperparathyroidism

    PubMed Central

    LEE, FANG; LEE, JIE-JEN; JAN, WOAN-CHING; WU, CHIH-JEN; CHEN, HAN-HSIANG; CHENG, SHIH-PING

    2016-01-01

    Hyperparathyroidism is characterized by the oversecretion of parathyroid hormone biochemically and increased cell proliferation histologically. Primary and secondary hyperparathyroidism exhibit distinct pathophysiology but share certain common microscopic features. The present study performed the first genome-wide expression analysis directly comparing the expression profile of primary and secondary hyperparathyroidism. Microarray gene expression analyses were performed in parathyroid tissues from 2 primary hyperparathyroidism patients and 3 secondary hyperparathyroidism patients. Unsupervised hierarchical clustering analysis identified two natural subgroups containing different types of hyperparathyroidism. Combined with additional data extracted from a publicly available database, a meta-signature was constructed to represent an intersection of two sets of differential expression profile. Multiple pathways were identified that are aberrantly regulated in hyperparathyroidism. In primary hyperparathyroidism, dysregulated pathways included cell adhesion molecules, peroxisome proliferator-activated receptor signaling pathway, and neuroactive ligand-receptor interaction. Pathways implicated in secondary hyperparathyroidism included tryptophan metabolism, tight junctions, renin-angiotensin system, steroid hormone biosynthesis, and O-glycan biosynthesis. The present study demonstrates that different pathophysiology is associated with differential gene profiling in hyperparathyroidism. Several pathways are involved in parathyroid dysregulation and may be future targets for therapeutic intervention. PMID:27347190

  8. Low molecular weight heparin restores antithrombin III activity from hyperglycemia induced alterations.

    PubMed

    Ceriello, A; Marchi, E; Palazzni, E; Quatraro, A; Giugliano, D

    1990-01-01

    Alteration of antithrombin III (ATIII) activity, glycemia level dependent, exists in diabetes mellitus. In this study the ability of a low molecular weight heparin (LMWH) (Fluxum, Alfa-Wassermann S.p.A., Bologna, Italy), as well as unfractioned héparin, to preserve ATIII activity from glucose-induced alterations, both in vitro and in vivo, is reported. The subcutaneous and intravenous LMWH and heparin administration increases basal depressed ATIII activity in diabetic patients. Heparin shows an equivalent effect on both anti-IIa and anti-Xa activity of ATIII, while LMWH is more effective in preserving the anti-Xa activity. Similarity, heparin preserves ATIII activity from hyperglycemia-induced alterations, during hyperglycemic clamp, and LMWH infusion is able to preserve a significant amount of anti-Xa activity from glucose-induced alterations. Since diabetic patients show a high incidence of thrombotic accidents, LMWH appears to be a promising innovation for the prevention of diabetic thrombophylia. PMID:2196192

  9. An antilock molecular braking system.

    PubMed

    Sun, Wei-Ting; Huang, Shou-Ling; Yao, Hsuan-Hsiao; Chen, I-Chia; Lin, Ying-Chih; Yang, Jye-Shane

    2012-08-17

    A light-driven molecular brake displaying an antilock function is constructed by introducing a nonradiative photoinduced electron transfer (PET) decay channel to compete with the trans (brake-off) → cis (brake-on) photoisomerization. A fast release of the brake can be achieved by deactivating the PET process through addition of protons. The cycle of irradiation-protonation-irradiation-deprotonation conducts the brake function and mimics the antilock braking system (ABS) of vehicles. PMID:22853709

  10. A mouse model of anxiety molecularly characterized by altered protein networks in the brain proteome.

    PubMed

    Szego, Eva M; Janáky, Tamás; Szabó, Zoltán; Csorba, Attila; Kompagne, Hajnalka; Müller, Géza; Lévay, György; Simor, Attila; Juhász, Gábor; Kékesi, Katalin A

    2010-02-01

    Recently, several attempts have been made to describe changes related to certain anxiety states in the proteome of experimental animal models. However, these studies are restricted by limitations regarding the number and correct identification of separated proteins. Moreover, the application of a systems biology approach to discover the molecular mechanisms of anxiety requires genetically homogenous inbred animal models. Therefore, we developed a novel mouse model of anxiety using a combination of crossbreeding (inbred for 35 generations) and behavioral selection. We found significant changes in 82 proteins in the total brain proteome compared to the control proteome. Thirty-four of these proteins had been previously identified in other anxiety, depression or repeated psychosocial stress studies. The identified proteins are associated with different cellular functions, including synaptic transmission, metabolism, proteolysis, protein biosynthesis and folding, cytoskeletal proteins, brain development and neurogenesis, oxidative stress, signal transduction. Our proteomics data suggest that alterations in serotonin receptor-associated proteins, in the carbohydrate metabolism, in the cellular redox system and in synaptic docking are all involved in anxiety. PMID:20015620

  11. General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis

    PubMed Central

    Brown, Emery N.; Purdon, Patrick L.; Van Dort, Christa J.

    2011-01-01

    Placing a patient in a state of general anesthesia is crucial for safely and humanely performing most surgical and many nonsurgical procedures. How anesthetic drugs create the state of general anesthesia is considered a major mystery of modern medicine. Unconsciousness, induced by altered arousal and/or cognition, is perhaps the most fascinating behavioral state of general anesthesia. We perform a systems neuroscience analysis of the altered arousal states induced by five classes of intravenous anesthetics by relating their behavioral and physiological features to the molecular targets and neural circuits at which these drugs are purported to act. The altered states of arousal are sedation-unconsciousness, sedation-analgesia, dissociative anesthesia, pharmaco-logic non-REM sleep, and neuroleptic anesthesia. Each altered arousal state results from the anesthetic drugs acting at multiple targets in the central nervous system. Our analysis shows that general anesthesia is less mysterious than currently believed. PMID:21513454

  12. Alterations of Dermal Connective Tissue Collagen in Diabetes: Molecular Basis of Aged-Appearing Skin

    PubMed Central

    Argyropoulos, Angela J.; Robichaud, Patrick; Balimunkwe, Rebecca Mutesi; Fisher, Gary J.; Hammerberg, Craig; Yan, Yan

    2016-01-01

    Alterations of the collagen, the major structural protein in skin, contribute significantly to human skin connective tissue aging. As aged-appearing skin is more common in diabetes, here we investigated the molecular basis of aged-appearing skin in diabetes. Among all known human matrix metalloproteinases (MMPs), diabetic skin shows elevated levels of MMP-1 and MMP-2. Laser capture microdissection (LCM) coupled real-time PCR indicated that elevated MMPs in diabetic skin were primarily expressed in the dermis. Furthermore, diabetic skin shows increased lysyl oxidase (LOX) expression and higher cross-linked collagens. Atomic force microscopy (AFM) further indicated that collagen fibrils were fragmented/disorganized, and key mechanical properties of traction force and tensile strength were increased in diabetic skin, compared to intact/well-organized collagen fibrils in non-diabetic skin. In in vitro tissue culture system, multiple MMPs including MMP-1 and MM-2 were induced by high glucose (25 mM) exposure to isolated primary human skin dermal fibroblasts, the major cells responsible for collagen homeostasis in skin. The elevation of MMPs and LOX over the years is thought to result in the accumulation of fragmented and cross-linked collagen, and thus impairs dermal collagen structural integrity and mechanical properties in diabetes. Our data partially explain why old-looking skin is more common in diabetic patients. PMID:27104752

  13. Physiological and Molecular Assessment of Altered Expression of Hsc70-1 in Arabidopsis. Evidence for Pleiotropic Consequences1

    PubMed Central

    Sung, Dong Yul; Guy, Charles L.

    2003-01-01

    Hsp70s function as molecular chaperones. The protective chaperone activities of hsp70 help to confer tolerance to heat, glucose deprivation, and drought. Overexpression of hsp70s in many organisms correlates with enhanced thermotolerance, altered growth, and development. To better understand the roles of hsp70 proteins in Arabidopsis, the molecular and physiological consequences of altered expression of the major heat shock cognate, Hsc70-1, were analyzed. Extensive efforts to achieve underexpression of Hsc70-1 mRNA using a full-length antisense cDNA resulted in no viable transgenic plants, suggesting that reduced expression is lethal. Constitutive overexpression of Hsc70-1 also appeared to be deleterious to viability, growth, and development because fewer transformants were recovered, and most were dwarfed with altered root systems. Despite being dwarfed, the overexpression plants progressed normally through four selected developmental stages. Heat treatment revealed that Hsc70-1 overexpression plants were more tolerant to heat shock (44°C for 10 min). The elevated basal levels of HSC70-1 in transgenic plants led to delayed heat shock response of several heat shock genes. The data in this study suggest that tight regulation of Hsc70-1 expression is critical for the viability of Arabidopsis and that the functions of HSC70-1 contribute to optimum growth, development, thermotolerance, and regulation of the heat shock response. PMID:12805626

  14. Reactions of small molecular systems

    SciTech Connect

    Wittig, C.

    1993-12-01

    This DOE program remains focused on small molecular systems relevant to combustion. Though a number of experimental approaches and machines are available for this research, the authors` activities are centered around the high-n Rydberg time-of-flight (HRTOF) apparatus in this laboratory. One student and one postdoc carry out experiments with this machine and also engage in small intra-group collaborations involving shared equipment. This past year was more productive than the previous two, due to the uninterrupted operation of the HRTOF apparatus. Results were obtained with CH{sub 3}OH, CH{sub 3}SH, Rg-HX complexes, HCOOH, and their deuterated analogs where appropriate. One paper is in print, three have been accepted for publication, and one is under review. Many preliminary results that augur well for the future were obtained with other systems such as HNO{sub 3}, HBr-HI complexes, toluene, etc. Highlights from the past year are presented below that display some of the features of this program.

  15. Petroleum alteration by thermochemical sulfate reduction - A comprehensive molecular study of aromatic hydrocarbons and polar compounds

    NASA Astrophysics Data System (ADS)

    Walters, Clifford C.; Wang, Frank C.; Qian, Kuangnan; Wu, Chunping; Mennito, Anthony S.; Wei, Zhibin

    2015-03-01

    Thermochemical sulfate reduction (TSR) alters petroleum composition as it proceeds towards the complete oxidation of hydrocarbons to CO2. The effects of TSR on the molecular and isotopic composition of volatile species are well known; however, the non-volatile higher molecular weight aromatic and polar species have not been well documented. To address this deficiency, a suite of onshore Gulf coast oils and condensates generated from and accumulating in Smackover carbonates was assembled to include samples that experienced varying levels of TSR alteration and in reservoir thermal cracking. The entire molecular composition of aromatic hydrocarbons and NSO species were characterized and semi-quantified using comprehensive GC × GC (FID and CSD) and APPI-FTICR-MS. The concentration of thiadiamondoids is a reliable indicator of the extent of TSR alteration. Once generated by TSR, thiadiamondoids remain thermally stable in all but the most extreme reservoir temperatures (>180 °C). Hydrocarbon concentrations and distributions are influenced by thermal cracking and TSR. With increasing TSR alteration, oils become enriched in monoaromatic hydrocarbons and the distribution of high molecular weight aromatic hydrocarbons shifts towards more condensed species with a decrease in the number of alkyl carbons. Organosulfur compounds are created by the TSR process. In addition to the increase in benzothiophenes and dibenzothiophenes noted in previous studies, TSR generates condensed species containing one or more sulfur atoms that likely are composed of a single or multiple thiophenic cores. We hypothesize that these species are generated from the partial oxidation of PAHs and dealkylation reactions, followed by sulfur incorporation and condensation reactions. The organosulfur species remaining in the TSR altered oils are "proto-solid bitumen" moieties that upon further condensation, oxidation or sulfur incorporation result in highly sulfur enriched solid bitumen, which is

  16. Mephedrone alters basal ganglia and limbic dynorphin systems

    PubMed Central

    German, Christopher L.; Alburges, Mario E.; Hoonakker, Amanda J.; Fleckenstein, Annette E.; Hanson, Glen R.

    2014-01-01

    Mephedrone (4-methymethcathinone) is a synthetic cathinone designer drug that disrupts central nervous system (CNS) dopamine (DA) signaling. Numerous central neuropeptide systems reciprocally interact with dopaminergic neurons to provide regulatory counterbalance, and are altered by aberrant DA activity associated with stimulant exposure. Endogenous opioid neuropeptides are highly concentrated within dopaminergic CNS regions and facilitate many rewarding and aversive properties associated with drug use. Dynorphin, an opioid neuropeptide and kappa receptor agonist, causes dysphoria and aversion to drug consumption through signaling within the basal ganglia and limbic systems, which is affected by stimulants. This study evaluated how mephedrone alters basal ganglia and limbic system dynorphin content, and the role of DA signaling in these changes. Repeated mephedrone administrations (4 × 25 mg/kg/injection, 2-h intervals) selectively increased dynorphin content throughout the dorsal striatum and globus pallidus, decreased dynorphin content within the frontal cortex, and did not alter dynorphin content within most limbic system structures. Pre-treatment with D1-like (SCH-23380) or D2-like (eticlopride) antagonists blocked mephedrone-induced changes in dynorphin content in most regions examined, indicating altered dynorphin activity is a consequence of excessive DA signaling. PMID:25155699

  17. Gravity-induced cellular and molecular processes in plants studied under altered gravity conditions

    NASA Astrophysics Data System (ADS)

    Vagt, Nicole; Braun, Markus

    -rupting the actomyosin system did not impair the sedimentation of statoliths and did not prevent the activation of gravireceptors. However, experiments in microgravity and inhibitor experiments have demonstrated that the actomyosin system optimizes the statolith-receptor interactions by keeping the sedimented statoliths in motion causing a consistent activation of different gravireceptor molecules. Thereby, a triggered gravitropic signal is created which is the basis for a highly sensitive control and readjustment mechanism. In addition, the results of recent parabolic flight studies on the effects of altered gravity conditions on the gene expres-sion pattern of Arabidopsis seedlings support these findings and provide new insight into the molecular basis of the plants response to different acceleration conditions. The work was financially supported by DLR on behalf of Bundesministerium für Wirtschaft und Technologie (50WB0815).

  18. Novel molecular events associated with altered steroidogenesis induced by exposure to atrazine in the intact and castrate male rat

    EPA Science Inventory

    Toxicology is increasingly focused on molecular events comprising adverse outcome pathways. Atrazine activates the hypothalamic-pituitary adrenal axis, but relationships to gonadal alterations are unknown. We characterized hormone profiles and adrenal (intact and castrate) and te...

  19. Effect of lipid bilayer alteration on transdermal delivery of a high-molecular-weight and lipophilic drug: studies with paclitaxel.

    PubMed

    Panchagnula, Ramesh; Desu, Hariraghuram; Jain, Amit; Khandavilli, Sateesh

    2004-09-01

    Skin forms an excellent barrier against drug permeation, due to the rigid lamellar structure of the stratum corneum (SC) lipids. Poor permeability of drugs can be enhanced through alteration in partition and diffusion coefficients, or concentration gradient of drug with an appropriate choice of solvent system, along with penetration enhancers. The aim of the current investigation was to assess applicability of lipid bilayer alteration by fatty acids and terpenes toward the permeation enhancement of a high-molecular-weight, lipophilic drug, paclitaxel (PCL) through rat skin. From among the fatty acids studied using ethanol/isopropyl myristate (1:1) vehicle, no significant enhancement in flux of PCL was observed (p > 0.05). In the case of cis mono and polyunsaturated fatty acids lag time was found to be similar to control (p > 0.05). This suggests that the permeation of a high-molecular-weight, lipophilic drug may not be enhanced by the alteration of the lipid bilayer, or the main barrier to permeation could lie in lower hydrophilic layers of skin. A significant increase in lag time was observed with trans unsaturated fatty acids unlike the cis isomers, and this was explained on the basis of conformation and preferential partitioning of fatty acids into skin. From among the terpenes, flux of PCL with cineole was significantly different from other studied terpenes and controls, and after treatment with menthol and menthone permeability was found to be reduced. Menthol and menthone cause loosening of the SC lipid bilayer due to breaking of hydrogen bonding between ceramides, resulting in penetration of water into the lipids of the SC lipid bilayer that leads to creation of new aqueous channels and is responsible for increased hydrophilicity of SC. This increased hydrophilicity of the SC bilayer might have resulted in unfavorable conditions for ethanol/isopropyl myristate (1:1) along with PCL to penetrate into skin, therefore permeability was reduced. The findings of

  20. Molecular Substrate Alteration by Solar Wind Radiation Documented on Flown Genesis Mission Array Materials

    NASA Technical Reports Server (NTRS)

    Calaway, Michael J.; Stansbery, Eileen K.

    2006-01-01

    The Genesis spacecraft sampling arrays were exposed to various regimes of solar wind during flight that included: 313.01 days of high-speed wind from coronal holes, 335.19 days of low-speed inter-stream wind, 191.79 days of coronal mass ejections, and 852.83 days of bulk solar wind at Lagrange 1 orbit. Ellipsometry measurements taken at NASA s Johnson Space Center show that all nine flown array materials from the four Genesis regimes have been altered by solar wind exposure during flight. These measurements show significant changes in the optical constant for all nine ultra-pure materials that flew on Genesis when compared with their non-flight material standard. This change in the optical constant (n and k) of the material suggests that the molecular structure of the all nine ultra-pure materials have been altered by solar radiation. In addition, 50 samples of float-zone and czochralski silicon bulk array ellipsometry results were modeled with an effective medium approximation layer (EMA substrate layer) revealing a solar radiation molecular damage zone depth below the SiO2 native oxide layer ranging from 392 to 613 . This bulk solar wind radiation penetration depth is comparable to the depth of solar wind implantation depth of Mg measured by SIMS and SARISA.

  1. Dynamical Localization in Molecular Systems.

    NASA Astrophysics Data System (ADS)

    Wang, Xidi

    In the first four chapters of this thesis we concentrate on the Davydov model which describes the vibrational energy quanta of Amide I bonds (C=O bonds on the alpha -helix) coupled to the acoustic phonon modes of the alpha-helix backbone in the form of a Frohlich Hamiltonian. Following a brief introduction in chapter one, in chapter two we formulate the dynamics of vibrational quanta at finite temperature by using coherent state products. The fluctuation-dissipation relation is derived. At zero temperature, in the continuum limit, we recover the original results of Davydov. We also achieve good agreement with numerical simulations. In chapter three, the net contraction of the lattice is calculated exactly at any temperature, and its relation to the so -call "topological stability" of the Davydov soliton is discussed. In the second section of the chapter three we calculate the overtone spectra of crystalline acetanilide (according to some opinions ACN provides experimental evidence for the existence of Davydov solitons). Good agreement with experimental data has been obtained. In chapter four we study the self-trapped vibrational excitations by the Quantum Monte Carlo technique. For a single excitation, the temperature dependence of different physical observables is calculated. The quasi-particle which resembles the Davydov soliton has been found to be fairly narrow using the most commonly used data for the alpha -helix; at temperatures above a few Kelvin, the quasi-particle reaches its smallest limit (extends over three sites), which implies diffusive motion of the small polaron-like quasi-particle at high temperatures. For the multi-excitation case, bound pairs and clusters of excitations are found at low temperatures; they gradually dissociate when the temperature of the system is increased as calculated from the density-density correlation function. In the last chapter of this thesis, we study a more general model of dynamical local modes in molecular systems

  2. Molecular basis for T cell response induced by altered peptide ligand of type II collagen.

    PubMed

    Park, Jeoung-Eun; Cullins, David; Zalduondo, Lillian; Barnett, Stacey L; Yi, Ae-Kyung; Kleinau, Sandra; Stuart, John M; Kang, Andrew H; Myers, Linda K

    2012-06-01

    Mounting evidence from animal models has demonstrated that alterations in peptide-MHC interactions with the T cell receptor (TCR) can lead to dramatically different T cell outcomes. We have developed an altered peptide ligand of type II collagen, referred to as A9, which differentially regulates TCR signaling in murine T cells leading to suppression of arthritis in the experimental model of collagen-induced arthritis. This study delineates the T cell signaling pathway used by T cells stimulated by the A9·I-A(q) complex. We have found that T cells activated by A9 bypass the requirement for Zap-70 and CD3-ζ and signal via FcRγ and Syk. Using collagen-specific T cell hybridomas engineered to overexpress either Syk, Zap-70, TCR-FcRγ, or CD3-ζ, we demonstrate that A9·I-A(q) preferentially activates FcRγ/Syk but not CD3-ζ/Zap-70. Moreover, a genetic absence of Syk or FcRγ significantly reduces the altered peptide ligand induction of the nuclear factor GATA3. By dissecting the molecular mechanism of A9-induced T cell signaling we have defined a new alternate pathway that is dependent upon FcRγ and Syk to secrete immunoregulatory cytokines. Given the interest in using Syk inhibitors to treat patients with rheumatoid arthritis, understanding this pathway may be critical for the proper application of this therapy. PMID:22511761

  3. A novel multi-modal platform to image molecular and elemental alterations in ischemic stroke.

    PubMed

    Caine, Sally; Hackett, Mark J; Hou, Huishu; Kumar, Saroj; Maley, Jason; Ivanishvili, Zurab; Suen, Brandon; Szmigielski, Aleksander; Jiang, Zhongxiang; Sylvain, Nicole J; Nichol, Helen; Kelly, Michael E

    2016-07-01

    Stroke is a major global health problem, with the prevalence and economic burden predicted to increase due to aging populations in western society. Following stroke, numerous biochemical alterations occur and damage can spread to nearby tissue. This zone of "at risk" tissue is termed the peri-infarct zone (PIZ). As the PIZ contains tissue not initially damaged by the stroke, it is considered by many as salvageable tissue. For this reason, much research effort has been undertaken to improve the identification of the PIZ and to elucidate the biochemical mechanisms that drive tissue damage in the PIZ in the hope of identify new therapeutic targets. Despite this effort, few therapies have evolved, attributed in part, to an incomplete understanding of the biochemical mechanisms driving tissue damage in the PIZ. Magnetic resonance imaging (MRI) has long been the gold standard to study alterations in gross brain structure, and is frequently used to study the PIZ following stroke. Unfortunately, MRI does not have sufficient spatial resolution to study individual cells within the brain, and reveals little information on the biochemical mechanisms driving tissue damage. MRI results may be complemented with histology or immuno-histochemistry to provide information at the cellular or sub-cellular level, but are limited to studying biochemical markers that can be successfully "tagged" with a stain or antigen. However, many important biochemical markers cannot be studied with traditional MRI or histology/histochemical methods. Therefore, we have developed and applied a multi-modal imaging platform to reveal elemental and molecular alterations that could not previously be imaged by other traditional methods. Our imaging platform incorporates a suite of spectroscopic imaging techniques; Fourier transform infrared imaging, Raman spectroscopic imaging, Coherent anti-stoke Raman spectroscopic imaging and X-ray fluorescence imaging. This approach does not preclude the use of

  4. High Molecular Weight Barley β-Glucan Alters Gut Microbiota Toward Reduced Cardiovascular Disease Risk

    PubMed Central

    Wang, Yanan; Ames, Nancy P.; Tun, Hein M.; Tosh, Susan M.; Jones, Peter J.; Khafipour, Ehsan

    2016-01-01

    The physiological cholesterol-lowering benefits of β-glucan have been well documented, however, whether modulation of gut microbiota by β-glucan is associated with these physiological effects remains unknown. The objectives of this study were therefore to determine the impact of β-glucan on the composition of gut microbiota in mildly hypercholesterolemic individuals and to identify if the altered microbiota are associated with bioactivity of β-glucan in improving risk factors of cardiovascular disease (CVD). Using a randomized, controlled crossover study design, individuals received for 5-week either a treatment breakfast containing 3 g high molecular weight (HMW), 3 g low molecular weight (LMW), 5 g LMW barley β-glucan, or wheat and rice. The American Heart Association (AHA) diet served as the background diet for all treatment groups. Phases were separated by 4-week washout periods. Fecal samples were collected at the end of each intervention phase and subjected to Illumina sequencing of 16S rRNA genes. Results revealed that at the phylum level, supplementation of 3 g/d HMW β-glucan increased Bacteroidetes and decreased Firmicutes abundances compared to control (P < 0.001). At the genus level, consumption of 3 g/d HMW β-glucan increased Bacteroides (P < 0.003), tended to increase Prevotella (P < 0.1) but decreased Dorea (P < 0.1), whereas diets containing 5 g LMW β-glucan and 3 g LMW β-glucan failed to alter the gut microbiota composition. Bacteroides, Prevotella, and Dorea composition correlated (P < 0.05) with shifts of CVD risk factors, including body mass index, waist circumference, blood pressure, as well as triglyceride levels. Our data suggest that consumption of HMW β-glucan favorably alters the composition of gut microbiota and this altered microbiota profile associates with a reduction of CVD risk markers. Together, our study suggests that β-glucan induced shifts in gut microbiota in a MW-dependent manner and that might be one of the

  5. High Molecular Weight Barley β-Glucan Alters Gut Microbiota Toward Reduced Cardiovascular Disease Risk.

    PubMed

    Wang, Yanan; Ames, Nancy P; Tun, Hein M; Tosh, Susan M; Jones, Peter J; Khafipour, Ehsan

    2016-01-01

    The physiological cholesterol-lowering benefits of β-glucan have been well documented, however, whether modulation of gut microbiota by β-glucan is associated with these physiological effects remains unknown. The objectives of this study were therefore to determine the impact of β-glucan on the composition of gut microbiota in mildly hypercholesterolemic individuals and to identify if the altered microbiota are associated with bioactivity of β-glucan in improving risk factors of cardiovascular disease (CVD). Using a randomized, controlled crossover study design, individuals received for 5-week either a treatment breakfast containing 3 g high molecular weight (HMW), 3 g low molecular weight (LMW), 5 g LMW barley β-glucan, or wheat and rice. The American Heart Association (AHA) diet served as the background diet for all treatment groups. Phases were separated by 4-week washout periods. Fecal samples were collected at the end of each intervention phase and subjected to Illumina sequencing of 16S rRNA genes. Results revealed that at the phylum level, supplementation of 3 g/d HMW β-glucan increased Bacteroidetes and decreased Firmicutes abundances compared to control (P < 0.001). At the genus level, consumption of 3 g/d HMW β-glucan increased Bacteroides (P < 0.003), tended to increase Prevotella (P < 0.1) but decreased Dorea (P < 0.1), whereas diets containing 5 g LMW β-glucan and 3 g LMW β-glucan failed to alter the gut microbiota composition. Bacteroides, Prevotella, and Dorea composition correlated (P < 0.05) with shifts of CVD risk factors, including body mass index, waist circumference, blood pressure, as well as triglyceride levels. Our data suggest that consumption of HMW β-glucan favorably alters the composition of gut microbiota and this altered microbiota profile associates with a reduction of CVD risk markers. Together, our study suggests that β-glucan induced shifts in gut microbiota in a MW-dependent manner and that might be one of the

  6. Genetic and molecular alterations in pancreatic cancer: Implications for personalized medicine

    PubMed Central

    Fang, Yantian; Yao, Qizhi; Chen, Zongyou; Xiang, Jianbin; William, Fisher E.; Gibbs, Richard A.; Chen, Changyi

    2013-01-01

    Recent advances in human genomics and biotechnologies have profound impacts on medical research and clinical practice. Individual genomic information, including DNA sequences and gene expression profiles, can be used for prediction, prevention, diagnosis, and treatment for many complex diseases. Personalized medicine attempts to tailor medical care to individual patients by incorporating their genomic information. In a case of pancreatic cancer, the fourth leading cause of cancer death in the United States, alteration in many genes as well as molecular profiles in blood, pancreas tissue, and pancreas juice has recently been discovered to be closely associated with tumorigenesis or prognosis of the cancer. This review aims to summarize recent advances of important genes, proteins, and microRNAs that play a critical role in the pathogenesis of pancreatic cancer, and to provide implications for personalized medicine in pancreatic cancer. PMID:24172537

  7. Frequent HLA class I alterations in human prostate cancer: molecular mechanisms and clinical relevance.

    PubMed

    Carretero, Francisco Javier; Del Campo, Ana Belen; Flores-Martín, Jose Francisco; Mendez, Rosa; García-Lopez, Cesar; Cozar, Jose Manuel; Adams, Victoria; Ward, Stephen; Cabrera, Teresa; Ruiz-Cabello, Francisco; Garrido, Federico; Aptsiauri, Natalia

    2016-01-01

    Reduced expression of HLA class I is an important immune escape mechanism from cytotoxic T cells described in various types of malignancy. It often correlates with poor prognosis and resistance to therapy. However, current knowledge about the frequency, underlying molecular mechanisms, and prognostic value of HLA class I and II alterations in prostate cancer (PC) is limited. Immunohistochemical analysis demonstrated that 88 % of the 42 studied cryopreserved prostate tumors have at least one type of HLA alteration as compared to adjacent normal prostate epithelium or benign hyperplasia. Total loss of HLA-I expression found in 50 % of tumors showed an association with increased incidence of tumor relapse, perineural invasion, and high D'Amico risk. The remaining HLA-I-positive tumors demonstrated locus and allelic losses detected in 26 and 12 % of samples, respectively. Loss of heterozygosity at chromosome 6 was detected in 32 % of the studied tumors. Molecular analysis revealed a reduced expression of B2M, TAP2, tapasin and NLRC5 mRNA in microdissected HLA-I-negative tumors. Analysis of twelve previously unreported cell lines derived from neoplastic and normal epithelium of cancerous prostate revealed different types of HLA-I aberration, ranging from locus and/or allelic downregulation to a total absence of HLA-I expression. The high incidence of HLA-I loss observed in PC, caused by both regulatory and structural defects, is associated with more aggressive disease development and may pose a real threat to patient health by increasing cancer progression and resistance to T-cell-based immunotherapy. PMID:26611618

  8. Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport

    PubMed Central

    Arregi, Igor; Falces, Jorge; Olazabal-Herrero, Anne; Alonso-Mariño, Marián; Taneva, Stefka G.; Rodríguez, José A.; Urbaneja, María A.; Bañuelos, Sonia

    2015-01-01

    Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML), where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES). To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs), and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations. PMID:26091065

  9. Identification of significantly mutated regions across cancer types highlights a rich landscape of functional molecular alterations

    PubMed Central

    Araya, Carlos L.; Cenik, Can; Reuter, Jason A.; Kiss, Gert; Pande, Vijay S.; Snyder, Michael P.; Greenleaf, William J.

    2015-01-01

    Cancer sequencing studies have primarily identified cancer-driver genes by the accumulation of protein-altering mutations. An improved method would be annotation-independent, sensitive to unknown distributions of functions within proteins, and inclusive of non-coding drivers. We employed density-based clustering methods in 21 tumor types to detect variably-sized significantly mutated regions (SMRs). SMRs reveal recurrent alterations across a spectrum of coding and non-coding elements, including transcription factor binding sites and untranslated regions mutated in up to ∼15% of specific tumor types. SMRs reveal spatial clustering of mutations at molecular domains and interfaces, often with associated changes in signaling. Mutation frequencies in SMRs demonstrate that distinct protein regions are differentially mutated among tumor types, as exemplified by a linker region of PIK3CA in which biophysical simulations suggest mutations affect regulatory interactions. The functional diversity of SMRs underscores both the varied mechanisms of oncogenic misregulation and the advantage of functionally-agnostic driver identification. PMID:26691984

  10. Chronic ethanol intake leads to structural and molecular alterations in the rat endometrium.

    PubMed

    Martinez, Marcelo; Milton, Flora A; Pinheiro, Patricia Fernanda F; Almeida-Francia, Camila C D; Cagnon-Quitete, Valeria H A; Tirapelli, Luiz F; Padovani, Carlos Roberto; Chuffa, Luiz Gustavo A; Martinez, Francisco Eduardo

    2016-05-01

    We described the effects of low- and high-dose ethanol intake on the structure and apoptosis signaling of the uterine endometrium of UChA and UChB rats (animals with voluntary ethanol consumption). Thirty adult female rats, 90 days old, were divided into three groups (n = 10/group): UChA rats fed with 10% (v/v) ethanol ad libitum (free choice for water or ethanol) drinking < 1.9 g/kg/day; UChB rats fed with 10% (v/v) ethanol ad libitum (free choice for water or ethanol) drinking from 2 to 5 g/kg/day; control rats without ethanol (only water). After 120 days of treatment, rats displaying estrus were euthanized. Uterine epithelial cells of the UCh rats showed dilated cisterns of the rough endoplasmic reticulum, presence of lipid droplets, altered nuclear chromatin, and disrupted mitochondria. The UCh rats exhibited intense atrophied epithelial cells with smaller areas and perimeters of cytoplasm and nuclei. The endometrium of UChA rats showed higher levels of caspase-3 while Xiap and Bcl2 varied from moderate to weak. Both UChA and UChB rats exhibited a stronger immunoreaction to Ki-67 and IGFR-1 on epithelial and stromal cells. Chronic ethanol intake leads to structural and molecular alterations in the uterine endometrium of UCh rats, regardless of low- or high-dose consumption, promoting reproductive disorders. PMID:27139238

  11. Cross-cancer profiling of molecular alterations within the human autophagy interaction network

    PubMed Central

    Lebovitz, Chandra B; Robertson, A Gordon; Goya, Rodrigo; Jones, Steven J; Morin, Ryan D; Marra, Marco A; Gorski, Sharon M

    2015-01-01

    Aberrant activation or disruption of autophagy promotes tumorigenesis in various preclinical models of cancer, but whether the autophagy pathway is a target for recurrent molecular alteration in human cancer patient samples is unknown. To address this outstanding question, we surveyed 211 human autophagy-associated genes for tumor-related alterations to DNA sequence and RNA expression levels and examined their association with patient survival outcomes in multiple cancer types with sequence data from The Cancer Genome Atlas consortium. We found 3 (RB1CC1/FIP200, ULK4, WDR45/WIPI4) and one (ATG7) core autophagy genes to be under positive selection for somatic mutations in endometrial carcinoma and clear cell renal carcinoma, respectively, while 29 autophagy regulators and pathway interactors, including previously identified KEAP1, NFE2L2, and MTOR, were significantly mutated in 6 of the 11 cancer types examined. Gene expression analyses revealed that GABARAPL1 and MAP1LC3C/LC3C transcripts were less abundant in breast cancer and non-small cell lung cancers than in matched normal tissue controls; ATG4D transcripts were increased in lung squamous cell carcinoma, as were ATG16L2 transcripts in kidney cancer. Unsupervised clustering of autophagy-associated mRNA levels in tumors stratified patient overall survival in 3 of 9 cancer types (acute myeloid leukemia, clear cell renal carcinoma, and head and neck cancer). These analyses provide the first comprehensive resource of recurrently altered autophagy-associated genes in human tumors, and highlight cancer types and subtypes where perturbed autophagy may be relevant to patient overall survival. PMID:26208877

  12. Specific age-related molecular alterations in the cerebellum of Down syndrome mouse models.

    PubMed

    Créau, Nicole; Cabet, Eva; Daubigney, Fabrice; Souchet, Benoit; Bennaï, Soumia; Delabar, Jean

    2016-09-01

    Down syndrome, or trisomy 21, has been modeled with various trisomic and transgenic mice to help understand the consequences of an altered gene dosage in brain development and function. Though Down syndrome has been associated with premature aging, little is known about the molecular and cellular alterations that target brain function. To help identify alterations at specific ages, we analyzed the cerebellum of Ts1Cje mice, trisomic for 77 HSA21 orthologs, at three ages-young (4 months), middle-age (12 months), and old (17 months)-compared to age-matched controls. Quantification of neuronal and glial markers (n=11) revealed increases in GFAP, with an age effect, and S100B, with age and genotype effects. The genotype effect on S100B with age was unexpected as Ts1Cje has only two copies of the S100b gene. Interestingly, the different increase in GFAP observed between Ts1Cje (trisomic segment includes Pcp4 gene) and controls was magnified in TgPCP4 mice (1 extra copy of the human PCP4 gene) at the same age. S100B increase was not found in the TgPCP4 confirming a difference of regulation with aging for GFAP and S100B and excluding the calcium signaling regulator, Pcp4, as a potential candidate for increase of S100B in the Ts1Cje. To understand these differences, comparison of GFAP and S100B immunostainings at young and middle-age were performed. Immunohistochemical detection of differences in GFAP and S100B localization with aging implicate S100B+ oligodendrocytes as a new phenotypic target in this specific aging process. PMID:27297494

  13. Monocyte enhancers are highly altered in systemic lupus erythematosus

    PubMed Central

    Shi, Lihua; Zhang, Zhe; Song, Li; Leung, Yiu Tak; Petri, Michelle A; Sullivan, Kathleen E

    2015-01-01

    Objective: Histone modifications set transcriptional competency and can perpetuate pathologic expression patterns. We defined systemic lupus erythematosus (SLE)-specific changes in H3K4me3 and K3K27me3, histone marks of gene activation and repression, respectively. Methods: We used ChIP-seq to define histone modifications in monocytes from SLE patients and controls. Results: Both promoters and enhancers exhibited significant changes in histone methylation in SLE. Regions with differential H3K4me3 in SLE were significantly enriched in potential interferon-related transcription factor binding sites and pioneer transcription factor sites. Conclusion: Enhancer activation defines the character of the cell and our data support extensive disease effects in monocytes, a particularly plastic lineage. Type I interferons not only drive altered gene expression but may also alter the character of the cell through chromatin modifications. PMID:26442457

  14. Visualising the molecular alteration of the calcite (104) - water interface by sodium nitrate.

    PubMed

    Hofmann, Sascha; Voïtchovsky, Kislon; Spijker, Peter; Schmidt, Moritz; Stumpf, Thorsten

    2016-01-01

    The reactivity of calcite, one of the most abundant minerals in the earth's crust, is determined by the molecular details of its interface with the contacting solution. Recently, it has been found that trace concentrations of NaNO3 severely affect calcite's (104) surface and its reactivity. Here we combine molecular dynamics (MD) simulations, X-ray reflectivity (XR) and in situ atomic force microscopy (AFM) to probe the calcite (104) - water interface in the presence of NaNO3. Simulations reveal density profiles of different ions near calcite's surface, with NO3(-) able to reach closer to the surface than CO3(2-) and in higher concentrations. Reflectivity measurements show a structural destabilisation of the (104) surfaces' topmost atomic layers in NaNO3 bearing solution, with distorted rotation angles of the carbonate groups and substantial displacement of the lattice ions. Nanoscale AFM results confirm the alteration of crystallographic characteristics, and the ability of dissolved NaNO3 to modify the structure of interfacial water was observed by AFM force spectroscopy. Our experiments and simulations consistently evidence a dramatic deterioration of the crystals' surface, with potentially important implications for geological and industrial processes. PMID:26877225

  15. Visualising the molecular alteration of the calcite (104) - water interface by sodium nitrate

    NASA Astrophysics Data System (ADS)

    Hofmann, Sascha; Voïtchovsky, Kislon; Spijker, Peter; Schmidt, Moritz; Stumpf, Thorsten

    2016-02-01

    The reactivity of calcite, one of the most abundant minerals in the earth’s crust, is determined by the molecular details of its interface with the contacting solution. Recently, it has been found that trace concentrations of NaNO3 severely affect calcite’s (104) surface and its reactivity. Here we combine molecular dynamics (MD) simulations, X-ray reflectivity (XR) and in situ atomic force microscopy (AFM) to probe the calcite (104) - water interface in the presence of NaNO3. Simulations reveal density profiles of different ions near calcite’s surface, with NO3- able to reach closer to the surface than CO32- and in higher concentrations. Reflectivity measurements show a structural destabilisation of the (104) surfaces’ topmost atomic layers in NaNO3 bearing solution, with distorted rotation angles of the carbonate groups and substantial displacement of the lattice ions. Nanoscale AFM results confirm the alteration of crystallographic characteristics, and the ability of dissolved NaNO3 to modify the structure of interfacial water was observed by AFM force spectroscopy. Our experiments and simulations consistently evidence a dramatic deterioration of the crystals’ surface, with potentially important implications for geological and industrial processes.

  16. Molecular alterations in gastric cancer with special reference to the early-onset subtype

    PubMed Central

    Skierucha, Małgorzata; Milne, Anya NA; Offerhaus, G Johan A; Polkowski, Wojciech P; Maciejewski, Ryszard; Sitarz, Robert

    2016-01-01

    Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC. PMID:26937134

  17. Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer

    PubMed Central

    Nosho, Katsuhiko; Sukawa, Yasutaka; Adachi, Yasushi; Ito, Miki; Mitsuhashi, Kei; Kurihara, Hiroyoshi; Kanno, Shinichi; Yamamoto, Itaru; Ishigami, Keisuke; Igarashi, Hisayoshi; Maruyama, Reo; Imai, Kohzoh; Yamamoto, Hiroyuki; Shinomura, Yasuhisa

    2016-01-01

    The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6% (44/511), which was lower than that in United States cohort studies (13%). Similar to the United States studies, F. nucleatum positivity in Japanese colorectal cancers was significantly associated with microsatellite instability (MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets (i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain microRNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. MicroRNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in

  18. Alterations of miRNAs reveal a dysregulated molecular regulatory network in Parkinson's disease striatum.

    PubMed

    Nair, Venugopalan D; Ge, Yongchao

    2016-08-26

    Molecular adaptations in the striatum mediated by dopamine (DA) denervation and/or levodopa (L-dopa) treatments have been implicated in the motor deficits found in Parkinson's disease (PD). Alterations in inflammatory response mechanisms and glutamatergic neurotransmission are reported to play important roles in mediating these changes. However, the mechanisms mediating the molecular adaptations in the striatum are not well understood. Small non-coding microRNAs (miRNAs) influence numerous biological processes including the development and maintenance of striatal neurons by regulating gene expression post-transcriptionally. To investigate miRNA function in human PD striatum, we examined the global expression of miRNAs in postmortem putamen (putamen along with caudate forms the striatum) tissues obtained from PD patients and neurologically normal controls using Nanostring miRNA assays. We found that 6 miRNAs were significantly (p≤0.05) upregulated and 7 miRNAs were downregulated in PD putamen when compared with control. The differential expression (DE) of the 4 highest scoring miRNAs was further confirmed by reverse transcription polymerase chain reaction. Ingenuity pathway analysis demonstrated that these miRNAs are enriched in the processes of inflammatory responses. We found that the expression of DE miRNAs in PD putamen negatively correlates with the expression of gene transcripts implicated in inflammatory response with p53 and NF-kB as central signaling molecules. Taken together, our results suggest that in PD striatum, the DE miRNAs are associated with the oxidative stress pathway. This mechanism may contribute to the molecular adaptations and related motor complications found in PD. PMID:27369327

  19. Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review.

    PubMed

    Maverakis, Emanual; Kim, Kyoungmi; Shimoda, Michiko; Gershwin, M Eric; Patel, Forum; Wilken, Reason; Raychaudhuri, Siba; Ruhaak, L Renee; Lebrilla, Carlito B

    2015-02-01

    Herein we will review the role of glycans in the immune system. Specific topics covered include: the glycosylation sites of IgE, IgM, IgD, IgE, IgA, and IgG; how glycans can encode "self" identity by functioning as either danger associated molecular patterns (DAMPs) or self-associated molecular patterns (SAMPs); the role of glycans as markers of protein integrity and age; how the glycocalyx can dictate the migration pattern of immune cells; and how the combination of Fc N-glycans and Ig isotype dictate the effector function of immunoglobulins. We speculate that the latter may be responsible for the well-documented association between alterations of the serum glycome and autoimmunity. Due to technological limitations, the extent of these autoimmune-associated glycan alterations and their role in disease pathophysiology has not been fully elucidated. Thus, we also review the current technologies available for glycan analysis, placing an emphasis on Multiple Reaction Monitoring (MRM), a rapid high-throughput technology that has great potential for glycan biomarker research. Finally, we put forth The Altered Glycan Theory of Autoimmunity, which states that each autoimmune disease will have a unique glycan signature characterized by the site-specific relative abundances of individual glycan structures on immune cells and extracellular proteins, especially the site-specific glycosylation patterns of the different immunoglobulin(Ig) classes and subclasses. PMID:25578468

  20. Chronic Morphine Alters the Presynaptic Protein Profile: Identification of Novel Molecular Targets Using Proteomics and Network Analysis

    PubMed Central

    Abul-Husn, Noura S.; Annangudi, Suresh P.; Ma'ayan, Avi; Ramos-Ortolaza, Dinah L.; Stockton, Steven D.; Gomes, Ivone; Sweedler, Jonathan V.; Devi, Lakshmi A.

    2011-01-01

    Opiates produce significant and persistent changes in synaptic transmission; knowledge of the proteins involved in these changes may help to understand the molecular mechanisms underlying opiate dependence. Using an integrated quantitative proteomics and systems biology approach, we explored changes in the presynaptic protein profile following a paradigm of chronic morphine administration that leads to the development of dependence. For this, we isolated presynaptic fractions from the striata of rats treated with saline or escalating doses of morphine, and analyzed the proteins in these fractions using differential isotopic labeling. We identified 30 proteins that were significantly altered by morphine and integrated them into a protein-protein interaction (PPI) network representing potential morphine-regulated protein complexes. Graph theory-based analysis of this network revealed clusters of densely connected and functionally related morphine-regulated clusters of proteins. One of the clusters contained molecular chaperones thought to be involved in regulation of neurotransmission. Within this cluster, cysteine-string protein (CSP) and the heat shock protein Hsc70 were downregulated by morphine. Interestingly, Hsp90, a heat shock protein that normally interacts with CSP and Hsc70, was upregulated by morphine. Moreover, treatment with the selective Hsp90 inhibitor, geldanamycin, decreased the somatic signs of naloxone-precipitated morphine withdrawal, suggesting that Hsp90 upregulation at the presynapse plays a role in the expression of morphine dependence. Thus, integration of proteomics, network analysis, and behavioral studies has provided a greater understanding of morphine-induced alterations in synaptic composition, and identified a potential novel therapeutic target for opiate dependence. PMID:22043286

  1. Molecular mechanisms of hypoxia-inducible factor-induced pulmonary arterial smooth muscle cell alterations in pulmonary hypertension.

    PubMed

    Veith, Christine; Schermuly, Ralph T; Brandes, Ralf P; Weissmann, Norbert

    2016-03-01

    Oxygen (O2) is essential for the viability and function of most metazoan organisms and thus is closely monitored at both the organismal and the cellular levels. However, alveoli often encounter decreased O2 levels (hypoxia), leading to activation of physiological or pathophysiological responses in the pulmonary arteries. Such changes are achieved by activation of transcription factors. The hypoxia-inducible factors (HIFs) are the most prominent hypoxia-regulated transcription factors in this regard. HIFs bind to hypoxia-response elements (HREs) in the promoter region of target genes, whose expression and translation allows the organism, amongst other factors, to cope with decreased environmental O2 partial pressure (pO2). However, prolonged HIF activation can contribute to major structural alterations, especially in the lung, resulting in the development of pulmonary hypertension (PH). PH is characterized by a rise in pulmonary arterial pressure associated with pulmonary arterial remodelling, concomitant with a reduced intravascular lumen area. Patients with PH develop right heart hypertrophy and eventually die from right heart failure. Thus, understanding the molecular mechanisms of HIF regulation in PH is critical for the identification of novel therapeutic strategies. This review addresses the relationship of hypoxia and the HIF system with pulmonary arterial dysfunction in PH. We particularly focus on the cellular and molecular mechanisms underlying the HIF-driven pathophysiological processes. PMID:26228924

  2. Integrative genomics identifies molecular alterations that challenge the linear model of melanoma progression.

    PubMed

    Rose, Amy E; Poliseno, Laura; Wang, Jinhua; Clark, Michael; Pearlman, Alexander; Wang, Guimin; Vega Y Saenz de Miera, Eleazar C; Medicherla, Ratna; Christos, Paul J; Shapiro, Richard; Pavlick, Anna; Darvishian, Farbod; Zavadil, Jiri; Polsky, David; Hernando, Eva; Ostrer, Harry; Osman, Iman

    2011-04-01

    Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathologic, and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (6.0; Affymetrix) with gene expression array (U133A 2.0; Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N = 114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, and ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P < 0.05; Spearman's rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene MTAP (methylthioadenosine phosphorylase) in SSM resulted in reduced cell growth. The differential expression of another metabolic-related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level by using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM. PMID:21343389

  3. Physiological and molecular alterations in plants exposed to high [CO2] under phosphorus stress.

    PubMed

    Pandey, Renu; Zinta, Gaurav; AbdElgawad, Hamada; Ahmad, Altaf; Jain, Vanita; Janssens, Ivan A

    2015-01-01

    Atmospheric [CO2] has increased substantially in recent decades and will continue to do so, whereas the availability of phosphorus (P) is limited and unlikely to increase in the future. P is a non-renewable resource, and it is essential to every form of life. P is a key plant nutrient controlling the responsiveness of photosynthesis to [CO2]. Increases in [CO2] typically results in increased biomass through stimulation of net photosynthesis, and hence enhance the demand for P uptake. However, most soils contain low concentrations of available P. Therefore, low P is one of the major growth-limiting factors for plants in many agricultural and natural ecosystems. The adaptive responses of plants to [CO2] and P availability encompass alterations at morphological, physiological, biochemical and molecular levels. In general low P reduces growth, whereas high [CO2] enhances it particularly in C3 plants. Photosynthetic capacity is often enhanced under high [CO2] with sufficient P supply through modulation of enzyme activities involved in carbon fixation such as ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). However, high [CO2] with low P availability results in enhanced dry matter partitioning towards roots. Alterations in below-ground processes including root morphology, exudation and mycorrhizal association are influenced by [CO2] and P availability. Under high P availability, elevated [CO2] improves the uptake of P from soil. In contrast, under low P availability, high [CO2] mainly improves the efficiency with which plants produce biomass per unit P. At molecular level, the spatio-temporal regulation of genes involved in plant adaptation to low P and high [CO2] has been studied individually in various plant species. Genome-wide expression profiling of high [CO2] grown plants revealed hormonal regulation of biomass accumulation through complex transcriptional networks. Similarly, differential transcriptional regulatory networks are involved in P

  4. Molecular dynamics simulations of norcamphor-cytochrome P-450 sub cam and mutations of P-450 sub cam designed to alter the product specificity

    SciTech Connect

    Bass, M.B.; Paulsen, M.D.; Ornstein, R.L.

    1991-07-01

    Molecular dynamics simulations were performed to investigate the possibility of altering the product specificity of cytochrome P-450{sub cam}. The design aims were to alter the product ratios of norcamphor to yield predominately 3-hydroxynorcamphor and to increase the coupling efficiency between NADH consumption and product formation. Two simulations of P-450{sub cam} mutations, Y96F and V247A, were conducted to test the predictive ability of the molecular dynamics simulations with this enzyme-substrate system. The theoretical results agree with the experimental results. Two further mutations were simulated: F87W and the double mutant F87W/Y96F. The results from these novel mutations suggest that the coupling of electron consumption to substrate hydroxylation can be increased. Further these mutations lead to substrate orientations which are consistent with substrate hydroxylation at the 3-position. 8 refs., 2 figs., 2 tabs.

  5. [Metastasis tumors of the central nervous system: molecular biology].

    PubMed

    Bello, M Josefa; González-Gómez, P; Rey, J A

    2004-12-01

    Metastases in the nervous system represent an important and growing problem in the clinical practice, being the cause of a great mortality in the developed countries. This article reviews the few data available on the molecular mechanisms involved in the pathogenesis of these tumours, leading to oncogene activation, inactivation of tumour suppressor genes, not only by the classical mechanisms, but also by the tumour cell epigenetic balance alteration. We conclude that all this knowledge will lead in the future to a better diagnosis, treatment and clinic evolution of these patients. PMID:15632995

  6. DNA methylation and gene deletion analysis of brain metastases in melanoma patients identifies mutually exclusive molecular alterations

    PubMed Central

    Marzese, Diego M.; Scolyer, Richard A.; Roqué, Maria; Vargas-Roig, Laura M.; Huynh, Jamie L.; Wilmott, James S.; Murali, Rajmohan; Buckland, Michael E.; Barkhoudarian, Garni; Thompson, John F.; Morton, Donald L.; Kelly, Daniel F.; Hoon, Dave S. B.

    2014-01-01

    Background The brain is a common target of metastases for melanoma patients. Little is known about the genetic and epigenetic alterations in melanoma brain metastases (MBMs). Unraveling these molecular alterations is a key step in understanding their aggressive nature and identifying novel therapeutic targets. Methods Genome-wide DNA methylation analyses of MBMs (n = 15) and normal brain tissues (n = 91) and simultaneous multigene DNA methylation and gene deletion analyses of metastatic melanoma tissues (99 MBMs and 43 extracranial metastases) were performed. BRAF and NRAS mutations were evaluated in MBMs by targeted sequencing. Results MBMs showed significant epigenetic heterogeneity. RARB, RASSF1, ESR1, APC, PTEN, and CDH13 genes were frequently hypermethylated. Deletions were frequently detected in the CDKN2A/B locus. Of MBMs, 46.1% and 28.8% had BRAF and NRAS missense mutations, respectively. Compared with lung and liver metastases, MBMs exhibited higher frequency of CDH13 hypermethylation and CDKN2A/B locus deletion. Mutual exclusivity between hypermethylated genes and CDKN2A/B locus deletion identified 2 clinically relevant molecular subtypes of MBMs. CDKN2A/B deletions were associated with multiple MBMs and frequently hypermethylated genes with shorter time to brain metastasis. Conclusions Melanoma cells that colonize the brain harbor numerous genetically and epigenetically altered genes. This study presents an integrated genomic and epigenomic analysis that reveals MBM-specific molecular alterations and mutually exclusive molecular subtypes. PMID:24968695

  7. Method of molecular specie alteration by nonresonant laser induced dielectric breakdown

    DOEpatents

    Ronn, Avigdor M.

    1980-01-01

    Irradiation of a molecular specie by itself or in the presence of a secondary material at a pressure above a threshold value for the particular system by a laser of predetermined minimum power and having a frequency displaced from an absorption line of the specie causes severance of the weakest bond and a yield of products containing at least one dissociative fragment from said specie. A Rogowski type TEA CO.sub.2 --N.sub.2 --He laser has been used successfully on a wide variety of molecular species. Solid, liquid and gaseous end products have been obtained depending upon the starting materials. When solids have been produced they are in the form of microfine particles or microfine aggregates. A neodymium glass laser has also been used successfully.

  8. Reaction dynamics in polyatomic molecular systems

    SciTech Connect

    Miller, W.H.

    1993-12-01

    The goal of this program is the development of theoretical methods and models for describing the dynamics of chemical reactions, with specific interest for application to polyatomic molecular systems of special interest and relevance. There is interest in developing the most rigorous possible theoretical approaches and also in more approximate treatments that are more readily applicable to complex systems.

  9. Long-Term Oil Contamination Alters the Molecular Ecological Networks of Soil Microbial Functional Genes.

    PubMed

    Liang, Yuting; Zhao, Huihui; Deng, Ye; Zhou, Jizhong; Li, Guanghe; Sun, Bo

    2016-01-01

    With knowledge on microbial composition and diversity, investigation of within-community interactions is a further step to elucidate microbial ecological functions, such as the biodegradation of hazardous contaminants. In this work, microbial functional molecular ecological networks were studied in both contaminated and uncontaminated soils to determine the possible influences of oil contamination on microbial interactions and potential functions. Soil samples were obtained from an oil-exploring site located in South China, and the microbial functional genes were analyzed with GeoChip, a high-throughput functional microarray. By building random networks based on null model, we demonstrated that overall network structures and properties were significantly different between contaminated and uncontaminated soils (P < 0.001). Network connectivity, module numbers, and modularity were all reduced with contamination. Moreover, the topological roles of the genes (module hub and connectors) were altered with oil contamination. Subnetworks of genes involved in alkane and polycyclic aromatic hydrocarbon degradation were also constructed. Negative co-occurrence patterns prevailed among functional genes, thereby indicating probable competition relationships. The potential "keystone" genes, defined as either "hubs" or genes with highest connectivities in the network, were further identified. The network constructed in this study predicted the potential effects of anthropogenic contamination on microbial community co-occurrence interactions. PMID:26870020

  10. Molecular and kinetic alterations of muscle AMP deaminase during chronic creatine depletion.

    PubMed

    Rush, J W; Tullson, P C; Terjung, R L

    1998-02-01

    We examined a possible mechanism to account for the maintenance of peak AMP deamination rate in fast-twitch muscle of rats fed the creatine analog beta-guanidinopropionic acid (beta-GPA), in spite of reduced abundance of the enzyme AMP deaminase (AMPD). AMPD enzymatic capacity (determined at saturating AMP concentration) and AMPD protein abundance (Western blot) were coordinately reduced approximately 80% in fast-twitch white gastrocnemius muscle by beta-GPA feeding over 7 wk. Kinetic analysis of AMPD in the soluble cell fraction demonstrated a single Michaelis-Menten constant (Km; approximately 1.5 mM) in control muscle extracts. An additional high-affinity Km (approximately 0.03 mM) was revealed at low AMP concentrations in extracts of beta-GPA-treated muscle. The kinetic alteration in AMPD reflects increased molecular activity at low AMP concentrations; this could account for high rates of deamination in beta-GPA-treated muscle in situ, despite the loss of AMPD enzyme protein. The elimination of this kinetic effect by treatment of beta-GPA-treated muscle extracts with acid phosphatase in vitro suggests that phosphorylation is involved in the kinetic control of skeletal muscle AMPD in vivo. PMID:9486137

  11. Correlation of Histologic Subtypes and Molecular Alterations in Pulmonary Adenocarcinoma: Therapeutic and Prognostic Implications.

    PubMed

    Kim, Jiyoon; Jang, Se Jin; Choi, Chang Min; Ro, Jae Y

    2016-09-01

    Major driver mutations of pulmonary adenocarcinomas have been identified and highlighted as actionable targets for precision cancer medicine. As phenotype is largely determined by genotype, genetic changes associated with morphologic features have recently received more attention from both pathologists and clinicians. The morphologic features of adenocarcinomas with mutations in EGFR or KRAS, or translocated ALK, have rarely been described. Pulmonary adenocarcinomas with EGFR mutations, the most common driver mutation encountered in Asian patients with pulmonary adenocarcinoma, show lepidic or papillary organotypic growth patterns. KRAS-mutated adenocarcinomas demonstrate nonorganotypic growth patterns, especially mucin-containing cells. P53 mutations are associated with aggressiveness rather than growth patterns. HER2 mutations are observed in mucinous adenocarcinoma and adenocarcinoma with micropapillary features. The histologic features of BRAF-mutated adenocarcinomas have not yet been established, but papillary, lepidic, solid, and acinar patterns have been observed. Adenocarcinomas with rearrangement of ALK, ROS1, and RET genes share similar histologic features, such as solid signet-ring cells and cribriform formation. However, adenocarcinomas with NRG1 rearrangements frequently show mucinous morphology. The histologic features and related mutations of adenocarcinomas with expression of programmed cell death-1 and programmed cell death ligands-1 may be helpful in guiding immunotherapeutic treatment. This review describes histopathologic features of adenocarcinomas and their correlation with molecular alterations. PMID:27403614

  12. Long-Term Oil Contamination Alters the Molecular Ecological Networks of Soil Microbial Functional Genes

    PubMed Central

    Liang, Yuting; Zhao, Huihui; Deng, Ye; Zhou, Jizhong; Li, Guanghe; Sun, Bo

    2016-01-01

    With knowledge on microbial composition and diversity, investigation of within-community interactions is a further step to elucidate microbial ecological functions, such as the biodegradation of hazardous contaminants. In this work, microbial functional molecular ecological networks were studied in both contaminated and uncontaminated soils to determine the possible influences of oil contamination on microbial interactions and potential functions. Soil samples were obtained from an oil-exploring site located in South China, and the microbial functional genes were analyzed with GeoChip, a high-throughput functional microarray. By building random networks based on null model, we demonstrated that overall network structures and properties were significantly different between contaminated and uncontaminated soils (P < 0.001). Network connectivity, module numbers, and modularity were all reduced with contamination. Moreover, the topological roles of the genes (module hub and connectors) were altered with oil contamination. Subnetworks of genes involved in alkane and polycyclic aromatic hydrocarbon degradation were also constructed. Negative co-occurrence patterns prevailed among functional genes, thereby indicating probable competition relationships. The potential “keystone” genes, defined as either “hubs” or genes with highest connectivities in the network, were further identified. The network constructed in this study predicted the potential effects of anthropogenic contamination on microbial community co-occurrence interactions. PMID:26870020

  13. Drug-induced and genetic alterations in stress-responsive systems: Implications for specific addictive diseases.

    PubMed

    Zhou, Yan; Proudnikov, Dmitri; Yuferov, Vadim; Kreek, Mary Jeanne

    2010-02-16

    From the earliest work in our laboratory, we hypothesized, and with studies conducted in both clinical research and animal models, we have shown that drugs of abuse, administered or self-administered, on a chronic basis, profoundly alter stress-responsive systems. Alterations of expression of specific genes involved in stress responsivity, with increases or decreases in mRNA levels, receptor, and neuropeptide levels, and resultant changes in hormone levels, have been documented to occur after chronic intermittent exposure to heroin, morphine, other opiates, cocaine, other stimulants, and alcohol in animal models and in human molecular genetics. The best studied of the stress-responsive systems in humans and mammalian species in general is undoubtedly the HPA axis. In addition, there are stress-responsive systems in other parts in the brain itself, and some of these include components of the HPA axis, such as CRF and CRF receptors, along with POMC gene and gene products. Several other stress-responsive systems are known to influence the HPA axis, such as the vasopressin-vasopressin receptor system. Orexin-hypocretin, acting at its receptors, may effect changes which suggest that it should be properly categorized as a stress-responsive system. However, less is known about the interactions and connectivity of some of these different neuropeptide and receptor systems, and in particular, about the possible connectivity of fast-acting (e.g., glutamate and GABA) and slow-acting (including dopamine, serotonin, and norepinephrine) neurotransmitters with each of these stress-responsive components and the resultant impact, especially in the setting of chronic exposure to drugs of abuse. Several of these stress-responsive systems and components, primarily based on our laboratory-based and human molecular genetics research of addictive diseases, will be briefly discussed in this review. PMID:19914222

  14. Drug-induced and Genetic Alterations in Stress-Responsive Systems: Implications for Specific Addictive Diseases

    PubMed Central

    Zhou, Yan; Proudnikov, Dmitri; Yuferov, Vadim; Kreek, Mary Jeanne

    2009-01-01

    From the earliest work in our laboratory, we hypothesized, and with studies conducted in both clinical research and animal models, we have shown that drugs of abuse, administered or self-administered, on a chronic basis, profoundly alter stress-responsive systems. Alterations of expression of specific genes involved in stress responsivity, with increases or decreases in mRNA levels, receptor and neuropeptide levels, and resultant changes in hormone levels, have been documented to occur after chronic intermittent exposure to heroin, morphine, other opiates, cocaine, other stimulants and alcohol in animal models and in human molecular genetics. The best studied of the stress-responsive systems in humans and mammalian species in general is undoubtedly the HPA axis. In addition, there are stress-responsive systems in other parts in the brain itself, and some of these include components of the HPA axis, such as CRF and CRF receptors, along with POMC gene and gene products. Several other stress-responsive systems are known to influence the HPA axis, such as the vasopressin-vasopressin receptor system. Orexin-hypocretin, acting at its receptors, may effect changes which suggest that it should be properly categorized as a stress-responsive system. However, less is known about the interactions and connectivity of some of these different neuropeptide and receptor systems, and in particular, about the possible connectivity of fast-acting (e.g., glutamate and GABA) and slow-acting (including dopamine, serotonin and norepinephrine) neurotransmitters with each of these stress-responsive components and the resultant impact, especially in the setting of chronic exposure to drugs of abuse. Several of these stress-responsive systems and components, primarily based on our laboratory-based and human molecular genetics research of addictive diseases, will be briefly discussed in this review. PMID:19914222

  15. Method and Apparatus Providing Deception and/or Altered Operation in an Information System Operating System

    DOEpatents

    Cohen, Fred; Rogers, Deanna T.; Neagoe, Vicentiu

    2008-10-14

    A method and/or system and/or apparatus providing deception and/or execution alteration in an information system. In specific embodiments, deceptions and/or protections are provided by intercepting and/or modifying operation of one or more system calls of an operating system.

  16. Mephedrone alters basal ganglia and limbic neurotensin systems

    PubMed Central

    German, Christopher L.; Hoonakker, Amanda H.; Fleckenstein, Annette E.; Hanson, Glen R.

    2014-01-01

    Mephedrone (4-methylmethcathinone) is a synthetic cathinone designer drug that alters presynaptic dopamine (DA) activity like many psychostimulants. However, little is known about the postsynaptic dopaminergic impacts of mephedrone. The neuropeptide neurotensin (NT) provides inhibitory feedback for basal ganglia and limbic DA pathways, and postsynaptic D1-like and D2-like receptor activity affects NT tissue levels. This study evaluated how mephedrone alters basal ganglia and limbic system NT content and the role of NT receptor activation in drug consumption behavior. Four 25 mg/kg injections of mephedrone increased NT content in basal ganglia (striatum, substantia nigra and globus pallidus) and the limbic regions (nucleus accumbens core), while a lower dosage (5 mg/kg/injection) only increased striatal NT content. Mephedrone-induced increases in basal ganglia NT levels were mediated by D1-like receptors in the striatum and the substantia nigra by both D1-like and D2-like receptors in the globus pallidus. Mephedrone increased substance P content, another neuropeptide, in the globus pallidus, but not in the dorsal striatum or substantia nigra. Finally, the NT receptor agonist PD149163 blocked mephedrone self-administration, suggesting reduced NT release, as indicated by increased tissue levels, likely contributing to patterns of mephedrone consumption. PMID:24678634

  17. The sympathetic nervous system alterations in human hypertension.

    PubMed

    Grassi, Guido; Mark, Allyn; Esler, Murray

    2015-03-13

    Several articles have dealt with the importance and mechanisms of the sympathetic nervous system alterations in experimental animal models of hypertension. This review addresses the role of the sympathetic nervous system in the pathophysiology and therapy of human hypertension. We first discuss the strengths and limitations of various techniques for assessing the sympathetic nervous system in humans, with a focus on heart rate, plasma norepinephrine, microneurographic recording of sympathetic nerve traffic, and measurements of radiolabeled norepinephrine spillover. We then examine the evidence supporting the importance of neuroadrenergic factors as promoters and amplifiers of human hypertension. We expand on the role of the sympathetic nervous system in 2 increasingly common forms of secondary hypertension, namely hypertension associated with obesity and with renal disease. With this background, we examine interventions of sympathetic deactivation as a mode of antihypertensive treatment. Particular emphasis is given to the background and results of recent therapeutic approaches based on carotid baroreceptor stimulation and radiofrequency ablation of the renal nerves. PMID:25767284

  18. THE SYMPATHETIC NERVOUS SYSTEM ALTERATIONS IN HUMAN HYPERTENSION

    PubMed Central

    Grassi, Guido; Mark, Allyn; Esler, Murray

    2015-01-01

    A number of articles have dealt with the importance and mechanisms of the sympathetic nervous system alterations in experimental animal models of hypertension. This review addresses the role of the sympathetic nervous system in the pathophysiology and therapy of human hypertension. We first discuss the strengths and limitations of various techniques for assessing the sympathetic nervous system in humans, with a focus on heart rate, plasma norepinephrine, microneurographic recording of sympathetic nerve traffic, and measurements of radiolabeled norepinephrine spillover. We then examine the evidence supporting the importance of neuroadrenergic factors as “promoters” and “amplifiers” of human hypertension. We expand on the role of the sympathetic nervous system in two increasingly common forms of secondary hypertension, namely hypertension associated with obesity and with renal disease. With this background, we examine interventions of sympathetic deactivation as a mode of antihypertensive treatment. Particular emphasis is given to the background and results of recent therapeutic approaches based on carotid baroreceptor stimulation and radiofrequency ablation of the renal nerves. PMID:25767284

  19. Developing accurate molecular mechanics force fields for conjugated molecular systems.

    PubMed

    Do, Hainam; Troisi, Alessandro

    2015-10-14

    A rapid method to parameterize the intramolecular component of classical force fields for complex conjugated molecules is proposed. The method is based on a procedure of force matching with a reference electronic structure calculation. It is particularly suitable for those applications where molecular dynamics simulations are used to generate structures that are therefore analysed by electronic structure methods, because it is possible to build force fields that are consistent with electronic structure calculations that follow classical simulations. Such applications are commonly encountered in organic electronics, spectroscopy of complex systems and photobiology (e.g. photosynthetic systems). We illustrate the method by parameterizing the force fields of a molecule used in molecular semiconductors (2,2-dicyanovinyl-capped S,N-heteropentacene or DCV-SN5), a polymeric semiconductor (thieno[3,2-b]thiophene-diketopyrrolopyrrole TT-DPP) and a chromophore embedded in a protein environment (15,16-dihydrobiliverdin or DBV) where several hundreds of parameters need to be optimized in parallel. PMID:26349916

  20. Reduced sensory stimulation alters the molecular make-up of glutamatergic hair cell synapses in the developing cochlea.

    PubMed

    Barclay, M; Constable, R; James, N R; Thorne, P R; Montgomery, J M

    2016-06-14

    Neural activity during early development is known to alter innervation pathways in the central and peripheral nervous systems. We sought to examine how reduced sound-induced sensory activity in the cochlea affected the consolidation of glutamatergic synapses between inner hair cells (IHC) and the primary auditory neurons as these synapses play a primary role in transmitting sound information to the brain. A unilateral conductive hearing loss was induced prior to the onset of sound-mediated stimulation of the sensory hair cells, by rupturing the tympanic membrane and dislocating the auditory ossicles in the left ear of P11 mice. Auditory brainstem responses at P15 and P21 showed a 40-50-dB increase in thresholds for frequencies 8-32kHz in the dislocated ear relative to the control ear. Immunohistochemistry and confocal microscopy were subsequently used to examine the effect of this attenuation of sound stimulation on the expression of RIBEYE, which comprises the presynaptic ribbons, Shank-1, a postsynaptic scaffolding protein, and the GluA2/3 and 4 subunits of postsynaptic AMPA receptors. Our results show that dislocation did not alter the number of pre- or postsynaptic protein puncta. However, dislocation did increase the size of RIBEYE, GluA4, GluA2/3 and Shank-1 puncta, with postsynaptic changes preceding presynaptic changes. Our data suggest that a reduction in sound stimulation during auditory development induces plasticity in the molecular make-up of IHC glutamatergic synapses, but does not affect the number of these synapses. Up-regulation of synaptic proteins with sound attenuation may facilitate a compensatory increase in synaptic transmission due to the reduced sensory stimulation of the IHC. PMID:27012610

  1. Modulation by metformin of molecular and histopathological alterations in the lung of cigarette smoke-exposed mice.

    PubMed

    Izzotti, Alberto; Balansky, Roumen; D'Agostini, Francesco; Longobardi, Mariagrazia; Cartiglia, Cristina; Micale, Rosanna T; La Maestra, Sebastiano; Camoirano, Anna; Ganchev, Gancho; Iltcheva, Marietta; Steele, Vernon E; De Flora, Silvio

    2014-06-01

    The anti-diabetic drug metformin is endowed with anti-cancer properties. Epidemiological and experimental studies, however, did not provide univocal results regarding its role in pulmonary carcinogenesis. We used Swiss H mice of both genders in order to detect early molecular alterations and tumors induced by mainstream cigarette smoke. Based on a subchronic toxicity study, oral metformin was used at a dose of 800 mg/kg diet, which is 3.2 times higher than the therapeutic dose in humans. Exposure of mice to smoke for 4 months, starting at birth, induced a systemic clastogenic damage, formation of DNA adducts, oxidative DNA damage, and extensive downregulation of microRNAs in lung after 10 weeks. Preneoplastic lesions were detectable after 7.5 months in both lung and urinary tract along with lung tumors, both benign and malignant. Modulation by metformin of 42 of 1281 pulmonary microRNAs in smoke-free mice highlighted a variety of mechanisms, including modulation of AMPK, stress response, inflammation, NFκB, Tlr9, Tgf, p53, cell cycle, apoptosis, antioxidant pathways, Ras, Myc, Dicer, angiogenesis, stem cell recruitment, and angiogenesis. In smoke-exposed mice, metformin considerably decreased DNA adduct levels and oxidative DNA damage, and normalized the expression of several microRNAs. It did not prevent smoke-induced lung tumors but inhibited preneoplastic lesions in both lung and kidney. In conclusion, metformin was able to protect the mouse lung from smoke-induced DNA and microRNA alterations and to inhibit preneoplastic lesions in lung and kidney but failed to prevent lung adenomas and malignant tumors induced by this complex mixture. PMID:24683044

  2. Modulation by metformin of molecular and histopathological alterations in the lung of cigarette smoke-exposed mice

    PubMed Central

    Izzotti, Alberto; Balansky, Roumen; D'Agostini, Francesco; Longobardi, Mariagrazia; Cartiglia, Cristina; Micale, Rosanna T; La Maestra, Sebastiano; Camoirano, Anna; Ganchev, Gancho; Iltcheva, Marietta; Steele, Vernon E; De Flora, Silvio

    2014-01-01

    The anti-diabetic drug metformin is endowed with anti-cancer properties. Epidemiological and experimental studies, however, did not provide univocal results regarding its role in pulmonary carcinogenesis. We used Swiss H mice of both genders in order to detect early molecular alterations and tumors induced by mainstream cigarette smoke. Based on a subchronic toxicity study, oral metformin was used at a dose of 800 mg/kg diet, which is 3.2 times higher than the therapeutic dose in humans. Exposure of mice to smoke for 4 months, starting at birth, induced a systemic clastogenic damage, formation of DNA adducts, oxidative DNA damage, and extensive downregulation of microRNAs in lung after 10 weeks. Preneoplastic lesions were detectable after 7.5 months in both lung and urinary tract along with lung tumors, both benign and malignant. Modulation by metformin of 42 of 1281 pulmonary microRNAs in smoke-free mice highlighted a variety of mechanisms, including modulation of AMPK, stress response, inflammation, NFκB, Tlr9, Tgf, p53, cell cycle, apoptosis, antioxidant pathways, Ras, Myc, Dicer, angiogenesis, stem cell recruitment, and angiogenesis. In smoke-exposed mice, metformin considerably decreased DNA adduct levels and oxidative DNA damage, and normalized the expression of several microRNAs. It did not prevent smoke-induced lung tumors but inhibited preneoplastic lesions in both lung and kidney. In conclusion, metformin was able to protect the mouse lung from smoke-induced DNA and microRNA alterations and to inhibit preneoplastic lesions in lung and kidney but failed to prevent lung adenomas and malignant tumors induced by this complex mixture. PMID:24683044

  3. 32 CFR Appendix B to Part 323 - Criteria for New and Altered Record Systems

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... alterations. b. Increases in numbers of individuals due to normal growth are not considered alterations unless... scope of population covered (for example, expansion of a system of records covering a single...

  4. 32 CFR Appendix B to Part 323 - Criteria for New and Altered Record Systems

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... alterations. b. Increases in numbers of individuals due to normal growth are not considered alterations unless... scope of population covered (for example, expansion of a system of records covering a single...

  5. MOLECULAR BONDING SYSTEM - INNOVATIVE TECHNOLOGY EVALUATION REPORT

    EPA Science Inventory

    This document presents an evaluation of the Molecular Bonding System (MBS) and its ability to chemically stabilize three metals-contaminated wstes/soils during a SITe demo. The MBS process treated approximately 500 tons each of soil/Fill, Slag, and Miscellaneous Smelter Waste wit...

  6. Molecular Sieve Regeneration System for assaying HTO from detritiation systems

    SciTech Connect

    Nasise, J.E.; Anderson, J.L.; Naruse, Y.

    1992-07-01

    A Molecular Sieve Regeneration System (MSRS) is being added to the existing Tritium Waste Treatment system (TWT) within the Tritium Systems Test Assembly (TSTA) at the Los Alamos National Laboratory. This system is an upgrade to the TWT to provide accurate measurements of the liquid waste generated from this system. Within the TWT, hydrogen isotopes are removed from the effluent gas stream by the catalytic conversion to water and the subsequent removal of water by molecular sieve trapping prior to the release to the environment. Within the TWT and similar systems, molecular sieve regeneration is required to rejuvenate the beds. The major difference of the MSRS and other regeneration systems is the capability of direct assay of long-term storage waste containers. This is accomplished with loop-flow regeneration, water collection, and tritiated water assay by scintillation and calorimetric techniques. This paper describes the MSRS in detail and how it is interfaced with the Tritium Waste Treatment system.

  7. Molecular Sieve Regeneration System for assaying HTO from detritiation systems

    SciTech Connect

    Nasise, J.E.; Anderson, J.L. ); Naruse, Y. )

    1992-01-01

    A Molecular Sieve Regeneration System (MSRS) is being added to the existing Tritium Waste Treatment system (TWT) within the Tritium Systems Test Assembly (TSTA) at the Los Alamos National Laboratory. This system is an upgrade to the TWT to provide accurate measurements of the liquid waste generated from this system. Within the TWT, hydrogen isotopes are removed from the effluent gas stream by the catalytic conversion to water and the subsequent removal of water by molecular sieve trapping prior to the release to the environment. Within the TWT and similar systems, molecular sieve regeneration is required to rejuvenate the beds. The major difference of the MSRS and other regeneration systems is the capability of direct assay of long-term storage waste containers. This is accomplished with loop-flow regeneration, water collection, and tritiated water assay by scintillation and calorimetric techniques. This paper describes the MSRS in detail and how it is interfaced with the Tritium Waste Treatment system.

  8. Molecular-beam gas-sampling system

    NASA Technical Reports Server (NTRS)

    Young, W. S.; Knuth, E. L.

    1972-01-01

    A molecular beam mass spectrometer system for rocket motor combustion chamber sampling is described. The history of the sampling system is reviewed. The problems associated with rocket motor combustion chamber sampling are reported. Several design equations are presented. The results of the experiments include the effects of cooling water flow rates, the optimum separation gap between the end plate and sampling nozzle, and preliminary data on compositions in a rocket motor combustion chamber.

  9. Maternal bisphenol A alters fetal endocrine system: Thyroid adipokine dysfunction.

    PubMed

    Ahmed, R G

    2016-09-01

    Because bisphenol A (BPA) has been detected in animals, the aim of this study was to investigate the possible effects of maternal BPA exposure on the fetal endocrine system (thyroid-adipokine axis). BPA (20 or 40 μg/kg body weight) was orally administered to pregnant rats from gestation day (GD) 1-20. In both treated groups, the dams and their fetuses had lower serum thyroxine (T4) and triiodothyronine (T3) levels, and higher thyrotropin (TSH) level than control dams and fetuses at GD 20. Some histopathological changes in fetal thyroid glands were observed in both maternal BPA groups at embryonic day (ED) 20, including fibroblast proliferation, hyperplasia, luminal obliteration, oedema, and degeneration. These disorders resulted in the suppression of fetal serum growth hormone (GH), insulin growth factor-1 (IGF1) and adiponectin (ADP) levels, and the elevation of fetal serum leptin, insulin and tumor necrosis factor-alpha (TNFα) levels in both treated groups with respect to control. The depraved effects of both treated groups were associated with reduced maternal and fetal body weight compared to the control group. These alterations were dose dependent. Thus, BPA might penetrate the placental barrier and perturb the fetal thyroid adipokine axis to influence fat metabolism and the endocrine system. PMID:27326465

  10. Computational Hemodynamic Simulation of Human Circulatory System under Altered Gravity

    NASA Technical Reports Server (NTRS)

    Kim. Chang Sung; Kiris, Cetin; Kwak, Dochan

    2003-01-01

    A computational hemodynamics approach is presented to simulate the blood flow through the human circulatory system under altered gravity conditions. Numerical techniques relevant to hemodynamics issues are introduced to non-Newtonian modeling for flow characteristics governed by red blood cells, distensible wall motion due to the heart pulse, and capillary bed modeling for outflow boundary conditions. Gravitational body force terms are added to the Navier-Stokes equations to study the effects of gravity on internal flows. Six-type gravity benchmark problems are originally presented to provide the fundamental understanding of gravitational effects on the human circulatory system. For code validation, computed results are compared with steady and unsteady experimental data for non-Newtonian flows in a carotid bifurcation model and a curved circular tube, respectively. This computational approach is then applied to the blood circulation in the human brain as a target problem. A three-dimensional, idealized Circle of Willis configuration is developed with minor arteries truncated based on anatomical data. Demonstrated is not only the mechanism of the collateral circulation but also the effects of gravity on the distensible wall motion and resultant flow patterns.

  11. Molecular aging of the mammalian vestibular system.

    PubMed

    Brosel, Sonja; Laub, Christoph; Averdam, Anne; Bender, Andreas; Elstner, Matthias

    2016-03-01

    Dizziness and imbalance frequently affect the elderly and contribute to falls and frailty. In many geriatric patients, clinical testing uncovers a dysfunction of the vestibular system, but no specific etiology can be identified. Neuropathological studies have demonstrated age-related degeneration of peripheral and central vestibular neurons, but the molecular mechanisms are poorly understood. In contrast, recent studies into age-related hearing loss strongly implicate mitochondrial dysfunction, oxidative stress and apoptotic cell death of cochlear hair cells. While some data suggest that analogous biological pathomechanisms may underlie vestibular dysfunction, actual proof is missing. In this review, we summarize the available data on the molecular causes of vestibular dysfunction. PMID:26739358

  12. The impact of systemic cortical alterations on perception

    NASA Astrophysics Data System (ADS)

    Zhang, Zheng

    2011-12-01

    Perception is the process of transmitting and interpreting sensory information, and the primary somatosensory (SI) area in the human cortex is the main sensory receptive area for the sensation of touch. The elaborate neuroanatomical connectivity that subserves the neuronal communication between adjacent and near-adjacent regions within sensory cortex has been widely recognized to be essential to normal sensory function. As a result, systemic cortical alterations that impact the cortical regional interaction, as associated with many neurological disorders, are expected to have significant impact on sensory perception. Recently, our research group has developed a novel sensory diagnostic system that employs quantitative sensory testing methods and is able to non-invasively assess central nervous system healthy status. The intent of this study is to utilize quantitative sensory testing methods that were designed to generate discriminable perception to objectively and quantitatively assess the impacts of different conditions on human sensory information processing capacity. The correlation between human perceptions with observations from animal research enables a better understanding of the underlying neurophysiology of human perception. Additional findings on different subject populations provide valuable insight of the underlying mechanisms for the development and maintenance of different neurological diseases. During the course of the study, several protocols were designed and utilized. And this set of sensory-based perceptual metrics was employed to study the effects of different conditions (non-noxious thermal stimulation, chronic pain stage, and normal aging) on sensory perception. It was found that these conditions result in significant deviations of the subjects' tactile information processing capacities from normal values. Although the observed shift of sensory detection sensitivity could be a result of enhanced peripheral activity, the changes in the effects

  13. Relaxation time in disordered molecular systems

    SciTech Connect

    Rocha, Rodrigo P.; Freire, José A.

    2015-05-28

    Relaxation time is the typical time it takes for a closed physical system to attain thermal equilibrium. The equilibrium is brought about by the action of a thermal reservoir inducing changes in the system micro-states. The relaxation time is intuitively expected to increase with system disorder. We derive a simple analytical expression for this dependence in the context of electronic equilibration in an amorphous molecular system model. We find that the disorder dramatically enhances the relaxation time but does not affect its independence of the nature of the initial state.

  14. Statistical theory of plasma-molecular systems

    NASA Astrophysics Data System (ADS)

    Klimontovich, Yu. L.; Wilhelmsson, H.; Yakimenko, I. P.; Zagorodny, A. G.

    1989-04-01

    The basic principles of kinetic theory are formulated for combined plasma-molecular systems consisting of both free and bound charged particles. The description of the subsystem of bound particles is bassed on the classical model of atomic oscillators (this makes it impossible to take into account ionization and recombination processes, byt the general formalism is still quite useful). In the framework of such a model, collective electromagnetic processes in infinite and bounded plasma-molecular matter are studied. The influence of boundaries on the collision integrals, on the kinetic coefficients and on the space distributions of particles is investigated in detail. The theory of electromagnetic fluctuations in bounded plasma-molecular systems is developed as well. This theory is used to obtain the correlation functions of electron density fluctuations and spontaneous emission spectra. A numerical analysis of spontaneous emission spectra is presented for systems with plane-parallel boundaries. The generalization of the fluctuation theory of bremsstrahlung radiation in a plasma to the case of plasma-molecular matter is also discussed.

  15. Global detection of molecular changes reveals concurrent alteration of several biological pathways in nonsmall cell lung cancer cells

    PubMed Central

    Ju, Z.; Kapoor, M.; Newton, K; Cheon, K.; Ramaswamy, A.; Lotan, R.; Strong, L. C.; Koo, J. S.

    2006-01-01

    To identify the molecular changes that occur in non-small cell lung carcinoma (NSCLC), we compared the gene expression profile of the NCI-H292 (H292) NSCLC cell line with that of normal human tracheobronchial epithelial (NHTBE) cells. The NHTBE cells were grown in a three-dimensional organotypic culture system that permits maintenance of the normal pseudostratified mucociliary phenotype characteristic of bronchial epithelium in vivo. Microarray analysis using the Affymetrix oligonucleotide chip U95Av2 revealed that 1,683 genes showed a > 1.5-fold change in expression in the H292 cell line relative to the NHTBE cells. Specifically, 418 genes were downregulated and 1,265 were upregulated in the H292 cells. The expression data for selected genes were validated in several different NSCLC cell lines using quantitative real-time PCR and Western analysis. Further analysis of the differentially expressed genes indicated that WNT responses, apoptosis, cell cycle regulation and cell proliferation were significantly altered in the H292 cells. Functional analysis using fluorescence-activated cell sorting confirmed concurrent changes in the activity of these pathways in the H292 line. These findings show that (1) NSCLC cells display deregulation of the WNT, apoptosis, proliferation and cell cycle pathways, as has been found in many other types of cancer cells, and (2) that organotypically cultured NHTBE cells can be used as a reference to identify genes and pathways that are differentially expressed in tumor cells derived from bronchogenic epithelium. PMID:16049682

  16. Time-resolved optical imaging provides a molecular snapshot of altered metabolic function in living human cancer cell models

    NASA Astrophysics Data System (ADS)

    Sud, Dhruv; Zhong, Wei; Beer, David G.; Mycek, Mary-Ann

    2006-05-01

    A fluorescence lifetime imaging microscopy (FLIM) method was developed and applied to investigate metabolic function in living human normal esophageal (HET-1) and Barrett’s adenocarcinoma (SEG-1) cells. In FLIM, image contrast is based on fluorophore excited state lifetimes, which reflect local biochemistry and molecular activity. Unique FLIM system attributes, including variable ultrafast time gating (≥ 200 ps), wide spectral tunability (337.1 - 960 nm), large temporal dynamic range (≥ 600 ps), and short data acquisition and processing times (15 s), enabled the study of two key molecules consumed at the termini of the oxidative phosphorylation pathway, NADH and oxygen, in living cells under controlled and calibrated environmental conditions. NADH is an endogenous cellular fluorophore detectable in living human tissues that has been shown to be a quantitative biomarker of dysplasia in the esophagus. Lifetime calibration of an oxygen-sensitive, ruthenium-based cellular stain enabled in vivo oxygen level measurements with a resolution of 8 μM over the entire physiological range (1 - 300 μM). Starkly higher intracellular oxygen and NADH levels in living SEG-1 vs. HET-1 cells were detected by FLIM and attributed to altered metabolic pathways in malignant cells.

  17. Ischemic preconditioning affects long-term cell fate through DNA damage-related molecular signaling and altered proliferation.

    PubMed

    Kapoor, Sorabh; Berishvili, Ekaterine; Bandi, Sriram; Gupta, Sanjeev

    2014-10-01

    Despite the potential of ischemic preconditioning for organ protection, long-term effects in terms of molecular processes and cell fates are ill defined. We determined consequences of hepatic ischemic preconditioning in rats, including cell transplantation assays. Ischemic preconditioning induced persistent alterations; for example, after 5 days liver histology was normal, but γ-glutamyl transpeptidase expression was observed, with altered antioxidant enzyme content, lipid peroxidation, and oxidative DNA adducts. Nonetheless, ischemic preconditioning partially protected from toxic liver injury. Similarly, primary hepatocytes from donor livers preconditioned with ischemia exhibited undesirably altered antioxidant enzyme content and lipid peroxidation, but better withstood insults. However, donor hepatocytes from livers preconditioned with ischemia did not engraft better than hepatocytes from control livers. Moreover, proliferation of hepatocytes from donor livers preconditioned with ischemia decreased under liver repopulation conditions. Hepatocytes from donor livers preconditioned with ischemia showed oxidative DNA damage with expression of genes involved in MAPK signaling that impose G1/S and G2/M checkpoint restrictions, including p38 MAPK-regulated or ERK-1/2-regulated cell-cycle genes such as FOS, MAPK8, MYC, various cyclins, CDKN2A, CDKN2B, TP53, and RB1. Thus, although ischemic preconditioning allowed hepatocytes to better withstand secondary insults, accompanying DNA damage and molecular events simultaneously impaired their proliferation capacity over the long term. Mitigation of ischemic preconditioning-induced DNA damage and deleterious molecular perturbations holds promise for advancing clinical applications. PMID:25128377

  18. Molecular interactions alter clay and polymer structure in polymer clay nanocomposites.

    PubMed

    Sikdar, Debashis; Katti, Kalpana S; Katti, Dinesh R

    2008-04-01

    In this work, using photoacoustic Fourier transform infrared spectroscopy (FTIR) we have studied the structural distortion of clay crystal structure in organically modified montmorillonite (OMMT) and polymer clay nanocomposites (PCN). To study the effect of organic modifiers on the distortion of crystal structure of clay, we have synthesized OMMTs and PCNs containing same polymer and clay but with three different organic modifiers (12-aminolauric acid, n-dodecylamine, and 1,12-diaminododecane), and conducted the FTIR study on these PCNs. Our previous molecular dynamics (MD) study on these PCNs reveals that significant nonbonded interactions (van der Waals, electrostatic interactions) exist between the different constituents (polymer, organic modifier, and clay) of nanocomposites. Previous work based on X-ray diffraction (XRD) and differential scanning calorimetry (DSC) on the same set of PCNs shows that crystallinity of polymer in PCNs have changed significantly in comparison to those in pristine polymer; and, the nonbonded interactions between different constituents of PCN are responsible for the change in crystal structure of polymer in PCN. In this work to evaluate the structural distortion of crystal structure of clay in OMMTs and PCNs, the positions of bands corresponding to different modes of vibration of Si-O bonds are determined from the deconvolution of broad Si-O bands in OMMTs and PCNs obtained from FTIR spectra. Intensity and area under the Si-O bands are indicative of orientation of clay crystal structures in OMMTs and PCNs. Significant changes in the Si-O bands are observed from each vibration mode in OMMTs and PCNs containing three different organic modifiers indicating that organic modifiers influence the structural orientation of silica tetrahedra in OMMTs and PCNs. Deconvolution of Si-O bands in OMMTs indicate a band at approximately 1200 cm(-1) that is orientation-dependent Si-O band. The specific changes in intensity and area under this band for

  19. 76 FR 4451 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... Altered System of Records AGENCY: Executive Systems and Fellowship Staff, Atlanta Human Resources Center... Services proposes to alter System of Records, 09-20-0112, ``Fellowship Program and Guest Researcher Records...-0112, ``, Fellowship Program and Guest Researcher Records, HHS/CDC/AHRC.'' This system is utilized...

  20. Laboratory Information Systems in Molecular Diagnostics: Why Molecular Diagnostics Data are Different.

    PubMed

    Lee, Roy E; Henricks, Walter H; Sirintrapun, Sahussapont J

    2016-03-01

    Molecular diagnostic testing presents new challenges to information management that are yet to be sufficiently addressed by currently available information systems for the molecular laboratory. These challenges relate to unique aspects of molecular genetic testing: molecular test ordering, informed consent issues, diverse specimen types that encompass the full breadth of specimens handled by traditional anatomic and clinical pathology information systems, data structures and data elements specific to molecular testing, varied testing workflows and protocols, diverse instrument outputs, unique needs and requirements of molecular test reporting, and nuances related to the dissemination of molecular pathology test reports. By satisfactorily addressing these needs in molecular test data management, a laboratory information system designed for the unique needs of molecular diagnostics presents a compelling reason to migrate away from the current paper and spreadsheet information management that many molecular laboratories currently use. This paper reviews the issues and challenges of information management in the molecular diagnostics laboratory. PMID:26849819

  1. Energy pooling upconversion in organic molecular systems.

    PubMed

    LaCount, Michael D; Weingarten, Daniel; Hu, Nan; Shaheen, Sean E; van de Lagemaat, Jao; Rumbles, Garry; Walba, David M; Lusk, Mark T

    2015-04-30

    A combination of molecular quantum electrodynamics, perturbation theory, and ab initio calculations was used to create a computational methodology capable of estimating the rate of three-body singlet upconversion in organic molecular assemblies. The approach was applied to quantify the conditions under which such relaxation rates, known as energy pooling, become meaningful for two test systems, stilbene-fluorescein and hexabenzocoronene-oligothiophene. Both exhibit low intramolecular conversion, but intermolecular configurations exist in which pooling efficiency is at least 90% when placed in competition with more conventional relaxation pathways. For stilbene-fluorescein, the results are consistent with data generated in an earlier experimental investigation. Exercising these model systems facilitated the development of a set of design rules for the optimization of energy pooling. PMID:25793313

  2. Intelligent systems for the molecular biologist

    SciTech Connect

    Brutlag, D.L.

    1995-12-31

    This tutorial was one of eight tutorials selected to be presented at the Third International Conference on Intelligent Systems for Molecular Biology which was held in the United Kingdom from July 16 to 19, 1995. In this paper, one objective is to identify properties of DNA sequences that determine their function, by computer-aided statistical analysis and to accurately predict its function, given a new sequence. A related problem is to predict protein structure and function from the sequence.

  3. Combination of Molecular Alterations and Smoking Intensity Predicts Bladder Cancer Outcome: A Report from the Los Angeles Cancer Surveillance Program

    PubMed Central

    Mitra, Anirban P.; Castelao, Jose E.; Hawes, Debra; Tsao-Wei, Denice D.; Jiang, Xuejuan; Shi, Shan-Rong; Datar, Ram H.; Skinner, Eila C.; Stein, John P.; Groshen, Susan; Yu, Mimi C.; Ross, Ronald K.; Skinner, Donald G.; Cortessis, Victoria K.; Cote, Richard J.

    2012-01-01

    Background Traditional single-marker and multimarker molecular profiling approaches in bladder cancer do not account for major risk factors and their influence on clinical outcome. This study examined the prognostic value of molecular alterations across all disease stages after accounting for clinicopathological factors and smoking, the most common risk factor for bladder cancer in the developed world, in a population-based cohort. Methods Primary bladder tumors from 212 cancer registry patients (median follow-up, 13.2 years) were immunohistochemically profiled for Bax, caspase-3, Apaf-1, Bcl-2, p53, p21, cyclooxygenase-2, vascular endothelial growth factor, and E-cadherin alterations. “Smoking intensity” quantified the impact of duration and daily frequency of smoking. Results Age, pathological stage, surgical modality, and adjuvant therapy administration were significantly associated with survival. Increasing smoking intensity was independently associated with worse outcome (P<0.001). Apaf-1, E-cadherin and p53 were prognostic for outcome (P=0.005, 0.014 and 0.032, respectively); E-cadherin remained prognostic following multivariable analysis (P=0.040). Combined alterations in all nine biomarkers were prognostic by univariable (P<0.001) and multivariable (P=0.006) analysis. A multivariable model that included all nine biomarkers and smoking intensity had greater accuracy in predicting prognosis than models comprising of standard clinicopathological covariates without or with smoking intensity (P<0.001 and P=0.018, respectively). Conclusions Apaf-1, E-cadherin and p53 alterations individually predicted survival in bladder cancer patients. Increasing number of biomarker alterations was significantly associated with worsening survival, although markers comprising the panel were not necessarily prognostic individually. Predictive value of the nine-biomarker panel with smoking intensity was significantly higher than that of routine clinicopathological parameters

  4. Long-term variation in above and belowground plant inputs alters soil organic matter biogeochemistry at the molecular-level

    NASA Astrophysics Data System (ADS)

    Simpson, M. J.; Pisani, O.; Lin, L.; Lun, O.; Simpson, A.; Lajtha, K.; Nadelhoffer, K. J.

    2015-12-01

    The long-term fate of soil carbon reserves with global environmental change remains uncertain. Shifts in moisture, altered nutrient cycles, species composition, or rising temperatures may alter the proportions of above and belowground biomass entering soil. However, it is unclear how long-term changes in plant inputs may alter the composition of soil organic matter (SOM) and soil carbon storage. Advanced molecular techniques were used to assess SOM composition in mineral soil horizons (0-10 cm) after 20 years of Detrital Input and Removal Treatment (DIRT) at the Harvard Forest. SOM biomarkers (solvent extraction, base hydrolysis and cupric (II) oxide oxidation) and both solid-state and solution-state nuclear magnetic resonance (NMR) spectroscopy were used to identify changes in SOM composition and stage of degradation. Microbial activity and community composition were assessed using phospholipid fatty acid (PLFA) analysis. Doubling aboveground litter inputs decreased soil carbon content, increased the degradation of labile SOM and enhanced the sequestration of aliphatic compounds in soil. The exclusion of belowground inputs (No roots and No inputs) resulted in a decrease in root-derived components and enhanced the degradation of leaf-derived aliphatic structures (cutin). Cutin-derived SOM has been hypothesized to be recalcitrant but our results show that even this complex biopolymer is susceptible to degradation when inputs entering soil are altered. The PLFA data indicate that changes in soil microbial community structure favored the accelerated processing of specific SOM components with littler manipulation. These results collectively reveal that the quantity and quality of plant litter inputs alters the molecular-level composition of SOM and in some cases, enhances the degradation of recalcitrant SOM. Our study also suggests that increased litterfall is unlikely to enhance soil carbon storage over the long-term in temperate forests.

  5. Molecular aspects of DNA splicing system

    NASA Astrophysics Data System (ADS)

    Yusof, Yuhani; Lim, Wen Li; Goode, T. Elizabeth; Sarmin, Nor Haniza; Heng, Fong Wan; Wahab, Mohd Firdaus Abd

    2015-05-01

    The pioneer model of deoxyribonucleic acid (DNA) splicing system in a framework of Formal Language Theory was introduced by Head that led to the existence of other models of splicing system, namely Paun, Pixton and Yusof-Goode. These entire models are inspired by the molecular biological process of DNA splicing. Hence, this paper focuses on the translucent DNA splicing process, particularly on the generated language. Starting with some preliminaries in a limit graph, this paper also provides the experimental design with the predicted and actual result.

  6. Understanding parity violation in molecular systems.

    PubMed

    Faglioni, Francesco; Lazzeretti, Paolo

    2002-01-01

    Parity-violation energy (E(PV)) due to weak nuclear interactions between nucleons and electrons in chiral molecular systems provides a fundamental tool to verify our understanding of electronic behavior in complex systems. We used both a relativistic and a nonrelativistic approach to study a number of simple molecules and analyze the corresponding E(PV) in terms of intuitive electrodynamic concepts. We developed a qualitative model to predict the sign of E(PV) and its behavior against selected geometric distortions. Our model provides a valuable tool to screen large sets of molecules and select interesting candidates for more expensive investigations. PMID:11800715

  7. [Molecular genetics of satori, a Drosophila mutant with altered sexual orientation].

    PubMed

    Yamamoto, D

    2000-02-01

    satori (sat) is a Drosophila mutant in which male sexual orientation changes from heterosexual to homosexual. Another phenotype of the satori mutant is the absence of the male-specific muscle of Lawrence (MOL). The formation of MOL is repressed in females by the action of a female-determinant protein. Transformer (Tra), while a Tra-target doublesex (dsx) has no role in the MOL formation. Molecular cloning of the fruitless (fru) gene responsible for the sat mutation revealed that it encodes a putative transcription factor with a BTB domain and Zn finger motifs, and that the second exon of this gene contains three repeats of the Tra-binding consensus sequence. These observations suggest that fru is a novel target of Tra in the sex determination cascade of Drosophila. MOL formation is known to occur when the sex of the innervating motoneuron is male regardless of the sex of the MOL itself. Taking into account the fact that Fru is preferentially expressed in the nervous system, Fru is likely involved in neuronal sex determination. We hypothesize that the sat mutation feminizes a class of neurons which otherwise promote heterosexual courtship and the formation of the MOL in males. PMID:10890021

  8. Skeletal muscle plasticity: cellular and molecular responses to altered physical activity paradigms

    NASA Technical Reports Server (NTRS)

    Baldwin, Kenneth M.; Haddad, Fadia

    2002-01-01

    The goal of this article is to examine our current understanding of the chain of events known to be involved in the adaptive process whereby specific genes and their protein products undergo altered expression; specifically, skeletal muscle adaptation in response to altered loading states will be discussed, with a special focus on the regulation of the contractile protein, myosin heavy chain gene expression. This protein, which is both an important structural and regulatory protein comprising the contractile apparatus, can be expressed as different isoforms, thereby having an impact on the functional diversity of the muscle. Because the regulation of the myosin gene family is under the control of a complex set of processes including, but not limited to, activity, hormonal, and metabolic factors, this protein will serve as a cellular "marker" for studies of muscle plasticity in response to various mechanical perturbations in which the quantity and type of myosin isoform, along with other important cellular proteins, are altered in expression.

  9. Electromagnetically induced gain in molecular systems

    NASA Astrophysics Data System (ADS)

    Mukherjee, Nandini; Patel, C. Kumar N.

    2009-12-01

    We report electromagnetically induced gain in a highly degenerate two-level rotational vibrational molecular system. Using two photon (Raman-type) interaction with right and left circularly polarized pump and probe waves, the Zeeman coherence is established within the manifold of degenerate sublevels belonging to a rotational vibrational eigenstate. We analytically and numerically calculate the third-order nonlinear optical susceptibility for a Doppler-broadened molecular transition for an arbitrary high rotational angular momentum (J≥20) . It is shown that for a Q -type open transition, a weak probe will experience an electromagnetically induced gain in presence of a strong copropagating pump wave. The inversionless gain originates due to cancellation of absorption from the interference of the coupled Λ - and V-type excitation channels in an N -type configuration. A detailed analysis of the optical susceptibility as a function of Doppler detuning explains how the gain bands are generated in a narrow transparency window from the overlapping contributions of different velocity groups. It is shown that the orientation dependent coherent interaction in presence of a strong pump induces narrow resonances for the probe susceptibility. The locations, intensity, and sign (positive or negative susceptibility) of these resonances are decided by the frequency detuning of the Doppler group and the strength of the coupling field. The availability of high power tunable quantum cascade lasers covering a spectral region from about 4 to 12μm opens up the possibility of investigating the molecular vibrational rotational transitions for a variety of coherent effects.

  10. Microelectromechanical systems integrating molecular spin crossover actuators

    NASA Astrophysics Data System (ADS)

    Manrique-Juarez, Maria D.; Rat, Sylvain; Mathieu, Fabrice; Saya, Daisuke; Séguy, Isabelle; Leïchlé, Thierry; Nicu, Liviu; Salmon, Lionel; Molnár, Gábor; Bousseksou, Azzedine

    2016-08-01

    Silicon MEMS cantilevers coated with a 200 nm thin layer of the molecular spin crossover complex [Fe(H2B(pz)2)2(phen)] (H2B(pz)2 = dihydrobis(pyrazolyl)borate and phen = 1,10-phenantroline) were actuated using an external magnetic field and their resonance frequency was tracked by means of integrated piezoresistive detection. The light-induced spin-state switching of the molecules from the ground low spin to the metastable high spin state at 10 K led to a well-reproducible shift of the cantilever's resonance frequency (Δfr = -0.52 Hz). Control experiments at different temperatures using coated as well as uncoated devices along with simple calculations support the assignment of this effect to the spin transition. This latter translates into changes in mechanical behavior of the cantilever due to the strong spin-state/lattice coupling. A guideline for the optimization of device parameters is proposed so as to efficiently harness molecular scale movements for large-scale mechanical work, thus paving the road for nanoelectromechanical systems (NEMS) actuators based on molecular materials.

  11. ONTOGENETIC ALTERATIONS IN MOLECULAR AND STRUCTURAL CORRELATES OF DENDRITIC GROWTH FOLLOWING DEVELOPMENTAL EXPOSURE TO POLYCHLORINATED BIPHENYLS.

    EPA Science Inventory

    This is the first report showing both molecular and structural changes in brain following developmental exposure to a neurotoxicant. It is known that perinatal exposure to a neurotoxicant, polychlorinated biphenyls (PCBs), is associated with decreased IQ scores, impaired learnin...

  12. Molecular Imaging System for Monitoring Tumor Angiogenesis

    NASA Astrophysics Data System (ADS)

    Aytac, Esra; Burcin Unlu, Mehmet

    2012-02-01

    In cancer, non-invasive imaging techniques that monitor molecular processes associated with the tumor angiogenesis could have a central role in the evaluation of novel antiangiogenic and proangiogenic therapies as well as early detection of the disease. Matrix metalloproteinases (MMP) can serve as specific biological targets for imaging of angiogenesis since expression of MMPs is required for angiogenesis and has been found to be upregulated in every type of human cancer and correlates with stage, invasive, metastatic properties and poor prognosis. However, for most cancers it is still unknown when, where and how MMPs are involved in the tumor angiogenesis [1]. Development of high-resolution, high sensitivity imaging techniques in parallel with the tumor models could prove invaluable for assessing the physical location and the time frame of MMP enzymatic acitivity. The goal of this study is to understand where, when and how MMPs are involved in the tumor angiogenesis. We will accomplish this goal by following two objectives: to develop a high sensitivity, high resolution molecular imaging system, to develop a virtual tumor simulator that can predict the physical location and the time frame of the MMP activity. In order to achieve our objectives, we will first develop a PAM system and develop a mathematical tumor model in which the quantitative data obtained from the PAM can be integrated. So, this work will develop a virtual tumor simulator and a molecular imaging system for monitoring tumor angiogenesis. 1.Kessenbrock, K., V. Plaks, and Z. Werb, MMP:regulators of the tumor microenvironment. Cell, 2010. 141(1)

  13. 32 CFR Appendix F to Part 310 - Format for New or Altered System Report

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 2 2013-07-01 2013-07-01 false Format for New or Altered System Report F Appendix F to Part 310 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) PRIVACY PROGRAM DOD PRIVACY PROGRAM Pt. 310, App. F Appendix F to Part 310—Format for New or Altered System Report (See paragraph...

  14. 32 CFR Appendix F to Part 310 - Format for New or Altered System Report

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 2 2014-07-01 2014-07-01 false Format for New or Altered System Report F Appendix F to Part 310 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) PRIVACY PROGRAM DOD PRIVACY PROGRAM Pt. 310, App. F Appendix F to Part 310—Format for New or Altered System Report (See paragraph...

  15. 76 FR 4462 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... Department of Health and Human Services proposes to alter System of Records, 09-20-0138, ``Epidemic... excepted. SUPPLEMENTARY INFORMATION: OWCD proposes to alter System of Records, No. 09-20-0138, ``Epidemic... for the Epidemic Intelligence Service Officer program, and to assess a candidate's suitability for...

  16. Molecular structures and metabolic characteristics of protein in brown and yellow flaxseed with altered nutrient traits.

    PubMed

    Khan, Nazir Ahmad; Booker, Helen; Yu, Peiqiang

    2014-07-16

    The objectives of this study were to investigate the chemical profiles; crude protein (CP) subfractions; ruminal CP degradation characteristics and intestinal digestibility of rumen undegraded protein (RUP); and protein molecular structures using molecular spectroscopy of newly developed yellow-seeded flax (Linum usitatissimum L.). Seeds from two yellow flaxseed breeding lines and two brown flaxseed varieties were evaluated. The yellow-seeded lines had higher (P < 0.001) contents of oil (44.54 vs 41.42% dry matter (DM)) and CP (24.94 vs 20.91% DM) compared to those of the brown-seeded varieties. The CP in yellow seeds contained lower (P < 0.01) contents of true protein subfraction (81.31 vs 92.71% CP) and more (P < 0.001) extensively degraded (70.8 vs 64.9% CP) in rumen resulting in lower (P < 0.001) content of RUP (29.2 vs 35.1% CP) than that in the brown-seeded varieties. However, the total supply of digestible RUP was not significantly different between the two seed types. Regression equations based on protein molecular structural features gave relatively good estimation for the contents of CP (R(2) = 0.87), soluble CP (R(2) = 0.92), RUP (R(2) = 0.97), and intestinal digestibility of RUP (R(2) = 0.71). In conclusion, molecular spectroscopy can be used to rapidly characterize feed protein molecular structures and predict their nutritive value. PMID:24931851

  17. Microgravity-induced alterations in signal transduction in cells of the immune system

    NASA Astrophysics Data System (ADS)

    Paulsen, Katrin; Thiel, Cora; Timm, Johanna; Schmidt, Peter M.; Huber, Kathrin; Tauber, Svantje; Hemmersbach, Ruth; Seibt, Dieter; Kroll, Hartmut; Grote, Karl-Heinrich; Zipp, Frauke; Schneider-Stock, Regine; Cogoli, Augusto; Hilliger, Andre; Engelmann, Frank; Ullrich, Oliver

    2010-11-01

    Since decades it is known that the activity of cells of the immune system is severely dysregulated in microgravity, however, the underlying molecular aspects have not been elucidated yet. The identification of gravity-sensitive molecular mechanisms in cells of the immune system is an important and indispensable prerequisite for the development of counteractive measures to prevent or treat disturbed immune cell function of astronauts during long-term space missions. Moreover, their sensitivity to altered gravity renders immune cells an ideal model system to understand if and how gravity on Earth is required for normal mammalian cell function and signal transduction. We investigated the effect of simulated weightlessness (2D clinostat) and of real microgravity (parabolic flights) on key signal pathways in a human monocytic and a T lymphocyte cell line. We found that cellular responses to microgravity strongly depend on the cell-type and the conditions in which the cells are subjected to microgravity. In Jurkat T cells, enhanced phosphorylation of the MAP kinases ERK-1/2, MEK and p38 and inhibition of nuclear translocation of NF-kB were the predominant responses to simulated weightlessness, in either stimulated or non-stimulated cells. In contrast, non-stimulated monocytic U937 cells responded to simulated weightlessness with enhanced overall tyrosine-phosphorylation and activation of c-jun, whereas PMA-stimulated U937 cells responded the opposite way with reduced tyrosine-phosphorylation and reduced activation of c-jun, compared with PMA-stimulated 1 g controls. P53 protein was phosphorylated rapidly in microgravity. The identification of gravi-sensitive mechanisms in cells of the immune system will not only enable us to understand and prevent the negative effects of long time exposure to microgravity on Astronauts, but could also lead to novel therapeutic targets in general.

  18. Systems Pharmacology in Small Molecular Drug Discovery.

    PubMed

    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-01-01

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level. PMID:26901192

  19. Systems Pharmacology in Small Molecular Drug Discovery

    PubMed Central

    Zhou, Wei; Wang, Yonghua; Lu, Aiping; Zhang, Ge

    2016-01-01

    Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level. PMID:26901192

  20. Adaptations of the vestibular system to short and long-term exposures to altered gravity

    NASA Astrophysics Data System (ADS)

    Bruce, L. L.

    2003-10-01

    Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival of a given organism. The development and maintenance of vestibular connections are controlled by environmental gravitational stimulation as well as genetically controlled molecular interactions. This paper describes the effects of hypergravity on axonal growth and dendritic morphology, respectively. Two aspects of this vestibular adaptation are examined: (1) How does long-term exposure to hypergravity affect the development of vestibular axons? (2) How does short-term exposure to extremely rapid changes in gravity, such as those that occur during shuttle launch and landing, affect dendrites of the vestibulocerebellar system? To study the effects of longterm exposures to altered gravity, embryonic rats that developed in hypergravity were compared to microgravity-exposed and control rats. Examination of the vestibular projections from epithelia devoted to linear and angular acceleration revealed that the terminal fields segregate differently in rat embryos that gestated in each of the gravitational environments.To study the effects of short-term exposures to altered gravity, mice were exposed briefly to strong vestibular stimuli and the vestibulocerebellum was examined for any resulting morphological changes. My data show that these stimuli cause intense vestibular excitation of cerebellar Purkinje cells, which induce up-regulation of clathrin-mediated endocytosis and other morphological changes that are comparable to those seen in long-term depression. This system provides a basis for studying how the vestibular environment can modify cerebellar function, allowing animals to adapt to new environments.

  1. Orthogonal photoswitching in a multifunctional molecular system

    PubMed Central

    Lerch, Michael M.; Hansen, Mickel J.; Velema, Willem A.; Szymanski, Wiktor; Feringa, Ben L.

    2016-01-01

    The wavelength-selective, reversible photocontrol over various molecular processes in parallel remains an unsolved challenge. Overlapping ultraviolet-visible spectra of frequently employed photoswitches have prevented the development of orthogonally responsive systems, analogous to those that rely on wavelength-selective cleavage of photo-removable protecting groups. Here we report the orthogonal and reversible control of two distinct types of photoswitches in one solution, that is, a donor–acceptor Stenhouse adduct (DASA) and an azobenzene. The control is achieved by using three different wavelengths of irradiation and a thermal relaxation process. The reported combination tolerates a broad variety of differently substituted photoswitches. The presented system is also extended to an intramolecular combination of photoresponsive units. A model application for an intramolecular combination of switches is presented, in which the DASA component acts as a phase-transfer tag, while the azobenzene moiety independently controls the binding to α-cyclodextrin. PMID:27401266

  2. 44 CFR 6.71 - Federal Register notice of establishment of new system or alteration of existing system.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 44 Emergency Management and Assistance 1 2014-10-01 2014-10-01 false Federal Register notice of... PRIVACY ACT OF 1974 Report on New Systems and Alterations of Existing Systems § 6.71 Federal Register... establishment or alteration of a system of records shall be published in the Federal Register, in...

  3. 44 CFR 6.71 - Federal Register notice of establishment of new system or alteration of existing system.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 44 Emergency Management and Assistance 1 2012-10-01 2011-10-01 true Federal Register notice of... PRIVACY ACT OF 1974 Report on New Systems and Alterations of Existing Systems § 6.71 Federal Register... establishment or alteration of a system of records shall be published in the Federal Register, in...

  4. 44 CFR 6.71 - Federal Register notice of establishment of new system or alteration of existing system.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Federal Register notice of... PRIVACY ACT OF 1974 Report on New Systems and Alterations of Existing Systems § 6.71 Federal Register... establishment or alteration of a system of records shall be published in the Federal Register, in...

  5. 44 CFR 6.71 - Federal Register notice of establishment of new system or alteration of existing system.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 44 Emergency Management and Assistance 1 2011-10-01 2011-10-01 false Federal Register notice of... PRIVACY ACT OF 1974 Report on New Systems and Alterations of Existing Systems § 6.71 Federal Register... establishment or alteration of a system of records shall be published in the Federal Register, in...

  6. Molecular mechanisms and in vivo mouse models of skin aging associated with dermal matrix alterations.

    PubMed

    Hwang, Kyung-A; Yi, Bo-Rim; Choi, Kyung-Chul

    2011-03-01

    Skin is the most superficial body organ and plays an important role in protecting the body from environmental damage and in forming social relations. With the increase of the aging population in our society, dermatological and cosmetic concerns of skin aging are rapidly increasing. Skin aging is a complex process combined with intrinsic and extrinsic factors. Intrinsic or chronological skin aging results from the passage of time and is influenced by genetic factors. Extrinsic skin aging is mainly determined by UV irradiation, also called photoaging. These two types of aging processes are superimposed on sun-exposed skin, and have a common feature of causing dermal matrix alterations that mostly contribute to the formation of wrinkles, laxity, and fragility of aged skin. The dermal matrix contains extracellular matrix proteins such as collagen, elastin, and proteoglycans that confer the strength and resiliency of skin. Skin aging associated with dermal matrix alterations and atrophy can be caused by cellular senescence of dermal cells like fibroblasts, and decreased synthesis and accelerated degradation of dermal matrix components, especially collagen fibers. Both intrinsic aging and photoaging exert influence during each step of dermal matrix alteration via different mechanisms. Mouse models of skin aging have been extensively developed to elucidate intrinsic aging and photoaging processes, to validate in vitro biochemical data, and to test the effects of pharmacological tools for retarding skin aging because they have the advantages of being genetically similar to humans and are easily available. PMID:21826153

  7. Temperature modulates the cell wall mechanical properties of rice coleoptiles by altering the molecular mass of hemicellulosic polysaccharides

    NASA Technical Reports Server (NTRS)

    Nakamura, Yukiko; Wakabayashi, Kazuyuki; Hoson, Takayuki

    2003-01-01

    The present study was conducted to investigate the mechanism inducing the difference in the cell wall extensibility of rice (Oryza sativa L. cv. Koshihikari) coleoptiles grown under various temperature (10-50 degrees C) conditions. The growth rate and the cell wall extensibility of rice coleoptiles exhibited the maximum value at 30-40 degrees C, and became smaller as the growth temperature rose or dropped from this temperature range. The amounts of cell wall polysaccharides per unit length of coleoptile increased in coleoptiles grown at 40 degrees C, but not at other temperature conditions. On the other hand, the molecular size of hemicellulosic polysaccharides was small at temperatures where the cell wall extensibility was high (30-40 degrees C). The autolytic activities of cell walls obtained from coleoptiles grown at 30 and 40 degrees C were substantially higher than those grown at 10, 20 and 50 degrees C. Furthermore, the activities of (1-->3),(1-->4)-beta-glucanases extracted from coleoptile cell walls showed a similar tendency. When oat (1-->3),(1-->4)-beta-glucans with high molecular mass were incubated with the cell wall enzyme preparations from coleoptiles grown at various temperature conditions, the extensive molecular mass downshifts were brought about only by the cell wall enzymes obtained from coleoptiles grown at 30-40 degrees C. There were close correlations between the cell wall extensibility and the molecular mass of hemicellulosic polysaccharides or the activity of beta -glucanases. These results suggest that the environmental temperature regulates the cell wall extensibility of rice coleoptiles by modifying mainly the molecular mass of hemicellulosic polysaccharides. Modulation of the activity of beta-glucanases under various temperature conditions may be involved in the alteration of the molecular size of hemicellulosic polysaccharides.

  8. Chronic phase advance alters circadian physiological rhythms and peripheral molecular clocks.

    PubMed

    Wolff, Gretchen; Duncan, Marilyn J; Esser, Karyn A

    2013-08-01

    Shifting the onset of light, acutely or chronically, can profoundly affect responses to infection, tumor progression, development of metabolic disease, and mortality in mammals. To date, the majority of phase-shifting studies have focused on acute exposure to a shift in the timing of the light cycle, whereas the consequences of chronic phase shifts alone on molecular rhythms in peripheral tissues such as skeletal muscle have not been studied. In this study, we tested the effect of chronic phase advance on the molecular clock mechanism in two phenotypically different skeletal muscles. The phase advance protocol (CPA) involved 6-h phase advances (earlier light onset) every 4 days for 8 wk. Analysis of the molecular clock, via bioluminescence recording, in the soleus and flexor digitorum brevis (FDB) muscles and lung demonstrated that CPA advanced the phase of the rhythm when studied immediately after CPA. However, if the mice were placed into free-running conditions (DD) for 2 wk after CPA, the molecular clock was not phase shifted in the two muscles but was still shifted in the lung. Wheel running behavior remained rhythmic in CPA mice; however, the endogenous period length of the free-running rhythm was significantly shorter than that of control mice. Core body temperature, cage activity, and heart rate remained rhythmic throughout the experiment, although the onset of the rhythms was significantly delayed with CPA. These results provide clues that lifestyles associated with chronic environmental desynchrony, such as shift work, can have disruptive effects on the molecular clock mechanism in peripheral tissues, including both types of skeletal muscle. Whether this can contribute, long term, to increased incidence of insulin resistance/metabolic disease requires further study. PMID:23703115

  9. Chronic phase advance alters circadian physiological rhythms and peripheral molecular clocks

    PubMed Central

    Wolff, Gretchen; Duncan, Marilyn J.

    2013-01-01

    Shifting the onset of light, acutely or chronically, can profoundly affect responses to infection, tumor progression, development of metabolic disease, and mortality in mammals. To date, the majority of phase-shifting studies have focused on acute exposure to a shift in the timing of the light cycle, whereas the consequences of chronic phase shifts alone on molecular rhythms in peripheral tissues such as skeletal muscle have not been studied. In this study, we tested the effect of chronic phase advance on the molecular clock mechanism in two phenotypically different skeletal muscles. The phase advance protocol (CPA) involved 6-h phase advances (earlier light onset) every 4 days for 8 wk. Analysis of the molecular clock, via bioluminescence recording, in the soleus and flexor digitorum brevis (FDB) muscles and lung demonstrated that CPA advanced the phase of the rhythm when studied immediately after CPA. However, if the mice were placed into free-running conditions (DD) for 2 wk after CPA, the molecular clock was not phase shifted in the two muscles but was still shifted in the lung. Wheel running behavior remained rhythmic in CPA mice; however, the endogenous period length of the free-running rhythm was significantly shorter than that of control mice. Core body temperature, cage activity, and heart rate remained rhythmic throughout the experiment, although the onset of the rhythms was significantly delayed with CPA. These results provide clues that lifestyles associated with chronic environmental desynchrony, such as shift work, can have disruptive effects on the molecular clock mechanism in peripheral tissues, including both types of skeletal muscle. Whether this can contribute, long term, to increased incidence of insulin resistance/metabolic disease requires further study. PMID:23703115

  10. Glycogene Expression Alterations Associated with Pancreatic Cancer Epithelial-Mesenchymal Transition in Complementary Model Systems

    PubMed Central

    Maupin, Kevin A.; Sinha, Arkadeep; Eugster, Emily; Miller, Jeremy; Ross, Julianna; Paulino, Vincent; Keshamouni, Venkateshwar G.; Tran, Nhan; Berens, Michael; Webb, Craig; Haab, Brian B.

    2010-01-01

    Background The ability to selectively detect and target cancer cells that have undergone an epithelial-mesenchymal transition (EMT) may lead to improved methods to treat cancers such as pancreatic cancer. The remodeling of cellular glycosylation previously has been associated with cell differentiation and may represent a valuable class of molecular targets for EMT. Methodology/Principal Findings As a first step toward investigating the nature of glycosylation alterations in EMT, we characterized the expression of glycan-related genes in three in-vitro model systems that each represented a complementary aspect of pancreatic cancer EMT. These models included: 1) TGFβ-induced EMT, which provided a look at the active transition between states; 2) a panel of 22 pancreatic cancer cell lines, which represented terminal differentiation states of either epithelial-like or mesenchymal-like; and 3) actively-migrating and stationary cells, which provided a look at the mechanism of migration. We analyzed expression data from a list of 587 genes involved in glycosylation (biosynthesis, sugar transport, glycan-binding, etc.) or EMT. Glycogenes were altered at a higher prevalence than all other genes in the first two models (p<0.05 and <0.005, respectively) but not in the migration model. Several functional themes were shared between the induced-EMT model and the cell line panel, including alterations to matrix components and proteoglycans, the sulfation of glycosaminoglycans; mannose receptor family members; initiation of O-glycosylation; and certain forms of sialylation. Protein-level changes were confirmed by Western blot for the mannose receptor MRC2 and the O-glycosylation enzyme GALNT3, and cell-surface sulfation changes were confirmed using Alcian Blue staining. Conclusions/Significance Alterations to glycogenes are a major component of cancer EMT and are characterized by changes to matrix components, the sulfation of GAGs, mannose receptors, O-glycosylation, and specific

  11. Alterations in the striatal dopamine system during intravenous methamphetamine exposure: effects of contingent and noncontingent administration.

    PubMed

    Laćan, Goran; Hadamitzky, Martin; Kuczenski, Ronald; Melega, William P

    2013-08-01

    The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long-term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.5 weeks. Escalating METH exposure was delivered by dynamic infusion (DI) that incorporated a "humanized" plasma METH half life or by intravenous self-administration (IVSA) that included binge intakes. Kinetic modeling of DI and IVSA for 24 h periods during the final week of METH exposure showed that plasma METH levels remained between 0.7 and 1.5 µM. Animals were sacrificed during their last METH administration for autoradiography assessment using [³H]ligands and D2 agonist-induced [³⁵S]GTPγS binding. DA transporter binding was decreased (DI, 34%; IVSA, 15%) while vesicular monoamine transporter binding and substantia nigra DA cell numbers were unchanged. Decreases were measured for D2 receptor (DI and IVSA, 15-20%) and [³⁵S]GTPγS binding (DI, 35%; IVSA, 18%). These similar patterns of DI and IVSA associated decreases in striatal DA markers reflect consequences of cumulative METH exposure and not the drug delivery method. For METH IVSA, individual differences were observed, yet each animal's total intake was similar within and across three 24-h binges. IVSA rodent models may be useful for identifying molecular mechanisms that are associated with METH binges in humans. PMID:23417852

  12. Alterations in the Striatal Dopamine System During Intravenous Methamphetamine Exposure: Effects of Contingent and Noncontingent Administration

    PubMed Central

    Laćan, Goran; Hadamitzky, Martin; Kuczenski, Ronald; Melega, William P.

    2014-01-01

    The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.5 weeks. Escalating METH exposure was delivered by dynamic infusion (DI) that incorporated a ‘humanized’ plasma METH half life, or by intravenous self-administration (IVSA) that included binge intakes. Kinetic modeling of DI and IVSA for 24 h periods during the final week of METH exposure showed that plasma METH levels remained between 0.7–1.5 μM. Animals were sacrificed during their last METH administration for autoradiography assessment using [3H]ligands and D2 agonist-induced [35S]GTPγS binding. DA transporter binding was decreased (DI, 34%; IVSA, 15%) while vesicular monoamine transporter binding and substantia nigra DA cell numbers were unchanged. Decreases were measured for D2 receptor (DI and IVSA, 15–20%) and [35S]GTPγS binding (DI, 35%; IVSA, 18%). These similar patterns of DI and IVSA associated decreases in striatal DA markers reflect consequences of cumulative METH exposure and not the drug delivery method. For METH IVSA, individual differences were observed, yet each animal’s total intake was similar within and across three 24 h binges. IVSA rodent models may be useful for identifying molecular mechanisms that are associated with METH binges in humans. PMID:23417852

  13. Molecular alterations in tumorigenic human bronchial and breast epithelial cells induced by high let radiation

    NASA Astrophysics Data System (ADS)

    Hei, T. K.; Zhao, Y. L.; Roy, D.; Piao, C. Q.; Calaf, G.; Hall, E. J.

    Carcinogenesis is a multi-stage process with sequence of genetic events governing the phenotypic expression of a series of transformation steps leading to the development of metastatic cancer. In the present study, immortalized human bronchial (BEP2D) and breast (MCF-10F) cells were irradiated with graded doses of either 150 keV/μm alpha particles or 1 GeV/nucleon 56Fe ions. Transformed cells developed through a series of successive steps before becoming tumorigenic in nude mice. Cell fusion studies indicated that radiation-induced tumorigenic phenotype in BEP2D cells could be completely suppressed by fusion with non-tumorigenic BEP2D cells. The differential expressions of known genes between tumorigenic bronchial and breast cells induced by alpha particles and their respective control cultures were compared using cDNA expression array. Among the 11 genes identified to be differentially expressed in BEP2D cells, three ( DCC, DNA-PK and p21 CIPI) were shown to be consistently down-regulated by 2 to 4 fold in all the 5 tumor cell lines examined. In contrast, their expressions in the fusion cell lines were comparable to control BEP2D cells. Similarly, expression levels of a series of genes were found to be altered in a step-wise manner among tumorigenic MCF-10F cells. The results are highly suggestive that functional alterations of these genes may be causally related to the carcinogenic process.

  14. Multiple molecular alterations of FHIT in betel-associated oral carcinoma.

    PubMed

    Chang, Kuo-Wei; Kao, Shou-Yen; Tzeng, Reuo-Jar; Liu, Chung-Ji; Cheng, Ann-Joy; Yang, Shun-Chun; Wong, Yong-Kie; Lin, Shu-Chun

    2002-03-01

    To determine the alterations of the FHIT (fragile histidine triad) gene in oral squamous cell carcinoma (OSCC), this study examined mutation, promoter methylation, mRNA transcription, and protein expression of FHIT in OSCC associated mostly with the use of betel and/or tobacco. Analyses of the coding exons (exons 5-9) identified a deletion of one base in intron 4 in one tumour and a deletion of exon 7 in two tumours. Using bisulphite genomic sequencing, 28% of the informative subjects exhibited promoter methylation. An aberrant FHIT transcript spanning from exon 3 to exon 10, which was verified by RT-PCR analysis, was identified in 36% of the OSCC subjects, 50% of the oral pre-invasive lesions, and 5% of the non-cancerous match tissue. An abnormal immunohistochemical level of Fhit was detected in 41% of OSCC subjects. A statistically significant association was found between aberrant transcription of the FHIT gene and an abnormal level of Fhit immunoreactivity. The results indicated that alteration of FHIT is a frequent occurrence in OSCC and thus suggests that the aberrance in FHIT transcription could be an early event of oral carcinogenesis. PMID:11857493

  15. Polyglutamine Expansion Alters the Dynamics and Molecular Architecture of Aggregates in Dentatorubropallidoluysian Atrophy*

    PubMed Central

    Hinz, Justyna; Lehnhardt, Lothar; Zakrzewski, Silke; Zhang, Gong; Ignatova, Zoya

    2012-01-01

    Preferential accumulation of mutant proteins in the nucleus has been suggested to be the molecular culprit that confers cellular toxicity in the neurodegenerative disorders caused by polyglutamine (polyQ) expansion. Here, we use dynamic imaging approaches, orthogonal cross-seeding, and composition analysis to examine the dynamics and structure of nuclear and cytoplasmic inclusions of atrophin-1, implicated in dentatorubropallidoluysian atrophy, a polyQ-based disease with complex clinical features. Our results reveal a large heterogeneity in the dynamics of the nuclear inclusions compared with the compact and immobile cytoplasmic aggregates. At least two types of inclusions of expanded atrophin-1 with different mobility of the molecular species and ability to exchange with the surrounding monomer pool coexist in the nucleus. Intriguingly, the enrichment of nuclear inclusions with slow dynamics parallels changes in the aggregate core architecture that are dominated by the polyQ stretch. We propose that the observed complexity in the dynamics of the nuclear inclusions provides a molecular explanation for the enhanced cellular toxicity of the nuclear aggregates in polyQ-based neurodegeneration. PMID:22134925

  16. 75 FR 15441 - Privacy Act of 1974; Report of an Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-29

    ...In accordance with the requirements of the Privacy Act of 1974, the Health Resources and Services Administration (HRSA) is publishing notice of a proposal to alter the system of records for Health Professions Planning and Evaluation (SORN 09-15-0046; 63FR14124). The purpose of these alterations is to change the name, to update addresses, authority for maintenance, to improve clarity......

  17. Primitive Liquid Water of the Solar System in an Aqueous Altered Carbonaceous Chondrite

    NASA Technical Reports Server (NTRS)

    Tsuchiyama, A.; Miyake, A.; Kitayama, A.; Matsuno, J.; Takeuchi, A.; Uesugi, K.; Suzuki, Y.; Nakano, T.; Zolensky, M. E.

    2016-01-01

    Non-destructive 3D observations of the aqueous altered CM chondrite Sutter's Mill using scanning imaging x-ray microscopy (SIXM) showed that some of calcite and enstatite grains contain two-phase inclusion, which is most probably composed of liquid water and bubbles. This water should be primitive water responsible for aqueous alteration in an asteroid in the early solar system.

  18. 76 FR 4460 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... HUMAN SERVICES Centers for Disease Control and Prevention Privacy Act of 1974; Report of Modified or... Global Health (COGH), Department of Health and Human Services (DHHS). ACTION: Notification of Proposed Altered System of Records. SUMMARY: The Department of Health and Human Services proposes to alter...

  19. 41 CFR 51-9.502 - Federal Register notice of establishment of new system or alteration of existing system.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 41 Public Contracts and Property Management 1 2013-07-01 2013-07-01 false Federal Register notice... Existing Systems § 51-9.502 Federal Register notice of establishment of new system or alteration of... notice shall be published in the Federal Register of the proposed establishment or alteration of a...

  20. 41 CFR 51-9.502 - Federal Register notice of establishment of new system or alteration of existing system.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 41 Public Contracts and Property Management 1 2014-07-01 2014-07-01 false Federal Register notice... Existing Systems § 51-9.502 Federal Register notice of establishment of new system or alteration of... notice shall be published in the Federal Register of the proposed establishment or alteration of a...

  1. 41 CFR 51-9.502 - Federal Register notice of establishment of new system or alteration of existing system.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 1 2010-07-01 2010-07-01 true Federal Register notice... Existing Systems § 51-9.502 Federal Register notice of establishment of new system or alteration of... notice shall be published in the Federal Register of the proposed establishment or alteration of a...

  2. 41 CFR 51-9.502 - Federal Register notice of establishment of new system or alteration of existing system.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 41 Public Contracts and Property Management 1 2011-07-01 2009-07-01 true Federal Register notice... Existing Systems § 51-9.502 Federal Register notice of establishment of new system or alteration of... notice shall be published in the Federal Register of the proposed establishment or alteration of a...

  3. 75 FR 1625 - Privacy Act of 1974; Report of Amended or Altered System; Medical, Health and Billing Records System

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-12

    ... HUMAN SERVICES Indian Health Service Privacy Act of 1974; Report of Amended or Altered System; Medical... Altered Privacy Act System of Records (PASOR), 09-17-0001. SUMMARY: Pursuant to the provisions of the Privacy Act of 1974, as amended, 5 U.S.C. 552a(e)(4), the IHS has amended and is publishing the...

  4. 78 FR 64196 - Privacy Act Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-28

    ..., Biographical Files and Social Networks. The amendment serves to modify the system of records by generally..., Biographical Files (78 FR 171). In that notice, the Department announced its intent to amend that system...

  5. Clinicopathological and molecular alterations in early gastric cancers with the microsatellite instability‐high phenotype

    PubMed Central

    Sugimoto, Ryo; Habano, Wataru; Endoh, Masaki; Eizuka, Makoto; Yamamoto, Eiichiro; Uesugi, Noriyuki; Ishida, Kazuyuki; Kawasaki, Tomonori; Matsumoto, Takayuki; Suzuki, Hiromu

    2015-01-01

    The relevance of the clinicopathological and molecular features of early gastric cancers (EGCs) having the microsatellite instability (MSI)‐high phenotype has not been clearly defined in sporadic gastric carcinogenesis. Here, we examined the clinicopathological and molecular characteristics of EGC according to MSI status in 330 patients with EGC (intestinal‐type adenocarcinoma). Tumors were classified as MSI‐high (45 cases), MSI‐low (9 cases), or microsatellite stable (MSS; 276 cases). The specimens were examined using a combination of polymerase chain reaction (PCR)‐microsatellite assays and PCR‐pyrosequencing to detect chromosomal allelic imbalances in multiple cancer‐related chromosomal loci, MSI, gene mutations (KRAS and BRAF) and methylation status [high methylation epigenome (HME), intermediate methylation epigenome and low methylation epigenome]. In addition, the expression levels of various target proteins were examined using immunohistochemistry. Interestingly, EGC with the MSI phenotype showed distinct papillary features. The expression of gastric mucin was more frequent in EGC with the MSI phenotype, while p53 overexpression was common in EGCs, irrespective of MSI status. The frequency of HME was significantly higher in EGCs with the MSI phenotype than in EGCs with the MSS phenotype. Although there was a low frequency of allelic imbalance in EGCs with the MSI phenotype, some markers of allelic imbalance were more frequently detected in EGCs with the MSI‐high phenotype than in EGCs with the MSS phenotype. KRAS and BRAF mutations were rare in EGCs. Thus, the MSI phenotype in EGC is a major precursor lesion in gastric cancer and is characterized by distinct clinicopathological and molecular features. PMID:26538087

  6. Targeted molecular profiling of rare genetic alterations in colorectal cancer using next-generation sequencing.

    PubMed

    Jauhri, Mayank; Bhatnagar, Akanksha; Gupta, Satish; Shokeen, Yogender; Minhas, Sachin; Aggarwal, Shyam

    2016-10-01

    Mutation frequencies of common genetic alterations in colorectal cancer have been in the spotlight for many years. This study highlights few rare somatic mutations, which possess the attributes of a potential CRC biomarker yet are often neglected. Next-generation sequencing was performed over 112 tumor samples to detect genetic alterations in 31 rare genes in colorectal cancer. Mutations were detected in 26/31 (83.9 %) uncommon genes, which together contributed toward 149 gene mutations in 67/112 (59.8 %) colorectal cancer patients. The most frequent mutations include KDR (19.6 %), PTEN (17 %), FBXW7 (10.7 %), SMAD4 (10.7 %), VHL (8 %), KIT (8 %), MET (7.1 %), ATM (6.3 %), CTNNB1 (4.5 %) and CDKN2A (4.5 %). RB1, ERBB4 and ERBB2 mutations were persistent in 3.6 % patients. GNAS, FGFR2 and FGFR3 mutations were persistent in 1.8 % patients. Ten genes (EGFR, NOTCH1, SMARCB1, ABL1, STK11, SMO, RET, GNAQ, CSF1R and FLT3) were found mutated in 0.9 % patients. Lastly, no mutations were observed in AKT, HRAS, MAP2K1, PDGFR and JAK2. Significant associations were observed between VHL with tumor site, ERBB4 and SMARCB1 with tumor invasion, CTNNB1 with lack of lymph node involvement and CTNNB1, FGFR2 and FGFR3 with TNM stage. Significantly coinciding mutation pairs include PTEN and SMAD4, PTEN and KDR, EGFR and RET, EGFR and RB1, FBXW7 and CTNNB1, KDR and FGFR2, FLT3 and CTNNB1, RET and RB1, ATM and SMAD4, ATM and CDKN2A, ERBB4 and SMARCB1. This study elucidates few potential colorectal cancer biomarkers, specifically KDR, PTEN, FBXW7 and SMAD4, which are found mutated in more than 10 % patients. PMID:27568332

  7. HER2, MET and FGFR2 oncogenic driver alterations define distinct molecular segments for targeted therapies in gastric carcinoma

    PubMed Central

    Liu, Y J; Shen, D; Yin, X; Gavine, P; Zhang, T; Su, X; Zhan, P; Xu, Y; Lv, J; Qian, J; Liu, C; Sun, Y; Qian, Z; Zhang, J; Gu, Y; Ni, X

    2014-01-01

    Background: Gastric cancer (GC) is a leading cause of cancer deaths worldwide. Since the approval of trastuzumab, targeted therapies are emerging as promising treatment options for the disease. This study aimed to explore the molecular segmentation of several known therapeutics targets, human epidermal growth factor receptor 2 (HER2), MET and fibroblast growth factor receptor 2 (FGFR2), within GC using clinically approved or investigational kits and scoring criteria. Knowledge of how these markers are segmented in the same cohort of GC patients could improve future clinical trial designs. Methods: Using immunohistochemistry (IHC) and FISH methods, overexpression and amplification of HER2, FGFR2 and MET were profiled in a cohort of Chinese GC samples. The correlations between anti-tumour sensitivity and the molecular segments of HER2, MET and FGFR2 alterations were further tested in a panel of GC cell lines and the patient-derived GC xenograft (PDGCX) model using the targeted inhibitors. Results: Of 172 GC patients, positivity for HER2, MET and FGFR2 alternations was found in 23 (13.4%), 21 (12.2%) and 9 (5.2%) patients, respectively. Positivity for MET was found in 3 of 23 HER2-positive GC patients. Co-positivity for FGFR2 and MET was found in 1 GC patient, and amplification of the two genes was found in different tumour cells. Our study in a panel of GC cell lines showed that in most cell lines, amplification or high expression of a particular molecular marker was mutually exclusive and in vitro sensitivity to the targeted agents lapatinib, PD173074 and crizotinib was only observed in cell lines with the corresponding high expression of the drugs' target protein. SGC031, an MET-positive PDGCX mouse model, responded to crizotinib but not to lapatinib or PD173074. Conclusions: Human epidermal growth factor receptor 2, MET and FGFR2 oncogenic driver alterations (gene amplification and overexpression) occur in three largely distinct molecular segments in GC. A

  8. Cell Cycle Control and Adhesion Molecule Expression in Cells of the Immune System are Sensitive to Altered Gravity

    NASA Astrophysics Data System (ADS)

    Ullrich, O.; Paulsen, K.; Thiel, C.; Herrmann, K.; Sang, C.; Han, G.; Hemmersbach, R.; von der Wiesche, M.; Kroll, H.; Zhuang, F.; Grote, K. H.; Cogoli, A.; Zipp, F.; Engelmann, F.

    2008-06-01

    Life on earth developed in the presence and under the constant influence of gravity. Thus, it is a fundamental biological question, whether gravity is required for cellular functions and signal transduction in mammalian cells. Since the first Spacelab-Mission 20 years ago, it is known that activation and function of T lymphocytes is severely suppressed in microgravity, but the underlying molecular mechanisms are not elucidated. Experiments have been performed using ground-based facilities such as fast-rotating clinostat and hyper-g-centrifuges, and real microgravity provided by parabolic flights. We found that 1.) cells of the immune system responded cell type specifically to altered gravity, 2.) microgravity induced a multitude of initial alterations in signal transduction, whereas 3.) hypergravity of 1.8g did not induce any changes of the pathways tested, and that 4.) most of the initially altered pathways in microgravity adapted to "normal" levels within 15min. However, some pathways remained altered and could explain cell cycle arrest of T lymphocytes as observed in several long-term space experiments.

  9. Characteristics of altered layers formed by sputtering with a massive molecular ion containing diverse elements with large mass differences

    SciTech Connect

    Fujiwara, Yukio; Kondou, Kouji; Nonaka, Hidehiko; Saito, Naoaki; Fujimoto, Toshiyuki; Kurokawa, Akira; Ichimura, Shingo; Tomita, Mitsuhiro

    2007-10-01

    Tetrairidium dodecacarbonyl (Ir{sub 4}(CO){sub 12}) is an organometallic compound called metal cluster complex which has a molecular weight of 1104.9. To investigate its irradiation effect, silicon substrates sputtered with 10 keV Ir{sub 4}(CO){sub 7}{sup +} were analyzed by high resolution Rutherford backscattering spectrometry. Experimental results were examined on the basis of a conventional theory of simultaneous implantation and sputtering. The introduction of oxygen gas during sputtering proved to form a thick oxide layer in the substrate, resulting in iridium segregation at the silicon-oxide interface and carbon accumulation near the surface. It was confirmed that oxygen partial pressure significantly affected the characteristics of an altered layer beneath a sputtered surface.

  10. Computer modeling of properties of complex molecular systems

    SciTech Connect

    Kulkova, E.Yu.; Khrenova, M.G.; Polyakov, I.V.

    2015-03-10

    Large molecular aggregates present important examples of strongly nonhomogeneous systems. We apply combined quantum mechanics / molecular mechanics approaches that assume treatment of a part of the system by quantum-based methods and the rest of the system with conventional force fields. Herein we illustrate these computational approaches by two different examples: (1) large-scale molecular systems mimicking natural photosynthetic centers, and (2) components of prospective solar cells containing titan dioxide and organic dye molecules. We demonstrate that modern computational tools are capable to predict structures and spectra of such complex molecular aggregates.

  11. [Alterations of the integument of fattening pigs in different housing systems].

    PubMed

    Mayer, C; Hauser, R

    2001-04-01

    Alterations of the integument of fattening pigs were investigated on a total of eleven farms with the following housing systems: "Krieger" system, fully slatted floors, partially slatted floors and kennel housing systems. For this purpose, the alterations of the integument of the animals were visually assessed at different times during fattening. In addition, spot investigations were carried out on three farms with deep litter systems. In the non-littered systems, significantly more changes at the limbs were observed than in the littered systems. The least damages occurred in the deep litter system. Similar as with cattle, soft and deformable lying areas seem to be a prerequisite for the prevention of such alterations. With respect to injuries caused by tailbiting, apart from possibilities of activity, other parameters such as air quality and space availability also play an important role. PMID:11344943

  12. Asbestos-Induced Cellular and Molecular Alteration of Immunocompetent Cells and Their Relationship with Chronic Inflammation and Carcinogenesis

    PubMed Central

    Matsuzaki, Hidenori; Maeda, Megumi; Lee, Suni; Nishimura, Yasumitsu; Kumagai-Takei, Naoko; Hayashi, Hiroaki; Yamamoto, Shoko; Hatayama, Tamayo; Kojima, Yoko; Tabata, Rika; Kishimoto, Takumi; Hiratsuka, Junichi; Otsuki, Takemi

    2012-01-01

    Asbestos causes lung fibrosis known as asbestosis as well as cancers such as malignant mesothelioma and lung cancer. Asbestos is a mineral silicate containing iron, magnesium, and calcium with a core of SiO2. The immunological effect of silica, SiO2, involves the dysregulation of autoimmunity because of the complications of autoimmune diseases found in silicosis. Asbestos can therefore cause alteration of immunocompetent cells to result in a decline of tumor immunity. Additionally, due to its physical characteristics, asbestos fibers remain in the lung, regional lymph nodes, and the pleural cavity, particularly at the opening sites of lymphatic vessels. Asbestos can induce chronic inflammation in these areas due to the production of reactive oxygen/nitrogen species. As a consequence, immunocompetent cells can have their cellular and molecular features altered by chronic and recurrent encounters with asbestos fibers, and there may be modification by the surrounding inflammation, all of which eventually lead to decreased tumor immunity. In this paper, the brief results of our investigation regarding reduction of tumor immunity of immunocompetent cells exposed to asbestos in vitro are discussed, as are our findings concerned with an investigation of chronic inflammation and analyses of peripheral blood samples derived from patients with pleural plaque and mesothelioma that have been exposed to asbestos. PMID:22500091

  13. Endometriosis as a detrimental condition for granulosa cell steroidogenesis and development: From molecular alterations to clinical impact.

    PubMed

    Sanchez, Ana Maria; Somigliana, Edgardo; Vercellini, Paolo; Pagliardini, Luca; Candiani, Massimo; Vigano, Paola

    2016-01-01

    Endometriosis is an estrogen-dependent chronic inflammatory condition that affects women in their reproductive period. Alterations in ovarian follicle morphology and function have been documented in affected women. The local intrafollicular environment has been as well examined by various groups. In the present review, we aimed to summarize the molecular evidence supporting the idea that endometriosis can negatively influence growth, steroidogenesis and the function of the granulosa cells (GCs). Reduced P450 aromatase expression, increased intracellular ROS generation and altered WNT signaling characterize the GCs of women with endometriosis. Clear evidence for an increased level of GC apoptosis has been provided in association with the downregulation of pro-survival factors. Other potentially negative effects include decreased progesterone production, locally decreased AMH production and lower inflammatory cytokine expression, although these have been only partially clarified. The possibility that endometriosis per se may influence IVF clinical results as a consequence of the detrimental impact on the local intrafollicular environment is also discussed. PMID:26407755

  14. Acute phenanthrene toxicity to juvenile diploid and triploid African catfish (Clarias gariepinus): Molecular, biochemical, and histopathological alterations.

    PubMed

    Karami, Ali; Romano, Nicholas; Hamzah, Hazilawati; Simpson, Stuart L; Yap, Chee Kong

    2016-05-01

    Information on the biological responses of polyploid animals towards environmental contaminants is scarce. This study aimed to compare reproductive axis-related gene expressions in the brain, plasma biochemical responses, and the liver and gill histopathological alterations in diploid and triploid full-sibling juvenile African catfish (Clarias gariepinus). Fish were exposed for 96 h to one of the two waterborne phenanthrene (Phe) concentrations [mean measured (SD): 6.2 (2.4) and 76 (4.2) μg/L]. In triploids, exposure to 76 μg/L Phe increased mRNA level of fushi tarazu-factor 1 (ftz-f1). Expression of tryptophan hydroxylase2 (tph2) was also elevated in both ploidies following the exposure to 76 μg/L Phe compared to the solvent control. In triploids, 76 μg/L Phe increased plasma alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels compared to the other Phe-exposed group. It also elevated lactate and glucose contents relative to the other groups. In diploids, however, biochemical biomarkers did not change. Phenanthrene exposures elevated glycogen contents and the prevalence of histopathological lesions in the liver and gills of both ploidies. This study showed substantial differences between diploids and triploids on biochemical and molecular biomarker responses, but similar histopathological alterations following acute Phe exposures. PMID:26845363

  15. Molecular alterations in areas generating fast ripples in an animal model of temporal lobe epilepsy.

    PubMed

    Winden, Kellen D; Bragin, Anatol; Engel, Jerome; Geschwind, Dan H

    2015-06-01

    The molecular basis of epileptogenesis is poorly characterized. Studies in humans and animal models have identified an electrophysiological signature that precedes the onset of epilepsy, which has been termed fast ripples (FRs) based on its frequency. Multiple lines of evidence implicate regions generating FRs in epileptogenesis, and FRs appear to demarcate the seizure onset zone, suggesting a role in ictogenesis as well. We performed gene expression analysis comparing areas of the dentate gyrus that generate FRs to those that do not generate FRs in a well-characterized rat model of epilepsy. We identified a small cohort of genes that are differentially expressed in FR versus non-FR brain tissue and used quantitative PCR to validate some of those that modulate neuronal excitability. Gene expression network analysis demonstrated conservation of gene co-expression between non-FR and FR samples, but examination of gene connectivity revealed changes that were most pronounced in the cm-40 module, which contains several genes associated with synaptic function and the differentially expressed genes Kcna4, Kcnv1, and Npy1r that are down-regulated in FRs. We then demonstrate that the genes within the cm-40 module are regulated by seizure activity and enriched for the targets of the RNA binding protein Elavl4. Our data suggest that seizure activity induces co-expression of genes associated with synaptic transmission and that this pattern is attenuated in areas displaying FRs, implicating the failure of this mechanism in the generation of FRs. PMID:25818007

  16. Reduced molecular size and altered disaccharide composition of cerebral chondroitin sulfate upon Alzheimer's pathogenesis in mice.

    PubMed

    Zhang, Zui; Ohtake-Niimi, Shiori; Kadomatsu, Kenji; Uchimura, Kenji

    2016-08-01

    Alzheimer's disease (AD) is a progressive disorder leading to cognitive impairment and neuronal loss. Cerebral extracellular accumulation and deposition of amyloid ß plaques is a pathological hallmark of AD. Chondroitin sulfate (CS) is an extracellular component abundant in the brain. CS is a sulfated glycosaminoglycan covalently attached to a core protein, forming chondroitin sulfate proteoglycan. The structure of CS is heterogeneous with sulfation modification and elongation of the chain. The structural diversity of CS allows it to play various roles in the brain. Increasing evidence has shown that CS promotes aggregation of amyloid ß peptides into higher-order species such as insoluble amyloid ß fibrils. Difficulties in the structural analysis of brain CS, as well as its heterogeneity, limit the study of potential roles of CS in AD pathology. Here we established a microanalysis method with reversed-phase ion-pair high performance liquid chromatography and found that CS in the brains of Tg2576 AD model mice show a lower molecular size and an increased ratio of CS-B motif di-sulfated disaccharide. Our findings provide insight into the structural changes of cerebral CS upon Alzheimer's pathogenesis. PMID:27578913

  17. Physiological and Molecular Alterations Promoted by Schizotetranychus oryzae Mite Infestation in Rice Leaves.

    PubMed

    Buffon, Giseli; Blasi, Édina A R; Adamski, Janete M; Ferla, Noeli J; Berger, Markus; Santi, Lucélia; Lavallée-Adam, Mathieu; Yates, John R; Beys-da-Silva, Walter O; Sperotto, Raul A

    2016-02-01

    Infestation of phytophagous mite Schizotetranychus oryzae in rice causes critical yield losses. To better understand this interaction, we employed Multidimensional Protein Identification Technology (MudPIT) approach to identify differentially expressed proteins. We detected 18 and 872 unique proteins in control and infested leaves, respectively, along with 32 proteins more abundant in control leaves. S. oryzae infestation caused decreased abundance of proteins related to photosynthesis (mostly photosystem II-related), carbon assimilation and energy production, chloroplast detoxification, defense, and fatty acid and gibberellin synthesis. On the contrary, infestation caused increased abundance of proteins involved in protein modification and degradation, gene expression at the translation level, protein partitioning to different organelles, lipid metabolism, actin cytoskeleton remodeling, and synthesis of jasmonate, amino acid, and molecular chaperones. Our results also suggest that S. oryzae infestation promotes cell-wall remodeling and interferes with ethylene biosynthesis in rice leaves. Proteomic data were positively correlated with enzymatic assays and RT-qPCR analysis. Our findings describe the protein expression patterns of infested rice leaves and suggest that the acceptor side of PSII is probably the major damaged target in the photosynthetic apparatus. These data will be useful in future biotechnological approaches aiming to induce phytophagous mite resistance in rice. PMID:26667653

  18. Cellular and molecular alterations in human epithelial cells transformed by high let radiation

    NASA Astrophysics Data System (ADS)

    Hei, T. K.; Piao, C. Q.; Sutter, T.; Willey, J. C.; Suzuki, K.

    An understanding of the radiobiological effects of high LET radiation is essential for human risk estimation and radiation protection. In the present study, we show that a single, 30 cGy dose of 150 keV/mum ^4He ions can malignantly transform human papillomavirus immortalized human bronchial epithelial [BEP2D] cells. Transformed cells produce progressively growing tumors in nude mice. The transformation frequency by the single dose of alpha particles is estimated to be approximately 4 x 10^-7. Based on the average cross-sectional area of BEP2D cells, it can be calculated that a mean traversal of 1.4 particles per cell is sufficient to induce tumorigenic conversion of these cells 3 to 4 months post-irradiation. Tumorigenic BEP2D cells overexpress mutated p53 tumor suppressor oncoproteins in addition to the cell cycle control gene cyclin D1 and D2. This model provides an opportunity to study the cellular and molecular changes at the various stages in radiation carcinogenesis involving human cells.

  19. The Diagnostic Use of Immunohistochemical Surrogates for Signature Molecular Genetic Alterations in Gliomas.

    PubMed

    Tanboon, Jantima; Williams, Erik A; Louis, David N

    2016-01-01

    A number of key mutations that affect treatment and prognosis have been identified in human gliomas. Two major ways to identify these mutations in a tumor sample are direct interrogation of the mutated DNA itself and immunohistochemistry to assess the effects of the mutated genes on proteins. Immunohistochemistry is an affordable, robust, and widely available technology that has been in place for decades. For this reason, the use of immunohistochemical approaches to assess molecular genetic changes has become an essential component of state-of-the-art practice. In contrast, even though DNA sequencing technologies are undergoing rapid development, many medical centers do not have access to such methodologies and may be thwarted by the relatively high costs of sending out such tests to reference laboratories. This review summarizes the current experience using immunohistochemistry of glioma samples to identify mutations in IDH1, TP53, ATRX, histone H3 genes, BRAF, EGFR, MGMT, CIC, and FUBP1 as well as guidelines for prudent use of DNA sequencing as a supplemental method. PMID:26671986

  20. Systematic Analysis of Sex-Linked Molecular Alterations and Therapies in Cancer

    PubMed Central

    Ma, Jonathan; Malladi, Sadhika; Beck, Andrew H

    2016-01-01

    Though patient sex influences response to cancer treatments, little is known of the molecular causes, and cancer therapies are generally given irrespective of patient sex. We assessed transcriptomic differences in tumors from men and women spanning 17 cancer types, and we assessed differential expression between tumor and normal samples stratified by sex across 7 cancers. We used the LincsCloud platform to perform Connectivity Map analyses to link transcriptomic signatures identified in male and female tumors with chemical and genetic perturbagens, and we performed permutation testing to identify perturbagens that showed significantly differential connectivity with male and female tumors. Our analyses predicted that females are sensitive and males are resistant to tamoxifen treatment of lung adenocarcinoma, a finding which is consistent with known male-female differences in lung cancer. We made several novel predictions, including that CDK1 and PTPN1 knockdown would be more effective in males with hepatocellular carcinoma, and SMAD3 and HSPA4 knockdown would be more effective in females with head and neck squamous cell carcinoma. Our results provide a new resource for researchers studying male-female biological and treatment response differences in human cancer. The complete results of our analyses are provided at the website accompanying this manuscript (http://becklab.github.io/SexLinked). PMID:26755347

  1. Antipsychotics-induced metabolic alterations: focus on adipose tissue and molecular mechanisms.

    PubMed

    Gonçalves, Pedro; Araújo, João Ricardo; Martel, Fátima

    2015-01-01

    The use of antipsychotic drugs for the treatment of mood disorders and psychosis has increased dramatically over the last decade. Despite its consumption being associated with beneficial neuropsychiatric effects in patients, atypical antipsychotics (which are the most frequently prescribed antipsychotics) use is accompanied by some secondary adverse metabolic effects such as weight gain, dyslipidemia and glucose intolerance. The molecular mechanisms underlying these adverse effects are not fully understood but have been suggested to involve a dysregulation of adipose tissue homeostasis. As such, the aim of this paper is to review and discuss the role of adipose tissue in the development of secondary adverse metabolic effects induced by atypical antipsychotics. Data analyzed in this article suggest that atypical antipsychotics may increase adipose tissue (particularly visceral adipose tissue) lipogenesis, differentiation/hyperplasia, pro-inflammatory mediator secretion and insulin resistance and decrease adipose tissue lipolysis. Consequently, patients receiving antipsychotic medication could be at risk of developing obesity, type 2 diabetes and cardiovascular disease. A better knowledge of the impact of these drugs on adipose tissue homeostasis may unveil strategies to develop novel antipsychotic drugs with less adverse metabolic effects and to develop adjuvant therapies (e.g. behavioral and nutritional therapies) to neuropsychiatric patients receiving antipsychotic medication. PMID:25523882

  2. Current Management Strategies in Breast Cancer by Targeting Key Altered Molecular Players

    PubMed Central

    Ali, Shazia; Mondal, Neelima; Choudhry, Hani; Rasool, Mahmood; Pushparaj, Peter N.; Khan, Mohammad A.; Mahfooz, Maryam; Sami, Ghufrana A.; Jarullah, Jummanah; Ali, Ashraf; Jamal, Mohammad S.

    2016-01-01

    Breast cancer is the second largest disease affecting women worldwide. It remains the most frequently reported and leading cause of death among women in both developed and developing countries. Tamoxifen and raloxifene are commonly used selective estrogen receptor modulators for treatment of breast cancer in women with high risk, although resistance occurs by tamoxifen after 5 years of therapy and both drugs cause uterine cancer and thromboembolic events. Aromatase inhibitors (AIs) are one of the optional modes used for breast cancer treatment. The combination of AIs along with tamoxifen can also be beneficial. Various therapeutic agents from different sources are being studied, which further need to be improved for potential outcome. For this, clinical trials based on large number of patients with optimal dose and lesser side effects have to be more in practice. Despite the clinical trials going on, there is need of better molecular models, which can identify high risk population, new agents with better benefit having less side effects, and improved biomarkers for treating breast cancer. PMID:26973813

  3. Septic Shock in Advanced Age: Transcriptome Analysis Reveals Altered Molecular Signatures in Neutrophil Granulocytes

    PubMed Central

    Vieira da Silva Pellegrina, Diogo; Severino, Patricia; Vieira Barbeiro, Hermes; Maziero Andreghetto, Flávia; Tadeu Velasco, Irineu; Possolo de Souza, Heraldo; Machado, Marcel Cerqueira César; Reis, Eduardo Moraes; Pinheiro da Silva, Fabiano

    2015-01-01

    Sepsis is one of the highest causes of mortality in hospitalized people and a common complication in both surgical and clinical patients admitted to hospital for non-infectious reasons. Sepsis is especially common in older people and its incidence is likely to increase substantially as a population ages. Despite its increased prevalence and mortality in older people, immune responses in the elderly during septic shock appear similar to that in younger patients. The purpose of this study was to conduct a genome-wide gene expression analysis of circulating neutrophils from old and young septic patients to better understand how aged individuals respond to severe infectious insult. We detected several genes whose expression could be used to differentiate immune responses of the elderly from those of young people, including genes related to oxidative phosphorylation, mitochondrial dysfunction and TGF-β signaling, among others. Our results identify major molecular pathways that are particularly affected in the elderly during sepsis, which might have a pivotal role in worsening clinical outcomes compared with young people with sepsis. PMID:26047321

  4. Molecular alterations in areas generating fast ripples in an animal model of temporal lobe epilepsy

    PubMed Central

    Winden, Kellen D.; Bragin, Anatol; Engel, Jerome; Geschwind, Dan H.

    2016-01-01

    The molecular basis of epileptogenesis is poorly characterized. Studies in humans and animal models have identified an electrophysiological signature that precedes the onset of epilepsy, which has been termed fast ripples (FRs) based on its frequency. Multiple lines of evidence implicate regions generating FRs in epileptogenesis, and FRs appear to demarcate the seizure onset zone, suggesting a role in ictogenesis as well. We performed gene expression analysis comparing areas of the dentate gyrus that generate FRs to those that do not generate FRs in a well-characterized rat model of epilepsy. We identified a small cohort of genes that are differentially expressed in FR versus non-FR brain tissue and used quantitative PCR to validate some of those that modulate neuronal excitability. Gene expression network analysis demonstrated conservation of gene co-expression between non-FR and FR samples, but examination of gene connectivity revealed changes that were most pronounced in the cm-40 module, which contains several genes associated with synaptic function and the differentially expressed genes Kcna4, Kcnv1, and Npy1r that are down-regulated in FRs. We then demonstrate that the genes within the cm-40 module are regulated by seizure activity and enriched for the targets of the RNA binding protein Elavl4. Our data suggest that seizure activity induces co-expression of genes associated with synaptic transmission and that this pattern is attenuated in areas displaying FRs, implicating the failure of this mechanism in the generation of FRs. PMID:25818007

  5. Molecular classification of thyroid lesions by combined testing for miRNA gene expression and somatic gene alterations

    PubMed Central

    Wylie, Dennis; Beaudenon‐Huibregtse, Sylvie; Haynes, Brian C.; Giordano, Thomas J.

    2016-01-01

    Abstract Multiple molecular markers contribute to the pathogenesis of thyroid cancer and can provide valuable information to improve disease diagnosis and patient management. We performed a comprehensive evaluation of miRNA gene expression in diverse thyroid lesions (n = 534) and developed predictive models for the classification of thyroid nodules, alone or in combination with genotyping. Expression profiling by reverse transcription‐quantitative polymerase chain reaction in surgical specimens (n = 257) identified specific miRNAs differentially expressed in 17 histopathological categories. Eight supervised machine learning algorithms were trained to discriminate benign from malignant lesions and evaluated for accuracy and robustness. The selected models showed invariant area under the receiver operating characteristic curve (AUC) in cross‐validation (0.89), optimal AUC (0.94) in an independent set of preoperative thyroid nodule aspirates (n = 235), and classified 92% of benign lesions as low risk/negative and 92% of malignant lesions as high risk/positive. Surgical and preoperative specimens were further tested for the presence of 17 validated oncogenic gene alterations in the BRAF, RAS, RET or PAX8 genes. The miRNA‐based classifiers complemented and significantly improved the diagnostic performance of the 17‐mutation panel (p < 0.001 for McNemar's tests). In a subset of resected tissues (n = 54) and in an independent set of thyroid nodules with indeterminate cytology (n = 42), the optimized ThyraMIR Thyroid miRNA Classifier increased diagnostic sensitivity by 30–39% and correctly classified 100% of benign nodules negative by the 17‐mutation panel. In contrast, testing with broad targeted next‐generation sequencing panels decreased diagnostic specificity by detecting additional mutations of unknown clinical significance in 19–39% of benign lesions. Our results demonstrate that, independent of mutational status, mi

  6. Molecular classification of thyroid lesions by combined testing for miRNA gene expression and somatic gene alterations.

    PubMed

    Wylie, Dennis; Beaudenon-Huibregtse, Sylvie; Haynes, Brian C; Giordano, Thomas J; Labourier, Emmanuel

    2016-04-01

    Multiple molecular markers contribute to the pathogenesis of thyroid cancer and can provide valuable information to improve disease diagnosis and patient management. We performed a comprehensive evaluation of miRNA gene expression in diverse thyroid lesions (n = 534) and developed predictive models for the classification of thyroid nodules, alone or in combination with genotyping. Expression profiling by reverse transcription-quantitative polymerase chain reaction in surgical specimens (n = 257) identified specific miRNAs differentially expressed in 17 histopathological categories. Eight supervised machine learning algorithms were trained to discriminate benign from malignant lesions and evaluated for accuracy and robustness. The selected models showed invariant area under the receiver operating characteristic curve (AUC) in cross-validation (0.89), optimal AUC (0.94) in an independent set of preoperative thyroid nodule aspirates (n = 235), and classified 92% of benign lesions as low risk/negative and 92% of malignant lesions as high risk/positive. Surgical and preoperative specimens were further tested for the presence of 17 validated oncogenic gene alterations in the BRAF, RAS, RET or PAX8 genes. The miRNA-based classifiers complemented and significantly improved the diagnostic performance of the 17-mutation panel (p < 0.001 for McNemar's tests). In a subset of resected tissues (n = 54) and in an independent set of thyroid nodules with indeterminate cytology (n = 42), the optimized ThyraMIR Thyroid miRNA Classifier increased diagnostic sensitivity by 30-39% and correctly classified 100% of benign nodules negative by the 17-mutation panel. In contrast, testing with broad targeted next-generation sequencing panels decreased diagnostic specificity by detecting additional mutations of unknown clinical significance in 19-39% of benign lesions. Our results demonstrate that, independent of mutational status, miRNA expression profiles are strongly

  7. Visualising the molecular alteration of the calcite (104) – water interface by sodium nitrate

    PubMed Central

    Hofmann, Sascha; Voïtchovsky, Kislon; Spijker, Peter; Schmidt, Moritz; Stumpf, Thorsten

    2016-01-01

    The reactivity of calcite, one of the most abundant minerals in the earth’s crust, is determined by the molecular details of its interface with the contacting solution. Recently, it has been found that trace concentrations of NaNO3 severely affect calcite’s (104) surface and its reactivity. Here we combine molecular dynamics (MD) simulations, X-ray reflectivity (XR) and in situ atomic force microscopy (AFM) to probe the calcite (104) – water interface in the presence of NaNO3. Simulations reveal density profiles of different ions near calcite’s surface, with NO3− able to reach closer to the surface than CO32− and in higher concentrations. Reflectivity measurements show a structural destabilisation of the (104) surfaces’ topmost atomic layers in NaNO3 bearing solution, with distorted rotation angles of the carbonate groups and substantial displacement of the lattice ions. Nanoscale AFM results confirm the alteration of crystallographic characteristics, and the ability of dissolved NaNO3 to modify the structure of interfacial water was observed by AFM force spectroscopy. Our experiments and simulations consistently evidence a dramatic deterioration of the crystals’ surface, with potentially important implications for geological and industrial processes. PMID:26877225

  8. Low molecular weight components of pollen alter bronchial epithelial barrier functions

    PubMed Central

    Blume, Cornelia; Swindle, Emily J; Gilles, Stefanie; Traidl-Hoffmann, Claudia; Davies, Donna E

    2015-01-01

    The bronchial epithelium plays a key role in providing a protective barrier against many environmental substances of anthropogenic or natural origin which enter the lungs during breathing. Appropriate responses to these agents are critical for regulation of tissue homeostasis, while inappropriate responses may contribute to disease pathogenesis. Here, we compared epithelial barrier responses to different pollen species, characterized the active pollen components and the signaling pathways leading to epithelial activation. Polarized bronchial cells were exposed to extracts of timothy grass (Phleum pratense), ragweed (Ambrosia artemisifolia), mugwort (Artemisia vulgaris), birch (Betula alba) and pine (Pinus sylvestris) pollens. All pollen species caused a decrease in ionic permeability as monitored trans-epithelial electrical resistance (TER) and induced polarized release of mediators analyzed by ELISA, with grass pollen showing the highest activity. Ultrafiltration showed that the responses were due to components <3kDa. However, lipid mediators, including phytoprostane E1, had no effect on TER, and caused only modest induction of mediator release. Reverse-phase chromatography separated 2 active fractions: the most hydrophilic maximally affected cytokine release whereas the other only affected TER. Inhibitor studies revealed that JNK played a more dominant role in regulation of barrier permeability in response to grass pollen exposure, whereas ERK and p38 controlled cytokine release. Adenosine and the flavonoid isorhamnetin present in grass pollen contributed to the overall effect on airway epithelial barrier responses. In conclusion, bronchial epithelial barrier functions are differentially affected by several low molecular weight components released by pollen. Furthermore, ionic permeability and innate cytokine production are differentially regulated. PMID:26451347

  9. Morphologic correlates of molecular alterations in extrauterine Müllerian carcinomas.

    PubMed

    Ritterhouse, Lauren L; Nowak, Jonathan A; Strickland, Kyle C; Garcia, Elizabeth P; Jia, Yonghui; Lindeman, Neal I; Macconaill, Laura E; Konstantinopoulos, Panagiotis A; Matulonis, Ursula A; Liu, Joyce; Berkowitz, Ross S; Nucci, Marisa R; Crum, Christopher P; Sholl, Lynette M; Howitt, Brooke E

    2016-08-01

    Extrauterine high-grade serous carcinomas can exhibit various histologic patterns including (1) classic architecture that is papillary, micropapillary and infiltrative and (2) solid, endometrioid, and transitional (ie, SET) patterns. Although the SET pattern has been associated with germline BRCA mutations, potential molecular underpinnings have not been fully investigated. DNA was isolated from 174 carcinomas of the fallopian tube, ovary, or peritoneum. Targeted next-generation sequencing was performed and single-nucleotide and copy number variants were correlated with morphologic subtype. Overall, 79% of tumors were classified as high-grade serous carcinoma (n=138), and the most common mutations in high-grade serous carcinomas were TP53 (94%), BRCA1 (25%), BRCA2 (11%), and ATM (7%). Among chemotherapy-naive high-grade serous carcinomas, 40 cases exhibited classic morphology and 40 cases had non-classic morphology (SET or ambiguous features). Mutations in homologous recombination pathways were seen across all tumor histotypes. High-grade serous carcinomas with homologous recombination mutations were six times more likely to be associated with non-classic histology (P=0.002) and were significantly more likely to be platinum sensitive and have improved progression-free survival (PFS) (P=0.007 and P=0.004, respectively). In a multivariate analysis adjusted for age, homologous recombination mutation status and increased copy number variants were independently associated with improved PFS (P=0.008 and P=0.005, respectively). These findings underscore the potential significance of variant morphologic patterns and comprehensive genomic analysis in high-grade serous carcinomas with potential implications for pathogenesis, as well as response to targeted therapies. PMID:27150160

  10. Genome-wide gene expression profiling reveals unsuspected molecular alterations in pemphigus foliaceus

    PubMed Central

    Malheiros, Danielle; Panepucci, Rodrigo A; Roselino, Ana M; Araújo, Amélia G; Zago, Marco A; Petzl-Erler, Maria Luiza

    2014-01-01

    Pemphigus foliaceus (PF) is a complex autoimmune disease characterized by bullous skin lesions and the presence of antibodies against desmoglein 1. In this study we sought to contribute to a better understanding of the molecular processes in endemic PF, as the identification of factors that participate in the pathogenesis is a prerequisite for understanding its biological basis and may lead to novel therapeutic interventions. CD4+ T lymphocytes are central to the development of the disease. Therefore, we compared genome-wide gene expression profiles of peripheral CD4+ T cells of various PF patient subgroups with each other and with that of healthy individuals. The patient sample was subdivided into three groups: untreated patients with the generalized form of the disease, patients submitted to immunosuppressive treatment, and patients with the localized form of the disease. Comparisons between different subgroups resulted in 135, 54 and 64 genes differentially expressed. These genes are mainly related to lymphocyte adhesion and migration, apoptosis, cellular proliferation, cytotoxicity and antigen presentation. Several of these genes were differentially expressed when comparing lesional and uninvolved skin from the same patient. The chromosomal regions 19q13 and 12p13 concentrate differentially expressed genes and are candidate regions for PF susceptibility genes and disease markers. Our results reveal genes involved in disease severity, potential therapeutic targets and previously unsuspected processes involved in the pathogenesis. Besides, this study adds original information that will contribute to the understanding of PF's pathogenesis and of the still poorly defined in vivo functions of most of these genes. PMID:24813052

  11. The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders

    PubMed Central

    2012-01-01

    Gastrointestinal symptoms and altered blood phospholipid profiles have been reported in patients with autism spectrum disorders (ASD). Most of the phospholipid analyses have been conducted on the fatty acid composition of isolated phospholipid classes following hydrolysis. A paucity of information exists on how the intact phospholipid molecular species are altered in ASD. We applied ESI/MS to determine how brain and blood intact phospholipid species were altered during the induction of ASD-like behaviors in rats following intraventricular infusions with the enteric bacterial metabolite propionic acid. Animals were infused daily for 8 days, locomotor activity assessed, and animals killed during the induced behaviors. Propionic acid infusions increased locomotor activity. Lipid analysis revealed treatment altered 21 brain and 30 blood phospholipid molecular species. Notable alterations were observed in the composition of brain SM, diacyl mono and polyunsaturated PC, PI, PS, PE, and plasmalogen PC and PE molecular species. These alterations suggest that the propionic acid rat model is a useful tool to study aberrations in lipid metabolism known to affect membrane fluidity, peroxisomal function, gap junction coupling capacity, signaling, and neuroinflammation, all of which may be associated with the pathogenesis of ASD. PMID:22747852

  12. Charged Particle Alterations of Surfaces in the Solar System

    NASA Technical Reports Server (NTRS)

    Johnson, R. E.

    1995-01-01

    The surfaces of 'airless' bodies in the solar system are exposed to the ambient plasma, micrometeorites, and the solar UV. The effects of these space weathering agents on surfaces in the solar system has been studied in this project. In the last three years work was carried out on volatile depletion at Mars, on sputtering of the lunar surface, on absorption by implanted S in vapor-deposited H2O and its relevance to observations of Europa's surface in the UV, and on the spectral changes produced on irradiating SO2 and its possible relevance to Io. In addition, the role of plasma-induced charging of E-ring grains was evaluated because of its relevance to E-ring particle source and the lifetime of the E-ring. Finally, the detection of sputtered material from Dione by the CAPS instrument on CASSINI was evaluated as a tool for analysis of satellite surface composition, and the role of sputtering on the ambient OH in the vicinity of the ice satellites and the E-ring was evaluated.

  13. Altered Nitric Oxide System in Cardiovascular and Renal Diseases

    PubMed Central

    Bae, Eun Hui; Ma, Seong Kwon; Kim, Soo Wan

    2016-01-01

    Nitric oxide (NO) is synthesized by a family of NO synthases (NOS), including neuronal, inducible, and endothelial NOS (n/i/eNOS). NO-mediated effects can be beneficial or harmful depending on the specific risk factors affecting the disease. In hypertension, the vascular relaxation response to acetylcholine is blunted, and that to direct NO donors is maintained. A reduction in the activity of eNOS is mainly responsible for the elevation of blood pressure, and an abnormal expression of iNOS is likely to be related to the progression of vascular dysfunction. While eNOS/nNOS-derived NO is protective against the development of atherosclerosis, iNOS-derived NO may be proatherogenic. eNOS-derived NO may prevent the progression of myocardial infarction. Myocardial ischemia/reperfusion injury is significantly enhanced in eNOS-deficient animals. An important component of heart failure is the loss of coronary vascular eNOS activity. A pressure-overload may cause severer left ventricular hypertrophy and dysfunction in eNOS null mice than in wild-type mice. iNOS-derived NO has detrimental effects on the myocardium. NO plays an important role in regulating the angiogenesis and slowing the interstitial fibrosis of the obstructed kidney. In unilateral ureteral obstruction, the expression of eNOS was decreased in the affected kidney. In triply n/i/eNOS null mice, nephrogenic diabetes insipidus developed along with reduced aquaporin-2 abundance. In chronic kidney disease model of subtotal-nephrectomized rats, treatment with NOS inhibitors decreased systemic NO production and induced left ventricular systolic dysfunction (renocardiac syndrome). PMID:27231671

  14. Molecular dynamics simulations highlight structural and functional alterations in deafness-related M34T mutation of connexin 26.

    PubMed

    Zonta, Francesco; Buratto, Damiano; Cassini, Chiara; Bortolozzi, Mario; Mammano, Fabio

    2014-01-01

    Mutations of the GJB2 gene encoding the connexin 26 (Cx26) gap junction protein, which is widely expressed in the inner ear, are the primary cause of hereditary non-syndromic hearing loss in several populations. The deafness-associated single amino acid substitution of methionine 34 (M34) in the first transmembrane helix (TM1) with a threonine (T) ensues in the production of mutant Cx26M34T channels that are correctly synthesized and assembled in the plasma membrane. However, mutant channels overexpressed in HeLa cells retain only 11% of the wild type unitary conductance. Here we extend and rationalize those findings by comparing wild type Cx26 (Cx26WT) and Cx26M34T mutant channels in silico, using molecular dynamics simulations. Our results indicate that the quaternary structure of the Cx26M34T hemichannel is altered at the level of the pore funnel due to the disruption of the hydrophobic interaction between M34 and tryptophan 3 (W3) in the N-terminal helix (NTH). Our simulations also show that external force stimuli applied to the NTHs can detach them from the inner wall of the pore more readily in the mutant than in the wild type hemichannel. These structural alterations significantly increase the free energy barrier encountered by permeating ions, correspondingly decreasing the unitary conductance of the Cx26M34T hemichannel. Our results accord with the proposal that the mutant resides most of the time in a low conductance state. However, the small displacement of the NTHs in our Cx26M34T hemichannel model is not compatible with the formation of a pore plug as in the related Cx26M34A mutant. PMID:24624091

  15. Context-Induced Reinstatement of Methamphetamine Seeking Is Associated with Unique Molecular Alterations in Fos-Expressing Dorsolateral Striatum Neurons

    PubMed Central

    Rubio, F. Javier; Liu, Qing-Rong; Li, Xuan; Cruz, Fabio C.; Leão, Rodrigo M.; Warren, Brandon L.; Kambhampati, Sarita; Babin, Klil R.; McPherson, Kylie B.; Cimbro, Raffaello; Bossert, Jennifer M.; Shaham, Yavin

    2015-01-01

    Context-induced reinstatement of drug seeking is a well established animal model for assessing the neural mechanisms underlying context-induced drug relapse, a major factor in human drug addiction. Neural activity in striatum has previously been shown to contribute to context-induced reinstatement of heroin, cocaine, and alcohol seeking, but not yet for methamphetamine seeking. In this study, we found that context-induced reinstatement of methamphetamine seeking increased expression of the neural activity marker Fos in dorsal but not ventral striatum. Reversible inactivation of neural activity in dorsolateral but not dorsomedial striatum using the GABA agonists muscimol and baclofen decreased context-induced reinstatement. Based on our previous findings that Fos-expressing neurons play a critical role in conditioned drug effects, we assessed whether context-induced reinstatement was associated with molecular alterations selectively induced within context-activated Fos-expressing neurons. We used fluorescence-activated cell sorting to isolate reinstatement-activated Fos-positive neurons from Fos-negative neurons in dorsal striatum and used quantitative PCR to assess gene expression within these two populations of neurons. Context-induced reinstatement was associated with increased expression of the immediate early genes Fos and FosB and the NMDA receptor subunit gene Grin2a in only Fos-positive neurons. RNAscope in situ hybridization confirmed that Grin2a, as well as Grin2b, expression were increased in only Fos-positive neurons from dorsolateral, but not dorsomedial, striatum. Our results demonstrate an important role of dorsolateral striatum in context-induced reinstatement of methamphetamine seeking and that this reinstatement is associated with unique gene alterations in Fos-expressing neurons. PMID:25855177

  16. Molecular dynamics simulations highlight structural and functional alterations in deafness–related M34T mutation of connexin 26

    PubMed Central

    Zonta, Francesco; Buratto, Damiano; Cassini, Chiara; Bortolozzi, Mario; Mammano, Fabio

    2014-01-01

    Mutations of the GJB2 gene encoding the connexin 26 (Cx26) gap junction protein, which is widely expressed in the inner ear, are the primary cause of hereditary non-syndromic hearing loss in several populations. The deafness–associated single amino acid substitution of methionine 34 (M34) in the first transmembrane helix (TM1) with a threonine (T) ensues in the production of mutant Cx26M34T channels that are correctly synthesized and assembled in the plasma membrane. However, mutant channels overexpressed in HeLa cells retain only 11% of the wild type unitary conductance. Here we extend and rationalize those findings by comparing wild type Cx26 (Cx26WT) and Cx26M34T mutant channels in silico, using molecular dynamics simulations. Our results indicate that the quaternary structure of the Cx26M34T hemichannel is altered at the level of the pore funnel due to the disruption of the hydrophobic interaction between M34 and tryptophan 3 (W3) in the N–terminal helix (NTH). Our simulations also show that external force stimuli applied to the NTHs can detach them from the inner wall of the pore more readily in the mutant than in the wild type hemichannel. These structural alterations significantly increase the free energy barrier encountered by permeating ions, correspondingly decreasing the unitary conductance of the Cx26M34T hemichannel. Our results accord with the proposal that the mutant resides most of the time in a low conductance state. However, the small displacement of the NTHs in our Cx26M34T hemichannel model is not compatible with the formation of a pore plug as in the related Cx26M34A mutant. PMID:24624091

  17. α-Cell Dysfunctions and Molecular Alterations in Male Insulinopenic Diabetic Mice Are Not Completely Corrected by Insulin.

    PubMed

    Dusaulcy, Rodolphe; Handgraaf, Sandra; Heddad-Masson, Mounia; Visentin, Florian; Vesin, Christian; Reimann, Franck; Gribble, Fiona; Philippe, Jacques; Gosmain, Yvan

    2016-02-01

    Glucagon and α-cell dysfunction are critical in the development of hyperglycemia during diabetes both in humans and rodents. We hypothesized that α-cell dysfunction leading to dysregulated glucagon secretion in diabetes is due to both a lack of insulin and intrinsic defects. To characterize α-cell dysfunction in diabetes, we used glucagon-Venus transgenic male mice and induced insulinopenic hyperglycemia by streptozotocin administration leading to alterations of glucagon secretion. We investigated the in vivo impact of insulinopenic hyperglycemia on glucagon-producing cells using FACS-sorted α-cells from control and diabetic mice. We demonstrate that increased glucagonemia in diabetic mice is mainly due to increases of glucagon release and biosynthesis per cell compared with controls without changes in α-cell mass. We identified genes coding for proteins involved in glucagon biosynthesis and secretion, α-cell differentiation, and potential stress markers such as the glucagon, Arx, MafB, cMaf, Brain4, Foxa1, Foxa3, HNF4α, TCF7L2, Glut1, Sglt2, Cav2.1, Cav2.2, Nav1.7, Kir6.2/Sur1, Pten, IR, NeuroD1, GPR40, and Sumo1 genes, which were abnormally regulated in diabetic mice. Importantly, insulin treatment partially corrected α-cell function and expression of genes coding for proglucagon, or involved in glucagon secretion, glucose transport and insulin signaling but not those coding for cMAF, FOXA1, and α-cell differentiation markers as well as GPR40, NEUROD1, CAV2.1, and SUMO1. Our results indicate that insulinopenic diabetes induce marked α-cell dysfunction and molecular alteration, which are only partially corrected by in vivo insulin treatment. PMID:26696123

  18. Molecular and Physiological Mechanisms of Membrane Receptor Systems Functioning

    PubMed Central

    Severin, E.S.; Savvateeva, M.V.

    2011-01-01

    Molecular physiology is a new interdisciplinary field of knowledge that looks into how complicated biological systems function. The living cell is a relatively simple, but at the same time very sophisticated biological system. After the sequencing of the human genome, molecular physiology has endeavored to investigate the systems of cellular interactions at a completely new level based on knowledge of the spatial organization and functions of receptors, their ligands, and protein-protein interactions. In recent years, the achievements in molecular physiology have centered on the study of sensor reception mechanisms and intercellular data transfer, as well as the immune system physiology, amongst other processes. PMID:22649671

  19. ToF-SIMS imaging of molecular-level alteration mechanisms in Le Bonheur de vivre by Henri Matisse

    NASA Astrophysics Data System (ADS)

    Voras, Zachary E.; deGhetaldi, Kristin; Wiggins, Marcie B.; Buckley, Barbara; Baade, Brian; Mass, Jennifer L.; Beebe, Thomas P.

    2015-11-01

    Time-of-flight secondary ion mass spectrometry (ToF-SIMS) has recently been shown to be a valuable tool for cultural heritage studies, especially when used in conjunction with established analytical techniques in the field. The ability of ToF-SIMS to simultaneously image inorganic and organic species within a paint cross section at micrometer-level spatial resolution makes it a uniquely qualified analytical technique to aid in further understanding the processes of pigment and binder alteration, as well as pigment-binder interactions. In this study, ToF-SIMS was used to detect and image both molecular and elemental species related to CdS pigment and binding medium alteration on the painting Le Bonheur de vivre (1905-1906, The Barnes Foundation) by Henri Matisse. Three categories of inorganic and organic components were found throughout Le Bonheur de vivre and co-localized in cross-sectional samples using high spatial resolution ToF-SIMS analysis: (1) species relating to the preparation and photo-induced oxidation of CdS yellow pigments (2) varying amounts of long-chain fatty acids present in both the paint and primary ground layer and (3) specific amino acid fragments, possibly relating to the painting's complex restoration history. ToF-SIMS's ability to discern both organic and inorganic species via cross-sectional imaging was used to compare samples collected from Le Bonheur de vivre to artificially aged reference paints in an effort to gather mechanistic information relating to alteration processes that have been previously explored using μXANES, SR-μXRF, SEM-EDX, and SR-FTIR. The relatively high sensitivity offered by ToF-SIMS imaging coupled to the high spatial resolution allowed for the positive identification of degradation products (such as cadmium oxalate) in specific paint regions that have before been unobserved. The imaging of organic materials has provided an insight into the extent of destruction of the original binding medium, as well as

  20. 75 FR 5606 - Privacy Act of 1974; Report of an Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-03

    ... to alter Campus Based Branch (CBB) loans and scholarships System of Records (SORN), 09-15-0069, at the Division of Student Loans and Scholarships (DSLS). The system includes information on student and faculty borrowers who participate/participated in CBB loan and scholarship programs. The records in...

  1. 32 CFR Appendix B to Part 323 - Criteria for New and Altered Record Systems

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... DEFENSE (CONTINUED) PRIVACY PROGRAM DEFENSE LOGISTICS AGENCY PRIVACY PROGRAM Pt. 323, App. B Appendix B to... restrictions. 1. The OMB may authorize a Federal agency to begin operation of a system of records before the... 32 National Defense 2 2012-07-01 2012-07-01 false Criteria for New and Altered Record Systems...

  2. 75 FR 13076 - Privacy Act of 1974; Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-18

    ... Register on February 21, 2006 (71 FR 8839) is amended as below. The system of records entitled COMMERCE... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF COMMERCE Privacy Act of 1974; Altered System of Records AGENCY: U.S. Census Bureau, Department of Commerce....

  3. 75 FR 5604 - Privacy Act of 1974; Report of an Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-03

    ...In accordance with the requirements of the Privacy Act of 1974, the Health Resources and Services Administration (HRSA) is proposing to alter a system of records for Disability Claims of the Nursing Student Loan Program in the Bureau of Health Professions, SORN 09-15-0038, at the Division of Student Loans and Scholarships (DSLS). This system includes information on applicants for cancellation......

  4. CDK8 expression in 470 colorectal cancers in relation to beta-catenin activation, other molecular alterations and patient survival.

    PubMed

    Firestein, Ron; Shima, Kaori; Nosho, Katsuhiko; Irahara, Natsumi; Baba, Yoshifumi; Bojarski, Emeric; Giovannucci, Edward L; Hahn, William C; Fuchs, Charles S; Ogino, Shuji

    2010-06-15

    Alterations in the Wnt/beta-catenin pathway define a key event in the pathogenesis of colon cancer. We have recently shown that CDK8, the gene encoding a cyclin-dependent kinase (CDK) component of the Mediator complex, acts as a colon cancer oncogene that is necessary for beta-catenin activity. Here, we tested the hypothesis that colorectal cancers with CDK8 expression have distinct clinical, prognostic and molecular attributes. Among 470 colorectal cancers identified in 2 prospective cohort studies, CDK8 expression was detected in 329 (70%) tumors by immunohistochemistry. Cox proportional hazards model and backward stepwise elimination were used to compute hazard ratio (HR) of deaths according to CDK8 status, initially adjusted for various patient and molecular features, including beta-catenin, p53, p21, p27 (CDK inhibitors), cyclin D1, fatty acid synthase (FASN), cyclooxygenase-2 (COX-2), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), LINE-1 methylation, and mutations in KRAS, BRAF and PIK3CA. CDK8 expression in colorectal cancer was independently associated with beta-catenin activation (p = 0.0002), female gender (p < 0.0001) and FASN overexpression (p = 0.0003). Among colon cancer patients, CDK8 expression significantly increased colon cancer-specific mortality in both univariate analysis [HR 1.70; 95% confidence interval (CI), 1.03-2.83; p = 0.039] and multivariate analysis (adjusted HR 2.05; 95% CI, 1.18-3.56; p = 0.011) that was adjusted for potential confounders including beta-catenin, COX-2, FASN, LINE-1 hypomethylation, CIMP and MSI. CDK8 expression was unrelated with clinical outcome among rectal cancer patients. These data support a potential link between CDK8 and beta-catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis. PMID:19790197

  5. Molecular alterations and expression of succinate dehydrogenase complex in wild-type KIT/PDGFRA/BRAF gastrointestinal stromal tumors.

    PubMed

    Celestino, Ricardo; Lima, Jorge; Faustino, Alexandra; Vinagre, João; Máximo, Valdemar; Gouveia, António; Soares, Paula; Lopes, José Manuel

    2013-05-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, disclosing somatic KIT, PDGFRA and BRAF mutations. Loss of function of succinate dehydrogenase (SDH) complex is an alternative molecular mechanism in GISTs, namely in carriers of germline mutations of the SDH complex that develop Carney-Stratakis dyad characterized by multifocal GISTs and multicentric paragangliomas (PGLs). We studied a series of 25 apparently sporadic primary wild-type (WT) KIT/PDGFRA/BRAF GISTs occurring in patients without personal or familial history of PGLs, re-evaluated clinicopathological features and analyzed molecular alterations and immunohistochemistry expression of SDH complex. As control, we used a series of well characterized 49 KIT/PDGFRA/BRAF-mutated GISTs. SDHB expression was absent in 20% and SDHB germline mutations were detected in 12% of WT GISTs. Germline SDHB mutations were significantly associated to younger age at diagnosis. A significant reduction in SDHB expression in WT GISTs was found when compared with KIT/PDGFRA/BRAF-mutated GISTs. No significant differences were found when comparing DOG-1 and c-KIT expression in WT, SDHB-mutated and KIT/PDGFRA/BRAF-mutated GISTs. Our results confirm the occurrence of germline SDH genes mutations in isolated, apparently sporadic WT GISTs. WT KIT/PDGFRA/BRAF GISTs without SDHB or SDHA/SDHB expression may correspond to Carney-Stratakis dyad or Carney triad. Most importantly, the possibility of PGLs (Carney-Stratakis dyad) and/or pulmonary chondroma (Carney triad) should be addressed in these patients and their kindred. PMID:22948025

  6. Increase in 4-coumaryl alcohol units during lignification in alfalfa (Medicago sativa) alters the extractability and molecular weight of lignin.

    PubMed

    Ziebell, Angela; Gracom, Kristen; Katahira, Rui; Chen, Fang; Pu, Yunqiao; Ragauskas, Art; Dixon, Richard A; Davis, Mark

    2010-12-10

    The lignin content of biomass can impact the ease and cost of biomass processing. Lignin reduction through breeding and genetic modification therefore has potential to reduce costs in biomass-processing industries (e.g. pulp and paper, forage, and lignocellulosic ethanol). We investigated compositional changes in two low-lignin alfalfa (Medicago sativa) lines with antisense down-regulation of p-coumarate 3-hydroxylase (C3H) or hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyltransferase (HCT). We investigated whether the difference in reactivity during lignification of 4-coumaryl alcohol (H) monomers versus the naturally dominant sinapyl alcohol and coniferyl alcohol lignin monomers alters the lignin structure. Sequential base extraction readily reduced the H monomer content of the transgenic lines, leaving a residual lignin greatly enriched in H subunits; the extraction profile highlighted the difference between the control and transgenic lines. Gel permeation chromatography of isolated ball-milled lignin indicated significant changes in the weight average molecular weight distribution of the control versus transgenic lines (CTR1a, 6000; C3H4a, 5500; C3H9a, 4000; and HCT30a, 4000). PMID:20921228

  7. Phenotypic and Molecular Alterations in the Mammary Tissue of R-Spondin1 Knock-Out Mice during Pregnancy.

    PubMed

    Chadi, Sead; Polyte, Jacqueline; Lefevre, Lucas; Castille, Johan; Ehanno, Aude; Laubier, Johann; Jaffrézic, Florence; Le Provost, Fabienne

    2016-01-01

    R-spondin1 (Rspo1) is a member of a secreted protein family which has pleiotropic functions in development and stem cell growth. Rspo1 knock-out mice are sex-reversed, but some remain sub-fertile, so they fail to nurse their pups. A lack of Rspo1 expression in the mammary gland results in an absence of duct side-branching development and defective alveolar formation. The aim of this study was to characterize the phenotypic and molecular alterations of mammary gland due to Rspo1 knock-out. Using the transcriptional profiling of mammary tissues, we identified misregulated genes in the mammary gland of Rspo1 knock-out mice during pregnancy. A stronger expression of mesenchymal markers was observed, without modifications to the structure of mammary epithelial tissue. Mammary epithelial cell immunohistochemical analysis revealed a persistence of virgin markers, which signify a delay in cell differentiation. Moreover, serial transplantation experiments showed that Rspo1 is associated with a regenerative potential of mammary epithelial cell control. Our finding also highlights the negatively regulated expression of Rspo1's partners, Lgr4 and RNF43, in the mammary gland during pregnancy. Moreover, we offer evidence that Tgf-β signalling is modified in the absence of Rspo1. Taken together, our results show an abrupt halt or delay to mammary development during pregnancy due to the loss of a further differentiated function. PMID:27611670

  8. Competition Effect in Atomic-Molecular System

    NASA Technical Reports Server (NTRS)

    Jia, Suotang; Qin, Lijuan; Qian, Zuliang; Wang, Zugeng; Wang, Gang; Zhou, Guosheng

    1996-01-01

    The competition effects among the processes of atomic ionization, optical pumped stimulated radiation (OPSR), four-wave frequency mixing (FWFM) and molecular stimulated diffuse band radiation at the atomic two-photon resonance of 3S approaches 4D in Na2 - Na mixture were observed. The dip at the two-photon resonance in the excitation spectrum for the diffuse-band radiation was interpreted as suppression of population in 4D state.

  9. [Molecular Approaches for the Diagnosis of Central Nervous System Infections].

    PubMed

    Ohkusu, Kiyofumi

    2015-07-01

    In recent years, molecular microbiology techniques have proven to be a useful supplement to conventional assays not only in identification of strains from culture, but also in direct detection of pathogens from clinical specimens. This review explores the application of molecular diagnostic techniques for infectious diseases in certain clinical contexts. It aims to assess how these molecular techniques can be integrated to enhance diagnostic capabilities for infectious diseases of the central nervous system. Finally, it emphasizes the need for close collaboration between physicians and clinical microbiologists when considering molecular diagnostics from unusual specimens/cases, because assays must be customized according to the clinical settings. PMID:26160810

  10. A Palaeoproterozoic multi-stage hydrothermal alteration system at Nalunaq gold deposit, South Greenland

    NASA Astrophysics Data System (ADS)

    Bell, Robin-Marie; Kolb, Jochen; Waight, Tod Earle; Bagas, Leon; Thomsen, Tonny B.

    2016-07-01

    Nalunaq is an orogenic, high gold grade deposit situated on the Nanortalik Peninsula, South Greenland. Mineralisation is hosted in shear zone-controlled quartz veins, located in fine- and medium-grained amphibolite. The deposit was the site of Greenland's only operating metalliferous mine until its closure in 2014, having produced 10.67 t of gold. This study uses a combination of field investigation, petrography and U/Pb zircon and titanite geochronology to define a multi-stage hydrothermal alteration system at Nalunaq. A clinopyroxene-plagioclase-garnet(-sulphide) alteration zone (CPGZ) developed in the Nanortalik Peninsula, close to regional peak metamorphism and prior to gold-quartz vein formation. The ca. 1783-1762-Ma gold-quartz veins are hosted in reactivated shear zones with a hydrothermal alteration halo of biotite-arsenopyrite-sericite-actinolite-pyrrhotite(-chlorite-plagioclase-löllingite-tourmaline-titanite), which is best developed in areas of exceptionally high gold grades. Aplite dykes dated to ca. 1762 Ma cross-cut the gold-quartz veins, providing a minimum age for mineralisation. A hydrothermal calcite-titanite alteration assemblage is dated to ca. 1766 Ma; however, this alteration is highly isolated, and as a result, its field relationships are poorly constrained. The hydrothermal alteration and mineralisation is cut by several generations of ca. 1745-Ma biotite granodiorite accompanied by brittle deformation. A ca. 1745-Ma lower greenschist facies hydrothermal epidote-calcite-zoisite alteration assemblage with numerous accessory minerals forms halos surrounding the late-stage fractures. The contrasting hydrothermal alteration styles at Nalunaq indicate a complex history of exhumation from amphibolite facies conditions to lower greenschist facies conditions in an orogenic belt which resembles modern Phanerozoic orogens.

  11. 77 FR 1073 - Privacy Act of 1974; Report of an Altered System of Records, Including Addition of Routine Uses...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-09

    ...The Food and Drug Administration (FDA) is announcing an alteration to an existing System of Records (System) titled ``Bioresearch Monitoring Information System, HHS/FDA'' (System No. 09- 10-0010). Among other updates, this alteration adds new routine uses for disclosures of certain relevant information to Agencies, authorities, and organizations with responsibilities related to clinical......

  12. Plasma-induced sputtering and chemical alteration of solar system surfaces

    NASA Astrophysics Data System (ADS)

    Johnson, R. E.; Cassidy, T. A.; Leblanc, F.

    The surfaces of a number of solar system bodies are directly exposed to relative intense plasmas as well as UV photon bombardment. This irradiation can produce a very tenuous atmosphere and can chemically alter the surface (Johnson 1990; 2002; Madey et al. 2002). Such processes have been shown to be critical in understanding the ambient gas and plasma as well as the reflectance properties of the icy Galilean satellites (e.g., Johnson et al. 2004), and similarly affect other icy bodies in the outer solar system. Plasma and UV sputtering have produced, for instance, detectable molecular oxygen atmospheres at Europa (e.g., Shematovich et al. 2005) and Ganymede and the molecular oxygen above Saturn's main rings (Johnson et al. 2006). This bombardment also sputters (Jurac et al. 2001) and charges (Jurac et al. 1995) the icy grains in Saturn's tenuous rings. Plasma and UV irradiation have been shown to produce the alkali atmospheres observed at the Moon and Mercury (e.g., Leblanc and Johnson 2002; Leblanc et al. 2003) as well as at Europa (e.g., Leblanc et al. 2005; Cassidy and Johnson 2005). In this paper I will review the data on the effect of plasmas on laboratory surfaces and then will describe its application to regoliths (Cassidy and Johnson 2005) on a number of solar system bodies. References: Cassidy, T.A. and R.E. Johnson, Monte Carlo madel of sputtering and other ejection processes within a regolith", Icarus 176, 499-507 (2005). Johnson, R.E., Energetic Charged-Particle Interactions with Atmospheres and Surfaces, Springer (1990). Johnson, R.E., Surface Boundary Layer Atmospheres, in Atmospheres in the Solar System: Comparative Aeronomy. Geophys. Mono. 130, 203-219 (2002). Johnson, R.E., R.W. Carlson, J.F. Cooper, C. Paranicas, M.H. Moore, and M.C. Wong, "Radiation Effects on the Surface of the Galilean Satellites", In Jupiter-The Planet, Satellites and Magnetosphere, Ed. F. Bagenal, T. Dowling, and W.B. McKinnon, Cambridge University, Cambridge. Chapter 20, pp

  13. Genetic Ablation of Calcium-independent Phospholipase A2γ Leads to Alterations in Hippocampal Cardiolipin Content and Molecular Species Distribution, Mitochondrial Degeneration, Autophagy, and Cognitive Dysfunction*

    PubMed Central

    Mancuso, David J.; Kotzbauer, Paul; Wozniak, David F.; Sims, Harold F.; Jenkins, Christopher M.; Guan, Shaoping; Han, Xianlin; Yang, Kui; Sun, Gang; Malik, Ibrahim; Conyers, Sara; Green, Karen G.; Schmidt, Robert E.; Gross, Richard W.

    2009-01-01

    Genetic ablation of calcium-independent phospholipase A2γ (iPLA2γ) results in profound alterations in hippocampal phospholipid metabolism and mitochondrial phospholipid homeostasis resulting in enlarged and degenerating mitochondria leading to autophagy and cognitive dysfunction. Shotgun lipidomics demonstrated multiple alterations in hippocampal lipid metabolism in iPLA2γ−/− mice including: 1) a markedly elevated hippocampal cardiolipin content with an altered molecular species composition characterized by a shift to shorter chain length molecular species; 2) alterations in both choline and ethanolamine glycerophospholipids, including a decreased plasmenylethanolamine content; 3) increased oxidized phosphatidylethanolamine molecular species; and 4) an increased content of ceramides. Electron microscopic examination demonstrated the presence of enlarged heteromorphic lamellar structures undergoing degeneration accompanied by the presence of ubiquitin positive spheroid inclusion bodies. Purification of these enlarged heteromorphic lamellar structures by buoyant density centrifugation and subsequent SDS-PAGE and proteomics identified them as degenerating mitochondria. Collectively, these results identify the obligatory role of iPLA2γ in neuronal mitochondrial lipid metabolism and membrane structure demonstrating that iPLA2γ loss of function results in a mitochondrial neurodegenerative disorder characterized by degenerating mitochondria, autophagy, and cognitive dysfunction. PMID:19840936

  14. 76 FR 4474 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ...The Department of Health and Human Services proposes to alter System of Records, 09-20-0159, ``Records of Subject in Certification, Testing, Studies of Personal Protective Devices, and Accident Investigations, HHS/CDC/NIOSH.'' HHS is proposing to add the following Breach Response Routine Use Language to comply with the Office of Management and Budget (OMB) Memoranda (M) 07-16, Safeguarding......

  15. 76 FR 4436 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ...The Department of Health and Human Services proposes to alter System of Records, 09-20-0055, ``Administrative Files for Research/ Demonstration and Training Grants, and Cooperative Agreements Applications, HHS/CDC/PGO.'' HHS is proposing to add the following Breach Response Routine Use Language to comply with the Office of Management and Budget (OMB) Memoranda (M) 07-16, Safeguarding Against......

  16. 76 FR 4435 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ...The Department of Health and Human Services proposes to alter System of Records, 09-20-0001, ``Certifying Interpreting Physician File, HHS/CDC/NIOSH.'' HHS is proposing to add the following Breach Response Routine Use Language to comply with the Office of Management and Budget (OMB) Memoranda (M) 07-16, Safeguarding Against and responding to the Breach of Personally Identifiable Information:......

  17. 76 FR 4471 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ...The Department of Health and Human Services proposes to alter System of Records, 09-20-0154, ``Medical and Laboratory Studies, HHS/ CDC/NIOSH.'' HHS is proposing to add the following Breach Response Routine Use Language to comply with the Office of Management and Budget (OMB) Memoranda (M) 07-16, Safeguarding Against and responding to the Breach of Personally Identifiable Information: To......

  18. 76 FR 4463 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... HUMAN SERVICES Centers for Disease Control and Prevention Privacy Act of 1974; Report of Modified or... Program Records--Report of Modified or Altered System of Records Narrative Statement I. Background and... required to maintain Privacy Act safeguards. Certain diseases or exposures may be reported to State...

  19. 76 FR 4445 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... Health and Human Services proposes to alter System of Records, 09-20-0102, ``Alien Mental Waiver Program... defending a claim against the Public Health Service based upon an individual's mental or physical condition... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH...

  20. Investigating molecular alterations to profile short- and long-term recurrence-free survival in patients with primary glioblastoma

    PubMed Central

    FRANCESCHI, SARA; MAZZANTI, CHIARA M.; LESSI, FRANCESCA; ARETINI, PAOLO; CARBONE, FRANCESCO G.; LA FERLA, MARCO; SCATENA, CRISTIAN; ORTENZI, VALERIO; VANNOZZI, RICCARDO; FANELLI, GIOVANNI; PASQUALETTI, FRANCESCO; BEVILACQUA, GENEROSO; ZAVAGLIA, KATIA; NACCARATO, ANTONIO G.

    2015-01-01

    Glioblastoma (GB) is the most aggressive type of primary brain tumor. Despite the progress in recent years regarding the diagnosis and treatment of GB, the recurrence rate remains high, due to the infiltrative and dispersive nature of the tumor, which typically results in poor patient prognosis. In the present study, 19 formalin-fixed, paraffin-embedded GB samples were selected from patients with GB tumors. The samples were classified into a short or long recurrence-free survival (RFS) group, based on the time of first recurrence of the disease in the patients. The 19 samples were molecularly characterized for mutations in the isocitrate dehydrogenase 1 (IDH1) gene, amplification of the epidermal growth factor receptor (EGFR) gene, presence of the EGFR variant III, and methylation of the promoter region of the O6-methylguanine-DNA methyltransferase (MGMT) gene. Then, the expression of 84 genes involved in cell-cell and cell-matrix interactions, and that of 84 microRNAs (miRNAs) associated with brain cancer, was profiled. In addition, a copy number variation analysis of 23 genes reported to undergo frequent genomic alterations in human glioma was also performed. Differences in the expression levels of a number of genes were detected across the short and long RFS groups. Among these genes, 5 in particular were selected, and a 5-genes combination approach was developed, which was able to differentiate between patients with short and long RFS outcome. The high levels of sensitivity and precision displayed by this 5-genes combination approach, which were confirmed with a cross-validation method, provide a strong foundation for further validation of the involvement of the aforementioned genes in GB in a larger patient population. In conclusion, the present study has demonstrated how the expression pattern of miRNAs and mRNAs in patients with GB defines a particular molecular hallmark that may increase or reduce the aggressive behavior of GB tumors, thus influencing the

  1. 41 CFR 51-9.502 - Federal Register notice of establishment of new system or alteration of existing system.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 41 Public Contracts and Property Management 1 2012-07-01 2009-07-01 true Federal Register notice of establishment of new system or alteration of existing system. 51-9.502 Section 51-9.502 Public Contracts and Property Management Other Provisions Relating to Public Contracts COMMITTEE FOR PURCHASE FROM PEOPLE WHO ARE BLIND OR SEVERELY DISABLED...

  2. 44 CFR 6.71 - Federal Register notice of establishment of new system or alteration of existing system.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 44 Emergency Management and Assistance 1 2013-10-01 2013-10-01 false Federal Register notice of establishment of new system or alteration of existing system. 6.71 Section 6.71 Emergency Management and Assistance FEDERAL EMERGENCY MANAGEMENT AGENCY, DEPARTMENT OF HOMELAND SECURITY GENERAL IMPLEMENTATION OF THE PRIVACY ACT OF 1974 Report on...

  3. Peptide-Based Technologies to Alter Adenoviral Vector Tropism: Ways and Means for Systemic Treatment of Cancer

    PubMed Central

    Reetz, Julia; Herchenröder, Ottmar; Pützer, Brigitte M.

    2014-01-01

    Due to the fundamental progress in elucidating the molecular mechanisms of human diseases and the arrival of the post-genomic era, increasing numbers of therapeutic genes and cellular targets are available for gene therapy. Meanwhile, the most important challenge is to develop gene delivery vectors with high efficiency through target cell selectivity, in particular under in situ conditions. The most widely used vector system to transduce cells is based on adenovirus (Ad). Recent endeavors in the development of selective Ad vectors that target cells or tissues of interest and spare the alteration of all others have focused on the modification of the virus broad natural tropism. A popular way of Ad targeting is achieved by directing the vector towards distinct cellular receptors. Redirecting can be accomplished by linking custom-made peptides with specific affinity to cellular surface proteins via genetic integration, chemical coupling or bridging with dual-specific adapter molecules. Ideally, targeted vectors are incapable of entering cells via their native receptors. Such altered vectors offer new opportunities to delineate functional genomics in a natural environment and may enable efficient systemic therapeutic approaches. This review provides a summary of current state-of-the-art techniques to specifically target adenovirus-based gene delivery vectors. PMID:24699364

  4. Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1.

    PubMed

    Dawson, N; Kurihara, M; Thomson, D M; Winchester, C L; McVie, A; Hedde, J R; Randall, A D; Shen, S; Seymour, P A; Hughes, Z A; Dunlop, J; Brown, J T; Brandon, N J; Morris, B J; Pratt, J A

    2015-01-01

    Considerable evidence implicates DISC1 as a susceptibility gene for multiple psychiatric diseases. DISC1 has been intensively studied at the molecular, cellular and behavioral level, but its role in regulating brain connectivity and brain network function remains unknown. Here, we utilize a set of complementary approaches to assess the functional brain network abnormalities present in mice expressing a truncated Disc1 gene (Disc1tr Hemi mice). Disc1tr Hemi mice exhibited hypometabolism in the prefrontal cortex (PFC) and reticular thalamus along with a reorganization of functional brain network connectivity that included compromised hippocampal-PFC connectivity. Altered hippocampal-PFC connectivity in Disc1tr Hemi mice was confirmed by electrophysiological analysis, with Disc1tr Hemi mice showing a reduced probability of presynaptic neurotransmitter release in the monosynaptic glutamatergic hippocampal CA1-PFC projection. Glutamate system dysfunction in Disc1tr Hemi mice was further supported by the attenuated cerebral metabolic response to the NMDA receptor (NMDAR) antagonist ketamine and decreased hippocampal expression of NMDAR subunits 2A and 2B in these animals. These data show that the Disc1 truncation in Disc1tr Hemi mice induces a range of translationally relevant endophenotypes underpinned by glutamate system dysfunction and altered brain connectivity. PMID:25989143

  5. Efficient Molecular Dynamics Simulations of Multiple Radical Center Systems Based on the Fragment Molecular Orbital Method

    SciTech Connect

    Nakata, Hiroya; Schmidt, Michael W; Fedorov, Dmitri G; Kitaura, Kazuo; Nakamura, Shinichiro; Gordon, Mark S

    2014-10-16

    The fully analytic energy gradient has been developed and implemented for the restricted open-shell Hartree–Fock (ROHF) method based on the fragment molecular orbital (FMO) theory for systems that have multiple open-shell molecules. The accuracy of the analytic ROHF energy gradient is compared with the corresponding numerical gradient, illustrating the accuracy of the analytic gradient. The ROHF analytic gradient is used to perform molecular dynamics simulations of an unusual open-shell system, liquid oxygen, and mixtures of oxygen and nitrogen. These molecular dynamics simulations provide some insight about how triplet oxygen molecules interact with each other. Timings reveal that the method can calculate the energy gradient for a system containing 4000 atoms in only 6 h. Therefore, it is concluded that the FMO-ROHF method will be useful for investigating systems with multiple open shells.

  6. Molecular mechanisms of the shrimp clotting system.

    PubMed

    Maningas, Mary Beth B; Kondo, Hidehiro; Hirono, Ikuo

    2013-04-01

    Shrimp, like other invertebrates, relies solely on its innate immune system, to combat invading pathogens. The invertebrate immune system has ancient origins that involve cellular and humoral responses. The clotting system of the humoral immune response is the first line of defense against pathogens and also serves to prevent blood loss during injury and wound healing. Tranglutaminase and clotting protein are molecules involved in the blood clotting system of crayfish and shrimp. Studies have shown that the shrimp clotting system is linked with the activation of antimicrobial peptides, similar to that of the horseshoe crab. Unlike the horseshoe crab and crayfish blood coagulation which are well studied systems, blood clotting in shrimp remains poorly understood. Here we review the shrimp clotting system and its involvement in innate immunity. PMID:23044383

  7. A priming dose of protons alters the early cardiac cellular and molecular response to 56Fe irradiation

    NASA Astrophysics Data System (ADS)

    Ramadan, Samy S.; Sridharan, Vijayalakshmi; Koturbash, Igor; Miousse, Isabelle R.; Hauer-Jensen, Martin; Nelson, Gregory A.; Boerma, Marjan

    2016-02-01

    Purpose: Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a "priming" dose of protons on the cardiac cellular and molecular response to a "challenge" dose of 56Fe in a mouse model. Methods: Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of 56Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of 56Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Results: Exposure to 56Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before 56Fe prevented all of the responses to 56Fe. Conclusions: This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions.

  8. Molecular background and physiological consequences of altered peripheral serotonin homeostasis in adult rats perinatally treated with tranylcypromine.

    PubMed

    Blazevic, S; Erjavec, I; Brizic, M; Vukicevic, S; Hranilovic, D

    2015-08-01

    Serotonin (5-hydroxytryptamine, 5-HT) is a biologically active molecule present in mammals in the brain and peripheral tissues where it exerts many physiological functions. Developmental exposure to 5-HT-enhancing agents has been reported to induce long-lasting changes in the brain, but the long-term effects of perinatal 5-HT enhancement on 5-HT balance and function in the peripheral compartment have not been explored. Perinatal treatment of rats with monoamine oxidase (MAO) inhibitor tranylcypromine (TCP), leads to persistent imbalance in central (increased 5-HT degradation and decreased 5-HT concentrations in the brain) and peripheral (increased platelet and decreased plasma 5-HT concentrations) 5-HT homeostasis. In this study, we explored the molecular background of peripheral 5-HT imbalance, and its possible consequences on bone remodeling and hematopoiesis. Jejunum, liver and blood samples were collected from TCP- and saline-treated rats on post-natal day 70. Relative mRNA levels for tryptophan hydroxylase 1 (TPH1) and MAO A were analyzed using quantitative RT-PCR, femoral trabecular bone parameters were measured using microcomputed tomography, while peripheral blood cell number was determined by cell counter. TCP-treated rats displayed significant decrease in expression of Tph1, and significant increase in percentage of bone volume, trabecular number, connectivity density, and leukocyte number. In addition, significant negative correlation was observed between relative concentrations of TPH1 mRNA and trabecular bone parameters. Our results: a) show that perinatal exposure to tranylcypromine leads to long-lasting compensatory decrease in Tph1 expression in the peripheral compartment, accompanied with alterations in bone remodeling and hematopoiesis, b) suggest that peripheral and central 5HT compartment use different strategies to compensate for 5-HT imbalances of the same cause, and c) indicate dominant role of peripheral over central 5-HT in the regulation

  9. Molecular/cytogenetic alterations accompanying the development of multidrug resistance in the J774.2 murine cell line.

    PubMed

    Slovak, M L; Lothstein, L; Horwitz, S B; Trent, J M

    1988-07-01

    Mouse macrophage-like J774.2 cells were selected for resistance to colchicine and examined by molecular/cytogenetic analysis to determine whether the acquisition of the multidrug resistant (mdr) phenotype was associated with specific chromosomal rearrangements. Cytogenetic studies of the J774.2 parental and two colchicine-resistant (CLCR) sublines--J7.Cl-30 (770-fold CLCR) and J7.Cl-100 (2500-fold CLCR)--demonstrated specific numeric and structural karyotypic alterations accompanying the emergence of mdr. The parental cells demonstrated a modal chromosome number of 63, while the modal number of the J7.Cl-30 subline was 53. The most striking difference between the parental and J7.Cl-30 subline was the presence of an average of 60 double minutes (DMs) per cell in the CLCR cells. The 2500-fold resistant J7.Cl-100 subline displayed a modal number of 50, which included structural rearrangements involving chromosomes 2 and 7 and concomitant replacement of DMs by a homogeneously staining region (HSR). Southern blotting analysis demonstrated a approximately 35-fold amplification of P-glycoprotein homologous sequences in the J7.Cl-30 subline and approximately 70-fold amplification in the J7.Cl-100 subline. Chromosomal in situ hybridization localized the amplified P-glycoprotein sequences to DMs (J7.Cl-30) and the HSR (J7.Cl-100) in these CLCR sublines. Our results suggest that CLCR in J774.2 cells results from overexpression of P-glycoprotein via gene amplification which was accompanied by chromosomal evolution from DMs to an HSR. PMID:2899184

  10. COMT val158met polymorphism and molecular alterations in the human dorsolateral prefrontal cortex: Differences in controls and in schizophrenia.

    PubMed

    Shukla, Abhay A; Jha, Manish; Birchfield, Thomas; Mukherjee, Shibani; Gleason, Kelly; Abdisalaam, Salim; Asaithamby, Aroumougame; Adams-Huet, Beverley; Tamminga, Carol A; Ghose, Subroto

    2016-05-01

    The single nucleotide val158met polymorphism in catechol o-methyltransferase (COMT) influences prefrontal cortex function. Working memory, dependent on the dorsolateral prefrontal cortex (DLPFC), has been repeatedly shown to be influenced by this COMT polymorphism. The high activity COMT val isoform is associated with lower synaptic dopamine levels. Altered synaptic dopamine levels are expected to lead to molecular adaptations within the synapse and within DLPFC neural circuitry. In this human post mortem study using high quality DLPFC tissue, we first examined the influence of the COMT val158met polymorphism on markers of dopamine neurotransmission, N-methyl-d-aspartate (NMDA) receptor subunits and glutamatic acid decarboxylase 67 (GAD67), all known to be critical to DLPFC circuitry and function. Next, we compared target gene expression profiles in a cohort of control and schizophrenia cases, each characterized by COMT genotype. We find that the COMT val allele in control subjects is associated with significant upregulation of GluN2A and GAD67 mRNA levels compared to met carriers. Comparisons between control and schizophrenia groups reveal that GluN2A, GAD67 and DRD2 are differentially regulated between diagnostic groups in a genotype specific manner. Chronic antipsychotic treatment in rodents did not explain these differences. These data demonstrate an association between COMTval158met genotype and gene expression profile in the DLPFC of controls, possibly adaptations to maintain DLPFC function. In schizophrenia val homozygotes, these adaptations are not seen and could reflect pathophysiologic mechanisms related to the known poorer performance of these subjects on DLPFC-dependent tasks. PMID:27021555

  11. Development and application of the alteration mineral information extraction system based on ASTER data

    NASA Astrophysics Data System (ADS)

    Wang, Wei; Zhou, Wei; Yang, Rihong; Yuan, Tao

    2015-10-01

    In recent years, multi-spectral data have been widely used to prospect the source rock or source region of porphyry copper deposits. In this paper, we present a system to extract the information of alteration mineral from multi-spectral data. The system is developed with the Visual C# 2010 and IDL8.0 platform, and is able to process the ASTER multi-spectral data which is a new multiband file after layer stacking. Based on the principal component analysis, the ASTER data is processed automatically in this system. The result shows two components, the classified information of argillic- and phyllic-altered mineral assemblage and propylitization mineral assemblage. Compared with the traditional processes, the system not only lowers the threshold of the application of remote sensing technology, but also improves the work efficiency significantly.

  12. Molecular recognition in chemical and biological systems.

    PubMed

    Persch, Elke; Dumele, Oliver; Diederich, François

    2015-03-01

    Structure-based ligand design in medicinal chemistry and crop protection relies on the identification and quantification of weak noncovalent interactions and understanding the role of water. Small-molecule and protein structural database searches are important tools to retrieve existing knowledge. Thermodynamic profiling, combined with X-ray structural and computational studies, is the key to elucidate the energetics of the replacement of water by ligands. Biological receptor sites vary greatly in shape, conformational dynamics, and polarity, and require different ligand-design strategies, as shown for various case studies. Interactions between dipoles have become a central theme of molecular recognition. Orthogonal interactions, halogen bonding, and amide⋅⋅⋅π stacking provide new tools for innovative lead optimization. The combination of synthetic models and biological complexation studies is required to gather reliable information on weak noncovalent interactions and the role of water. PMID:25630692

  13. Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease.

    PubMed

    Mafra, Denise; Lobo, Julie C; Barros, Amanda F; Koppe, Laetitia; Vaziri, Nosratola D; Fouque, Denis

    2014-01-01

    The normal intestinal microbiota plays a major role in the maintenance of health and disease prevention. In fact, the alteration of the intestinal microbiota has been shown to contribute to the pathogenesis of several pathological conditions, including obesity and insulin resistance, among others. Recent studies have revealed profound alterations of the gut microbial flora in patients and animals with chronic kidney disease (CKD). Alterations in the composition of the microbiome in CKD may contribute to the systemic inflammation and accumulation of gut-derived uremic toxins, which play a central role in the pathogenesis of accelerated cardiovascular disease and numerous other CKD-associated complications. This review is intended to provide a concise description of the potential role of the CKD-associated changes in the gut microbiome and its potential role the pathogenesis of inflammation and uremic toxicity. In addition, the potential efficacy of pre- and pro-biotics in the restoration of the microbiome is briefly described. PMID:24762311

  14. Interactive analysis of systems biology molecular expression data

    PubMed Central

    Zhang, Mingwu; Ouyang, Qi; Stephenson, Alan; Kane, Michael D; Salt, David E; Prabhakar, Sunil; Burgner, John; Buck, Charles; Zhang, Xiang

    2008-01-01

    Background Systems biology aims to understand biological systems on a comprehensive scale, such that the components that make up the whole are connected to one another and work through dependent interactions. Molecular correlations and comparative studies of molecular expression are crucial to establishing interdependent connections in systems biology. The existing software packages provide limited data mining capability. The user must first generate visualization data with a preferred data mining algorithm and then upload the resulting data into the visualization package for graphic visualization of molecular relations. Results Presented is a novel interactive visual data mining application, SysNet that provides an interactive environment for the analysis of high data volume molecular expression information of most any type from biological systems. It integrates interactive graphic visualization and statistical data mining into a single package. SysNet interactively presents intermolecular correlation information with circular and heatmap layouts. It is also applicable to comparative analysis of molecular expression data, such as time course data. Conclusion The SysNet program has been utilized to analyze elemental profile changes in response to an increasing concentration of iron (Fe) in growth media (an ionomics dataset). This study case demonstrates that the SysNet software is an effective platform for interactive analysis of molecular expression information in systems biology. PMID:18312669

  15. Effects of chemical alteration on fracture mechanical properties in hydrothermal systems

    NASA Astrophysics Data System (ADS)

    Callahan, O. A.; Eichhubl, P.; Olson, J. E.

    2015-12-01

    Fault and fracture networks often control the distribution of fluids and heat in hydrothermal and epithermal systems, and in related geothermal and mineral resources. Additional chemical influences on conduit evolution are well documented, with dissolution and precipitation of mineral species potentially changing the permeability of fault-facture networks. Less well understood are the impacts of chemical alteration on the mechanical properties governing fracture growth and fracture network geometry. We use double-torsion (DT) load relaxation tests under ambient air conditions to measure the mode-I fracture toughness (KIC) and subcritical fracture growth index (SCI) of variably altered rock samples obtained from outcrop in Dixie Valley, NV. Samples from southern Dixie Valley include 1) weakly altered granite, characterized by minor sericite in plagioclase, albitization and vacuolization of feldspars, and incomplete replacement of biotite with chlorite, and 2) granite from an area of locally intense propylitic alteration with chlorite-calcite-hematite-epidote assemblages. We also evaluated samples of completely silicified gabbro obtained from the Dixie Comstock epithermal gold deposit. In the weakly altered granite KIC and SCI are 1.3 ±0.2 MPam1/2 (n=8) and 59 ±25 (n=29), respectively. In the propylitic assemblage KIC is reduced to 0.6 ±0.1 MPam1/2 (n=11), and the SCI increased to 75 ±36 (n = 33). In both cases, the altered materials have lower fracture toughness and higher SCI than is reported for common geomechanical standards such as Westerly Granite (KIC ~1.7 MPam1/2; SCI ~48). Preliminary analysis of the silicified gabbro shows a significant increase in fracture toughness, 3.6 ±0.4 MPam1/2 (n=2), and SCI, 102 ±45 (n=19), compared to published values for gabbro (2.9 MPam1/2 and SCI = 32). These results suggest that mineralogical and textural changes associated with different alteration assemblages may result in spatially variable rates of fracture

  16. Challenges in calculating molecular systems with Coulomb interactions

    NASA Astrophysics Data System (ADS)

    Kirnosov, Nikita; Sharkey, Keeper; Adamowicz, Ludwik

    2014-03-01

    The highly accurate quantum mechanical calculations are not only crucial for high-resolution experimental data verification, but may also serve as a guide in the field of exotic systems exploration. Including all non-relativistic effects in a single-step variational approach and rigorously separating out the center of mass motion allows us to build a reliable model for calculating bound states of molecular systems with Coulomb interactions. In these calculations the wave function of the system is expanded in terms of explicitly correlated Gaussian (ECG) basis functions. Examples of calculations of energies and other properties of some molecular systems will be presented.

  17. Impact of DNA mismatch repair system alterations on human fertility and related treatments.

    PubMed

    Hu, Min-hao; Liu, Shu-yuan; Wang, Ning; Wu, Yan; Jin, Fan

    2016-01-01

    DNA mismatch repair (MMR) is one of the biological pathways, which plays a critical role in DNA homeostasis, primarily by repairing base-pair mismatches and insertion/deletion loops that occur during DNA replication. MMR also takes part in other metabolic pathways and regulates cell cycle arrest. Defects in MMR are associated with genomic instability, predisposition to certain types of cancers and resistance to certain therapeutic drugs. Moreover, genetic and epigenetic alterations in the MMR system demonstrate a significant relationship with human fertility and related treatments, which helps us to understand the etiology and susceptibility of human infertility. Alterations in the MMR system may also influence the health of offspring conceived by assisted reproductive technology in humans. However, further studies are needed to explore the specific mechanisms by which the MMR system may affect human infertility. This review addresses the physiological mechanisms of the MMR system and associations between alterations of the MMR system and human fertility and related treatments, and potential effects on the next generation. PMID:26739522

  18. Impact of DNA mismatch repair system alterations on human fertility and related treatments*

    PubMed Central

    Hu, Min-hao; Liu, Shu-yuan; Wang, Ning; Wu, Yan; Jin, Fan

    2016-01-01

    DNA mismatch repair (MMR) is one of the biological pathways, which plays a critical role in DNA homeostasis, primarily by repairing base-pair mismatches and insertion/deletion loops that occur during DNA replication. MMR also takes part in other metabolic pathways and regulates cell cycle arrest. Defects in MMR are associated with genomic instability, predisposition to certain types of cancers and resistance to certain therapeutic drugs. Moreover, genetic and epigenetic alterations in the MMR system demonstrate a significant relationship with human fertility and related treatments, which helps us to understand the etiology and susceptibility of human infertility. Alterations in the MMR system may also influence the health of offspring conceived by assisted reproductive technology in humans. However, further studies are needed to explore the specific mechanisms by which the MMR system may affect human infertility. This review addresses the physiological mechanisms of the MMR system and associations between alterations of the MMR system and human fertility and related treatments, and potential effects on the next generation. PMID:26739522

  19. A molecular atlas of Xenopus respiratory system development

    PubMed Central

    Rankin, Scott A.; Tran, Hong Thi; Wlizla, Marcin; Mancini, Pamela; Shifley, Emily T.; Bloor, Sean D.; Han, Lu; Vleminckx, Kris; Wert, Susan E.; Zorn, Aaron M.

    2014-01-01

    Background Respiratory system development is regulated by a complex series of endoderm – mesoderm interactions that are not fully understood. Recently Xenopus has emerged as an alternative model to investigate early respiratory system development, but the extent to which the morphogenesis and molecular pathways involved are conserved between Xenopus and mammals has not been systematically documented. Results In this study we provide a histological and molecular atlas of Xenopus respiratory system development, focusing on Nkx2.1+ respiratory cell fate specification in the developing foregut. We document the expression patterns of Wnt/β-catenin, FGF, and BMP signaling components in the foregut and show that the molecular mechanisms of respiratory lineage induction are remarkably conserved between Xenopus and mice. Finally, using a number of functional experiments we refine the epistatic relationships between FGF, Wnt and BMP signaling in early Xenopus respiratory system development. Conclusions We demonstrate that Xenopus trachea and lung development, before metamorphosis, is comparable at the cellular and molecular levels to embryonic stages of mouse respiratory system development between E8.5 to E10.5. This molecular atlas provides a fundamental starting point for further studies using Xenopus as a model to define the conserved genetic programs controlling early respiratory system development. PMID:25156440

  20. [Molecular physiology of glycine receptors in nervous system of vertebrates].

    PubMed

    2014-03-01

    Glycine receptor is the anion-selective channel, providing fast synaptic transmission in the central nervous system of vertebrates. Together with the nicotinic acetylcholine, GABA and serotonin (5-HT3R) receptors, it belongs to the superfamily of pentameric cys-loop receptors. It has been cloned one beta and four alpha subunits of glycine receptor, which are specifically distributed in different areas of the nervous system. Due to their specific molecular properties and distribution, different subunits ensure important physiological functions: from control of motor activity and regulation of neuronal differentiation to sensory information processing and modulation of pain sensitivity. In this review we briefly describe main functions of these transmembrane proteins, their distribution and molecular architecture. Special attention is paid to recent studies on the molecular physiology of these receptors, as well as on presenting of molecular domains responsible for their modulation and dysfunction. PMID:25508361

  1. [Molecular physiology of glycine receptors in nervous system of vertebrates].

    PubMed

    Maleeva, G V; Brezhestovskiĭ, P D

    2014-03-01

    Glycine receptor is the anion-selective channel, providing fast synaptic transmission in the central nervous system of vertebrates. Together with the nicotinic acetylcholine, GABA and serotonin (5-HT3R) receptors, it belongs to the superfamily of pentameric cys-loop receptors. It has been cloned one beta and four alpha subunits of glycine receptor, which are specifically distributed in different areas of the nervous system. Due to their specific molecular properties and distribution, different subunits ensure important physiological functions: from control of motor activity and regulation of neuronal differentiation to sensory information processing and modulation of pain sensitivity. In this review we briefly describe main functions of these transmembrane proteins, their distribution and molecular architecture. Special attention is paid to recent studies on the molecular physiology of these receptors, as well as on presenting of molecular domains responsible for their modulation and dysfunction. PMID:25464730

  2. Electromagnetically induced grating in a crystal of molecular magnets system

    NASA Astrophysics Data System (ADS)

    Liu, Jibing; Liu, Na; Shan, Chuanjia; Liu, Tangkun; Li, Hong; Zheng, Anshou; Xie, Xiao-Tao

    2016-07-01

    We investigate the response of the molecular system to the magnetic field modulation. Molecular magnets are subjected to a strong standing ac magnetic field and a weak probe magnetic field. The transmission and absorption of the weak probe magnetic field can be changed due to quantum coherence and the spatially modulating of the standing field. And a electromagnetically induced grating is formed in the crystal of molecular magnets via electromagnetically induced transparency (EIT). The diffraction efficiency of the grating can be adjusted efficiently by tuning the intensity of the standing wave field and the single photon detuning.

  3. Engineering and Assembly of Protein Modules into Functional Molecular Systems.

    PubMed

    Hirschi, Stephan; Stauffer, Mirko; Harder, Daniel; Müller, Daniel J; Meier, Wolfgang; Fotiadis, Dimitrios

    2016-01-01

    Synthetic biology approaches range from the introduction of unique features into organisms to the assembly of isolated biomacromolecules or synthetic building blocks into artificial biological systems with biomimetic or completely novel functionalities. Simple molecular systems can be based on containers on the nanoscale that are equipped with tailored functional modules for various applications in healthcare, industry or biological and medical research. The concept, or vision, of assembling native or engineered proteins and/or synthetic components as functional modules into molecular systems is discussed. The main focus is laid on the engineering of energizing modules generating chemical energy, transport modules using this energy to translocate molecules between compartments of a molecular system, and catalytic modules (bio-)chemically processing the molecules. Further key aspects of this discourse are possible approaches for the assembly of simple nanofactories and their applications in biotechnology and medical health. PMID:27363367

  4. A molecular dynamics study of polymer/graphene interfacial systems

    SciTech Connect

    Rissanou, Anastassia N.; Harmandaris, Vagelis

    2014-05-15

    Graphene based polymer nanocomposites are hybrid materials with a very broad range of technological applications. In this work, we study three hybrid polymer/graphene interfacial systems (polystyrene/graphene, poly(methyl methacrylate)/graphene and polyethylene/graphene) through detailed atomistic molecular dynamics (MD) simulations. Density profiles, structural characteristics and mobility aspects are being examined at the molecular level for all model systems. In addition, we compare the properties of the hybrid systems to the properties of the corresponding bulk ones, as well as to theoretical predictions.

  5. STALK : an interactive virtual molecular docking system.

    SciTech Connect

    Levine, D.; Facello, M.; Hallstrom, P.; Reeder, G.; Walenz, B.; Stevens, F.; Univ. of Illinois

    1997-04-01

    Several recent technologies-genetic algorithms, parallel and distributed computing, virtual reality, and high-speed networking-underlie a new approach to the computational study of how biomolecules interact or 'dock' together. With the Stalk system, a user in a virtual reality environment can interact with a genetic algorithm running on a parallel computer to help in the search for likely geometric configurations.

  6. Exploring the Photophysical Properties of Molecular Systems Using Excited State Accelerated ab Initio Molecular Dynamics

    PubMed Central

    2012-01-01

    In the present work, we employ excited state accelerated ab initio molecular dynamics (A-AIMD) to efficiently study the excited state energy landscape and photophysical topology of a variety of molecular systems. In particular, we focus on two important challenges for the modeling of excited electronic states: (i) the identification and characterization of conical intersections and crossing seams, in order to predict different and often competing radiationless decay mechanisms, and (ii) the description of the solvent effect on the absorption and emission spectra of chemical species in solution. In particular, using as examples the Schiff bases formaldimine and salicylidenaniline, we show that A-AIMD can be readily employed to explore the conformational space around crossing seams in molecular systems with very different photochemistry. Using acetone in water as an example, we demonstrate that the enhanced configurational space sampling may be used to accurately and efficiently describe both the prominent features and line-shapes of absorption and emission spectra. PMID:22904696

  7. Local and systemic biochemical alterations induced by Bothrops atrox snake venom in mice.

    PubMed

    de Souza, Carlos At; Kayano, Anderson M; Setúbal, Sulamita S; Pontes, Adriana S; Furtado, Juliana L; Kwasniewski, Fábio H; Zaqueo, Kayena D; Soares, Andreimar M; Stábeli, Rodrigo G; Zuliani, Juliana P

    2012-01-01

    The local and systemic alterations induced by Bothrops atrox snake venom (BaV) injection in mice were studied. BaV induced superoxide production by migrated neutrophils, mast cell degranulation and phagocytosis by macrophages. Moreover, BaV caused hemorrhage in dorsum of mice after 2hr post- injection. Three hours post-injection in gastrocnemius muscle, we also observed myonecrosis, which was assessed by the determination of serum and tissue CK besides the release of urea, but not creatinine and uric acid, indicating kidney alterations. BaV also induced the release of LDH and transaminases (ALT and AST) indicating tissue and liver abnormalities. In conclusion, the data indicate that BaV induces events of local and systemic importance. PMID:23487552

  8. Local and systemic biochemical alterations induced by Bothrops atrox snake venom in mice

    PubMed Central

    de Souza, Carlos AT; Kayano, Anderson M; Setúbal, Sulamita S; Pontes, Adriana S; Furtado, Juliana L; Kwasniewski, Fábio H; Zaqueo, Kayena D; Soares, Andreimar M; Stábeli, Rodrigo G; Zuliani, Juliana P

    2012-01-01

    The local and systemic alterations induced by Bothrops atrox snake venom (BaV) injection in mice were studied. BaV induced superoxide production by migrated neutrophils, mast cell degranulation and phagocytosis by macrophages. Moreover, BaV caused hemorrhage in dorsum of mice after 2hr post- injection. Three hours post-injection in gastrocnemius muscle, we also observed myonecrosis, which was assessed by the determination of serum and tissue CK besides the release of urea, but not creatinine and uric acid, indicating kidney alterations. BaV also induced the release of LDH and transaminases (ALT and AST) indicating tissue and liver abnormalities. In conclusion, the data indicate that BaV induces events of local and systemic importance. PMID:23487552

  9. 76 FR 4480 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ...The Department of Health and Human Services proposes to alter System of Records, 09-20-0162, ``Records of Subjects in Agent Orange, Vietnam Experience, and Selected Cancers Studies, HHS/CDC/CCEHIP/ NCEH.'' HHS is proposing to add the following Breach Response Routine Use Language to comply with the Office of Management and Budget (OMB) Memoranda (M) 07-16, Safeguarding Against and responding......

  10. 76 FR 4454 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ...The Department of Health and Human Services proposes to alter System of Records, 09-20-0117, ``Medical and Test Record Results of Individuals Involved in NIOSH Laboratory Studies, HHS/CDC/NIOSH.'' HHS is proposing to add the following Breach Response Routine Use Language to comply with the Office of Management and Budget (OMB) Memoranda (M) 07-16, Safeguarding Against and responding to the......

  11. 76 FR 4456 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ...The Department of Health and Human Services proposes to alter System of Records, 09-20-0118, ``Study at Work Sites Where Agents Suspected of Being Occupational Hazards Exist, HHS/CDC/NIOSH.'' HHS is proposing to add the following Breach Response Routine Use Language to comply with the Office of Management and Budget (OMB) Memoranda (M) 07- 16, Safeguarding Against and responding to the Breach......

  12. 76 FR 4466 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ...The Department of Health and Human Services proposes to alter System of Records, 09-20-0149, ``Morbidity Studies in Coal Mining, Metal and Non-metal Mining and General Industry, HHS/CDC/NIOSH.'' HHS is proposing to add the following Breach Response Routine Use Language to comply with the Office of Management and Budget (OMB) Memoranda (M) 07-16, Safeguarding Against and Responding to the......

  13. 76 FR 4469 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ...The Department of Health and Human Services proposes to alter System of Records, 09-20-0153, ``Mortality Studies in Coal Mining, Metal and Non-metal Mining and General Industry, HHS/CDC/NIOSH.'' HHS is proposing to add the following Breach Response Routine Use Language to comply with the Office of Management and Budget (OMB) Memoranda (M) 07-16, Safeguarding Against and responding to the......

  14. Alterations in the endocannabinoid system in the rat valproic acid model of autism.

    PubMed

    Kerr, D M; Downey, L; Conboy, M; Finn, D P; Roche, M

    2013-07-15

    The endocannabinoid system plays a crucial role in regulating emotionality and social behaviour, however it is unknown whether this system plays a role in symptoms associated with autism spectrum disorders. The current study evaluated if alterations in the endocannabinoid system accompany behavioural changes in the valproic acid (VPA) rat model of autism. Adolescent rats prenatally exposed to VPA exhibited impaired social investigatory behaviour, hypoalgesia and reduced lococmotor activity on exposure to a novel aversive arena. Levels of the endocananbinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG) in the hippocampus, frontal cortex or cerebellum were not altered in VPA- versus saline-exposed animals. However, the expression of mRNA for diacylglycerol lipase α, the enzyme primarily responsible for the synthesis of 2-AG, was reduced in the cerebellum of VPA-exposed rats. Furthermore, while the expression of mRNA for the 2-AG-catabolising enzyme monoacylglycerol lipase was reduced, the activity of this enzyme was increased, in the hippocampus of VPA-exposed animals. CB1 or CB2 receptor expression was not altered in any of the regions examined, however VPA-exposed rats exhibited reduced PPARα and GPR55 expression in the frontal cortex and PPARγ and GPR55 expression in the hippocampus, additional receptor targets of the endocannabinoids. Furthermore, tissue levels of the fatty acid amide hydrolase substrates, AEA, oleoylethanolamide and palmitoylethanolamide, were higher in the hippocampus of VPA-exposed rats immediately following social exposure. These data indicate that prenatal VPA exposure is associated with alterations in the brain's endocannabinoid system and support the hypothesis that endocannabinoid dysfunction may underlie behavioural abnormalities observed in autism spectrum disorders. PMID:23643692

  15. System and method for altering the tack of materials using an electrohydraulic discharge

    DOEpatents

    Banerjee, Sujit; Corcoran, Howard

    2003-01-01

    A system and method for altering the tack of a material, namely a polymer used as an adhesive, also known as stickies, or pitch. The present invention reduces the tack of the stickies and pitch by exposing the materials for a short duration to low-energy pulsed electrical discharges between a pair of electrodes that are submerged in a liquid medium, such as a fiber stream, water, a pulp slurry, or whitewater.

  16. System and method for altering the tack of materials using an electrohydraulic discharge

    DOEpatents

    Banerjee, Sujit; Corcoran, Howard

    2007-11-13

    A system and method for altering the tack of a material, namely a polymer used as an adhesive, also known as stickies, or pitch. The present invention reduces the tack of the stickies and pitch by exposing the materials for a short duration to low-energy pulsed electrical discharges between a pair of electrodes that are submerged in a liquid medium, such as a fiber stream, water, a pulp slurry, or whitewater.

  17. Nondynamical correlation energy in model molecular systems

    NASA Astrophysics Data System (ADS)

    Chojnacki, Henryk

    The hypersurfaces for the deprotonation processes have been studied at the nonempirical level for H3O+, NH+4, PH+4, and H3S+ cations within their correlation consistent basis set. The potential energy curves were calculated and nondynamical correlation energies analyzed. We have found that the restricted Hartree-Fock wavefunction leads to the improper dissociation limit and, in the three latest cases requires multireference description. We conclude that these systems may be treated as a good models for interpretation of the proton transfer mechanism as well as for testing one-determinantal or multireference cases.

  18. Continuous-terahertz-wave molecular imaging system for biomedical applications

    NASA Astrophysics Data System (ADS)

    Zhang, Rui; Zhang, Liangliang; Wu, Tong; Wang, Ruixue; Zuo, Shasha; Wu, Dong; Zhang, Cunlin; Zhang, Jue; Fang, Jing

    2016-07-01

    Molecular imaging techniques are becoming increasingly important in biomedical research and potentially in clinical practice. We present a continuous-terahertz (THz)-wave molecular imaging system for biomedical applications, in which an infrared (IR) laser is integrated into a 0.2-THz reflection-mode continuous-THz-wave imaging system to induce surface plasmon polaritons on the nanoparticles and further improve the intensity of the reflected signal from the water around the nanoparticles. A strong and rapid increment of the reflected THz signal in the nanoparticle solution upon the IR laser irradiation is demonstrated, using either gold or silver nanoparticles. This low-cost, simple, and stable continuous-THz-wave molecular imaging system is suitable for miniaturization and practical imaging applications; in particular, it shows great promise for cancer diagnosis and nanoparticle drug-delivery monitoring.

  19. Chaotic scattering in a molecular system

    NASA Astrophysics Data System (ADS)

    Barr, Alex M.; Na, Kyungsun; Reichl, L. E.; Jung, Christof

    2009-02-01

    We study the classical dynamics of bound state and scattering trajectories of the chlorine atom interacting with the HO molecule using a two-dimensional model in which the HO bond length is held fixed. The bound state system forms the HOCl molecule and at low energies is predominantly integrable. Below dissociation a number of bifurcations are observed, most notably a series of saddle-center bifurcations related to a 2:1 and at higher energies 3:1 resonance between bend and stretch motions. At energies above dissociation the classical phase space becomes dominated by a homoclinic tangle which induces a fractal distribution of singularities in all scattering functions. The structure of the homoclinic tangle is examined directly using Poincaré surfaces of section as well as indirectly through its influence on the time delay of the scattered chlorine atom and the angular momentum of the scattered HO molecule.

  20. Erythropoiesis: from molecular pathways to system properties.

    PubMed

    Koulnis, Miroslav; Porpiglia, Ermelinda; Hidalgo, Daniel; Socolovsky, Merav

    2014-01-01

    Erythropoiesis is regulated through a long-range negative feedback loop, whereby tissue hypoxia stimulates erythropoietin (Epo) secretion, which promotes an increase in erythropoietic rate. However, this long-range feedback loop, by itself, cannot account for the observed system properties of erythropoiesis, namely, a wide dynamic range, stability in the face of random perturbations, and a rapid stress response. Here, we show that three Epo-regulated erythroblast survival pathways each give rise to distinct system properties. The induction of Bcl-xL by signal transducer and activator of transcription 5 (Stat5) is responsive to the rate of change in Epo levels, rather than to its absolute level, and is therefore maximally but transiently activated in acute stress. By contrast, Epo-mediated suppression of the pro-survival Fas and Bim pathways is proportional to the levels of stress/Epo and persists throughout chronic stress. Together, these elements operate in a manner reminiscent of a "proportional-integral-derivative (PID)" feedback controller frequently found in engineering applications. A short-range negative autoregulatory loop within the early erythroblast compartment, operated by Fas/FasL, filters out random noise and controls a reserve pool of early erythroblasts that is poised to accelerate the response to acute stress. Both these properties have previously been identified as inherent to negative regulatory motifs. Finally, we show that signal transduction by Stat5 combines binary and graded modalities, thereby increasing signaling fidelity over the wide dynamic range of Epo found in health and disease. PMID:25480636

  1. FINE AMBIENT AIR PARTICULAR MATTER EXPOSURE INDUCES MOLECULAR ALTERATIONS INDICATIVE OF CARDIOVASCULAR DISEASE PROGRESSION IN ATHEROSCLEROTIC SUSCEPTIBLE MICE

    EPA Science Inventory

    Epidemiological, clinical, and toxicological studies have demonstrated that exposure to ambient air particulate matter (PM) can alter cardiovascular function and may influence cardiovascular disease (CVD). It has been shown that exposure to concentrated ambient air particles (CA...

  2. Enhanced Sampling Techniques in Molecular Dynamics Simulations of Biological Systems

    PubMed Central

    Bernardi, Rafael C.; Melo, Marcelo C. R.; Schulten, Klaus

    2014-01-01

    Background Molecular Dynamics has emerged as an important research methodology covering systems to the level of millions of atoms. However, insufficient sampling often limits its application. The limitation is due to rough energy landscapes, with many local minima separated by high-energy barriers, which govern the biomolecular motion. Scope of review In the past few decades methods have been developed that address the sampling problem, such as replica-exchange molecular dynamics, metadynamics and simulated annealing. Here we present an overview over theses sampling methods in an attempt to shed light on which should be selected depending on the type of system property studied. Major Conclusions Enhanced sampling methods have been employed for a broad range of biological systems and the choice of a suitable method is connected to biological and physical characteristics of the system, in particular system size. While metadynamics and replica-exchange molecular dynamics are the most adopted sampling methods to study biomolecular dynamics, simulated annealing is well suited to characterize very flexible systems. The use of annealing methods for a long time was restricted to simulation of small proteins; however, a variant of the method, generalized simulated annealing, can be employed at a relatively low computational cost to large macromolecular complexes. General Significance Molecular dynamics trajectories frequently do not reach all relevant conformational substates, for example those connected with biological function, a problem that can be addressed by employing enhanced sampling algorithms. PMID:25450171

  3. Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development

    PubMed Central

    Caldwell, Katharine E.; Labrecque, Matthew T.; Solomon, Benjamin R.; Ali, Abdulmehdi; Allan, Andrea M.

    2015-01-01

    The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50 ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11β-HSD1, while 11β-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11β-HSD1 and 11β-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11β-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of

  4. Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development.

    PubMed

    Caldwell, Katharine E; Labrecque, Matthew T; Solomon, Benjamin R; Ali, Abdulmehdi; Allan, Andrea M

    2015-01-01

    The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11β-HSD1, while 11β-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11β-HSD1 and 11β-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11β-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of

  5. Design theory and performance of cryogenic molecular adsorption refrigeration systems

    NASA Technical Reports Server (NTRS)

    Hartwig, W. H.; Woltman, A. W.; Masson, J. P.

    1978-01-01

    Closed-cycle operation of molecular adsorption refrigeration systems (MARS) has been demonstrated by using thermally cycled zeolites to adsorb and desorb various gases under pressures of 20-60 atm. This paper develops three aspects of the design theory: the physical theory of molecular adsorption of small molecules such as A, N2, N2O and NH3, the design relations for closed-cycle flow for three or more compressors, and the coefficient of performance. This work is intended to demonstrate nonmechanical gas compression for various cryogenic gases than can compete with mechanical systems with a different mix of advantages and disadvantages.

  6. A Novel Ex Ovo Banding Technique to Alter Intracardiac Hemodynamics in an Embryonic Chicken System.

    PubMed

    Menon, Vinal; Junor, Lorain; Balhaj, Marwa; Eberth, John F; Potts, Jay D

    2016-01-01

    The new model presented here can be used to understand the influence of hemodynamics on specific cardiac developmental processes, at the cellular and molecular level. To alter intracardiac hemodynamics, fertilized chicken eggs are incubated in a humidified chamber to obtain embryos of the desired stage (HH17). Once this developmental stage is achieved, the embryo is maintained ex ovo and hemodynamics in the embryonic heart are altered by partially constricting the outflow tract (OFT) with a surgical suture at the junction of the OFT and ventricle (OVJ). Control embryos are also cultured ex ovo but are not subjected to the surgical intervention. Banded and control embryos are then incubated in a humidified incubator for the desired period of time, after which 2D ultrasound is employed to analyze the change in blood flow velocity at the OVJ as a result of OFT banding. Once embryos are maintained ex ovo, it is important to ensure adequate hydration in the incubation chamber so as to prevent drying and eventually embryo death. Using this new banded model, it is now possible to perform analyses of changes in the expression of key players involved in valve development and to understand the role of hemodynamics on cellular responses in vivo, which could not be achieved previously. PMID:27213265

  7. Mineral formation and redox-sensitive trace elements in a near-surface hydrothermal alteration system

    SciTech Connect

    Gehring, A.U.; Schosseler, P.M.; Weidler, P.G.

    1999-07-01

    A recent hydrothermal mudpool at the southwestern slope of the Rincon de la Vieja volcano in Northwest Costa Rica exhibits an argillic alteration system formed by intense interaction of sulfuric acidic fluids with wall rock materials. Detailed mineralogical analysis revealed an assemblage with kaolinite, alunite, and opal-C as the major mineral phases. Electron paramagnetic resonance spectroscopy (EPR) showed 3 different redox-sensitive cations associated with the mineral phases, Cu{sup +} is structure-bound in opal-C, whereas VO{sup 2+} and Fe{sup 3+} are located in the kaolinite structure. The location of the redox-sensitive cations in different minerals of the assemblage is indicative of different chemical conditions. The formation of the alteration products can be described schematically as a 2-step process. In a first step alunite and opal-C were precipitated in a fluid with slightly reducing conditions and a low chloride availability. The second step is characterized by a decrease in K{sup +} activity and subsequent formation of kaolinite under weakly oxidizing to oxidizing redox conditions as indicated by structure-bound VO{sup 2+} and Fe{sup 3+}. The detection of paramagnetic trace elements structure-bound in mineral phases by EPR provide direct information about the prevailing redox conditions during alteration and can, therefore, be used as additional insight into the genesis of the hydrothermal, near-surface system.

  8. A novel method for performance improvement of optical CDMA system using alterable concatenated code

    NASA Astrophysics Data System (ADS)

    Qiu, Kun; Zhang, Chongfu

    2007-04-01

    A novel method using alterable concatenated code to pre-encode is proposed to reduce the impact of system impairment and multiple access interference (MAI) in optical code division multiple access (OCDMA) system, comprehensive comparisons between different concatenated code type and forward error correcting (FEC) scheme are studied by simulation. In the scheme, we apply concatenated coding to the embedded modulation scheme, and optical orthogonal code (OOC) is employed as address sequence code, an avalanche photodiode (APD) is selected as the system receiver. The bit error rate (BER) performance is derived taking into account the effect of some noises, dispersion power penalty and the MAI. From both theoretical analysis and numerical results, we can show that the proposed system has good performance at a BER of 10 -9 with a gain of 6.4 dB improvement achieved using the concatenated code as the pre-code, and this scheme permits implementation of a cost effective OCDMA system.

  9. Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphomas

    PubMed Central

    Braggio, Esteban; Van Wier, Scott; Ojha, Juhi; McPhail, Ellen; Asmann, Yan W.; Egan, Jan; da Silva, Jackline Ayres; Schiff, David; Lopes, M Beatriz; Decker, Paul A; Valdez, Riccardo; Tibes, Raoul; Eckloff, Bruce; Witzig, Thomas E.; Stewart, A Keith; Fonseca, Rafael; O’Neill, Brian Patrick

    2015-01-01

    Purpose Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the CNS. Whether there is a PCNSL-specific genomic signature and, if so, how it differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain. Experimental design We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing. Results Biallelic inactivation of TOX and PRKCD were recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. Additionally, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11 and translocations IgH-BCL6. Overall, BCR/TLR/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation. Conclusions In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas. PMID:25991819

  10. Structure of classical trajectories in multidimensional bound molecular systems

    SciTech Connect

    Ashton, C.J.; Muckerman, J.T.

    1983-07-21

    A computational method is described which enables visualization of the coordinate space envelopes of classical trajectories in multidimensional bound molecular systems. The method is exemplified by application to a realistic three-dimensional model of the vibrating water molecule, and its utility in the application of semiclassical quantization techniques is emphasized. 8 figures.

  11. Multi-Scale Molecular Deconstruction of the Serotonin Neuron System.

    PubMed

    Okaty, Benjamin W; Freret, Morgan E; Rood, Benjamin D; Brust, Rachael D; Hennessy, Morgan L; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N; Dymecki, Susan M

    2015-11-18

    Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-seq to deconstruct the mouse 5HT system at multiple levels of granularity-from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal principles underlying system organization, 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers sertonergic subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance. PMID:26549332

  12. Molecular clocks and the early evolution of metazoan nervous systems.

    PubMed

    Wray, Gregory A

    2015-12-19

    The timing of early animal evolution remains poorly resolved, yet remains critical for understanding nervous system evolution. Methods for estimating divergence times from sequence data have improved considerably, providing a more refined understanding of key divergences. The best molecular estimates point to the origin of metazoans and bilaterians tens to hundreds of millions of years earlier than their first appearances in the fossil record. Both the molecular and fossil records are compatible, however, with the possibility of tiny, unskeletonized, low energy budget animals during the Proterozoic that had planktonic, benthic, or meiofaunal lifestyles. Such animals would likely have had relatively simple nervous systems equipped primarily to detect food, avoid inhospitable environments and locate mates. The appearance of the first macropredators during the Cambrian would have changed the selective landscape dramatically, likely driving the evolution of complex sense organs, sophisticated sensory processing systems, and diverse effector systems involved in capturing prey and avoiding predation. PMID:26554040

  13. Experimental pathophysiology of systemic alterations induced by Bothrops asper snake venom.

    PubMed

    Gutiérrez, José María; Escalante, Teresa; Rucavado, Alexandra

    2009-12-01

    Moderate and severe envenomations by the snake Bothrops asper provoke systemic alterations, such as systemic bleeding, coagulopathy, hypovolemia, hemodynamic instability and shock, and acute renal failure. Systemic hemorrhage is a typical finding of these envenomations, and is primarily caused by the action of P-III snake venom metalloproteinases (SVMPs). This venom also contains a thrombin-like serine proteinase and a prothrombin-activating P-III SVMP, both of which cause defibrin(ogen)ation. Thrombocytopenia, predominantly induced by a C-type lectin-like protein, and platelet hypoaggregation, caused by the two defibrin(ogen)ating enzymes, also contribute to hemostatic disturbances, which potentiate the systemic bleeding induced by hemorrhagic SVMPs. Cardiovascular disturbances leading to shock are due to the combined effects of hemorrhagic toxins, other venom components that increase vascular permeability, the action of hypotensive agents in the venom and of endogenous mediators, and the potential cardiotoxic effect of some toxins. Renal alterations are likely to be caused by direct cytotoxicity of venom components in the kidney, and by renal ischemia resultant from hypovolemia and hypoperfusion. Lethality induced by B. asper venom is the consequence of several combined effects among which the action of P-III SVMPs is especially relevant. PMID:19303034

  14. Preparation of Low Molecular Weight Gelatin Using Microwave Discharge Electrodeless Lamp/TiO2 Photocatalyst Hybrid System.

    PubMed

    Lee, Do-Jin; Kim, Hangun; Park, Young-Kwon; Kim, Byung Hoon; Lee, Heon; Jungf, Sana-Chul

    2016-02-01

    In this study, an MDEL/TiO2 photocatalyst hybrid system was applied to the production of low molecular weight gelatin. The molecular weight of produed gelatin decreased with increasing microwave intensity and increasing treatment time. The abscission of the chemical bonds between the con- stituents of gelatin by photocatalytic reaction did not alter the characteristics of gelatin. Formation of any by-products due to side reaction was not observed. It is suggested that gelatin was depolymerized by hydroxyl radicals produced during the MDEL/TiO2 photochemical reaction. PMID:27433727

  15. Next steps in obesity prevention: altering early life systems to support healthy parents, infants, and toddlers.

    PubMed

    Nader, Philip R; Huang, Terry T-K; Gahagan, Sheila; Kumanyika, Shiriki; Hammond, Ross A; Christoffel, Katherine Kaufer

    2012-06-01

    There is an urgent need for effective, sustainable child obesity prevention strategies. Progress toward this goal requires strengthening current approaches to add a component that addresses pregnancy onward. Altering early-life systems that promote intergenerational transmission of obesity holds promise for interrupting the continuing cycle of the obesity epidemic. A 2011 Institute of Medicine (IOM) report emphasizes the need for interventions early in life to prevent obesity. A 2010 IOM report called for addressing gaps in existing obesity research evidence by using a systems perspective, simultaneously addressing interacting obesity promoting factors in multiple sectors and at multiple societal levels. A review of evidence from basic science, prevention, and systems research supports an approach that (1) begins at the earliest stages of development, and (2) uses a systems framework to simultaneously implement health behavior and environmental changes in communities. PMID:22799545

  16. Renal Oxidative Stress Induced by Long-Term Hyperuricemia Alters Mitochondrial Function and Maintains Systemic Hypertension

    PubMed Central

    Cristóbal-García, Magdalena; García-Arroyo, Fernando E.; Arellano-Buendía, Abraham S.; Madero, Magdalena; Rodríguez-Iturbe, Bernardo; Pedraza-Chaverrí, José; Zazueta, Cecilia; Johnson, Richard J.; Sánchez Lozada, Laura-Gabriela

    2015-01-01

    We addressed if oxidative stress in the renal cortex plays a role in the induction of hypertension and mitochondrial alterations in hyperuricemia. A second objective was to evaluate whether the long-term treatment with the antioxidant Tempol prevents renal oxidative stress, mitochondrial alterations, and systemic hypertension in this model. Long-term (11-12 weeks) and short-term (3 weeks) effects of oxonic acid induced hyperuricemia were studied in rats (OA, 750 mg/kg BW), OA+Allopurinol (AP, 150 mg/L drinking water), OA+Tempol (T, 15 mg/kg BW), or vehicle. Systolic blood pressure, renal blood flow, and vascular resistance were measured. Tubular damage (urine N-acetyl-β-D-glucosaminidase) and oxidative stress markers (lipid and protein oxidation) along with ATP levels were determined in kidney tissue. Oxygen consumption, aconitase activity, and uric acid were evaluated in isolated mitochondria from renal cortex. Short-term hyperuricemia resulted in hypertension without demonstrable renal oxidative stress or mitochondrial dysfunction. Long-term hyperuricemia induced hypertension, renal vasoconstriction, tubular damage, renal cortex oxidative stress, and mitochondrial dysfunction and decreased ATP levels. Treatments with Tempol and allopurinol prevented these alterations. Renal oxidative stress induced by hyperuricemia promoted mitochondrial functional disturbances and decreased ATP content, which represent an additional pathogenic mechanism induced by chronic hyperuricemia. Hyperuricemia-related hypertension occurs before these changes are evident. PMID:25918583

  17. Molecular absorption cryogenic cooler for liquid hydrogen propulsion systems

    NASA Technical Reports Server (NTRS)

    Klein, G. A.; Jones, J. A.

    1982-01-01

    A light weight, long life molecular absorption cryogenic cooler (MACC) system is described which can use low temperature waste heat to provide cooling for liquid hydrogen propellant tanks for interplanetary spacecraft. Detailed tradeoff studies were made to evaluate the refrigeration system component interactions in order to minimize the mass of the spacecraft cooler system. Based on this analysis a refrigerator system mass of 31 kg is required to provide the .48 watts of cooling required by a 2.3 meter diameter liquid hydrogen tank.

  18. Parallel molecular dynamics on a multi signalprocessor system

    NASA Astrophysics Data System (ADS)

    Scott, W.; Gunzinger, A.; Bäumle, B.; Kohler, P.; Müller, U. A.; Mühll, H.-R. Vonder; Eichenberger, A.; Guggenbühl, W.; Ironmonger, N.; Müller-Plathe, F.; van Gunsteren, W. F.

    1993-04-01

    This paper gives an overview of a parallel computer architecture called MUSIC (Multi Signalprocessor System with Intelligent Communication), which has been developed at the Swiss Federal Institute of Technology. The current version achieves a peak performance of 3.8 GFlops. We discuss the system software and tools used to program the system and then present our implementation of a molecular dynamics simulation program which uses the architecture of MUSIC in an efficient way. We demonstrate the correctness of our implementation and give measurements of the performance of the system. To the best of our knowledge, MUSIC outperforms the most powerful present-day vector supercomputers.

  19. Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood.

    PubMed

    Golubeva, Anna V; Crampton, Sean; Desbonnet, Lieve; Edge, Deirdre; O'Sullivan, Orla; Lomasney, Kevin W; Zhdanov, Alexander V; Crispie, Fiona; Moloney, Rachel D; Borre, Yuliya E; Cotter, Paul D; Hyland, Niall P; O'Halloran, Ken D; Dinan, Timothy G; O'Keeffe, Gerard W; Cryan, John F

    2015-10-01

    Early-life adverse experiences, including prenatal stress (PNS), are associated with a higher prevalence of neurodevelopmental, cardiovascular and metabolic disorders in affected offspring. Here, in a rat model of chronic PNS, we investigate the impact of late gestational stress on physiological outcomes in adulthood. Sprague-Dawley pregnant dams were subjected to repeated restraint stress from embryonic day 14 to day 20, and their male offspring were assessed at 4 months of age. PNS induced an exaggeration of the hypothalamic-pituitary-adrenal (HPA) axis response to stress, as well as an elevation of blood pressure and impairment of cognitive function. Altered respiratory control was also observed, as demonstrated by increased variability in basal respiratory frequency and abnormal frequency responses to both hypoxic and hypercapnic challenges. PNS also affected gastrointestinal neurodevelopment and function, as measured by a decrease in the innervation density of distal colon and an increase in the colonic secretory response to catecholaminergic stimulation. Finally, PNS induced long lasting alterations in the intestinal microbiota composition. 16S rRNA gene 454 pyrosequencing revealed a strong trend towards decreased numbers of bacteria in the Lactobacillus genus, accompanied by elevated abundance of the Oscillibacter, Anaerotruncus and Peptococcus genera in PNS animals. Strikingly, relative abundance of distinct bacteria genera significantly correlated with certain respiratory parameters and the responsiveness of the HPA axis to stress. Together, these findings provide novel evidence that PNS induces long-term maladaptive alterations in the gastrointestinal and respiratory systems, accompanied by hyper-responsiveness to stress and alterations in the gut microbiota. PMID:26135201

  20. Altered neural response of the appetitive emotional system in cocaine addiction: an fMRI Study.

    PubMed

    Asensio, Samuel; Romero, Maria J; Palau, Carmina; Sanchez, Amparo; Senabre, Isabel; Morales, Julia L; Carcelen, Raquel; Romero, Francisco J

    2010-10-01

    Research on addiction suggests that emotional alterations play an essential role in the development, maintenance, relapse and treatment outcome of substance abuse disorders. Although many neuroimaging studies focussed on the neural response to conditioned stimuli, much less is known about the neural response to natural affective stimuli in this pathological population. Previous research has demonstrated an altered emotional experience and autonomic response to emotional stimuli using the International Affective Picture System (IAPS) in drug abusers. Here we aimed, using functional magnetic resonance imaging (fMRI), to study the alterations in the neural responsitivity to pleasant (erotic), unpleasant and neutral IAPS stimuli in cocaine addiction. Thirty-two cocaine-dependent subjects and 26 matched controls completed an fMRI session during the presentation of a set of IAPS pictures as background, while performing a letter discrimination task. Consistent with previous studies, emotional pictures activated an emotional network including amygdala, medial prefrontal cortex, orbitofrontal cortex and occipito-temporal areas in both groups. However, compared with controls, the cocaine group showed a significant hypoactivation of the dorsal and ventral striatum (including the nucleus accumbens), thalamus, parietal cortex and dorso-medial prefrontal cortex (dmPFC) when processing pleasant pictures. The analysis of pleasant versus unpleasant stimuli suggested that between-group differences in the dmPFC and striatal activation may be attributed to arousal processing rather than valence. These results could reflect the neural basis for the reduced ability of cocaine-dependent subjects to experience pleasure by daily natural reinforcers, suggesting that these alterations in the emotion processing may play an important role in drug dependence, treatment and relapse. PMID:20579005

  1. Use of the MLPA Assay in the Molecular Diagnosis of Gene Copy Number Alterations in Human Genetic Diseases

    PubMed Central

    Stuppia, Liborio; Antonucci, Ivana; Palka, Giandomenico; Gatta, Valentina

    2012-01-01

    Multiplex Ligation-dependent Probe Amplification (MLPA) assay is a recently developed technique able to evidence variations in the copy number of several human genes. Due to this ability, MLPA can be used in the molecular diagnosis of several genetic diseases whose pathogenesis is related to the presence of deletions or duplications of specific genes. Moreover, MLPA assay can also be used in the molecular diagnosis of genetic diseases characterized by the presence of abnormal DNA methylation. Due to the large number of genes that can be analyzed by a single technique, MLPA assay represents the gold standard for molecular analysis of all pathologies derived from the presence of gene copy number variation. In this review, the main applications of the MLPA technique for the molecular diagnosis of human diseases are described. PMID:22489151

  2. Molecular cause and functional impact of altered synaptic lipid signaling due to a prg-1 gene SNP.

    PubMed

    Vogt, Johannes; Yang, Jenq-Wei; Mobascher, Arian; Cheng, Jin; Li, Yunbo; Liu, Xingfeng; Baumgart, Jan; Thalman, Carine; Kirischuk, Sergei; Unichenko, Petr; Horta, Guilherme; Radyushkin, Konstantin; Stroh, Albrecht; Richers, Sebastian; Sahragard, Nassim; Distler, Ute; Tenzer, Stefan; Qiao, Lianyong; Lieb, Klaus; Tüscher, Oliver; Binder, Harald; Ferreiros, Nerea; Tegeder, Irmgard; Morris, Andrew J; Gropa, Sergiu; Nürnberg, Peter; Toliat, Mohammad R; Winterer, Georg; Luhmann, Heiko J; Huai, Jisen; Nitsch, Robert

    2016-01-01

    Loss of plasticity-related gene 1 (PRG-1), which regulates synaptic phospholipid signaling, leads to hyperexcitability via increased glutamate release altering excitation/inhibition (E/I) balance in cortical networks. A recently reported SNP in prg-1 (R345T/mutPRG-1) affects ~5 million European and US citizens in a monoallelic variant. Our studies show that this mutation leads to a loss-of-PRG-1 function at the synapse due to its inability to control lysophosphatidic acid (LPA) levels via a cellular uptake mechanism which appears to depend on proper glycosylation altered by this SNP. PRG-1(+/-) mice, which are animal correlates of human PRG-1(+/mut) carriers, showed an altered cortical network function and stress-related behavioral changes indicating altered resilience against psychiatric disorders. These could be reversed by modulation of phospholipid signaling via pharmacological inhibition of the LPA-synthesizing molecule autotaxin. In line, EEG recordings in a human population-based cohort revealed an E/I balance shift in monoallelic mutPRG-1 carriers and an impaired sensory gating, which is regarded as an endophenotype of stress-related mental disorders. Intervention into bioactive lipid signaling is thus a promising strategy to interfere with glutamate-dependent symptoms in psychiatric diseases. PMID:26671989

  3. System and method for altering characteristics of materials using an electrohydraulic discharge

    DOEpatents

    Banerjee, Sujit

    2003-06-03

    System and method for oxidizing contaminants to alter specific properties, such as tack, of contaminants. The present invention reduces the tack of the stickies and pitch by exposing the materials for a short duration to low-energy pulsed electrical discharges between a pair of electrodes that are submerged in a liquid medium, such as a fiber stream, water, a pulp slurry, or whitewater. An electrical discharge in the liquid medium oxidizes materials, which may be dissolved or suspended therein, such as stickies, pitch, sulfide, ink, toner, and other substances, thereby reducing tack, odor, and/or zeta potential, as well as producing other desirable effect.

  4. Tank waste remediation system optimized processing strategy with an altered treatment scheme

    SciTech Connect

    Slaathaug, E.J.

    1996-03-01

    This report provides an alternative strategy evolved from the current Hanford Site Tank Waste Remediation System (TWRS) programmatic baseline for accomplishing the treatment and disposal of the Hanford Site tank wastes. This optimized processing strategy with an altered treatment scheme performs the major elements of the TWRS Program, but modifies the deployment of selected treatment technologies to reduce the program cost. The present program for development of waste retrieval, pretreatment, and vitrification technologies continues, but the optimized processing strategy reuses a single facility to accomplish the separations/low-activity waste (LAW) vitrification and the high-level waste (HLW) vitrification processes sequentially, thereby eliminating the need for a separate HLW vitrification facility.

  5. Investigations of the Effects of Altered Vestibular System Function on Hindlimb Anti-Gravity Muscles

    NASA Technical Reports Server (NTRS)

    Lowery, Mary Sue

    1998-01-01

    Exposure to different gravitational environments, both the microgravity of spaceflight and the hypergravity of centrifugation, result in altered vestibulo-spinal function which can be reversed by reacclimation to earth gravity (2). Control of orientation, posture, and locomotion are functions of the vestibular system which are altered by changes in gravitational environment. Not only is the vestibular system involved with coordination and proprioception, but the gravity sensing portion of the vestibular system also plays a major role in maintaining muscle tone through projections to spinal cord motoneurons that control anti-gravity muscles. I have been involved with investigations of several aspects of the link between vestibular inputs and muscle morphology and function during my work with Dr. Nancy Daunton this summer and the previous summer. We have prepared a manuscript for submission (4) to Aviation, Space, and Environmental Medicine based on work that I performed last summer in Dr. Daunton's lab. Techniques developed for that project will be utilized in subsequent experiments begun in the summer of 1998. I have been involved with the development of a pilot project to test the effects of vestibular galvanic stimulation (VGS) on anti-gravity muscles and in another project testing the effects of the ototoxic drug streptomycin on the otolith-spinal reflex and anti-gravity muscle morphology.

  6. Hybrid Metaheuristic Approach for Nonlocal Optimization of Molecular Systems.

    PubMed

    Dresselhaus, Thomas; Yang, Jack; Kumbhar, Sadhana; Waller, Mark P

    2013-04-01

    Accurate modeling of molecular systems requires a good knowledge of the structure; therefore, conformation searching/optimization is a routine necessity in computational chemistry. Here we present a hybrid metaheuristic optimization (HMO) algorithm, which combines ant colony optimization (ACO) and particle swarm optimization (PSO) for the optimization of molecular systems. The HMO implementation meta-optimizes the parameters of the ACO algorithm on-the-fly by the coupled PSO algorithm. The ACO parameters were optimized on a set of small difluorinated polyenes where the parameters exhibited small variance as the size of the molecule increased. The HMO algorithm was validated by searching for the closed form of around 100 molecular balances. Compared to the gradient-based optimized molecular balance structures, the HMO algorithm was able to find low-energy conformations with a 87% success rate. Finally, the computational effort for generating low-energy conformation(s) for the phenylalanyl-glycyl-glycine tripeptide was approximately 60 CPU hours with the ACO algorithm, in comparison to 4 CPU years required for an exhaustive brute-force calculation. PMID:26583559

  7. ANN expert system screening for illicit amphetamines using molecular descriptors

    NASA Astrophysics Data System (ADS)

    Gosav, S.; Praisler, M.; Dorohoi, D. O.

    2007-05-01

    The goal of this study was to develop and an artificial neural network (ANN) based on computed descriptors, which would be able to classify the molecular structures of potential illicit amphetamines and to derive their biological activity according to the similarity of their molecular structure with amphetamines of known toxicity. The system is necessary for testing new molecular structures for epidemiological, clinical, and forensic purposes. It was built using a database formed by 146 compounds representing drugs of abuse (mainly central stimulants, hallucinogens, sympathomimetic amines, narcotics and other potent analgesics), precursors, or derivatized counterparts. Their molecular structures were characterized by computing three types of descriptors: 38 constitutional descriptors (CDs), 69 topological descriptors (TDs) and 160 3D-MoRSE descriptors (3DDs). An ANN system was built for each category of variables. All three networks (CD-NN, TD-NN and 3DD-NN) were trained to distinguish between stimulant amphetamines, hallucinogenic amphetamines, and nonamphetamines. A selection of variables was performed when necessary. The efficiency with which each network identifies the class identity of an unknown sample was evaluated by calculating several figures of merit. The results of the comparative analysis are presented.

  8. Interfacial nanorheology: Probing molecular mobility in mesoscopic polymeric systems

    NASA Astrophysics Data System (ADS)

    Sills, Scott E.

    Investigating the finite size limited structural relaxations in mesoscopic polymer systems is central to nanotechnological applications involving thin films, complex structures, and nanoscale phase-separated systems; for example, polymer electrolyte membranes, optoelectronic devices, and ultrahigh-density thermomechanical data storage (terabit recording). In such systems, bulk statistical averaging and continuum models are jeopardized. Interfacial constraints lead to bulk-deviating molecular dynamics and dictate material and transport properties. The objective of this dissertation is to provide insight to the exotic mesoscopic behaviors in thin films by developing novel rheological and tribological analytical methods based on scanning probe microscopy (SPM). Activation energies are deduced for the molecular motions associated with internal friction dissipation, and the temperature resolved length scale for cooperative motion during the glass transition is directly obtained for polystyrene. These results confirm the dynamical heterogeneity of the glass transition and reveal a crossover from intra- to inter-molecular relaxation in the transition regime. The impact of dimensional constraints on molecular mobility in ultrathin polymer films is explored through interfacial glass-transition profiles. With these profiles, a structural model of the rheological changes near interfacial boundaries is constructed as function of molecular weight and crosslinking density. The manifestation of interfacial constraints in nanotechnological applications is illustrated for thermomechanical recording, where rheological gradients near the substrate dictate the contact pressure and strain shielding at the substrate compromises film stability. A foundation for the critical aspects of interfacial stability is developed, and mechanically graded interfaces and modulus-matching techniques are explored as a means of improving the stability, durability, and stress transmission characteristics

  9. The altered gravity effect on proliferative system of two-day pea germs

    NASA Astrophysics Data System (ADS)

    Artemenko, O. A.

    The study of clinorotation effect on proliferative system sensibility of plants is very important for understanding and future investigations of their development characteristics and for examination of cell cycle regulation molecular mechanisms. Determination of two-day pea germ mitotic activity of cells, correlation of mitosis phase and DNA content point to decrease of these parameters under clinorotation during the first 12 hours of the factor influence. Cell cycle stabilization after 12 hours of the experiment show high adaptation capacity of plant proliferative system.

  10. Cross linking molecular systems to form ultrathin dielectric layers

    NASA Astrophysics Data System (ADS)

    Feng, Danqin

    Dehydrogenation leads to cross linking of polymer or polymer like formation in very different systems: self-assembled monolayers and in closo -carboranes leading to the formation of semiconducting and dielectric boron carbide. We find evidence of intermolecular interactions for a self-assembled monolayer (SAM) formed from a large molecular adsorbate, [1,1';4',1"-terphenyl]-4,4"-dimethanethiol, from the dispersion of the molecular orbitals with changing the wave vector k and from the changes with temperature. With the formation self assembled molecular (SAM) layer, the molecular orbitals hybridize to electronic bands, with indications of significant band dispersion of the unoccupied molecular orbitals. Although organic adsorbates and thin films are generally regarded as "soft" materials, the effective Debye temperature, indicative of the dynamic motion of the lattice normal to the surface, can be very high, e.g. in the multilayer film formed from [1,1'-biphenyl]-4,4'-dimethanethiol (BPDMT). Depending on molecular orientation, the effective Debye temperature can be comparable to that of graphite due to the 'stiffness' of the benzene rings, but follows the expected Debye-Waller behavior for the core level photoemission intensities with temperature. This is not always the case. We find that a monomolecular film formed from [1,1';4',1"-terphenyl]-4,4"-dimethanethiol deviates from Debye-Waller temperature behavior and is likely caused by temperature dependent changes in molecular orientation. We also find evidence for the increase in dielectric character with polymerization (cross-linking) in spite of the decrease in the HOMO-LUMO gap upon irradiation of TPDMT. The changes in the HOMO-LUMO gap, with cross-linking, are roughly consistent with the band dispersion. The decomposition and cross-linking processes are also accompanied by changes in molecular orientation. The energetics of the three isomeric carborane cage compounds [ closo-1,2-orthocarborane, closo-1

  11. Easy creation of polymeric systems for molecular dynamics with Assemble!

    NASA Astrophysics Data System (ADS)

    Degiacomi, Matteo T.; Erastova, Valentina; Wilson, Mark R.

    2016-05-01

    We present Assemble!, a program greatly simplifying the preparation of molecular dynamics simulations of polymeric systems. The program is controlled either via command line or an intuitive Graphical User Interface, and runs on all major operating systems. Assemble! allows the creation of a desired system of polymer chains from constituent monomers, packs the chains into a box according to the required concentration and returns all the files needed for simulation with Gromacs. We illustrate the capabilities of Assemble! by demonstrating the easy preparation of a 300 monomers-long polyisoprene in hexane, and a heterogeneous mixture of polybutadiene.

  12. Accelerated Superposition State Molecular Dynamics for Condensed Phase Systems.

    PubMed

    Ceotto, Michele; Ayton, Gary S; Voth, Gregory A

    2008-04-01

    An extension of superposition state molecular dynamics (SSMD) [Venkatnathan and Voth J. Chem. Theory Comput. 2005, 1, 36] is presented with the goal to accelerate timescales and enable the study of "long-time" phenomena for condensed phase systems. It does not require any a priori knowledge about final and transition state configurations, or specific topologies. The system is induced to explore new configurations by virtue of a fictitious (free-particle-like) accelerating potential. The acceleration method can be applied to all degrees of freedom in the system and can be applied to condensed phases and fluids. PMID:26620930

  13. Cryogenic molecular separation system for radioactive 11C ion acceleration

    NASA Astrophysics Data System (ADS)

    Katagiri, K.; Noda, A.; Suzuki, K.; Nagatsu, K.; Boytsov, A. Yu.; Donets, D. E.; Donets, E. D.; Donets, E. E.; Ramzdorf, A. Yu.; Nakao, M.; Hojo, S.; Wakui, T.; Noda, K.

    2015-12-01

    A 11C molecular production/separation system (CMPS) has been developed as part of an isotope separation on line system for simultaneous positron emission tomography imaging and heavy-ion cancer therapy using radioactive 11C ion beams. In the ISOL system, 11CH4 molecules will be produced by proton irradiation and separated from residual air impurities and impurities produced during the irradiation. The CMPS includes two cryogenic traps to separate specific molecules selectively from impurities by using vapor pressure differences among the molecular species. To investigate the fundamental performance of the CMPS, we performed separation experiments with non-radioactive 12CH4 gases, which can simulate the chemical characteristics of 11CH4 gases. We investigated the separation of CH4 molecules from impurities, which will be present as residual gases and are expected to be difficult to separate because the vapor pressure of air molecules is close to that of CH4. We determined the collection/separation efficiencies of the CMPS for various amounts of air impurities and found desirable operating conditions for the CMPS to be used as a molecular separation device in our ISOL system.

  14. Selective excitation, relaxation, and energy channeling in molecular systems

    SciTech Connect

    Rhodes, W.C.

    1993-08-01

    Research involves theoretical studies of response, relaxation, and correlated motion in time-dependent behavior of large molecular systems ranging from polyatomic molecules to protein molecules in their natural environment. Underlying theme is subsystem modulation dynamics. Main idea is that quantum mechanical correlations between components of a system develop with time, playing a major role in determining the balance between coherent and dissipative forces. Central theme is interplay of coherence and dissipation in determining the nature of dynamic structuring and energy flow in molecular transformation mechanisms. Subsystem equations of motion are being developed to show how nonlinear, dissipative dynamics of a particular subsystem arise from correlated interactions with the rest of the system (substituent groups, solvent, lattice modes, etc.); one consequence is resonance structures and networks. Quantum dynamics and thermodynamics are being applied to understand control and energy transfer mechanisms in biological functions of protein molecules; these mechanisms are both global and local. Besides the above theory, the research deals with phenomenological aspects of molecular systems.

  15. Oral drug delivery systems comprising altered geometric configurations for controlled drug delivery.

    PubMed

    Moodley, Kovanya; Pillay, Viness; Choonara, Yahya E; du Toit, Lisa C; Ndesendo, Valence M K; Kumar, Pradeep; Cooppan, Shivaan; Bawa, Priya

    2012-01-01

    Recent pharmaceutical research has focused on controlled drug delivery having an advantage over conventional methods. Adequate controlled plasma drug levels, reduced side effects as well as improved patient compliance are some of the benefits that these systems may offer. Controlled delivery systems that can provide zero-order drug delivery have the potential for maximizing efficacy while minimizing dose frequency and toxicity. Thus, zero-order drug release is ideal in a large area of drug delivery which has therefore led to the development of various technologies with such drug release patterns. Systems such as multilayered tablets and other geometrically altered devices have been created to perform this function. One of the principles of multilayered tablets involves creating a constant surface area for release. Polymeric materials play an important role in the functioning of these systems. Technologies developed to date include among others: Geomatrix(®) multilayered tablets, which utilizes specific polymers that may act as barriers to control drug release; Procise(®), which has a core with an aperture that can be modified to achieve various types of drug release; core-in-cup tablets, where the core matrix is coated on one surface while the circumference forms a cup around it; donut-shaped devices, which possess a centrally-placed aperture hole and Dome Matrix(®) as well as "release modules assemblage", which can offer alternating drug release patterns. This review discusses the novel altered geometric system technologies that have been developed to provide controlled drug release, also focusing on polymers that have been employed in such developments. PMID:22312236

  16. Oral Drug Delivery Systems Comprising Altered Geometric Configurations for Controlled Drug Delivery

    PubMed Central

    Moodley, Kovanya; Pillay, Viness; Choonara, Yahya E.; du Toit, Lisa C.; Ndesendo, Valence M. K.; Kumar, Pradeep; Cooppan, Shivaan; Bawa, Priya

    2012-01-01

    Recent pharmaceutical research has focused on controlled drug delivery having an advantage over conventional methods. Adequate controlled plasma drug levels, reduced side effects as well as improved patient compliance are some of the benefits that these systems may offer. Controlled delivery systems that can provide zero-order drug delivery have the potential for maximizing efficacy while minimizing dose frequency and toxicity. Thus, zero-order drug release is ideal in a large area of drug delivery which has therefore led to the development of various technologies with such drug release patterns. Systems such as multilayered tablets and other geometrically altered devices have been created to perform this function. One of the principles of multilayered tablets involves creating a constant surface area for release. Polymeric materials play an important role in the functioning of these systems. Technologies developed to date include among others: Geomatrix® multilayered tablets, which utilizes specific polymers that may act as barriers to control drug release; Procise®, which has a core with an aperture that can be modified to achieve various types of drug release; core-in-cup tablets, where the core matrix is coated on one surface while the circumference forms a cup around it; donut-shaped devices, which possess a centrally-placed aperture hole and Dome Matrix® as well as “release modules assemblage”, which can offer alternating drug release patterns. This review discusses the novel altered geometric system technologies that have been developed to provide controlled drug release, also focusing on polymers that have been employed in such developments. PMID:22312236

  17. Chronic venlafaxine treatment fails to alter the levels of galanin system transcripts in normal rats.

    PubMed

    Petschner, Peter; Juhasz, Gabriella; Tamasi, Viola; Adori, Csaba; Tothfalusi, Laszlo; Hökfelt, Tomas; Bagdy, Gyorgy

    2016-06-01

    It is widely accepted that efficacy and speed of current antidepressants' therapeutic effect are far from optimal. Thus, there is a need for the development of antidepressants with new mechanisms of action. The neuropeptide galanin and its receptors (GalR1, GalR2 and GalR3) are among the promising targets. However, it is not clear whether or not the galanin system is involved in the antidepressant effect exerted by the currently much used inhibitors of the reuptake of serotonin and/or noradrenaline. To answer this question we administered the selective serotonin and noradrenaline reuptake inhibitor (SNRI) venlafaxine (40mg/kg/day via osmotic minipumps) to normal rats and examined the levels of the transcripts for galanin and GalR1-3 after a 3-week venlafaxine treatment in the dorsal raphe, hippocampus and frontal cortex. These areas are known to be involved in the effects of antidepressants and in depression itself. Venlafaxine failed to alter the expression of any of the galanin system genes in these areas. Our results show that one of the most efficient, currently used SNRIs does not alter transcript levels of galanin or its three receptors in normal rats. These findings suggest that the pro- and antidepressive-like effects of galanin reported in animal experiments may employ a novel mechanism(s). PMID:26891823

  18. Systemic Cytokine Profiles in Strongyloides stercoralis Infection and Alterations following Treatment.

    PubMed

    Anuradha, Rajamanickam; Munisankar, Saravanan; Bhootra, Yukti; Jagannathan, Jeeva; Dolla, Chandrakumar; Kumaran, Paul; Shen, Kui; Nutman, Thomas B; Babu, Subash

    2016-02-01

    Strongyloides stercoralis is a soil-transmitted helminth organism that infects ~50 to 100 million people worldwide. Despite its widespread prevalence, very little is known about the immune response that characterizes human S. stercoralis infection. To study the systemic cytokine profile characteristic of Strongyloides infection, we measured the circulating levels of a large panel of pro- and anti-inflammatory cytokines in asymptomatic, infected individuals (n = 32) and compared them to those in uninfected, controls (n = 24). Infected individuals exhibited significantly lower circulating levels of proinflammatory cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-1β [IL-1β]) and significantly higher levels of anti-inflammatory cytokines (IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-37, and transforming growth factor β [TGF-β]). Moreover, treatment of Strongyloides infection resulted in a significant reversal of the cytokine profile, with increased levels of proinflammatory (IFN-γ, TNF-α, IL-2, IL-17A, IL-17F, IL-22, IL-23, and IL-1β) and decreased levels of anti-inflammatory (IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-37, and TGF-β) cytokines following treatment. Thus, S. stercoralis infection is characterized by alterations in the levels of systemic cytokines, reflecting major alterations in the underlying immune response to this chronic helminth infection. PMID:26597982

  19. Interactive display of molecular models using a microcomputer system

    NASA Technical Reports Server (NTRS)

    Egan, J. T.; Macelroy, R. D.

    1980-01-01

    A simple, microcomputer-based, interactive graphics display system has been developed for the presentation of perspective views of wire frame molecular models. The display system is based on a TERAK 8510a graphics computer system with a display unit consisting of microprocessor, television display and keyboard subsystems. The operating system includes a screen editor, file manager, PASCAL and BASIC compilers and command options for linking and executing programs. The graphics program, written in USCD PASCAL, involves the centering of the coordinate system, the transformation of centered model coordinates into homogeneous coordinates, the construction of a viewing transformation matrix to operate on the coordinates, clipping invisible points, perspective transformation and scaling to screen coordinates; commands available include ZOOM, ROTATE, RESET, and CHANGEVIEW. Data file structure was chosen to minimize the amount of disk storage space. Despite the inherent slowness of the system, its low cost and flexibility suggests general applicability.

  20. Chitinase-like protein CTL1 plays a role in altering root system architecture in response to multiple environmental conditions.

    PubMed

    Hermans, Christian; Porco, Silvana; Verbruggen, Nathalie; Bush, Daniel R

    2010-02-01

    Plant root architecture is highly responsive to changes in nutrient availability. However, the molecular mechanisms governing the adaptability of root systems to changing environmental conditions is poorly understood. A screen for abnormal root architecture responses to high nitrate in the growth medium was carried out for a population of ethyl methanesulfonate-mutagenized Arabidopsis (Arabidopsis thaliana). The growth and root architecture of the arm (for anion altered root morphology) mutant described here was similar to wild-type plants when grown on low to moderate nitrate concentrations, but on high nitrate, arm exhibited reduced primary root elongation, radial swelling, increased numbers of lateral roots, and increased root hair density when compared to the wild-type control. High concentrations of chloride and sucrose induced the same phenotype. In contrast, hypocotyl elongation in the dark was decreased independently of nitrate availability. Positional cloning identified a point mutation in the AtCTL1 gene that encodes a chitinase-related protein, although molecular and biochemical analysis showed that this protein does not possess chitinase enzymatic activity. CTL1 appears to play two roles in plant growth and development based on the constitutive effect of the arm mutation on primary root growth and its conditional impact on root architecture. We hypothesize that CTL1 plays a role in determining cell wall rigidity and that the activity is differentially regulated by pathways that are triggered by environmental conditions. Moreover, we show that mutants of some subunits of the cellulose synthase complex phenocopy the conditional effect on root architecture under nonpermissive conditions, suggesting they are also differentially regulated in response to a changing environment. PMID:20007445

  1. Note: Energy convexity and density matrices in molecular systems

    NASA Astrophysics Data System (ADS)

    Bochicchio, Roberto C.; Rial, Diego

    2012-12-01

    A novel appropriate definition for the density matrix for an interacting Coulombic driven atomic or molecular system with non-integer number of particles is given. Our approach leads to a direct derivation of the proposal reported by Perdew et al. [Phys. Rev. Lett. 49, 1691 (1982)], 10.1103/PhysRevLett.49.1691 and points out its suitability and perspective advances.

  2. The Auditory Corticocollicular System: Molecular and Circuit-Level Considerations

    PubMed Central

    Stebbings, Kevin A.; Lesicko, Alexandria M.H.; Llano, Daniel A.

    2014-01-01

    We live in a world imbued with a rich mixture of complex sounds. Successful acoustic communication requires the ability to extract meaning from those sounds, even when degraded. One strategy used by the auditory system is to harness high-level contextual cues to modulate the perception of incoming sounds. An ideal substrate for this process is the massive set of top-down projections emanating from virtually every level of the auditory system. In this review, we provide a molecular and circuit-level description of one of the largest of these pathways: the auditory corticocollicular pathway. While its functional role remains to be fully elucidated, activation of this projection system can rapidly and profoundly change the tuning of neurons in the inferior colliculus. Several specific issues are reviewed. First, we describe the complex heterogeneous anatomical organization of the corticocollicular pathway, with particular emphasis on the topography of the pathway. We also review the laminar origin of the corticocollicular projection and discuss known physiological and morphological differences between subsets of corticocollicular cells. Finally, we discuss recent findings about the molecular micro-organization of the inferior colliculus and how it interfaces with corticocollicular termination patterns. Given the assortment of molecular tools now available to the investigator, it is hoped that his review will help guide future research on the role of this pathway in normal hearing. PMID:24911237

  3. Alterations in the hippocampal endocannabinoid system in diet-induced obese mice

    PubMed Central

    Massa, Federico; Mancini, Giacomo; Schmidt, Helmut; Steindel, Frauke; Mackie, Ken; Angioni, Carlo; Oliet, Stéphane H.R.; Geisslinger, Gerd; Lutz, Beat

    2010-01-01

    The endocannabinoid (eCB) system plays central roles in the regulation of food intake and energy expenditure. Its alteration in activity contributes to the development and maintenance of obesity. Stimulation of the cannabinoid receptor type 1 (CB1 receptor) increases feeding, enhances reward aspects of eating and promotes lipogenesis, while its blockade decreases appetite, sustains weight loss, increases insulin sensitivity, and alleviates dysregulation of lipid metabolism. The hypothesis has been put forward that the eCB system is over-active in obesity. Hippocampal circuits are not directly involved in the neuronal control of food intake and appetite, but they play important roles in hedonic aspects of eating. We investigated the possibility whether or not diet-induced obesity (DIO) alters the functioning of the hippocampal eCB system. We found that levels of the two eCBs, 2-arachidonoyl glycerol (2-AG) and anandamide, were increased in the hippocampus from DIO mice, with a concomitant increase of the 2-AG synthesizing enzyme diacylglycerol lipase-α and increased CB1 receptor immunoreactivity in CA1 and CA3 regions, while CB1 receptor agonist-induced GTPγS binding was unchanged. eCB-mediated synaptic plasticity was changed in the CA1 region, as depolarization-induced suppression of inhibition (DSI) and long-term depression of inhibitory synapses (I-LTD) were enhanced. Functionality of CB1 receptors in GABAergic neurons was furthermore revealed, as mice specifically lacking CB1 receptors on this neuronal population were partly resistant to DIO. Our results showed that DIO-induced changes in the eCB system does not affect only tissues directly involved in the metabolic regulation, but also brain regions mediating hedonic aspects of eating and influencing cognitive processes. PMID:20445053

  4. Molecular pathway alterations in CD4 T-cells of nonobese diabetic (NOD) mice in the preinsulitis phase of autoimmune diabetes.

    PubMed

    Kakoola, Dorothy N; Curcio-Brint, Anita; Lenchik, Nataliya I; Gerling, Ivan C

    2014-01-01

    Type 1 diabetes (T1D) is a multigenic disease caused by T-cell mediated destruction of the insulin producing pancreatic islet ß-cells. The earliest sign of islet autoimmunity in NOD mice, islet leukocytic infiltration or insulitis, is obvious at around 5 weeks of age. The molecular alterations that occur in T cells prior to insulitis and that may contribute to T1D development are poorly understood. Since CD4 T-cells are essential to T1D development, we tested the hypothesis that multiple genes/molecular pathways are altered in these cells prior to insulitis. We performed a genome-wide transcriptome and pathway analysis of whole, untreated CD4 T-cells from 2, 3, and 4 week-old NOD mice in comparison to two control strains (NOR and C57BL/6). We identified many differentially expressed genes in the NOD mice at each time point. Many of these genes (herein referred to as NOD altered genes) lie within known diabetes susceptibility (insulin-dependent diabetes, Idd) regions, e.g. two diabetes resistant loci, Idd27 (tripartite motif-containing family genes) and Idd13 (several genes), and the CD4 T-cell diabetogenic activity locus, Idd9/11 (2 genes, KH domain containing, RNA binding, signal transduction associated 1 and protein tyrosine phosphatase 4a2). The biological processes associated with these altered genes included, apoptosis/cell proliferation and metabolic pathways (predominant at 2 weeks); inflammation and cell signaling/activation (predominant at 3 weeks); and innate and adaptive immune responses (predominant at 4 weeks). Pathway analysis identified several factors that may regulate these abnormalities: eight, common to all 3 ages (interferon regulatory factor 1, hepatic nuclear factor 4, alpha, transformation related protein 53, BCL2-like 1 (lies within Idd13), interferon gamma, interleukin 4, interleukin 15, and prostaglandin E2); and two each, common to 2 and 4 weeks (androgen receptor and interleukin 6); and to 3 and 4 weeks (interferon alpha and

  5. Molecular pathway alterations in CD4 T-cells of nonobese diabetic (NOD) mice in the preinsulitis phase of autoimmune diabetes

    PubMed Central

    Kakoola, Dorothy N.; Curcio-Brint, Anita; Lenchik, Nataliya I.; Gerling, Ivan C.

    2014-01-01

    Type 1 diabetes (T1D) is a multigenic disease caused by T-cell mediated destruction of the insulin producing pancreatic islet ß-cells. The earliest sign of islet autoimmunity in NOD mice, islet leukocytic infiltration or insulitis, is obvious at around 5 weeks of age. The molecular alterations that occur in T cells prior to insulitis and that may contribute to T1D development are poorly understood. Since CD4 T-cells are essential to T1D development, we tested the hypothesis that multiple genes/molecular pathways are altered in these cells prior to insulitis. We performed a genome-wide transcriptome and pathway analysis of whole, untreated CD4 T-cells from 2, 3, and 4 week-old NOD mice in comparison to two control strains (NOR and C57BL/6). We identified many differentially expressed genes in the NOD mice at each time point. Many of these genes (herein referred to as NOD altered genes) lie within known diabetes susceptibility (insulin-dependent diabetes, Idd) regions, e.g. two diabetes resistant loci, Idd27 (tripartite motif-containing family genes) and Idd13 (several genes), and the CD4 T-cell diabetogenic activity locus, Idd9/11 (2 genes, KH domain containing, RNA binding, signal transduction associated 1 and protein tyrosine phosphatase 4a2). The biological processes associated with these altered genes included, apoptosis/cell proliferation and metabolic pathways (predominant at 2 weeks); inflammation and cell signaling/activation (predominant at 3 weeks); and innate and adaptive immune responses (predominant at 4 weeks). Pathway analysis identified several factors that may regulate these abnormalities: eight, common to all 3 ages (interferon regulatory factor 1, hepatic nuclear factor 4, alpha, transformation related protein 53, BCL2-like 1 (lies within Idd13), interferon gamma, interleukin 4, interleukin 15, and prostaglandin E2); and two each, common to 2 and 4 weeks (androgen receptor and interleukin 6); and to 3 and 4 weeks (interferon alpha and

  6. Generalized master equations for exciton dynamics in molecular systems

    NASA Astrophysics Data System (ADS)

    Schreiber, Michael; May, V.

    1995-02-01

    The paper demonstrates the applicability of a special type of density matrix theory for the derivation of generalized Master equations. The density matrix theory has been formulated for the description of the dissipative electron transfer dynamics in molecular complexes. The theoretical approach is based on a representation of the density matrix in appropriately taken diabatic electron-vibrational states. Dissipative effects are taken into account by a coupling of these states to further vibrational modes of the molecular complex as well as to environmental degrees of freedom. The approach is applied to a two-center system as well as to a molecular chain. Memory kernels are derived in second order with respect to the inter-center coupling. The kernels are discussed under the assumption of a quick intra-center relaxation for a part of the vibrational modes as well as for all vibrational modes. Standard expressions for the transition rates between different sites are extended to include finite life times of the vibrational levels. Results which have been obtained in the study of the so-called spin boson model can be simply reproduced. The application of the derived generalized Master equations to the investigation of the motion of Frenkel excitons in molecular chains is also presented.

  7. Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism.

    PubMed

    Sassoon, Daniel J; Goodwill, Adam G; Noblet, Jillian N; Conteh, Abass M; Herring, B Paul; McClintick, Jeanette N; Tune, Johnathan D; Mather, Kieren J

    2016-07-01

    This study tested the hypothesis that obesity alters the cardiac response to ischemia/reperfusion and/or glucagon like peptide-1 (GLP-1) receptor activation, and that these differences are associated with alterations in the obese cardiac proteome and microRNA (miRNA) transcriptome. Ossabaw swine were fed normal chow or obesogenic diet for 6 months. Cardiac function was assessed at baseline, during a 30-minutes coronary occlusion, and during 2 hours of reperfusion in anesthetized swine treated with saline or exendin-4 for 24 hours. Cardiac biopsies were obtained from normal and ischemia/reperfusion territories. Fat-fed animals were heavier, and exhibited hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. Plasma troponin-I concentration (index of myocardial injury) was increased following ischemia/reperfusion and decreased by exendin-4 treatment in both groups. Ischemia/reperfusion produced reductions in systolic pressure and stroke volume in lean swine. These indices were higher in obese hearts at baseline and relatively maintained throughout ischemia/reperfusion. Exendin-4 administration increased systolic pressure in lean swine but did not affect the blood pressure in obese swine. End-diastolic volume was reduced by exendin-4 following ischemia/reperfusion in obese swine. These divergent physiologic responses were associated with obesity-related differences in proteins related to myocardial structure/function (e.g. titin) and calcium handling (e.g. SERCA2a, histidine-rich Ca(2+) binding protein). Alterations in expression of cardiac miRs in obese hearts included miR-15, miR-27, miR-130, miR-181, and let-7. Taken together, these observations validate this discovery approach and reveal novel associations that suggest previously undiscovered mechanisms contributing to the effects of obesity on the heart and contributing to the actions of GLP-1 following ischemia/reperfusion. PMID:27234258

  8. Radiofrequency radiation alters the immune system. II. Modulation of in vivo lymphocyte circulation

    SciTech Connect

    Liburdy, R.P.

    1980-07-01

    In vivo lymphocyte circulation was significantly altered in mice exposed to whole-body radiofrequency radiation (RFR). In vivo lymphocyte circulation was followed by quantitating activity of sodium chromate-51-labeled lymphocytes in the lung, spleen, liver, and bone marrow of animals at different times after iv spleen lymphocyte injection. Immediately after cell injection, animals were exposed to 2.6-GHz RFR (CW) at 25 or 5 mW/cm/sup 2/ (3.8 W/kg) for 1 h. At 1,6, and 24 h aftr lymphocyte injection target organs were removed, weighed, and counted. Sham RFR, warm-air, and steroid-treated groups were included as controls. Hyperthermic RFR exposure (25 mW/cm/sup 2/, 2.0/sup 0/C increase in core temperature) led to a 37% reduction in lymphocytes leaving the lung to migrate into the spleen. In addition, a threefold increse in spleen lymphocytes entering the bone marrow occurred. Significantly, this pattern was also observed in the steroid-treated group; nonthermogenic RFR exposure (5 mWcm/sup 2/) and warm-air exposures did not lead to altered lymphocyte traffic. These results support the idea that steroid release associated with thermal stress and the process of thermoregulation is a significant operatnt factor responsible for RFR effects on the immune system.

  9. Localization of specialized intestinal metaplasia and the molecular alterations in Barrett esophagus in a Japanese population: an analysis of biopsy samples based on the "Seattle" biopsy protocol.

    PubMed

    Fukui, Shota; Watari, Jiro; Tomita, Toshihiko; Yamasaki, Takahisa; Okugawa, Takuya; Kondo, Takashi; Kono, Tomoaki; Tozawa, Katsuyuki; Ikehara, Hisatomo; Ohda, Yoshio; Oshima, Tadayuki; Fukui, Hirokazu; Das, Kiron M; Miwa, Hiroto

    2016-05-01

    It remains unclear why Barrett esophagus (BE)-associated adenocarcinoma (EAC) frequently occurs in the 0 to 3 o'clock area of the BE. The aims of this study were to clarify the localization of specialized intestinal metaplasia (SIM) as a precancerous lesion and of molecular alterations among different locations using 4-quadrant biopsies based on the "Seattle" protocol. We prospectively evaluated microsatellite instability; methylation status at the APC, CDKN2A, hMLH1, RUNX3, and MGMT genes; the immunoreactivity of the monoclonal antibody Das-1 for the colonic phenotype; and Ki-67 staining in 10 early EACs and 128 biopsy samples from 32 BE patients. Among the molecular changes, only APC gene hypermethylation was an independent predictive marker of EAC (odds ratio, 24.4; P = .01). SIM was more frequently identified in the 0 to 3 o'clock quadrant than in the 6 to 9 o'clock quadrant (P = .08). The Ki-67 index was higher in SIM than in the columnar-lined epithelium (CLE) without goblet cells (P < .0001) and in both SIM and CLE with Das-1 reactivity than in those without (P = .04 and P = .06, respectively). Furthermore, the index was relatively higher in the 0 to 3 o'clock quadrant than in the 6 to 9 o'clock quadrant in cases with Das-1 reactivity. RUNX3 methylation was more frequently found in SIM than in CLE (P = .04), whereas the incidence of the other biomarkers did not show a significant difference between the 0 to 3 o'clock and 6 to 9 o'clock areas, nor between SIM and CLE. SIM with Das-1 reactivity, but not molecular alterations, in the 0 to 3 o'clock quadrant may have higher proliferative activity compared to the other areas of the BE. PMID:27067780

  10. Clay alteration of volcaniclastic material in a submarine geothermal system, Bay of Plenty, New Zealand

    NASA Astrophysics Data System (ADS)

    Hocking, Michael W. A.; Hannington, Mark D.; Percival, Jeanne B.; Stoffers, Peter; Schwarz-Schampera, Ulrich; de Ronde, C. E. J.

    2010-04-01

    The Calypso Hydrothermal Vent Field (CHVF) is located along an offshore extension of the Taupo Volcanic Zone (TVZ), an area of abundant volcanism and geothermal activity on the North Island of New Zealand. The field occurs within a northeast-trending submarine depression on the continental shelf approximately 10-15 km southwest of the White Island volcano in the Bay of Plenty. The graben has been partially filled by tephra from regional subaerial volcanic eruptions, and active hydrothermal venting occurs at several locations along its length. The vents occur at water depths of 160 to 190 m and have temperatures up to 201 °C. Recovered samples from the vent field include variably cemented and veined volcaniclastic sediments containing an assemblage of clay minerals, amorphous silica, barite, As-Sb-Hg sulfides, and abundant native sulfur. The volcanic glass has been altered primarily to montmorillonite and mixed-layer illite-montmorillonite; illite, and possibly minor talc and mixed-layer chlorite-smectite or chlorite-vermiculite are also present. A hydrothermal versus diagenetic origin for the smectite is indicated by the presence of both illite and mixed-layer clays and by the correlation between the abundance of clay minerals and the abundance of native sulfur in the samples. The mineralization and alteration of the volcanic host rocks are similar to that observed in near-neutral pH geothermal systems on land in the TVZ (e.g., Broadlands-Ohaaki). However, the clay minerals in the CHVF have a higher concentration of Mg in the dioctahedral layer and a higher interlayer Na content than clay minerals from Broadlands-Ohaaki, reflecting the higher concentrations of Mg and Na in seawater compared to meteoric water. Minerals formed at very low pH (e.g., kaolinite and alunite), typical of steam-heated acid-sulfate type alteration in the TVZ geothermal environment, were not found. Mixing with seawater likely prevented the formation of such low-pH mineral assemblages. The

  11. Review and application of group theory to molecular systems biology.

    PubMed

    Rietman, Edward A; Karp, Robert L; Tuszynski, Jack A

    2011-01-01

    In this paper we provide a review of selected mathematical ideas that can help us better understand the boundary between living and non-living systems. We focus on group theory and abstract algebra applied to molecular systems biology. Throughout this paper we briefly describe possible open problems. In connection with the genetic code we propose that it may be possible to use perturbation theory to explore the adjacent possibilities in the 64-dimensional space-time manifold of the evolving genome. With regards to algebraic graph theory, there are several minor open problems we discuss. In relation to network dynamics and groupoid formalism we suggest that the network graph might not be the main focus for understanding the phenotype but rather the phase space of the network dynamics. We show a simple case of a C6 network and its phase space network. We envision that the molecular network of a cell is actually a complex network of hypercycles and feedback circuits that could be better represented in a higher-dimensional space. We conjecture that targeting nodes in the molecular network that have key roles in the phase space, as revealed by analysis of the automorphism decomposition, might be a better way to drug discovery and treatment of cancer. PMID:21696623

  12. Nanoparticles of copper stimulate angiogenesis at systemic and molecular level.

    PubMed

    Mroczek-Sosnowska, Natalia; Sawosz, Ewa; Vadalasetty, Krishna Prasad; Łukasiewicz, Monika; Niemiec, Jan; Wierzbicki, Mateusz; Kutwin, Marta; Jaworski, Sławomir; Chwalibog, André

    2015-01-01

    Copper is a key element affecting blood vessel growth and muscle development. However, the ions released from Cu salts are toxic. Given their specific physicochemical properties, nanoparticles of Cu (NanoCu) may have different bioactivity and affect the development of blood vessel and muscles in a different manner than Cu salts. The objective of the study was to evaluate the influence of NanoCu on embryo development and angiogenesis at the systemic and molecular level, in experiments using a chick embryo model. Fertilized chicken eggs were divided into a control group, and groups injected with a placebo, CuSO4 or NanoCu. Embryo development at the whole body level and molecular indices using an embryo chorioallantoic membrane model were measured during embryogenesis. The present study indicated for the first time that NanoCu have pro-angiogenic properties at the systemic level, to a greater degree than CuSO4 salt. The properties of NanoCu were confirmed at the molecular level, demonstrating significant effects on mRNA concentration and on mRNA gene expression of all pro-angiogenic and pro-proliferative genes measured herein. PMID:25741768

  13. Review and application of group theory to molecular systems biology

    PubMed Central

    2011-01-01

    In this paper we provide a review of selected mathematical ideas that can help us better understand the boundary between living and non-living systems. We focus on group theory and abstract algebra applied to molecular systems biology. Throughout this paper we briefly describe possible open problems. In connection with the genetic code we propose that it may be possible to use perturbation theory to explore the adjacent possibilities in the 64-dimensional space-time manifold of the evolving genome. With regards to algebraic graph theory, there are several minor open problems we discuss. In relation to network dynamics and groupoid formalism we suggest that the network graph might not be the main focus for understanding the phenotype but rather the phase space of the network dynamics. We show a simple case of a C6 network and its phase space network. We envision that the molecular network of a cell is actually a complex network of hypercycles and feedback circuits that could be better represented in a higher-dimensional space. We conjecture that targeting nodes in the molecular network that have key roles in the phase space, as revealed by analysis of the automorphism decomposition, might be a better way to drug discovery and treatment of cancer. PMID:21696623

  14. Nucleocytoplasmic Transport: A Paradigm for Molecular Logistics in Artificial Systems.

    PubMed

    Vujica, Suncica; Zelmer, Christina; Panatala, Radhakrishnan; Lim, Roderick Y H

    2016-01-01

    Artificial organelles, molecular factories and nanoreactors are membrane-bound systems envisaged to exhibit cell-like functionality. These constitute liposomes, polymersomes or hybrid lipo-polymersomes that display different membrane-spanning channels and/or enclose molecular modules. To achieve more complex functionality, an artificial organelle should ideally sustain a continuous influx of essential macromolecular modules (i.e. cargoes) and metabolites against an outflow of reaction products. This would benefit from the incorporation of selective nanopores as well as specific trafficking factors that facilitate cargo selectivity, translocation efficiency, and directionality. Towards this goal, we describe how proteinaceous cargoes are transported between the nucleus and cytoplasm by nuclear pore complexes and the biological trafficking machinery in living cells (i.e. nucleocytoplasmic transport). On this basis, we discuss how biomimetic control may be implemented to selectively import, compartmentalize and accumulate diverse macromolecular modules against concentration gradients in artificial organelles. PMID:27363369

  15. [Molecular hyperspectral imaging (MHSI) system and application in biochemical medicine].

    PubMed

    Liu, Hong-Ying; Li, Qing-Li; Wang, Yi-Ting; Liu, Jin-Gao; Xue, Yong-Qi

    2011-10-01

    A novel molecular hyperspectral imaging (MHSI) system based on AOTF (acousto-optic tunable filters) was presented. The system consists of microscope, AOTF-based spectrometer, matrix CCD, image collection card and computer. The spectral range of the MHSI is from 550 to 1 000 nm. The spectral resolution is less than 2 nm, and the spatial resolution is about 0.3 microm. This paper has also presented that spectral curves extracted from the corrected hyperspectral data of the sample, which have been preprocessed by the gray correction coefficient, can more truly represent biochemical characteristic of the sample. The system can supply not only single band images in the visible range, but also spectrum curve of random pixel of sample image. This system can be widely used in various fields of biomedicine, clinical medicine, material science and microelectronics. PMID:22250515

  16. Molecular physiology of vesicular glutamate transporters in the digestive system

    PubMed Central

    Li, Tao; Ghishan, Fayez K.; Bai, Liqun

    2005-01-01

    Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Packaging and storage of glutamate into glutamatergic neuronal vesicles require ATP-dependent vesicular glutamate uptake systems, which utilize the electrochemical proton gradient as a driving force. Three vesicular glutamate transporters (VGLUT1-3) have been recently identified from neuronal tissue where they play a key role to maintain the vesicular glutamate level. Recently, it has been demonstrated that glutamate signaling is also functional in peripheral neuronal and non-neuronal tissues, and occurs in sites of pituitary, adrenal, pineal glands, bone, GI tract, pancreas, skin, and testis. The glutamate receptors and VGLUTs in digestive system have been found in both neuronal and endocrinal cells. The glutamate signaling in the digestive system may have significant relevance to diabetes and GI tract motility disorders. This review will focus on the most recent update of molecular physiology of digestive VGLUTs. PMID:15793854

  17. Molecular mechanisms regulating myelination in the peripheral nervous system.

    PubMed

    Pereira, Jorge A; Lebrun-Julien, Frédéric; Suter, Ueli

    2012-02-01

    Glial cells and neurons are engaged in a continuous and highly regulated bidirectional dialog. A remarkable example is the control of myelination. Oligodendrocytes in the central nervous system (CNS) and Schwann cells (SCs) in the peripheral nervous system (PNS) wrap their plasma membranes around axons to organize myelinated nerve fibers that allow rapid saltatory conduction. The functionality of this system is critical, as revealed by numerous neurological diseases that result from deregulation of the system, including multiple sclerosis and peripheral neuropathies. In this review we focus on PNS myelination and present a conceptual framework that integrates crucial signaling mechanisms with basic SC biology. We will highlight signaling hubs and overarching molecular mechanisms, including genetic, epigenetic, and post-translational controls, which together regulate the interplay between SCs and axons, extracellular signals, and the transcriptional network. PMID:22192173

  18. Early Fear Memory Defects Are Associated with Altered Synaptic Plasticity and Molecular Architecture in the TgCRND8 Alzheimer's Disease Mouse Model

    PubMed Central

    Steele, John W.; Brautigam, Hannah; Short, Jennifer A.; Sowa, Allison; Shi, Mengxi; Yadav, Aniruddha; Weaver, Christina M.; Westaway, David; Fraser, Paul E.; St George-Hyslop, Peter H.; Gandy, Sam; Hof, Patrick R.; Dickstein, Dara L.

    2014-01-01

    Alzheimer's disease (AD) is a complex and slowly progressing dementing disorder that results in neuronal and synaptic loss, deposition in brain of aberrantly folded proteins, and impairment of spatial and episodic memory. Most studies of mouse models of AD have employed analyses of cognitive status and assessment of amyloid burden, gliosis, and molecular pathology during disease progression. Here, we sought to understand the behavioral, cellular, ultrastructural, and molecular changes that occur at a pathological stage equivalent to early stages of human AD. We studied the TgCRND8 mouse, a model of aggressive AD amyloidosis, at an early stage of plaque pathology (3 months of age) in comparison to their wild-type littermates and assessed changes in cognition, neuron and spine structure, and expression of synaptic glutamate receptor proteins. We found that, at this age, TgCRND8 mice display substantial plaque deposition in the neocortex and hippocampus and impairment on cued and contextual memory tasks. Of particular interest, we also observed a significant decrease in the number of neurons in the hippocampus. Furthermore, analysis of CA1 neurons revealed significant changes in apical and basal dendritic spine types, as well as altered expression of GluN1 and GluA2 receptors. This change in molecular architecture within the hippocampus may reflect a rising representation of inherently less stable thin spine populations, which can cause cognitive decline. These changes, taken together with toxic insults from amyloid-β protein, may underlie the observed neuronal loss. PMID:24415002

  19. On the sputter alteration of regoliths of outer solar system bodies

    NASA Technical Reports Server (NTRS)

    Hapke, B.

    1986-01-01

    The present theoretical and experimental consideration of processes that are expected to occur when the porous regoliths on outer solar system bodies lacking atmospheres are subjected to energetic ion bombardment indicates that porosity reduces the effective sputtering yield of a soil by more than an order of magnitude. Between 90 and 97 percent of the sputtered atoms are trapped within the regolith and subjected to differential desorption fractionation, which emerges as the most important path for the alteration of chemical and optical properties in sputtered regoliths. Sputtered porous mixtures of water, ammonia and methane frosts suffer a loss of H, and surface reactions of C, N, and O that should yield complex hydrocarbons and carbohydrates; such reactions may have played a role in the formation of carbonaceous chondrites' matrix material prior to agglomeration.

  20. Neuropsychological evaluation for detecting alterations in the central nervous system after chemical exposure.

    PubMed

    Bolla, K I

    1996-08-01

    Individuals with multiple chemical sensitivity (MCS) report decreased attention/concentration, memory loss, disorientation, confusion, fatigue, depression, irritability, decreased libido, sleep disturbances, headaches, and weakness. These neurobehavioral symptoms represent possible alterations in the central nervous system (CNS). The evaluation of neurobehavioral functioning using neuropsychological techniques provides an indirect method for determining the integrity of the CNS. However, caution must be used in interpreting neuropsychological test results, since this technique is extremely sensitive but is not specific. Clinically significant aberrant test performance may be noted after chemical exposure as well as with other diseases of the CNS. In addition, neuropsychiatric conditions such as anxiety and depression are often manifested as cognitive difficulties that are similar in pattern to the cognitive dysfunction caused by toxic chemicals. Herein, limitations and cautions in the interpretations of neuropsychological test results are discussed. PMID:8921555

  1. Pathogenesis of Bone Alterations in Gaucher Disease: The Role of Immune System

    PubMed Central

    Mucci, Juan Marcos; Rozenfeld, Paula

    2015-01-01

    Gaucher, the most prevalent lysosomal disorder, is an autosomal recessive inherited disorder due to a deficiency of glucocerebrosidase. Glucocerebrosidase deficiency leads to the accumulation of glucosylceramide primarily in cells of mononuclear-macrophage lineage. Clinical alterations are visceral, hematological, and skeletal. Bone disorder in Gaucher disease produces defects on bone metabolism and structure and patients suffer from bone pain and crisis. Skeletal problems include osteopenia, osteoporosis, osteolytic lesions, and osteonecrosis. On the other hand a chronic stimulation of the immune system is a well-accepted hallmark in this disease. In this review we summarize the latest findings in the mechanisms leading to the bone pathology in Gaucher disease in relationship with the proinflammatory state. PMID:26064996

  2. In Search of Concomitant Alterations of Dopaminergic and Neurotensinergic Systems in Stress Conditions.

    PubMed

    Rodríguez de Lores Arnaiz, Georgina; Antonelli, Marta C

    2016-02-01

    The aim of the present article is to review experimental evidence which suggest joint involvement of both the dopaminergic and neurotensinergic systems in stress conditions. At present, the concept of stress refers to an environmental demand exceeding the normal regulatory ability of an organism, particularly during unpredictable and uncontrollable situations. Chronic stress yields devastating effects including cognitive and working memory dysfunctions, for which neurotransmission mediated by the catecholamines dopamine and noradrenaline is crucial. Catecholamine synthesis depends on the rate-limiting enzyme, tyrosine hydroxylase, whose expression is associated with working memory and the response to chronic stress. Neurotensin is a tridecapeptide widely distributed in the nervous system, at both central and peripheral levels, which behaves as a neurotransmitter or neuromodulator. It mediates diverse biological actions including reward, locomotion, pain modulation and stress. Neurotensin and its high affinity NTS1 receptor are densely localized in areas that process emotion (amygdala nucleus), cognition (such as hippocampal nuclei and cortical areas) and the response to stress (hypothalamic nucleus). Experimental evidence indicates a crosstalk between the dopaminergic and the neurotensinergic systems either from an anatomical or a biochemical point of view. It is suggested that a concomitant alteration of dopaminergic and neurotensinergic systems takes place in diverse stress conditions. PMID:26869038

  3. Multi-modality systems for molecular tomographic imaging

    NASA Astrophysics Data System (ADS)

    Li, Mingze; Bai, Jing

    2009-11-01

    In vivo small animal imaging is a cornerstone in the study of human diseases by providing important clues on the pathogenesis, progression and treatment of many disorders. Molecular tomographic imaging can probe complex biologic interactions dynamically and to study diseases and treatment responses over time in the same animal. Current imaging technique including microCT, microMRI, microPET, microSPECT, microUS, BLT and FMT has its own advantages and applications, however, none of them can provide structural, functional and molecular information in one context. Multi-modality imaging, which utilizes the strengths of different modalities to provide a complete understanding of the object under investigation, emerges as an important alternative in small animal imaging. This article is to introduce the latest development of multimodality systems for small animal tomographic imaging. After a systematic review of imaging principles, systems and commerical products for each stand-alone method, we introduce some multimodality strategies in the latest years. In particular, two dual-modality systems, i.e. FMT-CT and FMT-PET are presented in detail. The end of this article concludes that though most multimodality systems are still in a laboratory research stage, they will surely undergo deep development and wide application in the near future.

  4. BIOMEX Experiment: Ultrastructural Alterations, Molecular Damage and Survival of the Fungus Cryomyces antarcticus after the Experiment Verification Tests

    NASA Astrophysics Data System (ADS)

    Pacelli, Claudia; Selbmann, Laura; Zucconi, Laura; De Vera, Jean-Pierre; Rabbow, Elke; Horneck, Gerda; de la Torre, Rosa; Onofri, Silvano

    2016-04-01

    The search for traces of extinct or extant life in extraterrestrial environments is one of the main goals for astrobiologists; due to their ability to withstand stress producing conditions, extremophiles are perfect candidates for astrobiological studies. The BIOMEX project aims to test the ability of biomolecules and cell components to preserve their stability under space and Mars-like conditions, while at the same time investigating the survival capability of microorganisms. The experiment has been launched into space and is being exposed on the EXPOSE-R2 payload, outside of the International Space Station (ISS) over a time-span of 1.5 years. Along with a number of other extremophilic microorganisms, the Antarctic cryptoendolithic black fungus Cryomyces antarcticus CCFEE 515 has been included in the experiment. Before launch, dried colonies grown on Lunar and Martian regolith analogues were exposed to vacuum, irradiation and temperature cycles in ground based experiments (EVT1 and EVT2). Cultural and molecular tests revealed that the fungus survived on rock analogues under space and simulated Martian conditions, showing only slight ultra-structural and molecular damage.

  5. Hepatic circadian-clock system altered by insulin resistance, diabetes and insulin sensitizer in mice.

    PubMed

    Tseng, Huey-Ling; Yang, Shu-Chuan; Yang, Shih-Hsien; Shieh, Kun-Ruey

    2015-01-01

    Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin-resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor γ (PPARγ) rather than PPARα. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways. PMID:25799429

  6. Hepatic Circadian-Clock System Altered by Insulin Resistance, Diabetes and Insulin Sensitizer in Mice

    PubMed Central

    Yang, Shih-Hsien; Shieh, Kun-Ruey

    2015-01-01

    Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin-resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor γ (PPARγ) rather than PPARα. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways. PMID:25799429

  7. Systemic Sclerosis Patients Present Alterations in the Expression of Molecules Involved in B-Cell Regulation

    PubMed Central

    Soto, Lilian; Ferrier, Ashley; Aravena, Octavio; Fonseca, Elianet; Berendsen, Jorge; Biere, Andrea; Bueno, Daniel; Ramos, Verónica; Aguillón, Juan Carlos; Catalán, Diego

    2015-01-01

    The activation threshold of B cells is tightly regulated by an array of inhibitory and activator receptors in such a way that disturbances in their expression can lead to the appearance of autoimmunity. The aim of this study was to evaluate the expression of activating and inhibitory molecules involved in the modulation of B cell functions in transitional, naive, and memory B-cell subpopulations from systemic sclerosis patients. To achieve this, blood samples were drawn from 31 systemic sclerosis patients and 53 healthy individuals. Surface expression of CD86, MHC II, CD19, CD21, CD40, CD22, Siglec 10, CD35, and FcγRIIB was determined by flow cytometry. IL-10 production was evaluated by intracellular flow cytometry from isolated B cells. Soluble IL-6 and IL-10 levels were measured by ELISA from supernatants of stimulated B cells. Systemic sclerosis patients exhibit an increased frequency of transitional and naive B cells related to memory B cells compared with healthy controls. Transitional and naive B cells from patients express higher levels of CD86 and FcγRIIB than healthy donors. Also, B cells from patients show high expression of CD19 and CD40, whereas memory cells from systemic sclerosis patients show reduced expression of CD35. CD19 and CD35 expression levels associate with different autoantibody profiles. IL-10+ B cells and secreted levels of IL-10 were markedly reduced in patients. In conclusion, systemic sclerosis patients show alterations in the expression of molecules involved in B-cell regulation. These abnormalities may be determinant in the B-cell hyperactivation observed in systemic sclerosis. PMID:26483788

  8. The system of molecular clouds in the Gould Belt

    NASA Astrophysics Data System (ADS)

    Bobylev, V. V.

    2016-08-01

    Based on high-latitude molecular clouds with highly accurate distance estimates taken from the literature, we have redetermined the parameters of their spatial orientation. This systemcan be approximated by a 350 × 235 × 140 pc ellipsoid inclined by the angle i = 17° ± 2° to the Galactic plane with the longitude of the ascending node l Ω = 337° ± 1°. Based on the radial velocities of the clouds, we have found their group velocity relative to the Sun to be ( u 0, v 0, w 0) = (10.6, 18.2, 6.8) ± (0.9, 1.7, 1.5) km s-1. The trajectory of the center of the molecular cloud system in the past in a time interval of ~60 Myr has been constructed. Using data on masers associated with low-mass protostars, we have calculated the space velocities of the molecular complexes in Orion, Taurus, Perseus, and Ophiuchus. Their motion in the past is shown to be not random.

  9. Does Acupuncture Alter Pain-related Functional Connectivity of the Central Nervous System? A Systematic Review.

    PubMed

    Villarreal Santiago, María; Tumilty, Steve; Mącznik, Aleksandra; Mani, Ramakrishnan

    2016-08-01

    Acupuncture has been studied for several decades to establish evidence-based clinical practice. This systematic review aims to evaluate evidence for the effectiveness of acupuncture in influencing the functional connectivity of the central nervous system in patients with musculoskeletal pain. A systematic search of the literature was conducted to identify studies in which the central response of acupuncture in patients with musculoskeletal pain was evaluated by neuroimaging techniques. Databases searched were AMED, CINAHL, Cochrane Library, EMBASE, MEDLINE, PEDro, Pubmed, SCOPUS, SPORTDiscuss, and Web of Science. Included studies were assessed by two independent reviewers for their methodological quality by using the Downs and Black questionnaire and for their levels of completeness and transparency in reporting acupuncture interventions by using Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) criteria. Seven studies met the inclusion criteria. Three studies were randomized controlled trials (RCTs) and four studies were nonrandomized controlled trials (NRCTs). The neuroimaging techniques used were functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). Positive effects on the functional connectivity of the central nervous system more consistently occurred during long-term acupuncture treatment. The results were heterogeneous from a descriptive perspective; however, the key findings support acupuncture's ability to alter pain-related functional connectivity in the central nervous system in patients with musculoskeletal pain. PMID:27555221

  10. Altering shoppers' supermarket purchases to fit nutritional guidelines: An interactive information system

    PubMed Central

    Winett, Richard A.; Geller, E. Scott; Mundy, Laurie L.; Moore, John F.; Wagner, Jana L.; Hite, Lee A.; Leahy, Michael; Neubauer, Tamara E.; Walberg, Janet L.; Walker, W. Bruce; Lombard, David

    1991-01-01

    This study reports the results of one effort to help supermarket shoppers alter food purchases to make purchases (and meals) that are lower in fat and higher in fiber. A prototype interactive information system using instructional video programs, feedback on purchases with specific goals for change, weekly programs, and the ability to track user interactions and intended purchases was evaluated. The major dependent measure was users' actual food purchases as derived from participants' highly detailed supermarket receipts. After a 5- to 7-week baseline phase, participants were randomly assigned to an experimental or control condition for the 7- to 8-week intervention phase. A follow-up phase began 5 to 8 weeks after participants completed the intervention and discontinued use of the system. The results indicated that experimental participants, when compared to control participants, decreased high fat purchases and increased high fiber purchases during intervention, with evidence for some maintenance of effect in follow-up. Plans for increasing the use and impact of the system are discussed. ImagesFigure 1 PMID:1647387

  11. Magnetic hysteresis in a lanthanide molecular magnet dimer system

    NASA Astrophysics Data System (ADS)

    Atkinson, James; Cebulka, Rebecca; Del Barco, Enrique; Roubeau, Olivier; Velasco, Veronica; Barrios, Leo; Aromi, Guillem

    Molecular magnets present a wonderful means for studying the dynamics of spin. Often synthesized as a crystal lattice of identical systems, ensemble measurements enable thorough detailing of the internal degrees of freedom. Here we present the results of characterization performed on a dimer system, CeTm(HL)2(H2L)NO3pyH2O (L = ligand, C45H31O15N3), consisting of two lanthanide spins (Cerium and Thulium) with expected local axial anisotropies tilted with respect to each other. Microwave EPR spectroscopy at low temperature reveals hysteresis in observed absorption features, with angle dependence studies indicating the presence of several ``easy axis'' orientations. We attempt to understand this system through modelling via a spin Hamiltonian, and to determine the strength and nature of the coupling between the lanthanide centers. This research was funded through NSF Grant # 24086159.

  12. A 3D visualization system for molecular structures

    NASA Technical Reports Server (NTRS)

    Green, Terry J.

    1989-01-01

    The properties of molecules derive in part from their structures. Because of the importance of understanding molecular structures various methodologies, ranging from first principles to empirical technique, were developed for computing the structure of molecules. For large molecules such as polymer model compounds, the structural information is difficult to comprehend by examining tabulated data. Therefore, a molecular graphics display system, called MOLDS, was developed to help interpret the data. MOLDS is a menu-driven program developed to run on the LADC SNS computer systems. This program can read a data file generated by the modeling programs or data can be entered using the keyboard. MOLDS has the following capabilities: draws the 3-D representation of a molecule using stick, ball and ball, or space filled model from Cartesian coordinates, draws different perspective views of the molecule; rotates the molecule on the X, Y, Z axis or about some arbitrary line in space, zooms in on a small area of the molecule in order to obtain a better view of a specific region; and makes hard copy representation of molecules on a graphic printer. In addition, MOLDS can be easily updated and readily adapted to run on most computer systems.

  13. Detection of subtle neurological alterations by the Catwalk XT gait analysis system

    PubMed Central

    2014-01-01

    Background A new version of the CatWalk XT system was evaluated as a tool for detecting very subtle alteration in gait based on higher speed sample rate; the system could also demonstrate minor changes in neurological function. In this study, we evaluated the neurological outcome of sciatic nerve injury intervened by local injection of hyaluronic acid. Using the CatWalk XT system, we looked for differences between treated and untreated groups and differences within the same group as a function of time so as to assess the power of the Catwalk XT system for detecting subtle neurological change. Methods Peripheral nerve injury was induced in 36 Sprague–Dawley rats by crushing the left sciatic nerve using a vessel clamp. The animals were randomized into one of two groups: Group I: crush injury as the control; Group II: crush injury and local application with hyaluronic acid. These animals were subjected to neurobehavior assessment, histomorphology evaluation, and electrophysiology study periodically. These data were retrieved for statistical analysis. Results The density of neurofilament and S-100 over the distal end of crushed nerve showed significant differences either in inter-group comparison at various time points or intra-group comparison from 7 to 28 days. Neuronal structure architecture, axon counts, intensity of myelination, electrophysiology, and collagen deposition demonstrate significant differences between the two groups. There was significant difference of SFI and angle of ankle in inter- group analysis from 7 to 28 days, but there were no significant differences in SFI and angle of ankle at time points of 7 and 14 days. In the Cat Walk XT analysis, the intensity, print area, stance duration, and swing duration all showed detectable differences at 7, 14, 21, and 28 days, whereas there were no significant difference at 7 and 14 days with CatWalk 7 testing. In addition, there were no significant differences of step sequence or regularity index

  14. Systems biology analysis of the proteomic alterations induced by MPP+, a Parkinson's disease-related mitochondrial toxin

    PubMed Central

    Monti, Chiara; Bondi, Heather; Urbani, Andrea; Fasano, Mauro; Alberio, Tiziana

    2015-01-01

    Parkinson's disease (PD) is a complex neurodegenerative disease whose etiology has not been completely characterized. Many cellular processes have been proposed to play a role in the neuronal damage and loss: defects in the proteosomal activity, altered protein processing, increased reactive oxygen species burden. Among them, the involvement of a decreased activity and an altered disposal of mitochondria is becoming more and more evident. The mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+), an inhibitor of complex I, has been widely used to reproduce biochemical alterations linked to PD in vitro and its precursor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), to induce a Parkinson-like syndrome in vivo. Therefore, we performed a meta-analysis of the literature of all the proteomic investigations of neuronal alterations due to MPP+ treatment and compared it with our results obtained with a mitochondrial proteomic analysis of SH-SY5Y cells treated with MPP+. By using open-source bioinformatics tools, we identified the biochemical pathways and the molecular functions mostly affected by MPP+, i.e., ATP production, the mitochondrial unfolded stress response, apoptosis, autophagy, and, most importantly, the synapse funcionality. Eventually, we generated protein networks, based on physical or functional interactions, to highlight the relationships among the molecular actors involved. In particular, we identified the mitochondrial protein HSP60 as the central hub in the protein-protein interaction network. As a whole, this analysis clarified the cellular responses to MPP+, the specific mitochondrial proteome alterations induced and how this toxic model can recapitulate some pathogenetic events of PD. PMID:25698928

  15. DNA barcode-based molecular identification system for fish species.

    PubMed

    Kim, Sungmin; Eo, Hae-Seok; Koo, Hyeyoung; Choi, Jun-Kil; Kim, Won

    2010-12-01

    In this study, we applied DNA barcoding to identify species using short DNA sequence analysis. We examined the utility of DNA barcoding by identifying 53 Korean freshwater fish species, 233 other freshwater fish species, and 1339 saltwater fish species. We successfully developed a web-based molecular identification system for fish (MISF) using a profile hidden Markov model. MISF facilitates efficient and reliable species identification, overcoming the limitations of conventional taxonomic approaches. MISF is freely accessible at http://bioinfosys.snu.ac.kr:8080/MISF/misf.jsp . PMID:21110132

  16. A complex systems approach to computational molecular biology

    SciTech Connect

    Lapedes, A. |

    1993-09-01

    We report on the containing research program at Santa Fe Institute that applies complex systems methodology to computational molecular biology. Two aspects are stressed here are the use of co-evolving adaptive neutral networks for determining predictable protein structure classifications, and the use of information theory to elucidate protein structure and function. A ``snapshot`` of the current state of research in these two topics is presented, representing the present state of two major research thrusts in the program of Genetic Data and Sequence Analysis at the Santa Fe Institute.

  17. Altered MicroRNA Expression Is Associated with Tumor Grade, Molecular Background and Outcome in Childhood Infratentorial Ependymoma

    PubMed Central

    Zakrzewska, Magdalena; Fendler, Wojciech; Zakrzewski, Krzysztof; Sikorska, Beata; Grajkowska, Wiesława; Dembowska-Bagińska, Bożenna; Filipek, Iwona; Stefańczyk, Łukasz; Liberski, Paweł P.

    2016-01-01

    Background Ependymal tumors are the third most common group of brain tumors in children, accounting for about 10% of all primary brain neoplasms. According to the current WHO classification, they comprise four entities with the most frequent ependymoma and anaplastic ependymoma. The most of pediatric tumors are located within the posterior fossa, with a tendency to infiltrate the vital brain structures. This limits surgical resection and poses a considerable clinical problem. Moreover, there are no appropriate outcome prognostic factors besides the extent of surgical resection. Despite definition of molecular subgroups, the majority of childhood ependymomas present a balanced genome, which makes it difficult to establish molecular prognostic factors. Methods The purpose of our study was to explore whether miRNA expression could be used as prognostic markers in pediatric infratentorial ependymomas. We also performed a mRNA expression pattern analysis of NELL2 and LAMA2 genes, with immunohistochemical illustrations of representative cases. The miRNA and mRNA expression was measured in 53 pediatric infratentorial ependymomas using a real-time quantitative PCR. Results Three miRNAs were shown to efficiently differentiate between grade II and III ependymomas: miR-17-5p, miR-19a-3p, and miR-106b-5p. Survival analysis showed that the probabilities of overall (p = 0.036) and event-free survival (p = 0.002) were reduced with higher than median miRNA expression levels of miR-17-5p. Using multivariate analysis adjusted for patient's age, sex, tumor grade and localization, we showed statistically significant associations with event-free survival (p = 0004) and borderline statistical significance with overall survival (p = 0.057) for miR-17-5p. Correlation analysis of miR-19a, miR-17-5p, miR-106b revealed that their expression levels were significantly correlated with EZH2 expression, suggested marker of PFA ependymomas. Furthermore, lower expression level of LAMA2 mRNA was

  18. The display of molecular models with the Ames Interactive Modeling System (AIMS)

    NASA Technical Reports Server (NTRS)

    Egan, J. T.; Hart, J.; Burt, S. K.; Macelroy, R. D.

    1982-01-01

    A visualization of molecular models can lead to a clearer understanding of the models. Sophisticated graphics devices supported by minicomputers make it possible for the chemist to interact with the display of a very large model, altering its structure. In addition to user interaction, the need arises also for other ways of displaying information. These include the production of viewgraphs, film presentation, as well as publication quality prints of various models. To satisfy these needs, the display capability of the Ames Interactive Modeling System (AIMS) has been enhanced to provide a wide range of graphics and plotting capabilities. Attention is given to an overview of the AIMS system, graphics hardware used by the AIMS display subsystem, a comparison of graphics hardware, the representation of molecular models, graphics software used by the AIMS display subsystem, the display of a model obtained from data stored in molecule data base, a graphics feature for obtaining single frame permanent copy displays, and a feature for producing multiple frame displays.

  19. Aortic smooth muscle cell alterations in mice systemically exposed to arsenic.

    PubMed

    Chen, Shih-Chieh; Huang, Shin-Yin; Lin, Wen-Ting; Yang, Rei-Cheng; Yu, Hsin-Su

    2016-05-01

    Previous epidemiological studies showed that chronic arsenic exposure is related to increased cardiovascular disease incidence. The detailed biochemical mechanisms by which arsenic exerts its effects remain unknown. Vascular disease progression is characterized by smooth muscle cell (SMC) phenotypic switching, vessel wall reorganization, and platelet-derived growth factor (PDGF) production. The objective of this study was to examine early biochemical and structural changes in the aortas of ICR mice systemically exposed to arsenic. Animals were fed sodium arsenite (20 mg/kg) via gavage 5 days/week or Milli-Q water only (control) for 8 weeks. Aortic proteins were subjected to two-dimensional (2-D) differential gel electrophoresis and proteomic studies. Two 2-D gel protein spots were identified as the same protein, smooth muscle (SM)22α, using proteomics. SM22α and Rho kinase 2 gene and protein expression were significantly decreased in the aortic tissue of arsenic-exposed mice compared with that of control mice. No atherosclerotic lesion formation or tissue injury was detected in the aortic wall of either the arsenic-fed or the control group. However, the percent (%) SMC area of the aortic wall was significantly decreased in arsenic-fed mice compared with that in control mice. Additionally, the expression levels of PDGF-BB and early growth response-1 (Egr-1) were significantly higher in the arsenic group than that in the control group. These findings reveal biochemical alterations of SM22α, PDGF, and Egr-1 in conjunction with decreased SMC area in the aortic wall of arsenic-fed mice. Arsenic may initiate aortic SMC alterations that subsequently lead to vascular dysfunction. PMID:26135927

  20. Alterations in central monoamine systems after postnatal lead acetate treatment in rats

    SciTech Connect

    Luthman, J. Univ. of Colorado Health Sciences Center, Denver, CO ); Lindqvist, E.; Olson, L. ); Gerhardt, G.A.; Hoffer, B.H. )

    1994-04-01

    The present study was undertaken to investigate the effect of postnatal lead exposure on central monoamine systems. Newborn male Sprague-Dawley rats were given 1 or 8 mg/kg lead acetate intraperitoneally for 20 days postnatally. Two groups of control rats received sodium acetate, or sodium acetate in oversized litters to compensate for lead-induced malnutrition in the high lead dose group, while nontreated animals also served as controls. At Day 21 or 51 regional tissue levels of monoamines were determined using HPLC techniques. No major changes were seen after the lead exposures in the levels of dopamine, noradrenaline, and serotonin, or metabolites of dopamine and serotonin, when compared to respective control groups. On the other hand, in the control group given sodium acetate in oversized litters some alterations of the monoamine levels were observed in frontal cortex and striatum at Day 21 compared to controls. At Day 51, the striatal homovanillic acid and 5-hydroxyindoleacetic acid levels were higher in the low lead dose group compared to those in the controls, No other changes in the monoamine levels were seen at Day 51. At 50-70 days postnatally, potassium-stimulated dopamine overflow was studied in striatum with in vivo chronoamperometry. In the high lead dose group the amplitudes of signals were lower in both the dorsal and ventral striatum compared to the controls, while no difference was seen in the clearance time of dopamine. The capacity of the dopamine terminals to respond to repeated stimulation was not affected by the lead exposure. Thus, the steady-state levels of monoamines were essentially unaltered after postnatal lead exposure in rats, while functional aspects of striatal dopamine transmission were affected after exposure to the higher dose of lead. These findings support the hypothesis that lead-induced changes in motor skills and exploratory behavior may be related to altered dopamine neurotransmission. 77 refs., 3 figs., 2 tabs.

  1. Toxoplasma gondii Infections Alter GABAergic Synapses and Signaling in the Central Nervous System

    PubMed Central

    Brooks, Justin M.; Carrillo, Gabriela L.; Su, Jianmin; Lindsay, David S.; Blader, Ira J.

    2015-01-01

    ABSTRACT During infections with the protozoan parasite Toxoplasma gondii, gamma-aminobutyric acid (GABA) is utilized as a carbon source for parasite metabolism and also to facilitate parasite dissemination by stimulating dendritic-cell motility. The best-recognized function for GABA, however, is its role in the nervous system as an inhibitory neurotransmitter that regulates the flow and timing of excitatory neurotransmission. When this pathway is altered, seizures develop. Human toxoplasmosis patients suffer from seizures, suggesting that Toxoplasma interferes with GABA signaling in the brain. Here, we show that while excitatory glutamatergic presynaptic proteins appeared normal, infection with type II ME49 Toxoplasma tissue cysts led to global changes in the distribution of glutamic acid decarboxylase 67 (GAD67), a key enzyme that catalyzes GABA synthesis in the brain. Alterations in GAD67 staining were not due to decreased expression but rather to a change from GAD67 clustering at presynaptic termini to a more diffuse localization throughout the neuropil. Consistent with a loss of GAD67 from the synaptic terminals, Toxoplasma-infected mice develop spontaneous seizures and are more susceptible to drugs that induce seizures by antagonizing GABA receptors. Interestingly, GABAergic protein mislocalization and the response to seizure-inducing drugs were observed in mice infected with type II ME49 but not type III CEP strain parasites, indicating a role for a polymorphic parasite factor(s) in regulating GABAergic synapses. Taken together, these data support a model in which seizures and other neurological complications seen in Toxoplasma-infected individuals are due, at least in part, to changes in GABAergic signaling. PMID:26507232

  2. The impact of theaflavins on systemic-and microcirculation alterations: The murine and randomized feasibility trials.

    PubMed

    Saito, Akiko; Nakazato, Risa; Suhara, Yoshitomo; Shibata, Masahiro; Fukui, Toshiki; Ishii, Takeshi; Asanuma, Toshimichi; Mochizuki, Kazuo; Nakayama, Tsutomu; Osakabe, Naomi

    2016-06-01

    Theaflavins are polyphenols found in black tea; their physiological activities were not well investigated. The present study in rats evaluated the influence of theaflavins on circulation. In addition, an intervention pilot study examined the influence of a theaflavin drink on postprandial hemodynamic change. In an animal study, a single oral dose of theaflavin rich fraction (TF, 10mg/kg) caused transient increase in mean blood pressure (MBP) and heart rate (HR). TF also elevated cremastric blood flow significantly, and the magnitude of this effect was in this order: theaflavin 3'-O-gallate (TF2B) >theaflavin-3-O-gallate (TF2A) >theaflavin (TF1)=theaflavin-3, 3'-di-O-gallate (TF3). In addition, these hemodynamic alterations in mammals totally disappeared when pretreated with carvedilol as an adrenaline blocker. We also treated 10-mg/kg/day TF to the rats for 2 weeks. At the end of the ingestion period, MBP was reduced significantly, and aortic eNOS level was elevated by the repeated ingestion of TF compared with distilled water. In the intervention trial, blood pressure of the volunteers was increased significantly 2 and 4h after ingestion of the TF drink (45mg/drink) compared with before treatment. A significant difference was observed in FMD between the placebo and theaflavin groups 4h after ingestion. These results suggested that theaflavin has potent activity to alter hemodynamics in both murine and healthy subjects. Further studies is needed to elucidate the details; however, the results of animal study suggested that the possible involvement of sympathetic nervous system in the hemodynamic changes caused by TF. PMID:27142743

  3. Changes in estrogen receptor signaling alters the timekeeping system in male mice.

    PubMed

    Blattner, Margaret S; Mahoney, Megan M

    2015-11-01

    Circadian rhythms are modulated by steroid hormones; however, the mechanisms of this action are not fully understood, particularly in males. In females estradiol regulates activity level, pattern of expression, and free running period (tau). We tested the hypothesis that activity level and distribution in male mice includes both classical and "non-classical" actions of estrogens at the estrogen receptor subtype 1 (ESR1). We used transgenic mice with mutations in their estrogen response pathways: ESR1 knock-out (ERKO) mice lack the ability to respond to estrogens via ESR1. "Non-classical" estrogen receptor knock-in (NERKI) mice have an inserted ESR1 receptor with a mutation in the estrogen-response-element binding domain, allowing activation via non-genomic and second messenger pathways. Gonadectomized male NERKI, ERKO, and wildtype (WT) littermates were given oil, or low or high dose estradiol and daily activity parameters were quantified. Estradiol shortened the ratio of activity in the light relative to dark (LD ratio), shortened tau, advanced the time of activity onset, and altered responsiveness to light cues administered in the late subjective night, suggesting modulation by an ESR1-independent mechanism. Estradiol treatment in NERKI but not WT males altered the timing of activity onset, LD ratio, and the behavioral response to light cues. These results may represent disruptions in the balance of genomic/nongenomic or ESR1/ESR2 signaling pathways. We also found a significant genotype effect on total activity, LD ratio, tau, and activity duration. These data provide new information about the role of ESR1-dependent and independent signaling pathways on the timekeeping system in male mice. PMID:26241171

  4. Molecular alterations underlie nodal and paranodal degeneration in type 1 diabetic neuropathy and are prevented by C-peptide.

    PubMed

    Sima, Anders A F; Zhang, Weixian; Li, Zhen-Guo; Murakawa, Yuichi; Pierson, Christopher R

    2004-06-01

    To explore the molecular abnormalities underlying the degeneration of the node of Ranvier, a characteristic aberration of type 1 diabetic neuropathy, we examined in type 1 BB/Wor and type 2 BBZDR/Wor rats changes in expression of key molecules that make up the nodal and paranodal apparatus of peripheral nerve. Their posttranslational modifications were examined in vitro. Their responsiveness to restored insulin action was examined in type 1 animals replenished with proinsulin C-peptide. In sciatic nerve, the expression of contactin, receptor protein tyrosine phosphatase beta, and the Na(+)-channel beta(1) subunit, paranodal caspr and nodal ankyrin(G) was unaltered in 2-month type 1 diabetic BB/Wor rats but significantly decreased after 8 months of diabetes. These abnormalities were prevented by C-peptide administered to type 1 BB/Wor rats and did not occur in duration- and hyperglycemia-matched type 2 BBZDR/Wor rats. The expression of the alpha-Na(+)-channel subunit was unaltered. In SH-SY5Y cells, only the combination of insulin and C-peptide normalized posttranslational O-linked N-acetylglucosamine modifications and maximized serine phosphorylation of ankyrin(G) and p85 binding to caspr. The beneficial effects of C-peptide resulted in significant normalization of the nerve conduction deficits. These data describe for the first time the progressive molecular aberrations underlying nodal and paranodal degenerative changes in type 1 diabetic neuropathy and demonstrate that they are preventable by insulinomimetic C-peptide. PMID:15161761

  5. 76 FR 24557 - Privacy Act of 1974; as Amended; Proposed Alteration to an Existing Privacy Act System of Records...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-02

    ... numbers; e.g., business, fax, and cell phone. The system also will contain business information such as...(es), and telephone numbers; e.g., business, fax and cell phone. The expanded category also will... ADMINISTRATION Privacy Act of 1974; as Amended; Proposed Alteration to an Existing Privacy Act System of...

  6. KCNH2-3.1 expression impairs cognition and alters neuronal function in a model of molecular pathology associated with schizophrenia

    PubMed Central

    Yang, Feng; Ren, Ming; Yuan, Peixiong; Tian, Qingjun; Bebensee, Audrey; Zhang, Grace Y.; Du, Jing; Glineburg, Paul; Xun, Randy; Akhile, Omoye; Akuma, Daniel; Pickel, James; Barrow, James C.; Papaleo, Francesco; Weinberger, Daniel R.

    2015-01-01

    Overexpression in humans of KCNH2-3.1, which encodes a primate-specific and brain-selective isoform of the human ether-a-go-go-related (hERG) potassium channel, is associated with impaired cognition, inefficient neural processing, and schizophrenia. Here, we describe a new mouse model that incorporates the KCNH2-3.1 molecular phenotype. KCNH2-3.1 transgenic mice are viable and display normal sensorimotor behaviors. However, they show alterations in neuronal structure and microcircuit function in the hippocampus and prefrontal cortex, areas affected in schizophrenia. Specifically, in slice preparations from the CA1 region of the hippocampus, KCNH2-3.1 transgenic mice have fewer mature dendrites and impaired theta burst stimulation long-term potentiation (TBS-LTP). Abnormal neuronal firing patterns characteristic of the fast deactivation kinetics of the KCNH2-3.1 isoform were also observed in prefrontal cortex. Transgenic mice showed significant deficits in a hippocampal-dependent object location task and a prefrontal cortex-dependent T-maze working memory task. Interestingly, the hippocampal-dependent alterations were not present in juvenile transgenic mice, suggesting a developmental trajectory to the phenotype. Suppressing KCNH2-3.1 expression in adult mice rescues both the behavioral and physiological phenotypes. These data provide insight into the mechanism of association of KCNH2-3.1 with variation in human cognition and neuronal physiology and may explain its role in schizophrenia. PMID:26857598

  7. Studying the Impact of Spaceflight Environment on Immune Functions Using New Molecular Diagnostics System

    NASA Astrophysics Data System (ADS)

    Cohen, Luchino

    Immune functions are altered during space flights. Latent virus reactivation, reduction in the number of immune cells, decreased cell activation and increased sensitivity of astronauts to infections following their return on Earth demonstrate that the immune system is less efficient during space flight. The causes of this immune deficiency are not fully understood and this dysfunction during long-term missions could result in the appearance of opportunistic infections or a decrease in the immuno-surveillance mechanisms that eradicate cancer cells. Therefore, the immune functions of astronauts will have to be monitored continuously during long-term missions in space, using miniature and semi-automated diagnostic systems. The objectives of this project are to study the causes of space-related immunodeficiency, to develop countermeasures to maintain an optimal immune function and to improve our capacity to detect infectious diseases during space missions through the monitoring of astronauts' immune system. In order to achieve these objectives, an Immune Function Diagnostic System (IFDS) will be designed to perform a set of immunological assays on board spacecrafts or on planet-bound bases. Through flow cytometric assays and molecular biology analyses, this diagnostic system could improve medical surveillance of astronauts and could be used to test countermeasures aimed at preventing immune deficiency during space missions. The capacity of the instrument to assess cellular fluorescence and to quantify the presence of soluble molecules in biological samples would support advanced molecular studies in space life sciences. Finally, such diagnostic system could also be used on Earth in remote areas or in mobile hospitals following natural disasters to fight against infectious diseases and other pathologies.

  8. Diffusion-controlled interface kinetics-inclusive system-theoretic propagation models for molecular communication systems

    NASA Astrophysics Data System (ADS)

    Chude-Okonkwo, Uche A. K.; Malekian, Reza; Maharaj, B. T.

    2015-12-01

    Inspired by biological systems, molecular communication has been proposed as a new communication paradigm that uses biochemical signals to transfer information from one nano device to another over a short distance. The biochemical nature of the information transfer process implies that for molecular communication purposes, the development of molecular channel models should take into consideration diffusion phenomenon as well as the physical/biochemical kinetic possibilities of the process. The physical and biochemical kinetics arise at the interfaces between the diffusion channel and the transmitter/receiver units. These interfaces are herein termed molecular antennas. In this paper, we present the deterministic propagation model of the molecular communication between an immobilized nanotransmitter and nanoreceiver, where the emission and reception kinetics are taken into consideration. Specifically, we derived closed-form system-theoretic models and expressions for configurations that represent different communication systems based on the type of molecular antennas used. The antennas considered are the nanopores at the transmitter and the surface receptor proteins/enzymes at the receiver. The developed models are simulated to show the influence of parameters such as the receiver radius, surface receptor protein/enzyme concentration, and various reaction rate constants. Results show that the effective receiver surface area and the rate constants are important to the system's output performance. Assuming high rate of catalysis, the analysis of the frequency behavior of the developed propagation channels in the form of transfer functions shows significant difference introduce by the inclusion of the molecular antennas into the diffusion-only model. It is also shown that for t > > 0 and with the information molecules' concentration greater than the Michaelis-Menten kinetic constant of the systems, the inclusion of surface receptors proteins and enzymes in the models

  9. Structural alterations in the male reproductive system of the freshwater crayfish, Cherax quadricarinatus (Decapoda, Parastacidae).

    PubMed

    Bugnot, Ana B; López Greco, Laura S

    2009-10-01

    No diseases affecting reproductive performance have been previously reported in freshwater crayfishes. This study aims to characterise one reproductive system abnormality found in males of Cherax quadricarinatus reared in captivity. Fifteen adult males of C. quadricarinatus (70-110 g) were purchased from San Mateo S.A. farm (Entre Ríos, Argentina) each season during 2007. Macroscopic analysis showed that 26.6% of the animals sacrificed in winter presented brownish distal vasa deferentia. Histological analysis showed different levels of structural abnormality in the epithelium of the vasa deferentia and spermatophore. Granular and hyaline haemocytes were identified within the vasa deferentia but no significant differences were found in the sperm count between normal and brownish vas deferens. Histological analysis of the crayfishes sacrificed in autumn also showed these modifications in 22% of the animals, however, they did not show the brownish colour under macroscopic analysis. The similarities between the male reproductive system syndrome in shrimps and the abnormalities found in C. quadricarinatus are notable. An unspecific response to thermic stress is a possible explanation of these structural alterations. PMID:19682455

  10. Gdf-15 deficiency does not alter vulnerability of nigrostriatal dopaminergic system in MPTP-intoxicated mice.

    PubMed

    Machado, Venissa; Gilsbach, Ralf; Das, Richa; Schober, Andreas; Bogatyreva, Lioudmila; Hauschke, Dieter; Krieglstein, Kerstin; Unsicker, Klaus; Spittau, Björn

    2016-08-01

    Growth/differentiation factor-15 (Gdf-15) is a member of the transforming growth factor-β (Tgf-β) superfamily and has been shown to be a potent neurotrophic factor for midbrain dopaminergic (DAergic) neurons both in vitro and in vivo. Gdf-15 has also been shown to be involved in inflammatory processes. The aim of this study was to identify the role of endogenous Gdf-15 in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease (PD) by comparing Gdf-15 (+/+) and Gdf-15 (-/-) mice. At 4 days and 14 days post-MPTP administration, both Gdf-15 (+/+) and Gdf-15 (-/-) mice showed a similar decline in DAergic neuron numbers and in striatal dopamine (DA) levels. This was followed by a comparable restorative phase at 90 days and 120 days, indicating that the absence of Gdf-15 does not affect the susceptibility or the recovery capacity of the nigrostriatal system after MPTP administration. The MPTP-induced microglial and astrocytic response was not significantly altered between the two genotypes. However, pro-inflammatory and anti-inflammatory cytokine profiling revealed the differential expression of markers in Gdf-15 (+/+) and Gdf-15 (-/-) mice after MPTP administration. Thus, the MPTP mouse model fails to uncover a major role of endogenous Gdf-15 in the protection of MPTP-lesioned nigrostriatal DAergic neurons, in contrast to its capacity to protect the 6-hydroxydopamine-intoxicated nigrostriatal system. PMID:27115420

  11. Altered systemic bioavailability and organ distribution of azathioprine in methotrexate-induced intestinal mucositis in rats

    PubMed Central

    Karbelkar, Sadaf A.; Majumdar, Anuradha S.

    2016-01-01

    Objective: Intestinal mucositis is a significant problem haunting clinicians for decades. One of the major reasons for its occurrence is high-dose chemotherapy. The study is aimed at investigating effect of intestinal mucositis on pharmacokinetics, organ distribution, and bioavailability of azathioprine (AZA) (6-mercaptopurine). Materials and Methods: Intestinal mucositis was induced with methotrexate (MTX) (2.5 mg/kg). The oral absorption of AZA and 6-mercaptopurine (metabolite) levels were determined in control and MTX-treated rats: ex vivo (noneverted sac technique) and in vivo (pharmacokinetics and organ-distribution) using high-performance liquid chromatography. Immunohistochemistry was conducted to evaluate peptide transporter expression on luminal membrane of small intestine. Results: Intestinal permeation of AZA into systemic circulation of rats was lower after MTX administration, widely found in intestinal segments of mucositis-induced rats leading to decline in systemic bioavailability of AZA. Immunohistochemistry findings indicated diminution of peptide transporter expression representing hampered absorption of drugs absorbed via this transporter. Conclusion: Study outcome has thrown light on altered fate of AZA when administered to individuals with mucositis which suggests modified drug therapy. These findings can further be investigated in different drug classes which might be administered concomitantly in mucositis and study outcome can be further confirmed in mucositis patients in clinical practice also. PMID:27298491

  12. Motor system alterations in retired former athletes: the role of aging and concussion history

    PubMed Central

    2013-01-01

    Background Retired athletes with a history of sports concussions experience cognitive and motor declines with aging, and the risk of severe neurodegenerative conditions is magnified in this population. The present study investigated the effects of aging on motor system metabolism and function in former university-level athletes who sustained their last concussion several decades prior to testing. Methods To test the hypothesis that age and remote concussions induce functional as well as metabolic alterations of the motor system, we used proton magnetic resonance spectroscopy to detect metabolic abnormalities in the primary motor cortex and the serial reaction time task (SRTT) to evaluate motor learning. Results Our results indicate that motor learning is significantly reduced in former concussed athletes relative to controls. In addition, glutamate/H2O ratio in M1 was disproportionately reduced in concussed athletes with advancing age and was found to strongly correlate with motor learning impairments. Conclusion Findings from this study provide evidence that the acquisition of a repeated motor sequence is compromised in the aging concussed brain and that its physiological underpinnings could implicate disproportionate reductions of M1 glutamate concentrations with advancing age. PMID:23972282

  13. Systems and synthetic biology approaches to alter plant cell walls and reduce biomass recalcitrance

    PubMed Central

    Kalluri, Udaya C; Yin, Hengfu; Yang, Xiaohan; Davison, Brian H

    2014-01-01

    Fine-tuning plant cell wall properties to render plant biomass more amenable to biofuel conversion is a colossal challenge. A deep knowledge of the biosynthesis and regulation of plant cell wall and a high-precision genome engineering toolset are the two essential pillars of efforts to alter plant cell walls and reduce biomass recalcitrance. The past decade has seen a meteoric rise in use of transcriptomics and high-resolution imaging methods resulting in fresh insights into composition, structure, formation and deconstruction of plant cell walls. Subsequent gene manipulation approaches, however, commonly include ubiquitous mis-expression of a single candidate gene in a host that carries an intact copy of the native gene. The challenges posed by pleiotropic and unintended changes resulting from such an approach are moving the field towards synthetic biology approaches. Synthetic biology builds on a systems biology knowledge base and leverages high-precision tools for high-throughput assembly of multigene constructs and pathways, precision genome editing and site-specific gene stacking, silencing and/or removal. Here, we summarize the recent breakthroughs in biosynthesis and remodelling of major secondary cell wall components, assess the impediments in obtaining a systems-level understanding and explore the potential opportunities in leveraging synthetic biology approaches to reduce biomass recalcitrance. PMID:25363806

  14. In silico screening of molecular imprinting prepolymerization systems: oseltamivir selective polymers through full-system molecular dynamics-based studies.

    PubMed

    Shoravi, Siamak; Olsson, Gustaf D; Karlsson, Björn C G; Bexborn, Fredrik; Abghoui, Younes; Hussain, Javed; Wiklander, Jesper G; Nicholls, Ian A

    2016-05-01

    All-component molecular dynamics studies were used to probe a library of oseltamivir molecularly imprinted polymer prepolymerization mixtures. Polymers included one of five functional monomers (acrylamide, hydroxyethylmethacrylate, methacrylic acid, 2-(triflouromethyl)acrylic acid, 4-vinylpyridine) and one of three porogens (acetonitrile, chloroform, methanol) combined with the crosslinking agent ethylene glycol dimethacrylate and initiator 2,2'-azobis(2-methylpropionitrile). Polymers were characterized by nitrogen gas sorption measurements and SEM, and affinity studies performed using radioligand binding in various media. In agreement with the predictions made from the simulations, polymers prepared in acetonitrile using either methacrylic or trifluoromethacrylic acid demonstrated the highest affinities for oseltamivir. Further, the ensemble of interactions observed in the methanol system provided an explanation for the morphology of polymers prepared in this solvent. The materials developed here offer potential for use in solid-phase extraction or for catalysis. The results illustrate the strength of this in silico strategy as a potential prognostic tool in molecularly imprinted polymer design. PMID:27043914

  15. Behavioral and molecular neuroepigenetic alterations in prenatally stressed mice: relevance for the study of chromatin remodeling properties of antipsychotic drugs.

    PubMed

    Dong, E; Tueting, P; Matrisciano, F; Grayson, D R; Guidotti, A

    2016-01-01

    We have recently reported that mice born from dams stressed during pregnancy (PRS mice), in adulthood, have behavioral deficits reminiscent of behaviors observed in schizophrenia (SZ) and bipolar (BP) disorder patients. Furthermore, we have shown that the frontal cortex (FC) and hippocampus of adult PRS mice, like that of postmortem chronic SZ patients, are characterized by increases in DNA-methyltransferase 1 (DNMT1), ten-eleven methylcytosine dioxygenase 1 (TET1) and exhibit an enrichment of 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) at neocortical GABAergic and glutamatergic gene promoters. Here, we show that the behavioral deficits and the increased 5MC and 5HMC at glutamic acid decarboxylase 67 (Gad1), reelin (Reln) and brain-derived neurotrophic factor (Bdnf) promoters and the reduced expression of the messenger RNAs (mRNAs) and proteins corresponding to these genes in FC of adult PRS mice is reversed by treatment with clozapine (5 mg kg(-1) twice a day for 5 days) but not by haloperidol (1 mg kg(-1) twice a day for 5 days). Interestingly, clozapine had no effect on either the behavior, promoter methylation or the expression of these mRNAs and proteins when administered to offspring of nonstressed pregnant mice. Clozapine, but not haloperidol, reduced the elevated levels of DNMT1 and TET1, as well as the elevated levels of DNMT1 binding to Gad1, Reln and Bdnf promoters in PRS mice suggesting that clozapine, unlike haloperidol, may limit DNA methylation by interfering with DNA methylation dynamics. We conclude that the PRS mouse model may be useful preclinically in screening for the potential efficacy of antipsychotic drugs acting on altered epigenetic mechanisms. Furthermore, PRS mice may be invaluable for understanding the etiopathogenesis of SZ and BP disorder and for predicting treatment responses at early stages of the illness allowing for early detection and remedial intervention. PMID:26756904

  16. Lacrimal Gland Inflammation Deregulates Extracellular Matrix Remodeling and Alters Molecular Signature of Epithelial Stem/Progenitor Cells

    PubMed Central

    Umazume, Takeshi; Thomas, William M.; Campbell, Sabrina; Aluri, Hema; Thotakura, Suharika; Zoukhri, Driss; Makarenkova, Helen P.

    2015-01-01

    Purpose The adult lacrimal gland (LG) is highly regenerative and is able to repair itself even after substantial damage; however, this ability to regenerate is lost with the development of dry eye conditions in chronically inflamed LGs.This study compares changes in the cell adhesion and cell matrix molecules and stem cell transcription factors in the LGs of healthy mice and of two mouse models of Sjögren's syndrome: nonobese diabetic (NOD) and MRL-lpr/lpr (MRL/lpr) mice during the early stage of inflammation. Methods The LGs from 12- to 13-week-old female MRL/lpr and male NOD mice along with their respective control strains were harvested and divided into three pieces and processed for quantitative (q) RT-PCR and qRT-PCR Arrays, histology, immunohistochemistry, and Western blotting. Results The extracellular matrix (ECM) and adhesion molecules RT2-PCR array combined with protein expression data revealed changes in the expression of integrins, matrix metalloproteinases, and other molecules, which are associated largely with invasion, attachment, and expansion of the lymphocytic cells, whereas changes in the stem cell transcription factors revealed substantial decrease in expression of transcription factors associated with epithelial stem/progenitor cell lineage. Conclusions We concluded that the expression of several important ECM components is significantly deregulated in the LG of two murine models of Sjögren's syndrome, suggesting an alteration of the epithelial stem/progenitor cell niche. This may result in profound effects on localization, activation, proliferation, and differentiation of the LG stem/progenitor cells and, therefore, LG regeneration. PMID:26747770

  17. INTERNATIONAL CONFERENCE ON INTELLIGENT SYSTEMS FOR MOLECULAR BIOLOGY (ISMB)

    SciTech Connect

    Debra Goldberg; Matthew Hibbs; Lukas Kall; Ravikumar Komandurglayavilli; Shaun Mahony; Voichita Marinescu; Itay Mayrose; Vladimir Minin; Yossef Neeman; Guy Nimrod; Marian Novotny; Stephen Opiyo; Elon Portugaly; Tali Sadka; Noboru Sakabe; Indra Sarkar; Marc Schaub; Paul Shafer; Olena Shmygelska; Gregory Singer; Yun Song; Bhattacharya Soumyaroop; Michael Stadler; Pooja Strope; Rong Su; Yuval Tabach; Hongseok Tae; Todd Taylor; Michael Terribilini; Asha Thomas; Nam Tran; Tsai-Tien Tseng; Akshay Vashist; Parthiban Vijaya; Kai Wang; Ting Wang; Lai Wei; Yong Woo; Chunlei Wu; Yoshihiro Yamanishi; Changhui Yan; Jack Yang; Mary Yang; Ping Ye; Miao Zhang

    2009-12-29

    The Intelligent Systems for Molecular Biology (ISMB) conference has provided a general forum for disseminating the latest developments in bioinformatics on an annual basis for the past 13 years. ISMB is a multidisciplinary conference that brings together scientists from computer science, molecular biology, mathematics and statistics. The goal of the ISMB meeting is to bring together biologists and computational scientists in a focus on actual biological problems, i.e., not simply theoretical calculations. The combined focus on “intelligent systems” and actual biological data makes ISMB a unique and highly important meeting, and 13 years of experience in holding the conference has resulted in a consistently well organized, well attended, and highly respected annual conference. The ISMB 2005 meeting was held June 25-29, 2005 at the Renaissance Center in Detroit, Michigan. The meeting attracted over 1,730 attendees. The science presented was exceptional, and in the course of the five-day meeting, 56 scientific papers, 710 posters, 47 Oral Abstracts, 76 Software demonstrations, and 14 tutorials were presented. The attendees represented a broad spectrum of backgrounds with 7% from commercial companies, over 28% qualifying for student registration, and 41 countries were represented at the conference, emphasizing its important international aspect. The ISMB conference is especially important because the cultures of computer science and biology are so disparate. ISMB, as a full-scale technical conference with refereed proceedings that have been indexed by both MEDLINE and Current Contents since 1996, bridges this cultural gap.

  18. The generation of meaningful information in molecular systems.

    PubMed

    Wills, Peter R

    2016-03-13

    The physico-chemical processes occurring inside cells are under the computational control of genetic (DNA) and epigenetic (internal structural) programming. The origin and evolution of genetic information (nucleic acid sequences) is reasonably well understood, but scant attention has been paid to the origin and evolution of the molecular biological interpreters that give phenotypic meaning to the sequence information that is quite faithfully replicated during cellular reproduction. The near universality and age of the mapping from nucleotide triplets to amino acids embedded in the functionality of the protein synthetic machinery speaks to the early development of a system of coding which is still extant in every living organism. We take the origin of genetic coding as a paradigm of the emergence of computation in natural systems, focusing on the requirement that the molecular components of an interpreter be synthesized autocatalytically. Within this context, it is seen that interpreters of increasing complexity are generated by series of transitions through stepped dynamic instabilities (non-equilibrium phase transitions). The early phylogeny of the amino acyl-tRNA synthetase enzymes is discussed in such terms, leading to the conclusion that the observed optimality of the genetic code is a natural outcome of the processes of self-organization that produced it. PMID:26857673

  19. Singlet molecular oxygen in photobiochemical systems: IR phosphorescence studies.

    PubMed

    Krasnovsky, A A

    1998-01-01

    Singlet molecular oxygen (1O2) is one of the most active intermediates involved in photosensitized oxygenation reactions in chemical and biological systems. Deactivation of singlet oxygen is accompanied by infrared phosphorescence (1270 nm) which is widely employed for 1O2 detection and study. This review considers techniques for phosphorescence detection, phosphorescence spectra, quantum yields and kinetics under laser excitation, the radiative and real 1O2 lifetimes in organic solvents and water, 1O2 quenching by biomolecules, and estimation of singlet oxygen lifetimes, diffusion lengths and phosphorescence quantum yields in blood plasma, cell cytoplasm, erythrocyte ghosts, retinal rod outer segments and chloroplast thylakoids. The experiments devoted to 1O2 phosphorescence detection in photosensitizer-containing living cells are discussed in detail. Information reviewed is important for understanding the mechanisms of photodestruction in biological systems and various applied problems of photobiology and photomedicine. PMID:10379647

  20. Optimizing Central Nervous System Drug Development Using Molecular Imaging.

    PubMed

    Hargreaves, R J; Hoppin, J; Sevigny, J; Patel, S; Chiao, P; Klimas, M; Verma, A

    2015-07-01

    Advances in multimodality fusion imaging technologies promise to accelerate the understanding of the systems biology of disease and help in the development of new therapeutics. The use of molecular imaging biomarkers has been proven to shorten cycle times for central nervous system (CNS) drug development and thereby increase the efficiency and return on investment from research. Imaging biomarkers can be used to help select the molecules, doses, and patients most likely to test therapeutic hypotheses by stopping those that have little chance of success and accelerating those with potential to achieve beneficial clinical outcomes. CNS imaging biomarkers have the potential to drive new medical care practices for patients in the latent phases of progressive neurodegenerative disorders by enabling the detection, preventative treatment, and tracking of disease in a paradigm shift from today's approaches that have to see the overt symptoms of disease before treating it. PMID:25869938

  1. Genomic Profiling Reveals Unique Molecular Alterations in Hepatoblastomas and Adjacent Hepatocellular Carcinomas in B6C3F1 Mice.

    PubMed

    Bhusari, Sachin; Pandiri, Arun R; Nagai, Hiroaki; Wang, Yu; Foley, Julie; Hong, Hue-Hua L; Ton, Thai-Vu; DeVito, Michael; Shockley, Keith R; Peddada, Shyamal D; Gerrish, Kevin E; Malarkey, David E; Hooth, Michelle J; Sills, Robert C; Hoenerhoff, Mark J

    2015-12-01

    The cell of origin of hepatoblastoma (HB) in humans and mice is unknown; it is hypothesized to be a transformed hepatocyte, oval cell, or hepatic progenitor cell. In mice, current dogma is that HBs arise from preexisting hepatocellular neoplasms as a result of further neoplastic transformation. However, there is little evidence supporting this direct relationship. To better understand the relationship between hepatocellular carcinoma (HCC) and HB and determine molecular similarities between mouse and human HB, global gene expression analysis and targeted mutation analysis were performed using HB, HCC, and adjacent liver from the same animals in a recent National Toxicology Program bioassay. There were significant differences in Hras and Ctnnb1 mutation spectra, and by microarray, HBs showed dysregulation of embryonic development, stem cell pluripotency, and genomic imprinting compared to HCC. Meta-analysis showed similarities between HB, early mouse embryonic liver, and hepatocyte-derived stem/progenitor cells compared to HCC. Our data show that there are striking differences between HB and HCC and suggest that HB is a significantly different entity that may arise from a hepatic precursor cell. Furthermore, mouse HB is similar to the human disease at the pathway level and therefore is likely a relevant model for evaluating human cancer hazard. PMID:26289556

  2. Structural and molecular alterations of primary afferent fibres in the spinal dorsal horn in vincristine-induced neuropathy in rat.

    PubMed

    Thibault, Karine; Rivals, Isabelle; M'Dahoma, Saïd; Dubacq, Sophie; Pezet, Sophie; Calvino, Bernard

    2013-11-01

    Vincristine is one of the most common anti-cancer drug therapies administered for the treatment of many types of cancer. Its dose-limiting side effect is the emergence of peripheral neuropathy, resulting in chronic neuropathic pain in many patients. This study sought to understand the mechanisms underlying the development of neuropathic pain by vincristine-induced neurotoxicity. We focused on signs of functional changes and revealed that deep layers of the spinal cord (III-IV) experience increased neuronal activity both in the absence of peripheral stimulation and, as a result of tactile mechanical stimulations. These laminae and superficial laminae I-II were also subject to structural changes as evidenced by an increase in immunoreactivity of Piccolo, a marker of active presynaptic elements. Further investigations performed, using DNA microarray technology, describe a large number of genes differentially expressed in dorsal root ganglions and in the spinal dorsal horn after vincristine treatment. Our study describes an important list of genes differentially regulated by vincristine treatment that will be useful for future studies and brings forward evidence for molecular and anatomical modifications of large diameter sensory neurons terminating in deep dorsal horn laminae, which could participate in the development of tactile allodynia. PMID:23975629

  3. Reduced molecular size and altered disaccharide composition of cerebral chondroitin sulfate upon Alzheimer’s pathogenesis in mice

    PubMed Central

    Zhang, Zui; Ohtake-Niimi, Shiori; Kadomatsu, Kenji; Uchimura, Kenji

    2016-01-01

    ABSTRACT Alzheimer’s disease (AD) is a progressive disorder leading to cognitive impairment and neuronal loss. Cerebral extracellular accumulation and deposition of amyloid ß plaques is a pathological hallmark of AD. Chondroitin sulfate (CS) is an extracellular component abundant in the brain. CS is a sulfated glycosaminoglycan covalently attached to a core protein, forming chondroitin sulfate proteoglycan. The structure of CS is heterogeneous with sulfation modification and elongation of the chain. The structural diversity of CS allows it to play various roles in the brain. Increasing evidence has shown that CS promotes aggregation of amyloid ß peptides into higher-order species such as insoluble amyloid ß fibrils. Difficulties in the structural analysis of brain CS, as well as its heterogeneity, limit the study of potential roles of CS in AD pathology. Here we established a microanalysis method with reversed-phase ion-pair high performance liquid chromatography and found that CS in the brains of Tg2576 AD model mice show a lower molecular size and an increased ratio of CS-B motif di-sulfated disaccharide. Our findings provide insight into the structural changes of cerebral CS upon Alzheimer’s pathogenesis. PMID:27578913

  4. 78 FR 47322 - Privacy Act of 1974; Report of an Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-05

    ... HUMAN SERVICES Health Resources and Services Administration Privacy Act of 1974; Report of an Altered...: In accordance with the requirements of the Privacy Act of 1974 (5 U.S.C. 552a), the Health Resources... deleted. The NPDB SORN was last published March 30, 2012 (77 FR 19295). The proposed alterations to...

  5. Fragmented Molecular Orbital with Diffusion Monte Carlo for large molecular systems

    NASA Astrophysics Data System (ADS)

    Benali, Anouar; Pruitt, Spencer R.; Fedorov, Dmitri G.

    Performing accurate quantum mechanics (QM) calculations on larger and larger systems, while maintaining a high level of accuracy is an ongoing effort in many ab initio fields. Many different attempts have been made to develop highly scalable and accurate methods. The fragment molecular orbital (FMO) method is an ab initio method capable of taking advantage of modern supercomputers, such as the Blue Gene Q system Mira at the Argonne National Laboratory Leadership Computing Facility (ALCF). FMO is based on dividing molecules into fragments and performing ab initio calculations on fragments, their dimers and, optionally, trimers. This decomposition makes it possible to perform QM calculations of real size biological molecules. In contrast to many other fragment-based methods, the effect of the environment is rigorously accounted for by computing the electrostatic potential (ESP) due to remaining fragments that are not explicitly included in a given monomer, dimer, or trimer calculation. The use of highly accurate levels of theory, such as Diffusion Monte Carlo (DMC-QMC), in conjunction with FMO allows for the goal of highly scalable and accurate all electron calculations demonstrated in this study, on a variety of relevant systems (H2O)[3-6] and protein using GAMESS and QMCPACK.

  6. Altered α-synuclein, parkin, and synphilin isoform levels in multiple system atrophy brains.

    PubMed

    Brudek, Tomasz; Winge, Kristian; Rasmussen, Nadja Bredo; Bahl, Justyna Maria Czarna; Tanassi, Julia; Agander, Tina Klitmøller; Hyde, Thomas M; Pakkenberg, Bente

    2016-01-01

    Together with Parkinson's disease (PD) and dementia with Lewy bodies, multiple system atrophy (MSA) is a member of a diverse group of neurodegenerative disorders termed α-synucleinopathies. Previously, it has been shown that α-synuclein, parkin, and synphilin-1 display disease-specific transcription patterns in frontal cortex in PD, dementia with Lewy bodies, and MSA, and thus may mediate the development of α-synucleinopathies. In this study, the differential expression of α-synuclein isoforms on transcriptional and translational levels was ascertained in MSA patients in comparison with PD cases and normal controls using isoform-specific primers and exon-specific antibodies in substantia nigra, striatum, cerebellar cortex, and nucleus dentatus. These regions are severely affected by α-synuclein pathology and neurodegeneration. Furthermore, we have also investigated transcript levels for parkin and synphilin-1 isoforms. In MSA brains, α-synuclein140 and α-synuclein 112 isoform levels were significantly increased, whereas levels of the α-synuclein 126 isoform were decreased in the substantia nigra, striatum, cerebellar cortex, and nucleus dentatus versus controls. Moreover, in MSA cases, we showed increased levels of parkin isoforms lacking the N-terminal ubiquitin-like domain and an aggregation-prone synphilin-1A isoform that causes neuronal toxicity in MSA. In PD brains, parkin transcript variant 3, 7, and 11 were significantly and specifically over-expressed in the striatum and cerebellar cortex, together with synphilin-1A and 1C. The changes of isoform expression profiles in neurodegenerative diseases suggest alterations in the regulation of transcription and/or splicing events, leading to regional/cellular events that may be important for the highly increased aggregation of α-synuclein in the brain. We report differential expression of α-synuclein, parkin, and synphilin-1 isoforms in multiple system atrophy (MSA) versus Parkinson's disease and normal

  7. A safety system for gas source molecular beam epitaxy

    NASA Astrophysics Data System (ADS)

    Biswas, Dhrubes; Morkoç, Hadis

    1991-08-01

    Gas source molecular beam epitaxy (GSMBE) is one of the newest developments in epitaxial growth technology wherein the group V sources such as arsine and phosphine are gaseous and in the form of hydrides, while the Group III sources such as indium, aluminum, gallium are all solids. However, the gases involved are very hazardous, extremely toxic, highly inflammable and explosive at elevated temperatures. Adequate care must be taken for the safe use of these gases so that this attractive technique can be properly utilized. This paper discusses the salient safety features of one such GSMBE system (installed in the Epicenter at the University of Illinois) consisting of a gas delivery system with its robust piping assembly, gas manifold and a scrubber. The system is integrated with a Multiple Point Toxic Gas Monitor (MPTGM) acting as the central alarm command system based on the concept of fail safe total safety. This alarm system is equipped with audio-visual alarms for a variety of monitored conditions and interlocks for automatic shutdown. A well-designed air flow pattern has been incorporated to provide good air quality in the laboratory and in the gas storage facility. Additionally a set of good laboratory practices ensured by administrative and personal control are instituted to reduce the hazards to an acceptable risk level.

  8. Molecular Characterization of a Lysozyme Gene and Its Altered Expression Profile in Crowded Beet Webworm (Loxostege sticticalis).

    PubMed

    Kong, Hailong; Lv, Min; Mao, Nian; Wang, Cheng; Cheng, Yunxia; Zhang, Lei; Jiang, Xingfu; Luo, Lizhi

    2016-01-01

    There is growing evidence that insects living in high-density populations exhibit an increase in immune function to counter a higher risk of disease. This phenomenon, known as density-dependent prophylaxis, has been experimentally tested in a number of insect species. Although density-dependent prophylaxis is especially prevalent in insects exhibiting density-dependent phase polyphenism, the molecular mechanism remains unclear. Our previous study demonstrated that the antibacterial activity of lysozyme is important for this process in the beet webworm Loxostege sticticalis. In this study, a lysozyme cDNA from L. sticticalis was cloned and characterized. The full-length cDNA is 1078 bp long and contains an open reading frame of 426 bp that encodes 142 amino acids. The deduced protein possesses structural characteristics of a typical c-type lysozyme and clusters with c-type lysozymes from other Lepidoptera. LsLysozyme was found to be expressed throughout all developmental stages, showing the highest level in pupae. LsLysozyme was also highly expressed in the midgut and fat body. Elevated LsLysozyme expression was observed in L. sticticalis larvae infected by Beauveria bassiana and in larvae reared under crowding conditions. In addition, the expression level of LsLysozyme in infected larvae reared at a density of 10 larvae per jar was significantly higher compared to those reared at a density of l or 30 larvae per jar. These results suggest that larval crowding affects the gene expression profile of this lysozyme. This study provides additional insight into the expression of an immune-associated lysozyme gene and helps us to better understand the immune response of L. sticticalis under crowding conditions. PMID:27575006

  9. Altered Expression of High Molecular Weight Heat Shock Proteins after OCT4B1 Suppression in Human Tumor Cell Lines

    PubMed Central

    Mirzaei, Mohammad Reza; Kazemi Arababadi, Mohammad; Asadi, Malek Hossein; Mowla, Seyed Javad

    2016-01-01

    Objective OCT4B1, a novel variant of OCT4, is expressed in cancer cell lines and tis- sues. Based on our previous reports, OCT4B1 appears to have a crucial role in regulating apoptosis as well as stress response [heat shock proteins (HSPs)] pathways. The aim of the present study was to determine the effects of OCT4B1 silencing on the expression of high molecular weight HSPs in three different human tumor cell lines. Materials and Methods In this experimental study, OCT4B1 expression was suppressed in AGS (gastric adenocarcinoma), 5637 (bladder tumor) and U-87MG (brain tumor) cell lines using RNAi strategy. Real-time polymerase chain reaction (PCR) array was em- ployed for expression level analysis and the fold changes were calculated using RT2 Pro- filer PCR array data analysis software version 3.5. Results Our data revealed up-regulation of HSPD1 (from HSP60 family) as well as HSPA14, HSPA1L, HSPA4, HSPA5 and HSPA8 (from HSP70 family) following OCT4B1 knock-down in all three cell lines. In contrast, the expression of HSP90AA1 and HSP90AB1 (from HSP90 family) as well as HSPA1B and HSPA6 (from HSP70 family) was down-regulated under similar conditions. Other stress-related genes showed varying ex- pression pattern in the examined tumor cell lines. Conclusion Our data suggest a direct or indirect correlation between the expression of OCT4B1 and HSP90 gene family. However, OCT4B1 expression was not strongly corre- lated with the expression of HSP70 and HSP60 gene families. PMID:26862520

  10. Proanthocyanidins Alter Adhesive/Dentin Bonding Strengths when Included in a Bonding System

    PubMed Central

    Hechler, Benjamin; Yao, Xiaomei; Wang, Yong

    2014-01-01

    Purpose To determine the effect of proanthocyanidins (PA) incorporation into a bonding system on dentin/adhesive bond stability following long-term storage in buffer and collagenase. Methods Human dentin surfaces were bonded with no PA (0-PA), PA incorporated in the primer (PA-primer), or PA incorporated in the adhesive (PA-adhesive), and composite build-ups were created. Following sectioning into beams, bonded specimens were stored in buffer or collagenase for 0, 1, 4, 26, or 52 weeks before being tested for microtensile bond strength (μTBS). ANOVA and Tukey’s HSD post-hoc were performed. Fractured surfaces were viewed with scanning electron microscopy (SEM). Results Both bonding system and storage time but not storage medium significantly affected μTBS. Initially, 0-PA and PA-primer were superior to PA-adhesive, and after 1 week both PA groups were inferior to 0-PA. However, after 4 weeks PA-adhesive had significantly increased and 0-PA significantly decreased such that all three groups were equal. Thereafter, both PA-primer/adhesive groups trended with an increase (the 0-PA group remaing consistent) such that at 52 weeks PA-primer samples were significantly stronger (p < 0.001) or nearly so (p = 0.08) when compared to 0-PA samples. SEM revealed that initial fractures tended to occur at the middle/bottom of the hybrid layer for 0-PA and PA-primer groups but at the top of the hybrid layer/in the adhesive for PA-adhesive. After 4 weeks, however, all groups fractured similarly at the middle/bottom of the hybrid layer. Clinical Significance PA incorporation into a bonding system significantly alters interfacial bonding strengths, and its incorporation may stabilize the interface and protect degradation over time under clinical conditions. PMID:23243975

  11. Abstinence from chronic cocaine self-administration alters striatal dopamine systems in rhesus monkeys.

    PubMed

    Beveridge, Thomas J R; Smith, Hilary R; Nader, Michael A; Porrino, Linda J

    2009-04-01

    Although dysregulation within the dopamine (DA) system is a hallmark feature of chronic cocaine exposure, the question of whether these alterations persist into abstinence remains largely unanswered. Nonhuman primates represent an ideal model in which to assess the effects of abstinence on the DA system following chronic cocaine exposure. In this study, male rhesus monkeys self-administered cocaine (0.3 mg/kg per injection, 30 reinforcers per session) under a fixed-interval 3-min schedule for 100 days followed by either 30 or 90 days abstinence. This duration of cocaine self-administration has been previously shown to decrease DA D2-like receptor densities and increase levels of D1-like receptors and DA transporters (DAT). Responding by control monkeys was maintained by food presentation under an identical protocol and the same abstinence periods. [(3)H]SCH 23390 binding to DA D1 receptors following 30 days of abstinence was significantly higher in all portions of the striatum, compared to control animals, whereas [(3)H]raclopride binding to DA D2 receptors was not different between groups. [(3)H]WIN 35 428 binding to DAT was also significantly higher throughout virtually all portions of the dorsal and ventral striatum following 30 days of abstinence. Following 90 days of abstinence, however, levels of DA D1 receptors and DAT were not different from control values. Although these results indicate that there is eventual recovery of the separate elements of the DA system, they also highlight the dynamic nature of these components during the initial phases of abstinence from chronic cocaine self-administration. PMID:18769473

  12. Abstinence from Chronic Cocaine Self-Administration Alters Striatal Dopamine Systems in Rhesus Monkeys

    PubMed Central

    Beveridge, Thomas JR; Smith, Hilary R; Nader, Michael A; Porrino, Linda J

    2013-01-01

    Although dysregulation within the dopamine (DA) system is a hallmark feature of chronic cocaine exposure, the question of whether these alterations persist into abstinence remains largely unanswered. Nonhuman primates represent an ideal model in which to assess the effects of abstinence on the DA system following chronic cocaine exposure. In this study, male rhesus monkeys self-administered cocaine (0.3 mg/kg per injection, 30 reinforcers per session) under a fixed-interval 3-min schedule for 100 days followed by either 30 or 90 days abstinence. This duration of cocaine self-administration has been previously shown to decrease DA D2-like receptor densities and increase levels of D1-like receptors and DA transporters (DAT). Responding by control monkeys was maintained by food presentation under an identical protocol and the same abstinence periods. [3H]SCH 23390 binding to DA D1 receptors following 30 days of abstinence was significantly higher in all portions of the striatum, compared to control animals, whereas [3H]raclopride binding to DA D2 receptors was not different between groups. [3H]WIN 35 428 binding to DAT was also significantly higher throughout virtually all portions of the dorsal and ventral striatum following 30 days of abstinence. Following 90 days of abstinence, however, levels of DA D1 receptors and DAT were not different from control values. Although these results indicate that there is eventual recovery of the separate elements of the DA system, they also highlight the dynamic nature of these components during the initial phases of abstinence from chronic cocaine self-administration. PMID:18769473

  13. A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance.

    PubMed

    Robin, Elodie; Marcillac, Fabrice; Raddatz, Eric

    2015-04-01

    To what extent hypoxia alters the adenosine (ADO) system and impacts on cardiac function during embryogenesis is not known. Ectonucleoside triphosphate diphosphohydrolase (CD39), ecto-5'-nucleotidase (CD73), adenosine kinase (AdK), adenosine deaminase (ADA), equilibrative (ENT1,3,4), and concentrative (CNT3) transporters and ADO receptors A1, A2A, A2B, and A3 constitute the adenosinergic system. During the first 4 days of development chick embryos were exposed in ovo to normoxia followed or not followed by 6 h hypoxia. ADO and glycogen content and mRNA expression of the genes were determined in the atria, ventricle, and outflow tract of the normoxic (N) and hypoxic (H) hearts. Electrocardiogram and ventricular shortening of the N and H hearts were recorded ex vivo throughout anoxia/reoxygenation ± ADO. Under basal conditions, CD39, CD73, ADK, ADA, ENT1,3,4, CNT3, and ADO receptors were differentially expressed in the atria, ventricle, and outflow tract. In H hearts ADO level doubled, glycogen decreased, and mRNA expression of all the investigated genes was downregulated by hypoxia, except for A2A and A3 receptors. The most rapid and marked downregulation was found for ADA in atria. H hearts were arrhythmic and more vulnerable to anoxia-reoxygenation than N hearts. Despite downregulation of the genes, exposure of isolated hearts to ADO 1) preserved glycogen through activation of A1 receptor and Akt-GSK3β-GS pathway, 2) prolonged activity and improved conduction under anoxia, and 3) restored QT interval in H hearts. Thus hypoxia-induced downregulation of the adenosinergic system can be regarded as a coping response, limiting the detrimental accumulation of ADO without interfering with ADO signaling. PMID:25632022

  14. Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer– and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

    PubMed Central

    Mimeault, Murielle; Batra, Surinder K

    2011-01-01

    Recent gene expression profiling analyses and gain- and loss-of-function studies performed with distinct prostate cancer (PC) cell models indicated that the alterations in specific gene products and molecular pathways often occur in PC stem/progenitor cells and their progenies during prostate carcinogenesis and metastases at distant sites, including bones. Particularly, the sustained activation of epidermal growth factor receptor (EGFR), hedgehog, Wnt/β-catenin, Notch, hyaluronan (HA)/CD44 and stromal cell–derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) during the epithelial-mesenchymal transition (EMT) process may provide critical functions for PC progression to locally invasive, metastatic and androgen-independent disease states and treatment resistance. Moreover, an enhanced glycolytic metabolism in PC stem/progenitor cells and their progenies concomitant with the changes in their local microenvironment, including the induction of tumor hypoxia and release of diverse soluble factors by tumor myofibroblasts, also may promote the tumor growth, angiogenesis and metastases. More particularly, these molecular transforming events may cooperate to upregulate Akt, nuclear factor (NF)-κB, hypoxia-inducible factors (HIFs) and stemness gene products such as Oct3/4, Sox2, Nanog and Bmi-1 in PC cells that contribute to their acquisition of high self-renewal, tumorigenic and invasive capacities and survival advantages during PC progression. Consequently, the molecular targeting of these deregulated gene products in the PC- and metastasis-initiating cells and their progenies represent new promising therapeutic strategies of great clinical interest for eradicating the total PC cell mass and improving current antihormonal treatments and docetaxel-based chemotherapies, thereby preventing disease relapse and the death of PC patients. PMID:21607288

  15. Ursodeoxycholic acid alleviates cholestasis-induced histophysiological alterations in the male reproductive system of bile duct-ligated rats.

    PubMed

    Saad, Ramadan A; Mahmoud, Yomna I

    2014-12-01

    Ursodeoxycholic acid is the most widely used drug for treating cholestatic liver diseases. However, its effect on the male reproductive system alterations associated with cholestasis has never been studied. Thus, this study aimed to investigate the effect of ursodeoxycholic acid on cholestasis-induced alterations in the male reproductive system. Cholestasis was induced by bile duct ligation. Bile duct-ligated rats had higher cholestasis biomarkers and lower levels of testosterone, LH and FSH than did the Sham rats. They also had lower reproductive organs weights, and lower sperm motility, density and normal morphology than those of Sham rats. Histologically, these animals suffered from testicular tubular atrophy, interstitial edema, thickening of basement membranes, vacuolation, and depletion of germ cells. After ursodeoxycholic acid administration, cholestasis-induced structural and functional alterations were significantly ameliorated. In conclusion, ursodeoxycholic acid can ameliorate the reproductive complications of chronic cholestasis in male patients, which represents an additional benefit to this drug. PMID:25461907

  16. Mustard vesicants alter expression of the endocannabinoid system in mouse skin.

    PubMed

    Wohlman, Irene M; Composto, Gabriella M; Heck, Diane E; Heindel, Ned D; Lacey, C Jeffrey; Guillon, Christophe D; Casillas, Robert P; Croutch, Claire R; Gerecke, Donald R; Laskin, Debra L; Joseph, Laurie B; Laskin, Jeffrey D

    2016-07-15

    Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants. PMID:27125198

  17. Mitochondrial (Dys)function in Adipocyte (De)differentiation and Systemic Metabolic Alterations

    PubMed Central

    De Pauw, Aurélia; Tejerina, Silvia; Raes, Martine; Keijer, Jaap; Arnould, Thierry

    2009-01-01

    In mammals, adipose tissue, composed of BAT and WAT, collaborates in energy partitioning and performs metabolic regulatory functions. It is the most flexible tissue in the body, because it is remodeled in size and shape by modifications in adipocyte cell size and/or number, depending on developmental status and energy fluxes. Although numerous reviews have focused on the differentiation program of both brown and white adipocytes as well as on the pathophysiological role of white adipose tissues, the importance of mitochondrial activity in the differentiation or the dedifferentiation programs of adipose cells and in systemic metabolic alterations has not been extensively reviewed previously. Here, we address the crucial role of mitochondrial functions during adipogenesis and in mature adipocytes and discuss the cellular responses of white adipocytes to mitochondrial activity impairment. In addition, we discuss the increase in scientific knowledge regarding mitochondrial functions in the last 10 years and the recent suspicion of mitochondrial dysfunction in several 21st century epidemics (ie, obesity and diabetes), as well as in lipodystrophy found in HIV-treated patients, which can contribute to the development of new therapeutic strategies targeting adipocyte mitochondria. PMID:19700756

  18. Altered central nervous system processing of baroreceptor input following hindlimb unloading in rats

    NASA Technical Reports Server (NTRS)

    Moffitt, J. A.; Schadt, J. C.; Hasser, E. M.

    1999-01-01

    The effect of cardiovascular deconditioning on central nervous system processing of baroreceptor afferent activity was evaluated following 14 days of hindlimb unloading (HU). Inactin-anesthetized rats were instrumented with catheters, renal sympathetic nerve electrodes, and aortic depressor nerve electrodes for measurement of mean arterial pressure, heart rate, renal sympathetic nerve activity (RSNA), and aortic depressor nerve activity (ADNA). Baroreceptor and baroreflex functions were assessed during infusion of phenylephrine and sodium nitroprusside. Central processing of baroreceptor afferent input was evaluated by linear regression relating RSNA to ADNA. The maximum baroreflex-elicited increase in RSNA was significantly reduced in HU rats (122 +/- 3.8 vs. 144 +/- 4.9% of baseline RSNA), whereas ADNA was not altered. The slope (-0.18 +/- 0.04 vs. -0.40 +/- 0.04) and y-intercept (121 +/- 3.2 vs. 146 +/- 4.3) of the linear regression relating increases in efferent RSNA to decreases in afferent ADNA during hypotension were significantly reduced in HU rats. There were no differences during increases in arterial pressure. Results demonstrate that the attenuation in baroreflex-mediated increases in RSNA following HU is due to changes in central processing of baroreceptor afferent information rather than aortic baroreceptor function.

  19. Hybrid particle-field molecular dynamics simulation for polyelectrolyte systems.

    PubMed

    Zhu, You-Liang; Lu, Zhong-Yuan; Milano, Giuseppe; Shi, An-Chang; Sun, Zhao-Yan

    2016-04-14

    To achieve simulations on large spatial and temporal scales with high molecular chemical specificity, a hybrid particle-field method was proposed recently. This method is developed by combining molecular dynamics and self-consistent field theory (MD-SCF). The MD-SCF method has been validated by successfully predicting the experimentally observable properties of several systems. Here we propose an efficient scheme for the inclusion of electrostatic interactions in the MD-SCF framework. In this scheme, charged molecules are interacting with the external fields that are self-consistently determined from the charge densities. This method is validated by comparing the structural properties of polyelectrolytes in solution obtained from the MD-SCF and particle-based simulations. Moreover, taking PMMA-b-PEO and LiCF3SO3 as examples, the enhancement of immiscibility between the ion-dissolving block and the inert block by doping lithium salts into the copolymer is examined by using the MD-SCF method. By employing GPU-acceleration, the high performance of the MD-SCF method with explicit treatment of electrostatics facilitates the simulation study of many problems involving polyelectrolytes. PMID:27001709

  20. A computational kinetic model of diffusion for molecular systems

    PubMed Central

    Teo, Ivan; Schulten, Klaus

    2013-01-01

    Regulation of biomolecular transport in cells involves intra-protein steps like gating and passage through channels, but these steps are preceded by extra-protein steps, namely, diffusive approach and admittance of solutes. The extra-protein steps develop over a 10–100 nm length scale typically in a highly particular environment, characterized through the protein's geometry, surrounding electrostatic field, and location. In order to account for solute energetics and mobility of solutes in this environment at a relevant resolution, we propose a particle-based kinetic model of diffusion based on a Markov State Model framework. Prerequisite input data consist of diffusion coefficient and potential of mean force maps generated from extensive molecular dynamics simulations of proteins and their environment that sample multi-nanosecond durations. The suggested diffusion model can describe transport processes beyond microsecond duration, relevant for biological function and beyond the realm of molecular dynamics simulation. For this purpose the systems are represented by a discrete set of states specified by the positions, volumes, and surface elements of Voronoi grid cells distributed according to a density function resolving the often intricate relevant diffusion space. Validation tests carried out for generic diffusion spaces show that the model and the associated Brownian motion algorithm are viable over a large range of parameter values such as time step, diffusion coefficient, and grid density. A concrete application of the method is demonstrated for ion diffusion around and through the Eschericia coli mechanosensitive channel of small conductance ecMscS. PMID:24089741

  1. A computational kinetic model of diffusion for molecular systems

    NASA Astrophysics Data System (ADS)

    Teo, Ivan; Schulten, Klaus

    2013-09-01

    Regulation of biomolecular transport in cells involves intra-protein steps like gating and passage through channels, but these steps are preceded by extra-protein steps, namely, diffusive approach and admittance of solutes. The extra-protein steps develop over a 10-100 nm length scale typically in a highly particular environment, characterized through the protein's geometry, surrounding electrostatic field, and location. In order to account for solute energetics and mobility of solutes in this environment at a relevant resolution, we propose a particle-based kinetic model of diffusion based on a Markov State Model framework. Prerequisite input data consist of diffusion coefficient and potential of mean force maps generated from extensive molecular dynamics simulations of proteins and their environment that sample multi-nanosecond durations. The suggested diffusion model can describe transport processes beyond microsecond duration, relevant for biological function and beyond the realm of molecular dynamics simulation. For this purpose the systems are represented by a discrete set of states specified by the positions, volumes, and surface elements of Voronoi grid cells distributed according to a density function resolving the often intricate relevant diffusion space. Validation tests carried out for generic diffusion spaces show that the model and the associated Brownian motion algorithm are viable over a large range of parameter values such as time step, diffusion coefficient, and grid density. A concrete application of the method is demonstrated for ion diffusion around and through the Eschericia coli mechanosensitive channel of small conductance ecMscS.

  2. Water Velocity and Bioturbation Alter Sediment Resuspension and Biogeochemistry in an Experimental Freshwater Mesocosm System

    NASA Astrophysics Data System (ADS)

    Spivak, A.; Vanni, M. J.

    2010-12-01

    Processes such as bioturbation and resuspension can affect organic matter decomposition by altering sediment redox conditions. Increased oxygen availability may, in turn, affect remineralization rates and larger scale processes such as benthic-pelagic coupling. However, relatively few studies have explicitly tested the simultaneous effects of bioturbation and water velocity on benthic biogeochemistry and sediment resuspension. Using a mesocosm system we conducted two experiments testing the effects of bioturbator identity on particulate and dissolved nutrient dynamics before and after a resuspension event (i.e. water velocity held constant at 0.12 m s-1 for 2 hr; Expt. 1) and rates of sediment resuspension with increasing water velocity (0.00 - 0.20 m s-1; Expt. 2). We manipulated bioturbator identity across four levels as sediments were undisturbed (control), manually punctured (2% of surface area), or disturbed by one of two fish species, either bluegill or catfish. For Expt. 1, the bioturbation treatments were applied for several days and measurements were made before and after the resuspension event. Initially, water column chlorophyll and total suspended sediment (TSS) concentrations were highest in the catfish treatments. Bioturbator identity did not affect the stoichiometry of TSS as strongly; C:N was unaffected by our treatments while N:P was lowest in the disturbed treatments. After the resuspension event, there was no difference in TSS concentrations or stoichiometric ratios across the bioturbation treatments. Dissolved nutrient flux rates were insensitive to the bioturbation treatments and were more strongly influenced by the resuspension event. For instance, sediment NO3- fluxes were negative (i.e. net flux into sediments) until after the resuspension event when they became positive. In Expt. 2, we gradually increased water velocity from 0.00 - 0.20 m s-1 and measured TSS concentrations only. TSS was initially highest in catfish treatments and lowest in

  3. Numerical Models of Human Circulatory System under Altered Gravity: Brain Circulation

    NASA Technical Reports Server (NTRS)

    Kim, Chang Sung; Kiris, Cetin; Kwak, Dochan; David, Tim

    2003-01-01

    A computational fluid dynamics (CFD) approach is presented to model the blood flow through the human circulatory system under altered gravity conditions. Models required for CFD simulation relevant to major hemodynamic issues are introduced such as non-Newtonian flow models governed by red blood cells, a model for arterial wall motion due to fluid-wall interactions, a vascular bed model for outflow boundary conditions, and a model for auto-regulation mechanism. The three-dimensional unsteady incompressible Navier-Stokes equations coupled with these models are solved iteratively using the pseudocompressibility method and dual time stepping. Moving wall boundary conditions from the first-order fluid-wall interaction model are used to study the influence of arterial wall distensibility on flow patterns and wall shear stresses during the heart pulse. A vascular bed modeling utilizing the analogy with electric circuits is coupled with an auto-regulation algorithm for multiple outflow boundaries. For the treatment of complex geometry, a chimera overset grid technique is adopted to obtain connectivity between arterial branches. For code validation, computed results are compared with experimental data for steady and unsteady non-Newtonian flows. Good agreement is obtained for both cases. In sin-type Gravity Benchmark Problems, gravity source terms are added to the Navier-Stokes equations to study the effect of gravitational variation on the human circulatory system. This computational approach is then applied to localized blood flows through a realistic carotid bifurcation and two Circle of Willis models, one using an idealized geometry and the other model using an anatomical data set. A three- dimensional anatomical Circle of Willis configuration is reconstructed from human-specific magnetic resonance images using an image segmentation method. The blood flow through these Circle of Willis models is simulated to provide means for studying gravitational effects on the brain

  4. A Molecular Code for Identity in the Vomeronasal System.

    PubMed

    Fu, Xiaoyan; Yan, Yuetian; Xu, Pei S; Geerlof-Vidavsky, Ilan; Chong, Wongi; Gross, Michael L; Holy, Timothy E

    2015-10-01

    In social interactions among mammals, individuals are recognized by olfactory cues, but identifying the key signals among thousands of compounds remains a major challenge. To address this need, we developed a new technique, component-activity matching (CAM), to select candidate ligands that "explain" patterns of bioactivity across diverse complex mixtures. Using mouse urine from eight different sexes and strains, we identified 23 components to explain firing rates in seven of eight functional classes of vomeronasal sensory neurons. Focusing on a class of neurons selective for females, we identified a novel family of vomeronasal ligands, steroid carboxylic acids. These ligands accounted for much of the neuronal activity of urine from some female strains, were necessary for normal levels of male investigatory behavior of female scents, and were sufficient to trigger mounting behavior. CAM represents the first step toward an exhaustive characterization of the molecular cues for natural behavior in a mammalian olfactory system. PMID:26435105

  5. 78 FR 63211 - Privacy Act of 1974; Report of an Altered CMS System of Records Notice

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-23

    ... FR 8538 (February 6, 2013) and amended and published at 78 FR 32256 (May 29, 2013). The alterations... sharing ministry; (7) employer information; (8) status as a veteran; (9) pregnancy status; (10)...

  6. Optical fiber-based photomechanical molecular delivery system

    NASA Astrophysics Data System (ADS)

    Nakano, Koki; Sato, Shunichi; Kawauchi, Satoko; Ashida, Hiroshi; Nishidate, Izumi

    2014-02-01

    Molecular delivery based on nanosecond pulsed laser-induced photomechanical waves (PMWs) enables endoscopic application by using an optical fiber for laser transmission. In our previous fiber system, a laser target, which was a black natural rubber film as a laser absorbing material covered with an optically transparent polyethylene terephthalate disk to confine the laser-induced plasma, was attached to the output end of a 1 mm core diameter quartz fiber. There were two problems in that system: 1) the outer diameter was large (~2.7 mm) and 2) available peak pressure rapidly decreased with increasing pulse number. In this study, we developed a new fiber delivery system to overcome these problems. As a laser absorbing material, we used a cap-type silicone rubber containing carbon black, into which the fiber output end can simply be inserted. The fiber end surface works to confine the laser-induced plasma. The outer diameter of the fiber system was reduced to ~1.4 mm. At an output laser fluence of 1.2 J/cm2, peak pressure of the first PMW pulse exceeded ~40 MPa. With successive 10 laser pulses, decreasing rate of the peak pressure was 22%, which was considerably lower than that with the previous fiber system (82%), enabling generation of at least successive 30 pulses of PMW with the same cap-type target. With this fiber system, we attempted transfer of plasmid DNA encoding EGFP (enhanced green fluorescence protein) to the rat skin as a test tissue in vivo, showing site-selective efficient gene expression.

  7. Adaptations of the vestibular system to short and long-term exposures to altered gravity

    NASA Astrophysics Data System (ADS)

    Bruce, L.

    Long-term space flight creates unique environmental conditions to which the vestibular system must adapt for optimal survival. We are studying two aspects of this vestibular adaptation: (1) How does long-term exposure to microgravity and hypergravity affect the development of vestibular afferents? (2) How does short- term exposure to extremely rapid changes in gravity, such as those that occur during launch and landing, affect the vestibular system. During space flight the gravistatic receptors in the otolith organs are effectively unloaded. In hypergravity conditions they are overloaded. However, the angular acceleration receptors of the semicircular canals receive relatively normal stimulation in both micro- and hypergravity.Rat embryos exposed to microgravity from gestation day 10 (prior to vestibular function) until gestation day 20 (vestibular system is somewhat functional) showed that afferents from the posterior vertical canal projecting to the medial vestibular nucleus developed similarly in microgravity, hypergravity, and in controls . However, afferents from the saccule showed delayed development in microgravity as compared to development in hypergravity and in controls. Cerebellar plasticity is crucial for modification of sensory-motor control and learning. Thus we explored the possibility that strong vestibular stimuli would modify cerebellar motor control (i.e., eye movement, postural control, gut motility) by altering the morphology of cerebellar Purkinje cells. To study the effects of short-term exposures to strong vestibular stimuli we focused on structural changes in the vestibulo-cerebellum that are caused by strong vestibular stimuli. Adult mice were exposed to various combinations of constant and/or rapidly changing angular and linear accelerations for 8.5 min (the time length of shuttle launch). Our data shows that these stimuli cause intense excitation of cerebellar Purkinje cells, inducing up-regulation of clathrin-mediated endocytosis

  8. Systemic inflammation alters central 5-HT function as determined by pharmacological MRI.

    PubMed

    Couch, Yvonne; Martin, Chris J; Howarth, Clare; Raley, Josie; Khrapitchev, Alexandre A; Stratford, Michael; Sharp, Trevor; Sibson, Nicola R; Anthony, Daniel C

    2013-07-15

    Considerable evidence indicates a link between systemic inflammation and central 5-HT function. This study used pharmacological magnetic resonance imaging (phMRI) to study the effects of systemic inflammatory events on central 5-HT function. Changes in blood oxygenation level dependent (BOLD) contrast were detected in selected brain regions of anaesthetised rats in response to intravenous administration of the 5-HT-releasing agent, fenfluramine (10 mg/kg). Further groups of rats were pre-treated with the bacterial lipopolysaccharide (LPS; 0.5 mg/kg), to induce systemic inflammation, or the selective 5-HT2A receptor antagonist MDL100907 prior to fenfluramine. The resultant phMRI data were investigated further through measurements of cortical 5-HT release (microdialysis), and vascular responsivity, as well as a more thorough investigation of the role of the 5-HT2A receptor in sickness behaviour. Fenfluramine evoked a positive BOLD response in the motor cortex (+15.9±2%) and a negative BOLD response in the dorsal raphe nucleus (-9.9±4.2%) and nucleus accumbens (-7.7±5.3%). In all regions, BOLD responses to fenfluramine were significantly attenuated by pre-treatment with LPS (p<0.0001), but neurovascular coupling remained intact, and fenfluramine-evoked 5-HT release was not affected. However, increased expression of the 5-HT2A receptor mRNA and decreased 5-HT2A-dependent behaviour (wet-dog shakes) was a feature of the LPS treatment and may underpin the altered phMRI signal. MDL100907 (0.5 mg/kg), 5-HT2A antagonist, significantly reduced the BOLD responses to fenfluramine in all three regions (p<0.0001) in a similar manner to LPS. Together these results suggest that systemic inflammation decreases brain 5-HT activity as assessed by phMRI. However, these effects do not appear to be mediated by changes in 5-HT release, but are associated with changes in 5-HT2A-receptor-mediated downstream signalling pathways. PMID:23473937

  9. Systemic inflammation alters central 5-HT function as determined by pharmacological MRI

    PubMed Central

    Couch, Yvonne; Martin, Chris J.; Howarth, Clare; Raley, Josie; Khrapitchev, Alexandre A.; Stratford, Michael; Sharp, Trevor; Sibson, Nicola R.; Anthony, Daniel C.

    2013-01-01

    Considerable evidence indicates a link between systemic inflammation and central 5-HT function. This study used pharmacological magnetic resonance imaging (phMRI) to study the effects of systemic inflammatory events on central 5-HT function. Changes in blood oxygenation level dependent (BOLD) contrast were detected in selected brain regions of anaesthetised rats in response to intravenous administration of the 5-HT-releasing agent, fenfluramine (10 mg/kg). Further groups of rats were pre-treated with the bacterial lipopolysaccharide (LPS; 0.5 mg/kg), to induce systemic inflammation, or the selective 5-HT2A receptor antagonist MDL100907 prior to fenfluramine. The resultant phMRI data were investigated further through measurements of cortical 5-HT release (microdialysis), and vascular responsivity, as well as a more thorough investigation of the role of the 5-HT2A receptor in sickness behaviour. Fenfluramine evoked a positive BOLD response in the motor cortex (+ 15.9 ± 2%) and a negative BOLD response in the dorsal raphe nucleus (− 9.9 ± 4.2%) and nucleus accumbens (− 7.7 ± 5.3%). In all regions, BOLD responses to fenfluramine were significantly attenuated by pre-treatment with LPS (p < 0.0001), but neurovascular coupling remained intact, and fenfluramine-evoked 5-HT release was not affected. However, increased expression of the 5-HT2A receptor mRNA and decreased 5-HT2A-dependent behaviour (wet-dog shakes) was a feature of the LPS treatment and may underpin the altered phMRI signal. MDL100907 (0.5 mg/kg), 5-HT2A antagonist, significantly reduced the BOLD responses to fenfluramine in all three regions (p < 0.0001) in a similar manner to LPS. Together these results suggest that systemic inflammation decreases brain 5-HT activity as assessed by phMRI. However, these effects do not appear to be mediated by changes in 5-HT release, but are associated with changes in 5-HT2A-receptor-mediated downstream signalling pathways. PMID:23473937

  10. Motor-Iconicity of Sign Language Does Not Alter the Neural Systems Underlying Tool and Action Naming

    ERIC Educational Resources Information Center

    Emmorey, Karen; Grabowski, Thomas; McCullough, Stephen; Damasio, Hannah; Ponto, Laurie; Hichwa, Richard; Bellugi, Ursula

    2004-01-01

    Positron emission tomography was used to investigate whether the motor-iconic basis of certain forms in American Sign Language (ASL) partially alters the neural systems engaged during lexical retrieval. Most ASL nouns denoting tools and ASL verbs referring to tool-based actions are produced with a handshape representing the human hand holding a…

  11. 32 CFR Appendix E to Part 310 - Sample of New or Altered System of Records Notice in Federal Register Format

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 2 2010-07-01 2010-07-01 false Sample of New or Altered System of Records Notice in Federal Register Format E Appendix E to Part 310 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) PRIVACY PROGRAM DOD PRIVACY PROGRAM Pt. 310, App. E Appendix E to Part 310—Sample of New...

  12. 32 CFR Appendix E to Part 310 - Sample of New or Altered System of Records Notice in Federal Register Format

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 2 2011-07-01 2011-07-01 false Sample of New or Altered System of Records Notice in Federal Register Format E Appendix E to Part 310 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) PRIVACY PROGRAM DOD PRIVACY PROGRAM Pt. 310, App. E Appendix E to Part 310—Sample of New...

  13. A high pressure modulated molecular beam mass spectrometric sampling system

    NASA Technical Reports Server (NTRS)

    Stearns, C. A.; Kohl, F. J.; Fryburg, G. C.; Miller, R. A.

    1977-01-01

    The current state of understanding of free-jet high pressure sampling is critically reviewed and modifications of certain theoretical and empirical considerations are presented. A high pressure, free-jet expansion, modulated molecular beam, mass spectrometric sampling apparatus was constructed and this apparatus is described in detail. Experimental studies have demonstrated that the apparatus can be used to sample high temperature systems at pressures up to one atmosphere. Condensible high temperature gaseous species have been routinely sampled and the mass spectrometric detector has provided direct identification of sampled species. System sensitivity is better than one tenth of a part per million. Experimental results obtained with argon and nitrogen beams are presented and compared to theoretical predictions. These results and the respective comparison are taken to indicate acceptable performance of the sampling apparatus. Results are also given for two groups of experiments related to hot corrosion studies. The formation of gaseous sodium sulfate in doped methane-oxygen flames was characterized and the oxidative vaporization of metals was studied in an atmospheric pressure flowing gas system to which gaseous salt partial pressures were added.

  14. Genomic Alteration in Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Inferred from Karyotyping, Molecular Cytogenetics, and Array Comparative Genomic Hybridization.

    PubMed

    Singchat, Worapong; Hitakomate, Ekarat; Rerkarmnuaychoke, Budsaba; Suntronpong, Aorarat; Fu, Beiyuan; Bodhisuwan, Winai; Peyachoknagul, Surin; Yang, Fengtang; Koontongkaew, Sittichai; Srikulnath, Kornsorn

    2016-01-01

    Genomic alteration in head and neck squamous cell carcinoma (HNSCC) was studied in two cell line pairs (HN30-HN31 and HN4-HN12) using conventional C-banding, multiplex fluorescence in situ hybridization (M-FISH), and array comparative genomic hybridization (array CGH). HN30 and HN4 were derived from primary lesions in the pharynx and base of tongue, respectively, and HN31 and HN12 were derived from lymph-node metastatic lesions belonging to the same patients. Gain of chromosome 1, 7, and 11 were shared in almost all cell lines. Hierarchical clustering revealed that HN31 was closely related to HN4, which shared eight chromosome alteration cases. Large C-positive heterochromatins were found in the centromeric region of chromosome 9 in HN31 and HN4, which suggests complex structural amplification of the repetitive sequence. Array CGH revealed amplification of 7p22.3p11.2, 8q11.23q12.1, and 14q32.33 in all cell lines involved with tumorigenesis and inflammation genes. The amplification of 2p21 (SIX3), 11p15.5 (H19), and 11q21q22.3 (MAML2, PGR, TRPC6, and MMP family) regions, and deletion of 9p23 (PTPRD) and 16q23.1 (WWOX) regions were identified in HN31 and HN12. Interestingly, partial loss of PTPRD (9p23) and WWOX (16q23.1) genes was identified in HN31 and HN12, and the level of gene expression tended to be the down-regulation of PTPRD, with no detectable expression of the WWOX gene. This suggests that the scarcity of PTPRD and WWOX genes might have played an important role in progression of HNSCC, and could be considered as a target for cancer therapy or a biomarker in molecular pathology. PMID:27501229

  15. Genomic Alteration in Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Inferred from Karyotyping, Molecular Cytogenetics, and Array Comparative Genomic Hybridization

    PubMed Central

    Rerkarmnuaychoke, Budsaba; Suntronpong, Aorarat; Fu, Beiyuan; Bodhisuwan, Winai; Peyachoknagul, Surin; Yang, Fengtang; Koontongkaew, Sittichai; Srikulnath, Kornsorn

    2016-01-01

    Genomic alteration in head and neck squamous cell carcinoma (HNSCC) was studied in two cell line pairs (HN30-HN31 and HN4-HN12) using conventional C-banding, multiplex fluorescence in situ hybridization (M-FISH), and array comparative genomic hybridization (array CGH). HN30 and HN4 were derived from primary lesions in the pharynx and base of tongue, respectively, and HN31 and HN12 were derived from lymph-node metastatic lesions belonging to the same patients. Gain of chromosome 1, 7, and 11 were shared in almost all cell lines. Hierarchical clustering revealed that HN31 was closely related to HN4, which shared eight chromosome alteration cases. Large C-positive heterochromatins were found in the centromeric region of chromosome 9 in HN31 and HN4, which suggests complex structural amplification of the repetitive sequence. Array CGH revealed amplification of 7p22.3p11.2, 8q11.23q12.1, and 14q32.33 in all cell lines involved with tumorigenesis and inflammation genes. The amplification of 2p21 (SIX3), 11p15.5 (H19), and 11q21q22.3 (MAML2, PGR, TRPC6, and MMP family) regions, and deletion of 9p23 (PTPRD) and 16q23.1 (WWOX) regions were identified in HN31 and HN12. Interestingly, partial loss of PTPRD (9p23) and WWOX (16q23.1) genes was identified in HN31 and HN12, and the level of gene expression tended to be the down-regulation of PTPRD, with no detectable expression of the WWOX gene. This suggests that the scarcity of PTPRD and WWOX genes might have played an important role in progression of HNSCC, and could be considered as a target for cancer therapy or a biomarker in molecular pathology. PMID:27501229

  16. Using molecular tools to assess biofilms in onsite systems.

    PubMed

    Flapper, T G; McKay, A; Hall, S; Hill, P

    2007-01-01

    Onsite sewage treatment is growing in diversity, and in regulatory control across Australia. This is occurring for both blackwater and greywater treatment, as the drought impact deepens and more of the community are exposed to options for 'managing' their own water. Regulators in each State are drafting and implementing Guidelines to cover a range of on-site system scenarios. In addition, more and more decentralised options are being tendered for sewage management in the commercial world. In this project we aim to use novel molecular tools, in combination with traditional physical/chemical/biological methods, to understand onsite treatment in a more detailed manner. The system tested is a new peat based biofilter which can be used for greywater or blackwater application, and can be retrofitted to current sewage systems. This project has been based on the AquaReuse greywater system for demonstration purposes, showing the strength of the information gained from the use of novel tools. The two systems investigated are installed at a caravan park in New South Wales (NSW) and a domestic residence in Tamborine, Queensland (OLD). A 20-week intensive sampling and analysis program was followed. The project monitored standard analytes such as biochemical oxygen demand (BOD5), suspended solids (SS) and thermotolerant coliforms (TC). Additionally, we studied the biological community using fluorescent in situ hybridisation (FISH) on a monthly basis and full-cycle ribosomal RNA analysis (rRNA) for one sample to assess the biological community inhabitants. rRNA analysis at the NSW facility demonstrated a highly diverse biological community, in keeping with its long established operating period. In contrast, FISH analysis at the OLD installation showed a less diverse and younger community. rRNA and FISH identified organisms that are mostly associated with nutrient removing functions. PMID:17506424

  17. Molecular tailoring of interfaces for thin film on substrate systems

    NASA Astrophysics Data System (ADS)

    Grady, Martha Elizabeth

    Thin film on substrate systems appear most prevalently within the microelectronics industry, which demands that devices operate in smaller and smaller packages with greater reliability. The reliability of these multilayer film systems is strongly influenced by the adhesion of each of the bimaterial interfaces. During use, microelectronic components undergo thermo-mechanical cycling, which induces interfacial delaminations leading to failure of the overall device. The ability to tailor interfacial properties at the molecular level provides a mechanism to improve thin film adhesion, reliability and performance. This dissertation presents the investigation of molecular level control of interface properties in three thin film-substrate systems: photodefinable polyimide films on passivated silicon substrates, self-assembled monolayers at the interface of Au films and dielectric substrates, and mechanochemically active materials on rigid substrates. For all three materials systems, the effect of interfacial modifications on adhesion is assessed using a laser-spallation technique. Laser-induced stress waves are chosen because they dynamically load the thin film interface in a precise, noncontacting manner at high strain rates and are suitable for both weak and strong interfaces. Photodefinable polyimide films are used as dielectrics in flip chip integrated circuit packages to reduce the stress between silicon passivation layers and mold compound. The influence of processing parameters on adhesion is examined for photodefinable polyimide films on silicon (Si) substrates with three different passivation layers: silicon nitride (SiNx), silicon oxynitride (SiOxNy), and the native silicon oxide (SiO2). Interfacial strength increases when films are processed with an exposure step as well as a longer cure cycle. Additionally, the interfacial fracture energy is assessed using a dynamic delamination protocol. The high toughness of this interface (ca. 100 J/m2) makes it difficult

  18. Study of lnter-Molecular Dynamics within Alkylsiloxane Self-Assembled Monolayer and Elastomer Systems

    NASA Astrophysics Data System (ADS)

    Roman, Michael

    In this work, molecular motion, and in particular, glassy relaxations are studied in two novel experimental systems. Both experimental systems offer a significant degree of control over molecule-molecule, or group-group (where group refers to a portion of a molecule), interactions by controlling density and the type of inter-molecular interaction. Both systems have rigid elements that decrease the tendency of bulk materials to spontaneously change their density with temperature. Thus, density can be maintained and controlled and the effect of density and temperature can be (at least in part) de-convolved. The goal of this work is to experimentally observe the transition from simple, local relaxations to glassy dynamics as density is increased and to understand how this transition differs as the inter-molecular interactions are altered. In both approaches, the system is fabricated from individual parts where the nature, spacing, and particular arrangement of the parts can be controlled and the resultant changes in molecular motion can be observed. Building up a custom system from parts enables fundamental investigation into the glass transition (as discussed above) and also makes possible the development of materials that have engineered responses as a function of temperature. As a short-hand, we refer to the two systems as the monolayer or SAM (short for Self-Assembled Monolayer) and elastomer approaches. In Chapters 4-7 we discuss results from the monolayer approach. Chapter 8 summarizes results from the elastomer approach. In particular, Chapter 4 introduces you to dielectric spectroscopy and briefly summarizes the previous work by former students in the Clarke group which identified the local and glass relaxations in silane monolayers of substituted alkyl chains as analogous to the local and glassy relaxations in polymeric systems containing phase segregated alkyl chains, and similar to the local and glass modes in poly(ethylene). The remainder of Chapter 4

  19. On the sputter alteration of regoliths of outer solar system bodies

    NASA Technical Reports Server (NTRS)

    Hapke, Bruce

    1987-01-01

    Several processes that are expected to occur when the porous regoliths of outer solar system bodies (without atmospheres) are subjected to energetic ion bombardment are discussed. The conclusions reached in much of the literature addressing sputtering are quantitatively or qualitatively incorrect because effects of soil porosity have been neglected. It is shown theoretically and experimentally that porosity reduces the effective sputtering yield of a soil by more than an order of magnitude. Between 90 and 97% of the sputtered atoms are trapped within the regolith, where they are factionated by differential desorption. Experiments indicate that more volatile species have higher desorption probabilities. This process is the most important way in which alteration of chemical and optical properties occurs when a regolith is sputtered. When a basic silicate soil is irradiated these effects lead to sputter-deposited films enriched in metallic iron, while O, Na and K are preferentially lost. The Na and K are present in the atmosphere above the sputtered silicate in quantities much greater than their abundances in the regolith. Icy regoliths of SO2 should be enriched in elemental S and/or S2O. This prediction is supported by the probable identification of S2O and polysulfur oxide bands in the IR spectra of H-sputtered SO2 reported by Moore. When porous mixtures of water, ammonia and methane frosts are sputtered, the loss of H and surface reactions of C, N and O in the deposits should produce complex hydrocarbons and carbohydrates, some of which may be quite dark. Such reactions may have played a role in the formation of the matrix material of carbonaceous chondrites prior to agglomeration.

  20. Sexual differentiation of the brain: a model for drug-induced alterations of the reproductive system

    SciTech Connect

    Gorski, R.A.

    1986-12-01

    The process of the sexual differentiation of the brain represents a valuable model system for the study of the chemical modification of the mammalian brain. Although there are numerous functional and structural sex differences in the adult brain, these are imposed on an essentially feminine or bipotential brain by testicular hormones during a critical phase of perinatal development in the rat. It is suggested that a relatively marked structural sex difference in the rat brain, the sexually dimorphic nucleus of the preoptic area (SDN-POA), is a morphological signature of the permanent or organizational action of estradiol derived from the aromatization of testicular testosterone. The SDN-POA of the male rat is severalfold larger in volume and is composed of more neurons than that of the female. The observation that the mitotic formation of the neurons of the SDN-POA is specifically prolonged has enabled us to identify the time course and pathway of neuronal migration into the nucleus. Study of the development of the SDN-POA suggests that estradiol in the male increases the number of neurons which survive a phase of neuronal death by exerting a neurite growth promoting action and/or a direct neuronotrophic action. Finally, although it is clear that gonadal hormones have dramatic permanent effects on the brain during perinatal development, even after puberty and in adulthood gonadal steroids can alter neuronal structure and, perhaps as a corollary to this, have permanent effects on reproductive function. Although the brain may be most sensitive to gonadal hormones or exogenous chemical factors during perinatal development, such as sensitivity does not appear limited to this period.

  1. The endocannabinoid system is altered in the post-mortem prefrontal cortex of alcoholic subjects.

    PubMed

    Erdozain, Amaia M; Rubio, Marina; Valdizan, Elsa M; Pazos, Angel; Meana, J Javier; Fernández-Ruiz, Javier; Alexander, Stephen P H; Callado, Luis F

    2015-07-01

    There is strong biochemical, pharmacological and genetic evidence for the involvement of the endocannabinoid system (ECS) in alcohol dependence. However, the majority of studies have been performed in animal models. The aim of the present study was to assess the state of the CB1 receptor, the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and the extracellular signal-regulated kinase (ERK) and cyclic-AMP response element-binding protein (CREB) in the post-mortem prefrontal cortex of alcoholic subjects. Experiments were performed in samples from 44 subjects classified in four experimental groups: (1) non-suicidal alcoholic subjects (n = 11); (2) suicidal alcoholic subjects (n = 11); (3) non-alcoholic suicide victims (n = 11); and (4) control subjects (n = 11). We did not observe statistically significant differences in CB1 mRNA relative expression among the four experimental groups. Conversely, our results showed an increase in CB1 receptor protein expression in the prefrontal cortex of the suicidal alcoholic group (127.2 ± 7.3%), with no changes in functionality with regard to either G protein activation or the inhibition of adenylyl cyclase. In parallel, alcoholic subjects presented lower levels of MAGL activity, regardless of the cause of death. A significant decrease in the active form of ERK and CREB levels was also observed in both alcoholic groups. Taken together, our data are consistent with a role for the ECS in the neurobiological mechanisms underlying alcoholism. Moreover, the alterations reported here should be of great interest for the therapeutic treatment of this chronic psychiatric disease. PMID:25041461

  2. Hypothyroidism alters antioxidant defence system in rat brainstem during postnatal development and adulthood.

    PubMed

    Jena, Srikanta; Bhanja, Shravani

    2014-08-01

    The present investigation was carried out to evaluate alterations in oxidative stress parameter [lipid peroxidation (LPx)] and antioxidant enzyme activities [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)] in rat brainstem in response to neonatal hypothyroidism during development (from birth to 7, 15 and 30 days old) and adulthood (90 days old). Hypothyroidism in rats was induced by feeding the lactating mothers (from the day of parturition till weaning, 25 days old) or directly to the pups with 0.05 % [6-n-propyl 2-thiouracil (PTU)] in drinking water. Increased level of LPx was observed in brainstem of 7 days old hypothyroid rats, accompanied by augmented activities of SOD and GPx. In 15 and 30 days old hypothyroid rat brainstem, a significant decline in LPx was observed. Significantly increased activities of CAT and GPx were observed in 15 and 30 days PTU-treated rats. Decreased level of LPx was observed in brainstem of rats treated with PTU from birth to 30 days followed by withdrawal up to 90 days of age (transient hypothyroidism) as compared to control and persistent treatment of PTU up to 90 days of age. Activities of CAT and GPx were decreased in persistent hypothyroid rats of 90 days old with respect to control and transient hypothyroid rats. On the other hand, SOD activity was decreased in both persistent and transient hypothyroid rats with respect to control rats. These results suggest that the PTU-induced neonatal hypothyroidism modulates the antioxidant defence system during postnatal development and adulthood in brainstem of rats. PMID:24595920

  3. Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features

    PubMed Central

    Ganesh, Santhi K.; Xu, Zhi; Schoenhoff, Florian; Griswold, Benjamin F.; Yang, Jiandong; Tong, Lan; Yang, Min-Lee; Hunker, Kristina; Sloper, Leslie; Kuo, Shinie; Raza, Rafi; Milewicz, Dianna M.; Francomano, Clair A.; Dietz, Harry C.; Van Eyk, Jennifer; McDonnell, Nazli B.

    2014-01-01

    Fibromuscular dysplasia (FMD) is a rare, nonatherosclerotic arterial disease for which the molecular basis is unknown. We comprehensively studied 47 subjects with FMD, including physical examination, spine magnetic resonance imaging, bone densitometry, and brain magnetic resonance angiography. Inflammatory biomarkers in plasma and transforming growth factor β (TGF-β) cytokines in patient-derived dermal fibroblasts were measured by ELISA. Arterial pathology other than medial fibrodysplasia with multifocal stenosis included cerebral aneurysm, found in 12.8% of subjects. Extra-arterial pathology included low bone density (P<0.001); early onset degenerative spine disease (95.7%); increased incidence of Chiari I malformation (6.4%) and dural ectasia (42.6%); and physical examination findings of a mild connective tissue dysplasia (95.7%). Screening for mutations causing known genetically mediated arteriopathies was unrevealing. We found elevated plasma TGF-β1 (P=0.009), TGF-β2 (P=0.004) and additional inflammatory markers, and increased TGF-β1 (P=0.0009) and TGF-β2 (P=0.0001) secretion in dermal fibroblast cell lines from subjects with FMD compared to age- and gender-matched controls. Detailed phenotyping of patients with FMD allowed us to demonstrate that FMD is a systemic disease with alterations in common with the spectrum of genetic syndromes that involve altered TGF-β signaling and offers TGF-β as a marker of FMD.—Ganesh, S. K., Morissette, R., Xu, Z., Schoenhoff, F., Griswold, B. F., Yang, J., Tong, L., Yang, M.-L., Hunker, K., Sloper, L., Kuo, S., Raza, R., Milewicz, D. M., Francomano, C. A., Dietz, H. C., Van Eyk, J., McDonnell, N. B. Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features. PMID:24732132

  4. Encapsulated membrane proteins: A simplified system for molecular simulation.

    PubMed

    Lee, Sarah C; Khalid, Syma; Pollock, Naomi L; Knowles, Tim J; Edler, Karen; Rothnie, Alice J; R T Thomas, Owen; Dafforn, Timothy R

    2016-10-01

    Over the past 50years there has been considerable progress in our understanding of biomolecular interactions at an atomic level. This in turn has allowed molecular simulation methods employing full atomistic modelling at ever larger scales to develop. However, some challenging areas still remain where there is either a lack of atomic resolution structures or where the simulation system is inherently complex. An area where both challenges are present is that of membranes containing membrane proteins. In this review we analyse a new practical approach to membrane protein study that offers a potential new route to high resolution structures and the possibility to simplify simulations. These new approaches collectively recognise that preservation of the interaction between the membrane protein and the lipid bilayer is often essential to maintain structure and function. The new methods preserve these interactions by producing nano-scale disc shaped particles that include bilayer and the chosen protein. Currently two approaches lead in this area: the MSP system that relies on peptides to stabilise the discs, and SMALPs where an amphipathic styrene maleic acid copolymer is used. Both methods greatly enable protein production and hence have the potential to accelerate atomic resolution structure determination as well as providing a simplified format for simulations of membrane protein dynamics. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Róg. PMID:26946242

  5. Structural and molecular interrogation of intact biological systems.

    PubMed

    Chung, Kwanghun; Wallace, Jenelle; Kim, Sung-Yon; Kalyanasundaram, Sandhiya; Andalman, Aaron S; Davidson, Thomas J; Mirzabekov, Julie J; Zalocusky, Kelly A; Mattis, Joanna; Denisin, Aleksandra K; Pak, Sally; Bernstein, Hannah; Ramakrishnan, Charu; Grosenick, Logan; Gradinaru, Viviana; Deisseroth, Karl

    2013-05-16

    Obtaining high-resolution information from a complex system, while maintaining the global perspective needed to understand system function, represents a key challenge in biology. Here we address this challenge with a method (termed CLARITY) for the transformation of intact tissue into a nanoporous hydrogel-hybridized form (crosslinked to a three-dimensional network of hydrophilic polymers) that is fully assembled but optically transparent and macromolecule-permeable. Using mouse brains, we show intact-tissue imaging of long-range projections, local circuit wiring, cellular relationships, subcellular structures, protein complexes, nucleic acids and neurotransmitters. CLARITY also enables intact-tissue in situ hybridization, immunohistochemistry with multiple rounds of staining and de-staining in non-sectioned tissue, and antibody labelling throughout the intact adult mouse brain. Finally, we show that CLARITY enables fine structural analysis of clinical samples, including non-sectioned human tissue from a neuropsychiatric-disease setting, establishing a path for the transmutation of human tissue into a stable, intact and accessible form suitable for probing structural and molecular underpinnings of physiological function and disease. PMID:23575631

  6. Molecular Communication Modeling of Antibody-Mediated Drug Delivery Systems.

    PubMed

    Chahibi, Youssef; Akyildiz, Ian F; Balasubramaniam, Sasitharan; Koucheryavy, Yevgeni

    2015-07-01

    Antibody-mediated Drug Delivery Systems (ADDS) are emerging as one of the most encouraging therapeutic solutions for treating several diseases such as human cancers. ADDS use small molecules (antibodies) that propagate in the body and bind selectively to their corresponding receptors (antigens) expressed at the surface of the diseased cells. In this paper, the Molecular Communication (MC) paradigm, where information is conveyed through the concentration of molecules, is advocated for the engineering of ADDS and modeling their complex behavior, to provide a realistic model without the over-complication of system biology models, and the limitations of experimental approaches. The peculiarities of antibodies, including their anisotropic transport and complex electrochemical structure, are taken into account to develop an analytical model of the ADDS transport and antigen-binding kinetics. The end-to-end response of ADDS, from the drug injection to the drug absorption, is mathematically derived based on the geometry of the antibody molecule, the electrochemical structure of the antibody-antigen complex, and the physiology of the patient. The accuracy of the MC model is validated by finite-element (COMSOL) simulations. The implications of the complex interplay between the transport and kinetics parameters on the performance of ADDS are effectively captured by the proposed MC model. The MC model of ADDS will enable the discovery and optimization of drugs in a versatile, cost-efficient, and reliable manner. PMID:25675450

  7. Chronic ethanol exposure during adolescence through early adulthood in female rats induces emotional and memory deficits associated with morphological and molecular alterations in hippocampus.

    PubMed

    Oliveira, Ana Ca; Pereira, Maria Cs; Santana, Luana N da Silva; Fernandes, Rafael M; Teixeira, Francisco B; Oliveira, Gedeão B; Fernandes, Luanna Mp; Fontes-Júnior, Enéas A; Prediger, Rui D; Crespo-López, Maria E; Gomes-Leal, Walace; Lima, Rafael R; Maia, Cristiane do Socorro Ferraz

    2015-06-01

    There is increasing evidence that heavy ethanol exposure in early life may produce long-lasting neurobehavioral consequences, since brain structural maturation continues until adolescence. It is well established that females are more susceptible to alcohol-induced neurotoxicity and that ethanol consumption is increasing among women, especially during adolescence. In the present study, we investigated whether chronic ethanol exposure during adolescence through early adulthood in female rats may induce hippocampal histological damage and neurobehavioral impairments. Female rats were treated with distilled water or ethanol (6.5 g/kg/day, 22.5% w/v) by gavage from the 35(th)-90(th) day of life. Ethanol-exposed animals displayed reduced exploration of the central area and increased number of fecal boluses in the open field test indicative of anxiogenic responses. Moreover, chronic high ethanol exposure during adolescence induced marked impairments on short-term memory of female rats addressed on social recognition and step-down inhibitory avoidance tasks. These neurobehavioral deficits induced by ethanol exposure during adolescence through early adulthood were accompanied by the reduction of hippocampal formation volume as well as the loss of neurons, astrocytes and microglia cells in the hippocampus. These results indicate that chronic high ethanol exposure during adolescence through early adulthood in female rats induces long-lasting emotional and memory deficits associated with morphological and molecular alterations in the hippocampus. PMID:25922423

  8. Formation, Alteration and Delivery of Exogenous High Molecular Weight Organic Compounds: Objectives of the Tanpopo Mission from the Point of View of Chemical Evolution

    NASA Astrophysics Data System (ADS)

    Kobayashi, Kensei; K. Sarker, Palash; Ono, Keisuke; Kawamoto, Yukinori; Obayashi, Yumiko; Kaneko, Takeo; Yoshida, Satoshi; Mita, Hajime; Yabuta, Hikaru; Yamagishi, Akihiko

    A wide variety of organic compounds have been detected in such extraterrestrial bodies as carbonaceous chondrites and comets. Amino acids have been confirmed in extracts from carbonaceous chondrites and cometary dusts. It was suggested that these organics were formed in quite cold environments. We irradiated possible interstellar media, such as a frozen mixture of methanol, ammonia and water, with high-energy particles. Amino acid precursors with high molecular weights were detected in the irradiated products. Such complex amino acid precursors are much more stable than free amino acids against radiation, and heat. It is suggested that interplanetary dust particles (IDPs) brought much more organics than meteorites and comets. However, characteristics of organic compounds in IDPs are little known, since they have been collected only in terrestrial biosphere. We are planning the Tanpopo Mission, where IDPs would be collected in aerogel equipped on the Exposure Facility of the International Space Station. In addition, amino acids and their relating compounds would be exposed to space environments to see their possible alteration processes.

  9. EDITORIAL: 18th European Conference on Dynamics of Molecular Systems 18th European Conference on Dynamics of Molecular Systems

    NASA Astrophysics Data System (ADS)

    Varandas, A. J. C.

    2011-08-01

    This special section of Comments on Atomic, Molecular and Optical Physics (CAMOP) in Physica Scripta collects some of the papers that have been presented at the 18th European Conference on Dynamics of Molecular Systems MOLEC 2010 held in September 2010 in Curia, Portugal, as part of a series of biennial MOLEC conferences. This started in 1976 in Trento, Italy, and has continued, visiting 17 cities in 11 countries, namely Denmark, The Netherlands, Israel, France, Italy, Germany, Czech Republic, Spain, United Kingdom, Turkey and Russia. Following the MOLEC tradition, the scientific programme of the Curia meeting focused on experimental and theoretical studies of molecular interactions, collision dynamics, spectroscopy, and related fields. It included invited speakers from 22 countries, who were asked to summarize the problems reported in their presentations with the objective of revealing the current thinking of leading researchers in atomic, molecular and optical physics. It is hoped that their authoritative contributions presented in this CAMOP special section will also appeal to non-specialists through their clear and broad introductions to the field as well as references to the accessible literature. This CAMOP special section comprises ten contributions, which cover theoretical studies on the electronic structure of molecules and clusters as well as dynamics of elastic, inelastic and reactive encounters between atoms, molecules, ions, clusters and surfaces. Specifically, it includes electronic structure calculations using the traditional coupled-cluster method (Barreto et al 028111), the electron-attached equation-of-motion coupled cluster method (Hansen et al 028110), the diffusion Monte Carlo method (López-Durán et al 028107) and the path-integral Monte Carlo method (Barragán et al 028109). The contributions on molecular dynamics include on-the-fly quasi-classical trajectories on a five-atom molecule (Yu 028104), quantum reaction dynamics on triatomics

  10. How to Make a Non-Antigenic Protein (Auto) Antigenic: Molecular Complementarity Alters Antigen Processing and Activates Adaptive-Innate Immunity Synergy.

    PubMed

    Root-Bernstein, Robert

    2015-01-01

    Evidence is reviewed that complementary proteins and peptides form complexes with increased antigenicity and/or autoimmunogenicity. Five case studies are highlighted: 1) diphtheria toxin-antitoxin (antibody), which induces immunity to the normally non-antigenic toxin, and autoimmune neuritis; 2) tryptophan peptide of myelin basic protein and muramyl dipeptide ("adjuvant peptide"), which form a complex that induces experimental allergic encephalomyelitis; 3) an insulin and glucagon complex that is far more antigenic than either component individually; 4) various causes of experimental autoimmune myocarditis such as C protein in combination with its antibody, or coxsackie B virus in combination with the coxsackie and adenovirus receptor; 5) influenza A virus haemagglutinin with the outer membrane protein of the Haemophilus influenzae, which increases antigenicity. Several mechanisms cooperate to alter immunogenicity. Complexation alters antigen processing, protecting the components against proteolysis, altering fragmentation and presenting novel antigens to the immune system. Complementary antigens induce complementary adaptive immune responses (complementary antibodies and/or T cell receptors) that produce circulating immune complexes (CIC). CIC stimulate innate immunity. Concurrently, complementary antigens stimulate multiple Toll-like receptors that synergize to over-produce cytokines, which further stimulate adaptive immunity. Thus innate and adaptive immunity form a positive feedback loop. If components of the complex mimic a host protein, then autoimmunity may result. Enhanced antigenicity for production of improved vaccines and/or therapeutic autoimmunity (e.g., against cancer cells) might be achieved by using information from antibody or TCR recognition sites to complement an antigen; by panning for complements in randomized peptide libraries; or using antisense peptide strategies to design complements. PMID:26179268

  11. Design of optimal collimation for dedicated molecular breast imaging systems

    PubMed Central

    Weinmann, Amanda L.; Hruska, Carrie B.; O’Connor, Michael K.

    2009-01-01

    Molecular breast imaging (MBI) is a functional imaging technique that uses specialized small field-of-view gamma cameras to detect the preferential uptake of a radiotracer in breast lesions. MBI has potential to be a useful adjunct method to screening mammography for the detection of occult breast cancer. However, a current limitation of MBI is the high radiation dose (a factor of 7–10 times that of screening mammography) associated with current technology. The purpose of this study was to optimize the gamma camera collimation with the aim of improving sensitivity while retaining adequate resolution for the detection of sub-10-mm lesions. Square-hole collimators with holes matched to the pixilated cadmium zinc telluride detector elements of the MBI system were designed. Data from MBI patient studies and parameters of existing dual-head MBI systems were used to guide the range of desired collimator resolutions, source-to-collimator distances, pixel sizes, and collimator materials that were examined. General equations describing collimator performance for a conventional gamma camera were used in the design process along with several important adjustments to account for the specialized imaging geometry of the MBI system. Both theoretical calculations and a Monte Carlo model were used to measure the geometric efficiency (or sensitivity) and resolution of each designed collimator. Results showed that through optimal collimation, collimator sensitivity could be improved by factors of 1.5–3.2, while maintaining a collimator resolution of either ≤5 or ≤7.5 mm at a distance of 3 cm from the collimator face. These gains in collimator sensitivity permit an inversely proportional drop in the required dose to perform MBI. PMID:19378745

  12. Design of optimal collimation for dedicated molecular breast imaging systems

    SciTech Connect

    Weinmann, Amanda L.; Hruska, Carrie B.; O'Connor, Michael K.

    2009-03-15

    Molecular breast imaging (MBI) is a functional imaging technique that uses specialized small field-of-view gamma cameras to detect the preferential uptake of a radiotracer in breast lesions. MBI has potential to be a useful adjunct method to screening mammography for the detection of occult breast cancer. However, a current limitation of MBI is the high radiation dose (a factor of 7-10 times that of screening mammography) associated with current technology. The purpose of this study was to optimize the gamma camera collimation with the aim of improving sensitivity while retaining adequate resolution for the detection of sub-10-mm lesions. Square-hole collimators with holes matched to the pixilated cadmium zinc telluride detector elements of the MBI system were designed. Data from MBI patient studies and parameters of existing dual-head MBI systems were used to guide the range of desired collimator resolutions, source-to-collimator distances, pixel sizes, and collimator materials that were examined. General equations describing collimator performance for a conventional gamma camera were used in the design process along with several important adjustments to account for the specialized imaging geometry of the MBI system. Both theoretical calculations and a Monte Carlo model were used to measure the geometric efficiency (or sensitivity) and resolution of each designed collimator. Results showed that through optimal collimation, collimator sensitivity could be improved by factors of 1.5-3.2, while maintaining a collimator resolution of either {<=}5 or {<=}7.5 mm at a distance of 3 cm from the collimator face. These gains in collimator sensitivity permit an inversely proportional drop in the required dose to perform MBI.

  13. Progressive alterations of central nervous system structure and function are caused by charged particle radiation

    NASA Astrophysics Data System (ADS)

    Nelson, G. A.; Cns Nscor Team

    severity of the disease-associated pathological changes. The third goal is to quantify molecular markers that underly cellular and system changes. The team will quantify the frequency and structural spectrum of mutations in hippocampal samples using the E. coli β -galactosidase gene present in a transgenic mouse's tissues. Finally, by using transcription profiling hybridization, the status of a set of 96 genes involved in cytokine signaling during inflammation will be assessed.

  14. Spectroscopic Studies of Molecular Systems relevant in Astrobiology

    NASA Astrophysics Data System (ADS)

    Fornaro, Teresa

    2016-01-01

    In the Astrobiology context, the study of the physico-chemical interactions involving "building blocks of life" in plausible prebiotic and space-like conditions is fundamental to shed light on the processes that led to emergence of life on Earth as well as to molecular chemical evolution in space. In this PhD Thesis, such issues have been addressed both experimentally and computationally by employing vibrational spectroscopy, which has shown to be an effective tool to investigate the variety of intermolecular interactions that play a key role in self-assembling mechanisms of nucleic acid components and their binding to mineral surfaces. In particular, in order to dissect the contributions of the different interactions to the overall spectroscopic signals and shed light on the intricate experimental data, feasible computational protocols have been developed for the characterization of the spectroscopic properties of such complex systems. This study has been carried out through a multi-step strategy, starting the investigation from the spectroscopic properties of the isolated nucleobases, then studying the perturbation induced by the interaction with another molecule (molecular dimers), towards condensed phases like the molecular solid, up to the case of nucleic acid components adsorbed on minerals. A proper modeling of these weakly bound molecular systems has required, firstly, a validation of dispersion-corrected Density Functional Theory methods for simulating anharmonic vibrational properties. The isolated nucleobases and some of their dimers have been used as benchmark set for identifying a general, reliable and effective computational procedure based on fully anharmonic quantum mechanical computations of the vibrational wavenumbers and infrared intensities within the generalized second order vibrational perturbation theory (GVPT2) approach, combined with the cost-effective dispersion-corrected density functional B3LYP-D3, in conjunction with basis sets of

  15. Spectroscopic Studies of Molecular Systems relevant in Astrobiology

    NASA Astrophysics Data System (ADS)

    Fornaro, Teresa

    2016-01-01

    In the Astrobiology context, the study of the physico-chemical interactions involving "building blocks of life" in plausible prebiotic and space-like conditions is fundamental to shed light on the processes that led to emergence of life on Earth as well as to molecular chemical evolution in space. In this PhD Thesis, such issues have been addressed both experimentally and computationally by employing vibrational spectroscopy, which has shown to be an effective tool to investigate the variety of intermolecular interactions that play a key role in self-assembling mechanisms of nucleic acid components and their binding to mineral surfaces. In particular, in order to dissect the contributions of the different interactions to the overall spectroscopic signals and shed light on the intricate experimental data, feasible computational protocols have been developed for the characterization of the spectroscopic properties of such complex systems. This study has been carried out through a multi-step strategy, starting the investigation from the spectroscopic properties of the isolated nucleobases, then studying the perturbation induced by the interaction with another molecule (molecular dimers), towards condensed phases like the molecular solid, up to the case of nucleic acid components adsorbed on minerals. A proper modeling of these weakly bound molecular systems has required, firstly, a validation of dispersion-corrected Density Functional Theory methods for simulating anharmonic vibrational properties. The isolated nucleobases and some of their dimers have been used as benchmark set for identifying a general, reliable and effective computational procedure based on fully anharmonic quantum mechanical computations of the vibrational wavenumbers and infrared intensities within the generalized second order vibrational perturbation theory (GVPT2) approach, combined with the cost-effective dispersion-corrected density functional B3LYP-D3, in conjunction with basis sets of

  16. 75 FR 60468 - Privacy Act of 1974; Report of an Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-30

    ... HUMAN SERVICES Health Resources and Services Administration Privacy Act of 1974; Report of an Altered... requirements of the Privacy Act of 1974, the Health Resources and Services Administration (HRSA) is proposing... accordance with the National Childhood Vaccine Injury Act of 1986, as amended (42 U.S.C. 300aa-10, et...

  17. Dietary bovine lactoferrin alters mucosal and systemic immune cell responses in neonatal piglets.

    PubMed

    Comstock, Sarah S; Reznikov, Elizabeth A; Contractor, Nikhat; Donovan, Sharon M

    2014-04-01

    Lactoferrin (LF) is a multifunctional immune protein found at high concentrations in human milk. Herein, the effect of dietary bovine LF (bLF) on mucosal and systemic immune development was investigated. Colostrum-deprived piglets were fed formula containing 130 [control (Ctrl)], 367 (LF1), or 1300 (LF3) mg of bLF/(kg body weight · d). To provide passive immunity, sow serum was provided orally during the first 36 h of life. Blood, spleen, mesenteric lymph node (MLN), and ascending colon (Asc) contents were collected on day 7 (n = 10-14/group) and day 14 (n = 10-12/group). Immune cell populations were quantified by flow cytometry and immunoglobulins (Igs) were measured by ELISA. Additionally, immune cells were isolated from spleen and MLNs (n = 7/group) on day 7 and stimulated ex vivo with phytohemagglutinin or lipopolysaccharide (LPS) ± LF for 72 h. Secreted cytokine concentrations were quantified by multiplex assay. Lymphocyte populations [cluster determinant (CD)4, CD8, and natural killer cells] developed normally and were unaffected by dietary bLF. LF3 piglets tended to have 1.4 to 2 times more serum IgG than Ctrl piglets (P = 0.07) or LF1 piglets (P = 0.03), but IgA in Asc contents was unaffected by bLF. Asc IgA was 4 times higher on day 14 than day 7. Spleen cells from LF3 piglets produced 2 times more interleukin (IL)-10 and tumor necrosis factor (TNF)-α ex vivo than those from Ctrl or LF1 piglets. MLN cells from LF1 and LF3 piglets produced 40% more IL-10 and tended to produce 40% more IL-6 (P = 0.05) than those from Ctrl piglets. However, ex vivo bLF did not affect the cytokine response of spleen or MLN cells to LPS. In summary, dietary bLF alters the capacity of MLN and spleen immune cells to respond to stimulation, supporting a role for LF in the initiation of protective immune responses in these immunologically challenged neonates. PMID:24553692

  18. Soil Warming Alters the Nitrogen Cycle: Ecosystem Implications and Feedbacks to the Climate System

    NASA Astrophysics Data System (ADS)

    Butler, S. M.; Melillo, J. M.; Johnson, J. E.; Mohan, J. E.; Steudler, P. A.; Bowles, F. P.

    2008-12-01

    Increases in soil temperatures associated with global warming have the potential to accelerate nitrogen turnover in soils, which could alter other biogeochemical processes and eventually affect the structure of these forests. Over the past five years we have been studying soil and plant responses to soil warming in large plots in a deciduous stand at Harvard Forest in central Massachusetts. We have heated the soil 5°C above ambient and measured nitrogen cycling parameters including in situ net nitrogen mineralization and nitrification, nitrogen leaching and nitrous oxide (N2O) fluxes. We have also measured various aspects of the carbon cycle including soil respiration and carbon accumulation in vegetation. Over the first five years of the study, we observed a mean annual increase in the net nitrogen mineralized in the warmed plot of 23.8 kg N ha-1. While nitrification rates were low throughout the five years in the control plot, they increased in the warmed plot to account for over 25% of the total net nitrogen mineralized in year five. The increase in nitrogen mineralization stimulated tree growth and carbon storage in woody tissue in the warmed plot. The increased carbon storage in the trees compensated for more than half of the carbon lost from the soils due to accelerated decay of soil organic matter and so reduced the magnitude of the positive feedback to the climate system due to soil warming. We hypothesize that the increase in nitrification we observed will eventually "open" the nitrogen cycle and make gaseous and solution losses more likely. To date, however, we have measured no major losses of nitrous oxide or solution losses of nitrate in response to soil warming. Trees with the capacity to use nitrate may have a competitive advantage in a warmer world. Nitrate-using plants have an inducible enzyme that transforms nitrate to ammonium, a key building block for producing essential amino acids and proteins. Studies by our research group and by others have

  19. Short-term Hydropower Reservoir Operations in Chile's Central Interconnected System: Tradeoffs between Hydrologic Alteration and Economic Performance

    NASA Astrophysics Data System (ADS)

    Olivares, M. A.

    2011-12-01

    Hydropower accounts for about 50% of the installed capacity in Chile's Central Interconnected System (CIS) and new developments are envisioned in the near future. Large projects involving reservoirs are perceived negatively by the general public. In terms of operations, hydropower scheduling takes place at monthly, weekly, daily and hourly intervals, and operations at each level affect different environmental processes. Due to its ability to quickly and inexpensively respond to short-term changes in demand, hydropower reservoirs often are operated to provide power during periods of peak demand. This operational scheme, known as hydropeaking, changes the hydrologic regime by altering the rate and frequency of changes in flow magnitude on short time scales. To mitigate impacts on downstream ecosystems, operational constraints -typically minimum instream flows and maximum ramping rates- are imposed on hydropower plants. These operational restrictions limit reduce operational flexibility and can reduce the economic value of energy generation by imposing additional costs on the operation of interconnected power systems. Methods to predict the degree of hydrologic alteration rely on statistical analyses of instream flow time series. Typically, studies on hydrologic alteration use historical operational records for comparison between pre- and post-dam conditions. Efforts to assess hydrologic alteration based on future operational schemes of reservoirs are scarce. This study couples two existing models: a mid-term operations planning and a short-term economic dispatch to simulate short-term hydropower reservoir operations under different future scenarios. Scenarios of possible future configurations of the Chilean CIS are defined with emphasis on the introduction of non-conventional renewables (particularly wind energy) and large hydropower projects in Patagonia. Both models try to reproduce the actual decision making process in the Chilean Central Interconnected System

  20. Molecular characteristics of phosphoenolpyruvate: mannose phosphotransferase system in Streptococcus bovis.

    PubMed

    Asanuma, Narito; Yoshii, Takahiro; Hino, Tsuneo

    2004-07-01

    To elucidate the regulatory mechanism of catabolite control in Streptococcus bovis, we investigated the molecular properties and gene expression of the mannose-specific phosphoenolpyruvate (PEP)-dependent sugar: phosphotransferase system (PTS). The mannose PTS gene cluster (man) was found to comprise a gene encoding enzyme (E) II AB (manL) and genes encoding EIIC (manM), EIID (manN), and a putative regulator (manO). The gene cluster (man operon) was transcribed from one transcriptional start site, which was located 40 bp upstream of the manL start codon. However, two transcriptional start sites were found between manN and manO in primer extension analysis, and the manO may be transcribed independently from the man operon. The man operon and manO were constitutively transcribed without being affected by culture conditions, such as the sugar supplied (glucose, galactose, fructose, maltose, lactose, sucrose, or mannose), growth rate, or pH. PMID:15297922

  1. Development of a Molecular System for Studying Microbial Arsenate Respiration

    NASA Astrophysics Data System (ADS)

    Saltikov, C. W.; Newman, D. K.

    2002-12-01

    The toxic element arsenic is a major contaminant of many groundwaters and surface waters throughout the world. Arsenic enrichment is primarily of geological origin resulting from weathering processes and geothermal activity. Not surprisingly, microorganisms inhabiting anoxic arsenic-contaminated environments have evolved to exploit arsenate during respiration. Numerous bacteria have been isolated that use arsenate as a terminal electron acceptor for respiratory growth. The diversity of this metabolism appears to be widespread throughout the microbial tree of life, suggesting respiratory arsenate reduction is ancient in origin. Yet little is known about the molecular mechanisms for how these organisms respire arsenate. We have developed a model system in Shewanella trabarsenatis, strain ANA-3, a facultative anaerobe that respires arsenate and tolerates high concentrations of arsenite (10 mM). Through loss-of-function studies, we have identified genes involved in both arsenic resistance and arsenate respiration. The genes that confer resistance to arsenic are homologous to the well-characterized ars operon of E. coli. However, the respiratory arsenate reductase is predicted to encode a novel protein that shares homologous regions (~ 40 % similarity) to molybdopterin anaerobic reductases specific for DMSO, thiosulfate, nitrate, and polysulfide. I will discuss our emerging model for how strain ANA-3 respires arsenate and the relationship between arsenite resistance and arsenate respiration. I will also highlight the relevance of this type of analysis for biogeochemical studies.

  2. Molecular targets to promote central nervous system regeneration.

    PubMed

    Ferraro, Gino B; Alabed, Yazan Z; Fournier, Alyson E

    2004-01-01

    Trauma in the adult mammalian central nervous system (CNS) results in devastating clinical consequences due to the failure of injured axons to spontaneously regenerate. This regenerative failure can be attributed to both a lack of positive cues and to the presence of inhibitory cues that actively prevent regeneration. Substantial progress has been made in elucidating the molecular identity of negative cues present at the CNS injury site following injury. In the past several years, multiple myelin-associated inhibitors including Nogo, Myelin-associated glycoprotein and Oligodendrocyte-myelin glycoprotein have been characterized. Furthermore a neuronal receptor complex and several intracellular substrates leading to outgrowth inhibition have been identified. Rapid progress has also been made in identifying the role of neurotrophins and other positive cues in promoting axonal regrowth. The most recent advances in our understanding of positive stimuli for axon regeneration come from transplantation studies at the CNS lesion site. A number of artificial substrates, tissues, and cells including fetal cells, neural stem cells, Schwann cells and olfactory-ensheathing cells have been tested in animal models of CNS injury. Based on our expanded knowledge of inhibitory influences and on the positive characteristics of various transplants, a number of interventions have been tested to promote recovery in models of CNS trauma. These advances represent the first steps in developing a viable therapy to promote axon regeneration following CNS trauma. PMID:16181067

  3. On the origin of molecular "handedness" in living systems.

    PubMed

    Noyes, H P; Bonner, W A

    1975-10-29

    Elementary particle effects (beta-decay) provide at best only a weakly handed radiation in the biologically effective energy ranges. Global magnetic effects coupled to sunlight are randomized by paleomagnetic reversals. Hence a persistent terrestrial handed bias at possible local biopoetic sites offers a more promising explanation for the origin of the "handedness" of the molecules found among living systems on earth. Magnetite in lava flows maintains a handed bias for surface catalysis through many magnetic reversals. Magnetite contaminated with sulfur has already been proposed by Granick as a biopoetic site because it provides a weak source of chemical energy derived by photochemical conversion. Indirect evidence for this hypothesis has been provided by the molecular structure of ferredoxin - a single strand of the 14 primordial amino acids wrapped around an FeS core. Lava flows have been suggested as biopoetic sites by Fox, since their temperature and chemical composition might allow for the rapid synthesis of prebiotic compounds at the surface of the primitive earth. The additional fact that magnetite in lave flows also provides a persistent handed site for surface catalysis offers a further argument for the experimental investigation of this specific biopoetic environment. PMID:1202234

  4. Molecular and Cellular Designs of Insect Taste Receptor System

    PubMed Central

    Isono, Kunio; Morita, Hiromi

    2010-01-01

    The insect gustatory receptors (GRs) are members of a large G-protein coupled receptor family distantly related to the insect olfactory receptors. They are phylogenetically different from taste receptors of most other animals. GRs are often coexpressed with other GRs in single receptor neurons. Taste receptors other than GRs are also expressed in some neurons. Recent molecular studies in the fruitfly Drosophila revealed that the insect taste receptor system not only covers a wide ligand spectrum of sugars, bitter substances or salts that are common to mammals but also includes reception of pheromone and somatosensory stimulants. However, the central mechanism to perceive and discriminate taste information is not yet elucidated. Analysis of the primary projection of taste neurons to the brain shows that the projection profiles depend basically on the peripheral locations of the neurons as well as the GRs that they express. These results suggest that both peripheral and central design principles of insect taste perception are different from those of olfactory perception. PMID:20617187

  5. Inducibility of a molecular bioreporter system by heavy metals

    SciTech Connect

    Klimowski, L.; Rayms-Keller, A.; Olson, K.E.; Yang, R.S.H.; Tessari, J.; Carlson, J.; Beaty, B.

    1996-02-01

    The authors have developed a molecular bioreporter model for detecting an invertebrate response to heavy metals in streams. The bioreporter system, pMt2-luc, utilizes a Drosophila melanogaster metallothionein promoter to regulate luciferase expression in stably transformed mosquito cells.The LucC5 clone, which was isolated from pMt2-luc transformed, hygromycin-resistant C6/36 (Aedes albopictus) cells, demonstrated a 12-fold increase in luciferase-specific activity 48 h after exposure to 13 ppm copper (Cu). In addition to Cu, exposure of LucC5 cells to 19 ppm lead (Pb) or 3 ppm mercury (Hg) for 48 h induced luciferase expression threefold and fourfold, respectively. Exposures of up to 30 ppm arsenic (As), 8 ppm cadmium (Cd), 7 ppm chromium (Cr), or 5 ppm nickel (Ni) had no effect on luciferase induction. LucC5 cells exposed to metal mixtures of 13 ppm Cu and 19 ppm Pb yielded an additive response with a 14-fold increase in luciferase expression. When organic chemicals such as phenol (3 ppm) were mixed with 13 ppm Cu, 19 ppm Pb, or 3 ppm Hg a significant reduction in luciferase activity was noted. Additionally, atomic absorption spectroscopy suggested that two of the metals, Cu and Pb, show marked differences in accumulation within the LucC5 cell line.

  6. Molecular photoionization studies of nucleobases and correlated systems

    SciTech Connect

    Poliakoff, Erwin D.

    2015-03-11

    We proposed molecular photoionization studies in order to probe correlated events in fundamental scattering phenomena. In particular, we suggested that joint theoretical-experimental studies would provide a window into the microscopic aspects that are of central importance in AMO and chemical physics generally, and would generate useful data for wide array of important DOE topics, such as ultrafast dynamics, high harmonic generation, and probes of nonadiabatic processes. The unifying theme is that correlations between electron scattering dynamics and molecular geometry highlight inherently molecular aspects of the photoelectron behavior.

  7. Nanoparticle inhalation alters systemic arteriolar vasoreactivity through sympathetic and cyclooxygenase-mediated pathways

    PubMed Central

    Knuckles, Travis L.; Yi, Jinghai; Frazer, David G.; Leonard, Howard D.; Chen, Bean T.; Castranova, Vince; Nurkiewicz, Timothy R.

    2016-01-01

    The widespread increase in the production and use of nanomaterials has increased the potential for nanoparticle exposure; however, the biological effects of nanoparticle inhalation are poorly understood. Rats were exposed to nanosized titanium dioxide aerosols (10 µg lung burden); at 24 h post-exposure, the spinotrapezius muscle was prepared for intravital microscopy. Nanoparticle exposure did not alter perivascular nerve stimulation (PVNS)-induced arteriolar constriction under normal conditions; however, adrenergic receptor inhibition revealed a more robust effect. Nanoparticle inhalation reduced arteriolar dilation in response to active hyperaemia (AH). In both PVNS and AH experiments, nitric oxide synthase (NOS) inhibition affected only controls. Whereas cyclooxygenase (COX) inhibition only attenuated AH-induced arteriolar dilation in nanoparticle-exposed animals. This group displayed an enhanced U46619 constriction and attenuated iloprost-induced dilation. Collectively, these studies indicate that nanoparticle exposure reduces microvascular NO bioavailability and alters COX-mediated vasoreactivity. Furthermore, the enhanced adrenergic receptor sensitivity suggests an augmented sympathetic responsiveness. PMID:21830860

  8. Clinical and molecular characterization of a cohort of patients with novel nucleotide alterations of the Dystrophin gene detected by direct sequencing

    PubMed Central

    2011-01-01

    Background Duchenne and Becker Muscular dystrophies (DMD/BMD) are allelic disorders caused by mutations in the dystrophin gene, which encodes a sarcolemmal protein responsible for muscle integrity. Deletions and duplications account for approximately 75% of mutations in DMD and 85% in BMD. The implementation of techniques allowing complete gene sequencing has focused attention on small point mutations and other mechanisms underlying complex rearrangements. Methods We selected 47 patients (41 families; 35 DMD, 6 BMD) without deletions and duplications in DMD gene (excluded by multiplex ligation-dependent probe amplification and multiplex polymerase chain reaction analysis). This cohort was investigated by systematic direct sequence analysis to study sequence variation. We focused our attention on rare mutational events which were further studied through transcript analysis. Results We identified 40 different nucleotide alterations in DMD gene and their clinical correlates; altogether, 16 mutations were novel. DMD probands carried 9 microinsertions/microdeletions, 19 nonsense mutations, and 7 splice-site mutations. BMD patients carried 2 nonsense mutations, 2 splice-site mutations, 1 missense substitution, and 1 single base insertion. The most frequent stop codon was TGA (n = 10 patients), followed by TAG (n = 7) and TAA (n = 4). We also analyzed the molecular mechanisms of five rare mutational events. They are two frame-shifting mutations in the DMD gene 3'end in BMD and three novel splicing defects: IVS42: c.6118-3C>A, which causes a leaky splice-site; c.9560A>G, which determines a cryptic splice-site activation and c.9564-426 T>G, which creates pseudoexon retention within IVS65. Conclusion The analysis of our patients' sample, carrying point mutations or complex rearrangements in DMD gene, contributes to the knowledge on phenotypic correlations in dystrophinopatic patients and can provide a better understanding of pre-mRNA maturation defects and dystrophin

  9. Matrilysin/Matrix Metalloproteinase-7(MMP7) Cleavage of Perlecan/HSPG2 Creates A Molecular Switch to Alter Prostate Cancer Cell Behavior

    PubMed Central

    Grindel, B.J.; Martinez, J.R.; Pennington, C.L.; Muldoon, M.; Stave, J.; Chung, L.W.; Farach-Carson, M.C.

    2015-01-01

    Perlecan/HSPG2, a large heparan sulfate (HS) proteoglycan, normally is expressed in the basement membrane (BM) underlying epithelial and endothelial cells. During prostate cancer (PCa) cell invasion, a variety of proteolytic enzymes are expressed that digest BM components including perlecan. An enzyme upregulated in invasive PCa cells, matrilysin/matrix metalloproteinase-7 (MMP-7), was examined as a candidate for perlecan proteolysis both in silico and in vitro. Purified perlecan showed high sensitivity to MMP-7 digestion even when fully decorated with HS or when presented in native context connected with other BM proteins. In both conditions, MMP-7 produced discrete perlecan fragments corresponding to an origin in immunoglobulin (Ig) repeat region domain IV. While not predicted by in silico analysis, MMP-7 cleaved every subpart of recombinantly generated perlecan domain IV. Other enzymes relevant to PCa that were tested had limited ability to cleave perlecan including prostate specific antigen, hepsin, or fibroblast activation protein α. A long C-terminal portion of perlecan domain IV, Dm IV-3, induced a strong clustering phenotype in the metastatic PCa cell lines, PC-3 and C4-2. MMP-7 digestion of Dm IV-3 reverses the clustering effect into one favoring cell dispersion. In a C4-2 Transwell® invasion assay, perlecan-rich human BM extract that was pre-digested with MMP-7 showed loss of barrier function and permitted a greater level of cell penetration than untreated BM extract. We conclude that enzymatic processing of perlecan in the BM or territorial matrix by MMP-7 as occurs in the invasive tumor microenvironment acts as a molecular switch to alter PCa cell behavior and favor cell dispersion and invasiveness. PMID:24833109

  10. Molecular genetic alterations in egfr CA-SSR-1 microsatellite and egfr copy number changes are associated with aggressiveness in thymoma

    PubMed Central

    Conti, Salvatore; Gallo, Enzo; Sioletic, Stefano; Facciolo, Francesco; Palmieri, Giovannella; Lauriola, Libero; Evoli, Amelia; Martucci, Robert; Di Benedetto, Anna; Novelli, Flavia; Giannarelli, Diana; Deriu, Gloria; Granone, Pierluigi; Ottaviano, Margaret; Muti, Paola; Pescarmona, Edoardo

    2016-01-01

    Background The key role of egfr in thymoma pathogenesis has been questioned following the failure in identifying recurrent genetic alterations of egfr coding sequences and relevant egfr amplification rate. We investigated the role of the non-coding egfr CA simple sequence repeat 1 (CA-SSR-1) in a thymoma case series. Methods We used sequencing and egfr-fluorescence in situ hybridization (FISH) to genotype 43 thymomas; (I) for polymorphisms and somatic loss of heterozygosity of the non-coding egfr CA-SSR-1 microsatellite and (II) for egfr gene copy number changes. Results We found two prevalent CA-SSR-1 genotypes: a homozygous 16 CA repeat and a heterozygous genotype, bearing alleles with 16 and 20 CA repeats. The average combined allele length was correlated with tumor subtype: shorter sequences were significantly associated with the more aggressive WHO thymoma subtype group including B2/B3, B3 and B3/C histotypes. Four out of 29 informative cases analysed for somatic CA-SSR-1 loss of heterozygosity showed allelic imbalance (AI), 3/4 with loss of the longer allele. By egfr-FISH analysis, 9 out of 33 cases were FISH positive. Moreover, the two integrated techniques demonstrated that 3 out of 4 CA-SSR-1-AI positive cases with short allele relative prevalence showed significantly low or high chromosome 7 “polysomy”/increased gene copy number by egfr-FISH. Conclusions Our molecular and genetic and follow up data indicated that CA-SSR-1-allelic imbalance with short allele relative prevalence significantly correlated with EGFR 3+ immunohistochemical score, increased egfr Gene Copy Number, advanced stage and with relapsing/metastatic behaviour in thymomas. PMID:27076933

  11. The molecular branching ratio method for calibration of optical systems in the vacuum ultraviolet

    NASA Technical Reports Server (NTRS)

    Mumma, M. J.

    1972-01-01

    The intensity distribution of bands belonging to six molecular band systems is discussed with special emphasis on their usefulness for intensity calibration of optical systems in the vacuum ultraviolet (1000A Lambda 3000A). The theory of molecular band intensities is outlined and the technique of measuring the spectral response curve is described. Several methods for establishing an absolute intensity calibration are discussed.

  12. Systemic Inhibition of Canonical Notch Signaling Results in Sustained Callus Inflammation and Alters Multiple Phases of Fracture Healing

    PubMed Central

    Dishowitz, Michael I.; Mutyaba, Patricia L.; Takacs, Joel D.; Barr, Andrew M.; Engiles, Julie B.; Ahn, Jaimo; Hankenson, Kurt D.

    2013-01-01

    The Notch signaling pathway is an important regulator of embryological bone development, and many aspects of development are recapitulated during bone repair. We have previously reported that Notch signaling components are upregulated during bone fracture healing. However, the significance of the Notch pathway in bone regeneration has not been described. Therefore, the objective of this study was to determine the importance of Notch signaling in regulating bone fracture healing by using a temporally controlled inducible transgenic mouse model (Mx1-Cre;dnMAMLf/-) to impair RBPjκ-mediated canonical Notch signaling. The Mx1 promoter was synthetically activated resulting in temporally regulated systemic dnMAML expression just prior to creation of bilateral tibial fractures. This allowed for mice to undergo unaltered embryological and post-natal skeletal development. Results showed that systemic Notch inhibition prolonged expression of inflammatory cytokines and neutrophil cell inflammation, and reduced the proportion of cartilage formation within the callus at 10 days-post-fracture (dpf) Notch inhibition did not affect early bone formation at 10dpf, but significantly altered bone maturation and remodeling at 20dpf. Increased bone volume fraction in dnMAML fractures, which was due to a moderate decrease in callus size with no change in bone mass, coincided with increased trabecular thickness but decreased connectivity density, indicating that patterning of bone was altered. Notch inhibition decreased total osteogenic cell density, which was comprised of more osteocytes rather than osteoblasts. dnMAML also decreased osteoclast density, suggesting that osteoclast activity may also be important for altered fracture healing. It is likely that systemic Notch inhibition had both direct effects within cell types as well as indirect effects initiated by temporally upstream events in the fracture healing cascade. Surprisingly, Notch inhibition did not alter cell proliferation

  13. Molecular mechanisms underlying the role of nitric oxide in the cardiovascular system.

    PubMed

    Stoclet, J C; Troncy, E; Muller, B; Brua, C; Kleschyov, A L

    1998-11-01

    In the cardiovascular system, nitric oxide (NO) is involved in the short and long-term regulation of haemodynamics, and in a number of their pathological alterations. Investigation into the biochemistry of NO-synthase isoforms has confirmed that they also all produce superoxide anion (O(*)). The free radical NO can interact with many targets on which novel information has been recently obtained. The major results of these interactions are not only the well known activation of guanylyl cyclase, but also the formation of potentially cytotoxic peroxynitrite (ONOO(-)), and the formation of S-nitrosothiols and non-haem iron-dinitrosyl dithiolate complexes. Tissue O(2), O(*), low molecular weight thiols and transition metals (especially FeII) play a pivotal role in directing NO towards targets responsible for biological effects, or storage or release from these stores. In addition, circulating forms of NO have been proposed with S-nitrosation of blood proteins. All these mechanisms provide potential pharmacological targets for future therapeutic strategies. PMID:15991928

  14. Variational path integral molecular dynamics and hybrid Monte Carlo algorithms using a fourth order propagator with applications to molecular systems.

    PubMed

    Kamibayashi, Yuki; Miura, Shinichi

    2016-08-21

    In the present study, variational path integral molecular dynamics and associated hybrid Monte Carlo (HMC) methods have been developed on the basis of a fourth order approximation of a density operator. To reveal various parameter dependence of physical quantities, we analytically solve one dimensional harmonic oscillators by the variational path integral; as a byproduct, we obtain the analytical expression of the discretized density matrix using the fourth order approximation for the oscillators. Then, we apply our methods to realistic systems like a water molecule and a para-hydrogen cluster. In the HMC, we adopt two level description to avoid the time consuming Hessian evaluation. For the systems examined in this paper, the HMC method is found to be about three times more efficient than the molecular dynamics method if appropriate HMC parameters are adopted; the advantage of the HMC method is suggested to be more evident for systems described by many body interaction. PMID:27544094

  15. Charged-particle induced alterations of surfaces in the outer solar system

    NASA Technical Reports Server (NTRS)

    Johnson, R. E.

    1991-01-01

    Researchers calculated the plasma bombardment profiles of the surfaces of the icy Saturnian satellites in order to interpret reflection spectra and the effect of charged particles on the surfaces (mantles) of Pluto and of comets in the Oort cloud. Pluto's exposure to cosmic rays results in a slow alteration of the reflectance if the methane condensed on its surface. The UV absorbed in the atmosphere can produce precipitates. The researchers showed that, depending on the rates of the competing regolith processes and rates for replenishment of the methane, the surface can appear bright, red, or dark. Using laboratory data, they showed that the amount of darkening occurring in one orbit is small. Therefore, transport, burial, and re-exposure of organic sediments must control the reflectance, and the average reflectance is established by the radiation altered species accumulated over many orbits with the observed spatial, and possible temporal, differences in albedo due to transport. The cosmic rays, although producing changes in reflectance slowly, do so inevitably. Therefore, the fact that the surface is not dark everywhere implies that it is active and the exposure rates vs. depth into the surface of Pluto can be used to constrain turnover rates. Comets in the Oort cloud experience similar rates.

  16. Environmental Molecular Sciences Laboratory Operations System: Version 4.0 - system requirements specification

    SciTech Connect

    Kashporenko, D.

    1996-07-01

    This document is intended to provide an operations standard for the Environmental Molecular Sciences Laboratory OPerations System (EMSL OPS). It is directed toward three primary audiences: (1) Environmental Molecular Sciences Laboratory (EMSL) facility and operations personnel; (2) laboratory line managers and staff; and (3) researchers, equipment operators, and laboratory users. It is also a statement of system requirements for software developers of EMSL OPS. The need for a finely tuned, superior research environment as provided by the US Department of Energy`s (DOE) Environmental Molecular Sciences Laboratory has never been greater. The abrupt end of the Cold War and the realignment of national priorities caused major US and competing overseas laboratories to reposition themselves in a highly competitive research marketplace. For a new laboratory such as the EMSL, this means coming into existence in a rapidly changing external environment. For any major laboratory, these changes create funding uncertainties and increasing global competition along with concomitant demands for higher standards of research product quality and innovation. While more laboratories are chasing fewer funding dollars, research ideas and proposals, especially for molecular-level research in the materials and biological sciences, are burgeoning. In such an economically constrained atmosphere, reduced costs, improved productivity, and strategic research project portfolio building become essential to establish and maintain any distinct competitive advantage. For EMSL, this environment and these demands require clear operational objectives, specific goals, and a well-crafted strategy. Specific goals will evolve and change with the evolution of the nature and definition of DOE`s environmental research needs. Hence, EMSL OPS is designed to facilitate migration of these changes with ease into every pertinent job function, creating a facile {open_quotes}learning organization.{close_quotes}

  17. Transport diffusion in one dimensional molecular systems: Power law and validity of Fick's law

    NASA Astrophysics Data System (ADS)

    Xu, Zhi-cheng; Zheng, Dong-qin; Ai, Bao-quan; Hu, Bambi; Zhong, Wei-rong

    2015-10-01

    The transport diffusion in one-dimensional molecular systems is investigated through non-equilibrium molecular dynamics and Monte Carlo methods. We have proposed the power law relationship of the transport diffusion coefficient with the temperature, the mass and the transport length, D* ∝ T*m*-1L*β, where β equals to 0.8 for small systems and zero for large systems. It is found that Fick's law is valid in long transport length but invalid in short transport length. Our results can provide a new perspective for understanding the microscopic mechanism of the molecular transport phenomena in low-dimensional systems.

  18. Molecular profiles to biology and pathways: a systems biology approach.

    PubMed

    Van Laere, Steven; Dirix, Luc; Vermeulen, Peter

    2016-01-01

    Interpreting molecular profiles in a biological context requires specialized analysis strategies. Initially, lists of relevant genes were screened to identify enriched concepts associated with pathways or specific molecular processes. However, the shortcoming of interpreting gene lists by using predefined sets of genes has resulted in the development of novel methods that heavily rely on network-based concepts. These algorithms have the advantage that they allow a more holistic view of the signaling properties of the condition under study as well as that they are suitable for integrating different data types like gene expression, gene mutation, and even histological parameters. PMID:27311441

  19. The levonorgestrel-releasing intrauterine system is associated with delayed endocervical clearance of Chlamydia trachomatis without alterations in vaginal microbiota.

    PubMed

    Liechty, Emma R; Bergin, Ingrid L; Bassis, Christine M; Chai, Daniel; LeBar, William; Young, Vincent B; Bell, Jason D

    2015-11-01

    Progestin-based contraception may impact women's susceptibility to sexually transmitted infection. We evaluated the effect of the levonorgestrel intrauterine system (LNG-IUS) on cervical persistence of Chlamydia trachomatis (CT) in a baboon model. Female olive baboons (Papio anubis) with or without an LNG-IUS received CT or sham inoculations. CT was detected in cervical epithelium with weekly nucleic acid amplification testing (NAAT) and culture. Presence of the LNG-IUS was associated with prolonged persistence of CT. Median time to post-inoculation clearance of CT as detected by NAAT was 10 weeks (range 7-12) for animals with an LNG-IUS and 3 weeks (range 0-12) for non-LNG-IUS animals (P = 0.06). Similarly, median time to post-inoculation clearance of CT by culture was 9 weeks (range 3-12) for LNG-IUS animals and 1.5 weeks (range 0-10) for non-LNG-IUS animals (P = 0.04). We characterized the community structure of the vaginal microbiota with the presence of the LNG-IUS to determine if alterations in CT colonization dynamics were associated with changes in vaginal commensal bacteria. Vaginal swabs were collected weekly for microbiome analysis. Endocervical CT infection was not correlated with alterations in the vaginal microbiota. Together, these results suggest that LNG-IUS may facilitate CT endocervical persistence through a mechanism distinct from vaginal microbial alterations. PMID:26371177

  20. Temporal and spatial distribution of alteration, mineralization and fluid inclusions in the transitional high-sulfidation epithermal-porphyry copper system at Red Mountain, Arizona

    USGS Publications Warehouse

    Lecumberri-Sanchez, Pilar; Newton, M. Claiborne, III; Westman, Erik C.; Kamilli, Robert J.; Canby, Vertrees M.; Bodnar, Robert J.

    2013-01-01

    Red Mountain, Arizona, is a Laramide porphyry Cu system (PCD) that has experienced only a modest level of erosion compared to most other similar deposits in the southwestern United States. As a result, the upper portion of the magmatic–hydrothermal system, which represents the transition from shallower high-sulfidation epithermal mineralization to deeper porphyry Cu mineralization, is well preserved. Within the Red Mountain system, alteration, mineralization and fluid inclusion assemblages show a systematic distribution in both time and space. Early-potassic alteration (characterized by the minerals biotite and magnetite) is paragenetically earlier than late-potassic alteration (K-feldspar–anhydrite) and both are followed by later phyllic (sericite–pyrite) alteration. Advanced argillic alteration (pyrophyllite–alunite–other clay minerals) is thought to be coeval with or postdate phyllic alteration. Minerals characteristic of advanced argillic alteration are present in the near surface. Phyllic alteration extends to greater depths compared to advanced argillic alteration. Early-potassic and late-potassic alteration are only observed in the deepest part of the system. Considerable overlap of phyllic alteration with both early-potassic and late-potassic alteration zones is observed. The hypogene mineralization contains 0.4–1.2% Cu and is spatially and temporally related to the late-potassic alteration event. Molybdenum concentration is typically In the deepest part of the system, an early generation of low-to-moderate density and salinity liquid + vapor inclusions with opaque daughter minerals is followed in time by halite-bearing inclusions that also contain opaque daughter minerals indicating that an early intermediate-density magmatic fluid evolved to a high-density, high-salinity mineralizing fluid. The increase in density and salinity of fluids with time observed in the deeper parts of the system may be the result of immiscibility (“boiling”) of

  1. Parasite-induced alteration of odour responses in an amphipod-acanthocephalan system.

    PubMed

    Stone, Charles F; Moore, Janice

    2014-11-01

    Odour-related behaviours in aquatic invertebrates are important and effective anti-predator behaviours. Parasites often alter invertebrate host behaviours to increase transmission to hosts. This study investigated the responses of the amphipod Hyalella azteca when presented with two predator chemical cues: (i) alarm pheromones produced by conspecifics and (ii) kairomones produced by a predatory Green Sunfish (Lepomis cyanellus). We compared the responses of amphipods uninfected and infected with the acanthocepalan parasite Leptorhynchiodes thecatus. Uninfected amphipods reduced activity and increased refuge use after detecting both the alarm pheromones and predator kairomones. Infected amphipods spent significantly more time being active and less time on the refuge than uninfected amphipods, and behaved as if they had not detected the chemical stimulus. Therefore, L. thecatus infections disrupt the amphipods' anti-predator behaviours and likely make their hosts more susceptible to predation. PMID:25200352

  2. Alcohol abuse and smoking alter inflammatory mediator production by pulmonary and systemic immune cells.

    PubMed

    Gaydos, Jeanette; McNally, Alicia; Guo, Ruixin; Vandivier, R William; Simonian, Philip L; Burnham, Ellen L

    2016-03-15

    Alcohol use disorders (AUDs) and tobacco smoking are associated with an increased predisposition for community-acquired pneumonia and the acute respiratory distress syndrome. Mechanisms are incompletely established but may include alterations in response to pathogens by immune cells, including alveolar macrophages (AMs) and peripheral blood mononuclear cells (PBMCs). We sought to determine the relationship of AUDs and smoking to expression of IFNγ, IL-1β, IL-6, and TNFα by AMs and PBMCs from human subjects after stimulation with lipopolysaccharide (LPS) or lipoteichoic acid (LTA). AMs and PBMCs from healthy subjects with AUDs and controls, matched on smoking, were cultured with LPS (1 μg/ml) or LTA (5 μg/ml) in the presence and absence of the antioxidant precursor N-acetylcysteine (10 mM). Cytokines were measured in cell culture supernatants. Expression of IFNγ, IL-1β, IL-6, and TNFα in AMs and PBMCs was significantly increased in response to stimulation with LPS and LTA. AUDs were associated with augmented production of proinflammatory cytokines, particularly IFNγ and IL-1β, by AMs and PBMCs in response to LPS. Smoking diminished the impact of AUDs on AM cytokine expression. Expression of basal AM and PBMC Toll-like receptors-2 and -4 was not clearly related to differences in cytokine expression; however, addition of N-acetylcysteine with LPS or LTA led to diminished AM and PBMC cytokine secretion, especially among current smokers. Our findings suggest that AM and PBMC immune cell responses to LPS and LTA are influenced by AUDs and smoking through mechanisms that may include alterations in cellular oxidative stress. PMID:26747782

  3. Evidence of Altered Corticomotor System Connectivity in Early-Stage Alzheimer’s Disease

    PubMed Central

    Vidoni, Eric D.; Thomas, George P.; Honea, Robyn A.; Loskutova, Natalia; Burns, Jeffrey M.

    2012-01-01

    Background and Purpose There is increasing evidence for subtle motor dysfunction early in Alzheimer’s Disease (AD), including common motor behaviors that were once considered unaffected early in the disease process. Our objective was to assess if functional neural networks underlying motor behavior are altered by AD. Methods We investigated AD-related differences in regional brain activation during motor performance. Nine older adults with early-stage AD and 10 without dementia underwent fMRI while performing a visually-directed simple motor task (hand squeeze). Results Despite some similarity in brain activation during motor performance, we found that individuals without dementia exhibited greater activation in accessory motor regions supplementary motor area and cerebellum compared to those with AD. We also assessed disease-related differences in regions where activity was functionally integrated with primary motor cortex. Using a psycho-physiological interaction analysis, we found that those with AD displayed increased co-activation with primary motor cortex of bilateral motor and visual regions. Discussion and Conclusions These AD-related changes in regional co-activation during motor execution in may represent inefficiency in the motor network as a consequence of the disease process. Alternatively, they may represent compensatory activation. These findings provide further evidence that in early-stages of AD, neuromotor function is altered in AD even during simple motor behaviors. The results may have implications for performance of more complex tasks, and may be associated with the well-characterized decline in dual task performance in those with AD. PMID:22333920

  4. Systemic and Vascular Alterations in Rat models Exposed to Libby Amphibole

    EPA Science Inventory

    Acute pulmonary injury and chronic diseases can impact systemic vasculature and extra pulmonary organ systems due to the hemodynamic properties of the pulmonary capillary network that allows mediators to release into the circulation. Exposure to Libby amphibole (LA) is associated...

  5. 75 FR 57806 - Privacy Act of 1974; Report of an Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-22

    .... The last update of this SORN 09-15-0059 was December 23, 1998 (63 FR 71145). DATES: HRSA has filed an... NUMBER: 09-15-0059 SYSTEM NAME: Strategic Work Information and Folder Transfer System (SWIFT), HHS/...

  6. 75 FR 30411 - Privacy Act of 1974; Report of a Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-01

    ... system was established and published in the Federal Register (FR) at 63 FR 40297 (July 28, 1998). The... retain identifiable data indefinitely in accordance with 69 FR 3434. SYSTEM MANAGERS AND ADDRESS... assign a new CMS identification number to this system to simplify the obsolete and confusing...

  7. A Comparative Study of Successful Central Nervous System Drugs Using Molecular Modeling

    ERIC Educational Resources Information Center

    Kim, Hyosub; Sulaimon, Segun; Menezes, Sandra; Son, Anne; Menezes, Warren J. C.

    2011-01-01

    Molecular modeling is a powerful tool used for three-dimensional visualization and for exploring electrostatic forces involved in drug transport. This tool enhances student understanding of structure-property relationships, as well as actively engaging them in class. Molecular modeling of several central nervous system (CNS) drugs is used to…

  8. Teaching Applied Genetics and Molecular Biology to Agriculture Engineers. Application of the European Credit Transfer System

    ERIC Educational Resources Information Center

    Weiss, J.; Egea-Cortines, M.

    2008-01-01

    We have been teaching applied molecular genetics to engineers and adapted the teaching methodology to the European Credit Transfer System. We teach core principles of genetics that are universal and form the conceptual basis of most molecular technologies. The course then teaches widely used techniques and finally shows how different techniques…

  9. Molecular-Flow Properties of RIB Type Vapor-Transport Systems Using a Fast-Valve

    SciTech Connect

    Alton, Gerald D; Bilheux, Hassina Z; Zhang, Y.; Liu, Yuan

    2014-01-01

    The advent of the fast-valve device, described previously, permits measurement of molecular-flow times of chemically active or inactive gaseous species through radioactive ion beam (RIB) target ion source systems, independent of size, geometry and materials of construction. Thus, decay losses of short-half-life RIBs can be determined for a given target/vapor-transport system in advance of on-line operation, thereby ascertaining the feasibility of the system design for successful processing of a given isotope. In this article, molecular-flow-time theory and experimentally measured molecular-flow time data are given for serial- and parallel-coupled Ta metal RIB vapor-transport systems similar to those used at ISOL based RIB facilities. In addition, the effect of source type on the molecular-flow time properties of a given system is addressed, and a chemical passivation method for negating surface adsorption enthalpies for chemically active gaseous species on Ta surfaces is demonstrated.

  10. Molecular domains of myelinated axons in the peripheral nervous system.

    PubMed

    Salzer, James L; Brophy, Peter J; Peles, Elior

    2008-11-01

    Myelinated axons are organized into a series of specialized domains with distinct molecular compositions and functions. These domains, which include the node of Ranvier, the flanking paranodal junctions, the juxtaparanodes, and the internode, form as the result of interactions with myelinating Schwann cells. This domain organization is essential for action potential propagation by saltatory conduction and for the overall function and integrity of the axon. PMID:18803321

  11. Molecular cooperativity in the dynamics of glass-forming systems

    NASA Astrophysics Data System (ADS)

    Hong, Liang; Gujrati, Purushottam; Novikov, Vladimier; Sokolov, Alexei

    2010-03-01

    The mechanism behind the sharp slowing down of the main structural relaxation in a glass-forming liquid upon approaching the glass transition remains a great puzzle. Most of the theories relate this mechanism to the cooperativity in molecular motion. On the other hand, the collective vibration in the pico-second time region, the so-called boson peak, is also described as a cooperative process. In our recent work (L. Hong, et al., J. Chem. Phys., in print), we demonstrated that the collective vibrations and the main structural relaxation involve a similar length scale of cooperative molecular motions. More importantly, we found that the cooperativity length scale in different materials directly correlates to only one part of the mechanism of slowing down the structural relaxation, i.e., the dependence of the structural relaxation on volume. In this presentation, we will further demonstrate that this correlation holds true not only for different chemical species, but also for the same chemical specie with different molecular weight or under pressure. The results are compared to predictions of theoretical models.

  12. Molecular systems evaluation of oligomerogenic APPE693Q and fibrillogenic APPKM670/671NL/PSEN1Δexon9 mouse models identifies shared molecular features with human Alzheimer’s brain molecular pathology

    PubMed Central

    Readhead, Ben; Haure-Mirande, Jean-Vianney; Zhang, Bin; Haroutunian, Vahram; Gandy, Sam; Schadt, Eric E.; Dudley, Joel T.; Ehrlich, Michelle E.

    2016-01-01

    Identification and characterization of molecular mechanisms that connect genetic risk factors to initiation and evolution of disease pathophysiology represent major goals and opportunities for improving therapeutic and diagnostic outcomes in Alzheimer’s disease (AD). Integrative genomic analysis of the human AD brain transcriptome holds potential for revealing novel mechanisms of dysfunction that underlie the onset and/or progression of the disease. We performed an integrative genomic analysis of brain tissue derived transcriptomes measured from two lines of mice expressing distinct mutant AD-related proteins. The first line expresses oligomerogenic mutant APPE693Q inside neurons, leading to accumulation of amyloid beta (Aβ) oligomers and behavioral impairment, but never develops parenchymal fibrillar amyloid deposits. The second line expresses APPKM670/671NL/PSEN1Δexon9 in neurons and accumulates fibrillar Aβ amyloid and amyloid plaques accompanied by neuritic dystrophy and behavioral impairment. We performed RNA-sequencing analyses of dentate gyrus and entorhinal cortex from each line and from wild type mice. We then performed an integrative genomic analysis to identify dysregulated molecules and pathways, comparing transgenic mice with wild type controls as well as to each other. We also compared these results with datasets derived from human AD brain. Differential gene and exon expression analysis revealed pervasive alterations in APP/Aβ metabolism, epigenetic control of neurogenesis, cytoskeletal organization, and extracellular matrix regulation. Comparative molecular analysis converged on FMR1 (Fragile X Mental Retardation-1), an important negative regulator of APP translation and oligomerogenesis in the post-synaptic space. Integration of these transcriptomic results with human postmortem AD gene networks, differential expression and differential splicing signatures identified significant similarities in pathway dysregulation, including extracellular

  13. The nutritional background of the host alters the disease course in a fish-myxosporean system.

    PubMed

    Estensoro, Itziar; Benedito-Palos, Laura; Palenzuela, Oswaldo; Kaushik, Sadasivam; Sitjà-Bobadilla, Ariadna; Pérez-Sánchez, Jaume

    2011-01-10

    The aim of the present work was to determine if a practical plant protein-based diet containing vegetable oils (VO) as the major lipid source could alter the disease course when challenged with the myxosporean Enteromyxum leei, a wide-spread parasite in the Mediterranean basin causing heavy economic losses. Gilthead sea bream (Sparus aurata) fed for 9 months either a fish oil (FO) diet or a blend of VOs at 66% of replacement (66VO diet) were challenged by exposure to parasite-contaminated water effluent. All fish were periodically and non-lethally sampled to obtain biometrical data and to know their infection status. After 102 days of exposure, fish were euthanized and haematological, biometrical, histological, immunological, glutathione and anti-oxidant data were obtained from tissue, blood and serum samples. Anorexia appeared in both exposed groups, but feed intake reduction was higher in 66VO fish. The signs of disease (lower growth, condition factor, specific growth rate, haematocrit) as well as the disease course were worse in fish from 66VO group, with a higher prevalence and intensity of infection, a higher percentage of fish harbouring the parasite in the entire intestinal tract, and a faster establishment of the parasite. Parasite intensity of infection was negatively correlated with growth parameters and haematocrit in both groups, and with complement, lysozyme and hepatic total glutathione in 66VO fish. PMID:20947256

  14. Neuroplastic alterations in the limbic system following cocaine or alcohol exposure.

    PubMed

    Stuber, Garret D; Hopf, F Woodward; Tye, Kay M; Chen, Billy T; Bonci, Antonello

    2010-01-01

    Neuroplastic changes in the CNS are thought to be a fundamental component of learning and memory. While pioneering studies in the hippocampus and cerebellum have detailed many of the basic mechanisms that can lead to alterations in synaptic transmission based on previous activity, only more recently has synaptic plasticity been monitored after behavioral manipulation or drug exposure. In this chapter, we review evidence that drugs of abuse are powerful modulators of synaptic plasticity. Both the dopaminergic neurons of the ventral tegmental area as well medium spiny neurons in nucleus accumbens show enhanced excitatory synaptic strength following passive or active exposure to drugs such as cocaine and alcohol. In the VTA, both the enhancement of excitatory synaptic strength and the acquisition of drug-related behaviors depend on signaling through the N-methyl-D: -aspartate receptors (NMDARs) which are mechanistically thought to lead to increased synaptic insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Synaptic insertion of AMPARs by drugs of abuse can be long lasting, depending on the route of administration, number of drug exposures, or whether the drugs are received passively or self-administered. PMID:21161748

  15. Method for photo-altering a biological system to improve biological effect

    DOEpatents

    Hill, Richard A.; Doiron, Daniel R.; Crean, David H.

    2000-08-01

    Photodynamic therapy is a new adjunctive therapy for filtration surgery that does not use chemotherapy agents or radiation, but uses pharmacologically-active sensitizing compounds to produce a titratable, localized, transient, post operative avascular conjunctiva. A photosensitizing agent in a biological system is selectively activated by delivering the photosensitive agent to the biological system and laser activating only a spatially selected portion of the delivered photosensitive agent. The activated portion of the photosensitive agent reacts with the biological system to obtain a predetermined biological effect. As a result, an improved spatial disposition and effectuation of the biological effect by the photosensitive agent in the biological system is achieved.

  16. 75 FR 5094 - Privacy Act of 1974; Report of an Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-01

    ..., AND DISPOSING OF RECORDS IN THE SYSTEM: Storage: Records are maintained in database servers, file... sensitive data is encrypted using Oracle Transparent Data Encryption functionality. Access to records...

  17. 76 FR 4446 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... Tuberculosis Follow-up Program, HHS/CDC/NCHSTP.'' HHS is proposing to add the following Breach Response Routine...-20-0103, ``Alien Tuberculosis Follow-up Program, HHS/CDC/ NCHSTP.'' To provide a record system for the surveillance and periodic medical evaluation of immigrant aliens with tuberculosis. This System...

  18. Inorganic fertilizer and poultry-litter manure amendments alter the soil microbial communities in agricultural systems

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effects of agricultural land management practices on soil prokaryotic diversity are not well described. We investigated three land usage systems (row cropped, ungrazed pasture, and cattle-grazed pasture) and two fertilizer systems (inorganic fertilizer or IF and poultry-litter or PL) and compare...

  19. 76 FR 4452 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... computer to control unauthorized access to the system. Attempts to gain access by unauthorized individuals... security package is implemented on CDC's mainframe computer to control unauthorized access to the system... HUMAN SERVICES Centers for Disease Control and Prevention Privacy Act of 1974; Report of Modified...

  20. Improved metabolic health alters host metabolism in parallel with changes in systemic xeno-metabolites of gut origin.

    PubMed

    Campbell, Caitlin; Grapov, Dmitry; Fiehn, Oliver; Chandler, Carol J; Burnett, Dustin J; Souza, Elaine C; Casazza, Gretchen A; Gustafson, Mary B; Keim, Nancy L; Newman, John W; Hunter, Gary R; Fernandez, Jose R; Garvey, W Timothy; Harper, Mary-Ellen; Hoppel, Charles L; Meissen, John K; Take, Kohei; Adams, Sean H

    2014-01-01

    Novel plasma metabolite patterns reflective of improved metabolic health (insulin sensitivity, fitness, reduced body weight) were identified before and after a 14-17 wk weight loss and exercise intervention in sedentary, obese insulin-resistant women. To control for potential confounding effects of diet- or microbiome-derived molecules on the systemic metabolome, sampling was during a tightly-controlled feeding test week paradigm. Pairwise and multivariate analysis revealed intervention- and insulin-sensitivity associated: (1) Changes in plasma xeno-metabolites ("non-self" metabolites of dietary or gut microbial origin) following an oral glucose tolerance test (e.g. higher post-OGTT propane-1,2,3-tricarboxylate [tricarballylic acid]) or in the overnight-fasted state (e.g., lower γ-tocopherol); (2) Increased indices of saturated very long chain fatty acid elongation capacity; (3) Increased post-OGTT α-ketoglutaric acid (α-KG), fasting α-KG inversely correlated with Matsuda index, and altered patterns of malate, pyruvate and glutamine hypothesized to stem from improved mitochondrial efficiency and more robust oxidation of glucose. The results support a working model in which improved metabolic health modifies host metabolism in parallel with altering systemic exposure to xeno-metabolites. This highlights that interpretations regarding the origins of peripheral blood or urinary "signatures" of insulin resistance and metabolic health must consider the potentially important contribution of gut-derived metabolites toward the host's metabolome. PMID:24416208

  1. Impaired sense of smell and altered olfactory system in RAG-1−∕− immunodeficient mice

    PubMed Central

    Rattazzi, Lorenza; Cariboni, Anna; Poojara, Ridhika; Shoenfeld, Yehuda; D'Acquisto, Fulvio

    2015-01-01

    Immune deficiencies are often associated with a number of physical manifestations including loss of sense of smell and an increased level of anxiety. We have previously shown that T and B cell-deficient recombinase activating gene (RAG-1)−∕− knockout mice have an increased level of anxiety-like behavior and altered gene expression involved in olfaction. In this study, we expanded these findings by testing the structure and functional development of the olfactory system in RAG-1−∕− mice. Our results show that these mice have a reduced engagement in different types of odors and this phenotype is associated with disorganized architecture of glomerular tissue and atrophy of the main olfactory epithelium. Most intriguingly this defect manifests specifically in adult age and is not due to impairment in the patterning of the olfactory neuron staining at the embryo stage. Together these findings provide a formerly unreported biological evidence for an altered function of the olfactory system in RAG-1−∕− mice. PMID:26441494

  2. Altered TNF-Alpha, Glucose, Insulin and Amino Acids in Islets Langerhans Cultured in a Microgravity Model System

    NASA Technical Reports Server (NTRS)

    Tobin, Brian W.; Leeper-Woodford, Sandra K.; Hashemi, Brian B.; Smith, Scott M.; Sams, Clarence F.

    2001-01-01

    The present studies were designed to determine effects of a microgravity model system upon lipopolysaccharide (LPS) stimulated tumor necrosis factor alpha (TNF-alpha) activity and indices of insulin and fuel homeostasis of pancreatic islets of Langerhans. Islets (1726+/-1 17,150 u IEU) from Wistar Furth rats were treated as: 1) HARV (High Aspect Ratio Vessel cell culture) , 2) HARV plus LPS, 3) static culture, 4) static culture plus LPS. TNF-alpha (L929 cytotoxicity assay) was significantly increased in LPS-induced HARV and static cultures, yet the increase was more pronounced in the static culture group (p<0.05). A decrease in insulin concentration was demonstrated in the LPS stimulated HARV culture (p<0.05). We observed a greater glucose concentration and increased disappearance of arginine in islets cultured in HARVs. While nitrogenous compound analysis indicated a ubiquitous reliance upon glutamine in all experimental groups, arginine was converted to ornithine at a two-fold greater rate in the islets cultured in the HARV microgravity model system (p<0.05). These studies demonstrate alterations in LPS induced TNF-alpha production of pancreatic islets of Langerhans, favoring a lesser TNF activity in the HARV. These alterations in fuel homeostasis may be promulgated by gravity averaged cell culture methods or by three dimensional cell assembly.

  3. Improved Metabolic Health Alters Host Metabolism in Parallel with Changes in Systemic Xeno-Metabolites of Gut Origin

    PubMed Central

    Fiehn, Oliver; Chandler, Carol J.; Burnett, Dustin J.; Souza, Elaine C.; Casazza, Gretchen A.; Gustafson, Mary B.; Keim, Nancy L.; Newman, John W.; Hunter, Gary R.; Fernandez, Jose R.; Garvey, W. Timothy; Harper, Mary-Ellen; Hoppel, Charles L.; Meissen, John K.; Take, Kohei; Adams, Sean H.

    2014-01-01

    Novel plasma metabolite patterns reflective of improved metabolic health (insulin sensitivity, fitness, reduced body weight) were identified before and after a 14–17 wk weight loss and exercise intervention in sedentary, obese insulin-resistant women. To control for potential confounding effects of diet- or microbiome-derived molecules on the systemic metabolome, sampling was during a tightly-controlled feeding test week paradigm. Pairwise and multivariate analysis revealed intervention- and insulin-sensitivity associated: (1) Changes in plasma xeno-metabolites (“non-self” metabolites of dietary or gut microbial origin) following an oral glucose tolerance test (e.g. higher post-OGTT propane-1,2,3-tricarboxylate [tricarballylic acid]) or in the overnight-fasted state (e.g., lower γ-tocopherol); (2) Increased indices of saturated very long chain fatty acid elongation capacity; (3) Increased post-OGTT α-ketoglutaric acid (α-KG), fasting α-KG inversely correlated with Matsuda index, and altered patterns of malate, pyruvate and glutamine hypothesized to stem from improved mitochondrial efficiency and more robust oxidation of glucose. The results support a working model in which improved metabolic health modifies host metabolism in parallel with altering systemic exposure to xeno-metabolites. This highlights that interpretations regarding the origins of peripheral blood or urinary “signatures” of insulin resistance and metabolic health must consider the potentially important contribution of gut-derived metabolites toward the host's metabolome. PMID:24416208

  4. Synthesis of Charge Transfer Dyes for Use as Molecular Sensors in Biological Systems

    NASA Technical Reports Server (NTRS)

    Christie, Joseph J.

    2003-01-01

    This is a continuation of last year's project to synthesize tetraaryl substituted benzodifurans for use as molecular probes in biological systems. The project will involve the synthesis and chemical characterization of dyes and precursor molecules.

  5. Mixed 2D molecular systems: Mechanic, thermodynamic and dielectric properties

    NASA Astrophysics Data System (ADS)

    Beňo, Juraj; Weis, Martin; Dobročka, Edmund; Haško, Daniel

    2008-08-01

    Study of Langmuir monolayers consisting of stearic acid (SA) and dipalmitoylphosphatidylcholine (DPPC) molecules was done by surface pressure-area isotherms ( π- A), the Maxwell displacement current (MDC) measurement, X-ray reflectivity (XRR) and atomic force microscopy (AFM) to investigate the selected mechanic, thermodynamic and dielectric properties based on orientational structure of monolayers. On the base of π- A isotherms analysis we explain the creation of stable structures and found optimal monolayer composition. The dielectric properties represented by MDC generated monolayers were analyzed in terms of excess dipole moment, proposing the effect of dipole-dipole interaction. XRR and AFM results illustrate deposited film structure and molecular ordering.

  6. Alterations of hydraulic soil properties influenced by land-use changes and agricultural management systems

    NASA Astrophysics Data System (ADS)

    Weninger, Thomas; Kreiselmeier, Janis; Chandrasekhar, Parvathy; Jülich, Stefan; Schwärzel, Kai; Schwen, Andreas

    2016-04-01

    Estimation and modeling of soil water movement and the hydrologic balance of soils requires sound knowledge about hydraulic soil properties (HSP). The soil water characteristics, the hydraulic conductivity function and the pore size distribution (PSD) are commonly used instruments for the mathematical representation of HSP. Recent research highlighted the temporal variability of these functions caused by meteorological or land-use influences. State of the art modeling software for the continuous simulation of soil water movement uses a stationary approach for the HSP which means that their time dependent alterations and the subsequent effects on soil water balance is not considered. Mathematical approaches to describe the evolution of PSD are nevertheless known, but there is a lack of sound data basis for parameter estimation. Based on extensive field and laboratory measurements at 5 locations along a climatic gradient across Austria and Germany, this study will quantify short-term changes in HSP, detect driving forces and introduce a method to predict the effects of soil and land management actions on the soil water balance. Amongst several soil properties, field-saturated and unsaturated hydraulic conductivities will be determined using a hood infiltration experiments in the field as well as by evaporation and dewpoint potentiometer method in the lab. All measurements will be carried out multiple times over a span of 2 years which will allow a detailed monitoring of changes in HSP. Experimental sites where we expect significant inter-seasonal changes will be equipped with sensors for soil moisture and matric potential. The choice of experimental field sites follows the intention to involve especially the effects of tillage operations, different cultivation strategies, microclimatically effective structures and land-use changes. The international project enables the coverage of a broad range of soil types as well as climate conditions and hence will have broad

  7. Stress response and humoral immune system alterations related to chronic hypergravity in mice.

    PubMed

    Guéguinou, Nathan; Bojados, Mickaël; Jamon, Marc; Derradji, Hanane; Baatout, Sarah; Tschirhart, Eric; Frippiat, Jean-Pol; Legrand-Frossi, Christine

    2012-01-01

    Spaceflights are known to induce stress and immune dysregulation. Centrifugation, as hindlimb unloading, is a good ground based-model to simulate altered gravity which occurs during space missions. The aim of this study was to investigate the consequences of a long-term exposure to different levels of hypergravity on the stress response and the humoral immunity in a mouse model. For this purpose, adult C57Bl/6J male mice were subjected for 21 days either to control conditions or to 2G or 3G acceleration gravity forces. Corticosterone level and anxiety behavior revealed a stress response which was associated with a decrease of body weight, after 21-day of centrifugation at 3G but not at 2G. Spleen lymphocyte lipopolysaccharide (LPS) responsiveness was diminished by 40% in the 2G group only, whereas a decrease was noted when cells were stimulated with concanavalin A for both 2G and 3G groups (about 25% and 20%, respectively) compared to controls. Pro-inflammatory chemokines (MCP-1 and IP-10) and Th1 cytokines (IFNγ and IL2) were slightly decreased in the 2G group and strongly decreased in the 3G mouse group. Regarding Th2 cytokines (IL4, IL5) no further significant modification was observed, whereas the immunosuppressive cytokine IL10 was slightly increased in the 3G mice. Finally, serum IgG concentration was twice higher whereas IgA concentration was slightly increased (about 30%) and IgM were unchanged in 2G mice compared to controls. No difference was observed in the 3G group with these isotypes. Consequently, functional immune dysregulations and stress responses were dependent of the gravity level. PMID:21724335

  8. Light-powered autonomous and directional molecular motion of a dissipative self-assembling system.

    PubMed

    Ragazzon, Giulio; Baroncini, Massimo; Silvi, Serena; Venturi, Margherita; Credi, Alberto

    2015-01-01

    Biomolecular motors convert energy into directed motion and operate away from thermal equilibrium. The development of dynamic chemical systems that exploit dissipative (non-equilibrium) processes is a challenge in supramolecular chemistry and a premise for the realization of artificial nanoscale motors. Here, we report the relative unidirectional transit of a non-symmetric molecular axle through a macrocycle powered solely by light. The molecular machine rectifies Brownian fluctuations by energy and information ratchet mechanisms and can repeat its working cycle under photostationary conditions. The system epitomizes the conceptual and practical elements forming the basis of autonomous light-powered directed motion with a minimalist molecular design. PMID:25420035

  9. GW100: Benchmarking G0W0 for Molecular Systems.

    PubMed

    van Setten, Michiel J; Caruso, Fabio; Sharifzadeh, Sahar; Ren, Xinguo; Scheffler, Matthias; Liu, Fang; Lischner, Johannes; Lin, Lin; Deslippe, Jack R; Louie, Steven G; Yang, Chao; Weigend, Florian; Neaton, Jeffrey B; Evers, Ferdinand; Rinke, Patrick

    2015-12-01

    We present the GW100 set. GW100 is a benchmark set of the ionization potentials and electron affinities of 100 molecules computed with the GW method using three independent GW codes and different GW methodologies. The quasi-particle energies of the highest-occupied molecular orbitals (HOMO) and lowest-unoccupied molecular orbitals (LUMO) are calculated for the GW100 set at the G0W0@PBE level using the software packages TURBOMOLE, FHI-aims, and BerkeleyGW. The use of these three codes allows for a quantitative comparison of the type of basis set (plane wave or local orbital) and handling of unoccupied states, the treatment of core and valence electrons (all electron or pseudopotentials), the treatment of the frequency dependence of the self-energy (full frequency or more approximate plasmon-pole models), and the algorithm for solving the quasi-particle equation. Primary results include reference values for future benchmarks, best practices for convergence within a particular approach, and average error bars for the most common approximations. PMID:26642984

  10. Systemic and Vascular Alterations in Healthy and Cardiovascular Compromised Rats Exposed to Libby Amphibole

    EPA Science Inventory

    Rationale: Acute pulmonary injury and chronic disease can impact systemic vasculature because the lung capillary network can release inflammogenic and vasoactive mediators into the circulation. Occupational exposure to Libby amphibole (LA) type asbestos is associated with increas...

  11. Relationship between dopamine deficit and the expression of depressive behavior resulted from alteration of serotonin system.

    PubMed

    Lee, Minkyung; Ryu, Young Hoon; Cho, Won Gil; Kang, Yeo Wool; Lee, Soo Jin; Jeon, Tae Joo; Lyoo, Chul Hyoung; Kim, Chul Hoon; Kim, Dong Goo; Lee, Kyochul; Choi, Tae Hyun; Choi, Jae Yong

    2015-09-01

    Depression frequently accompanies in Parkinson's disease (PD). Previous research suggested that dopamine (DA) and serotonin systems are closely linked with depression in PD. However, comprehensive studies about the relationship between these two neurotransmitter systems are limited. Therefore, the purpose of this study is to evaluate the effect of dopaminergic destruction on the serotonin system. The interconnection between motor and depression was also examined. Two PET scans were performed in the 6-hydroxydopamine (6-OHDA) lesioned and sham operated rats: [(18) F]FP-CIT for DA transporters and [(18) F]Mefway for serotonin 1A (5-HT(1A)) receptors. Here, 6-OHDA is a neurotoxin for dopaminergic neurons. Behavioral tests were used to evaluate the severity of symptoms: rotational number for motor impairment and immobility time, acquired from the forced swim test for depression. Region-of-interests were drawn in the striatum and cerebellum for the DA system and hippocampus and cerebellum for the 5-HT system. The cerebellum was chosen as a reference region. Nondisplaceable binding potential in the striatum and hippocampus were compared between 6-OHDA and sham groups. As a result, the degree of DA depletion was negatively correlated with rotational behavior (R(2)  = 0.79, P = 0.003). In 6-OHDA lesioned rats, binding values for 5-HT(1A) receptors was 22% lower than the sham operated group. This decrement of 5-HT(1A) receptor binding was also correlated with the severity of depression (R(2)  = 0.81, P = 0.006). Taken together, this research demonstrated that the destruction of dopaminergic system causes the reduction of the serotonergic system resulting in the expression of depressive behavior. The degree of dopaminergic dysfunction was positively correlated with the impairment of the serotonin system. Severity of motor symptoms was also closely related to depressive behavior. PMID:26089169

  12. Ascending monoaminergic systems alterations in Alzheimer's disease. translating basic science into clinical care.

    PubMed

    Trillo, Ludwig; Das, Devsmita; Hsieh, Wayne; Medina, Brian; Moghadam, Sarah; Lin, Bill; Dang, Van; Sanchez, Martha Millan; De Miguel, Zurine; Ashford, J Wesson; Salehi, Ahmad

    2013-09-01

    Extensive neuropathological studies have established a compelling link between abnormalities in structure and function of subcortical monoaminergic (MA-ergic) systems and the pathophysiology of Alzheimer's disease (AD). The main cell populations of these systems including the locus coeruleus, the raphe nuclei, and the tuberomamillary nucleus undergo significant degeneration in AD, thereby depriving the hippocampal and cortical neurons from their critical modulatory influence. These studies have been complemented by genome wide association studies linking polymorphisms in key genes involved in the MA-ergic systems and particular behavioral abnormalities in AD. Importantly, several recent studies have shown that improvement of the MA-ergic systems can both restore cognitive function and reduce AD-related pathology in animal models of neurodegeneration. This review aims to explore the link between abnormalities in the MA-ergic systems and AD symptomatology as well as the therapeutic strategies targeting these systems. Furthermore, we will examine possible mechanisms behind basic vulnerability of MA-ergic neurons in AD. PMID:23707776

  13. Density functional theory based study of molecular interactions, recognition, engineering, and quantum transport in π molecular systems.

    PubMed

    Cho, Yeonchoo; Cho, Woo Jong; Youn, Il Seung; Lee, Geunsik; Singh, N Jiten; Kim, Kwang S

    2014-11-18

    CONSPECTUS: In chemical and biological systems, various interactions that govern the chemical and physical properties of molecules, assembling phenomena, and electronic transport properties compete and control the microscopic structure of materials. The well-controlled manipulation of each component can allow researchers to design receptors or sensors, new molecular architectures, structures with novel morphology, and functional molecules or devices. In this Account, we describe the structures and electronic and spintronic properties of π-molecular systems that are important for controlling the architecture of a variety of carbon-based systems. Although DFT is an important tool for describing molecular interactions, the inability of DFT to accurately represent dispersion interactions has made it difficult to properly describe π-interactions. However, the recently developed dispersion corrections for DFT have allowed us to include these dispersion interactions cost-effectively. We have investigated noncovalent interactions of various π-systems including aromatic-π, aliphatic-π, and non-π systems based on dispersion-corrected DFT (DFT-D). In addition, we have addressed the validity of DFT-D compared with the complete basis set (CBS) limit values of coupled cluster theory with single, double, and perturbative triple excitations [CCSD(T)] and Møller-Plesset second order perturbation theory (MP2). The DFT-D methods are still unable to predict the correct ordering in binding energies within the benzene dimer and the cyclohexane dimer. Nevertheless, the overall DFT-D predicted binding energies are in reasonable agreement with the CCSD(T) results. In most cases, results using the B97-D3 method closely reproduce the CCSD(T) results with the optimized energy-fitting parameters. On the other hand, vdW-DF2 and PBE0-TS methods estimate the dispersion energies from the calculated electron density. In these approximations, the interaction energies around the equilibrium

  14. Molecular solid-state inverter-converter system

    NASA Technical Reports Server (NTRS)

    Birchenough, A. G.

    1973-01-01

    A modular approach for aerospace electrical systems has been developed, using lightweight high efficiency pulse width modulation techniques. With the modular approach, a required system is obtained by paralleling modules. The modular system includes the inverters and converters, a paralleling system, and an automatic control and fault-sensing protection system with a visual annunciator. The output is 150 V dc, or a low distortion three phase sine wave at 120 V, 400 Hz. Input power is unregulated 56 V dc. Each module is rated 2.5 kW or 3.6 kVA at 0.7 power factor.

  15. Classical molecular simulations of complex industrially-important systems on the Intel Paragon

    SciTech Connect

    Cochran, H.D.; LoCascio, P.F.; Cummings, P.T.

    1996-06-01

    Advances in parallel supercomputing now make possible molecular-based engineering and science calculations that will soon revolutionize many technologies, such as those involving polymers and those involving aqueous electrolytes. We have developed a suite of message-passing codes for classical molecular simulation of such complex fluids and amorphous materials and have completed a number of demonstration calculations of problems of scientific and technological importance with each. In this overview paper we will outline the techniques for classical molecular simulation of these industrially-important systems on the Inter Paragon and we will summarize some of the important scientific and technical results of the varied applications, including the following: (1) Parallel codes for quatemion dynamics using techniques for handling long-range Coulombic forces allow study of ion pairing in supercritical aqueous electrolyte solutions. Ion pairing lies at the heart of technological problems with corrosion and solids deposition in industrial processes utilizing high temperature water. (2) Non-equilibrium, multiple time step molecular dynamics lets us investigate the rheology of molecular fluids. Such calculations enable the molecular-based design of new synthetic lubricants of importance in the automotive engines of the future. (3) Chain molecule Monte Carlo simulations in the Gibbs ensemble now permit calculation of phase equilibrium of long-chain molecular systems. With complementary equilibrium molecular dynamics (with multiple time steps) we have been able to gain fundamental insight into the technologically-important problem of liquid-liquid phase separation in polymer blends.

  16. Molecular ion battery: a rechargeable system without using any elemental ions as a charge carrier

    PubMed Central

    Yao, Masaru; Sano, Hikaru; Ando, Hisanori; Kiyobayashi, Tetsu

    2015-01-01

    Is it possible to exceed the lithium redox potential in electrochemical systems? It seems impossible to exceed the lithium potential because the redox potential of the elemental lithium is the lowest among all the elements, which contributes to the high voltage characteristics of the widely used lithium ion battery. However, it should be possible when we use a molecule-based ion which is not reduced even at the lithium potential in principle. Here we propose a new model system using a molecular electrolyte salt with polymer-based active materials in order to verify whether a molecular ion species serves as a charge carrier. Although the potential of the negative-electrode is not yet lower than that of lithium at present, this study reveals that a molecular ion can work as a charge carrier in a battery and the system is certainly a molecular ion-based “rocking chair” type battery. PMID:26043147

  17. Molecular ion battery: a rechargeable system without using any elemental ions as a charge carrier

    NASA Astrophysics Data System (ADS)

    Yao, Masaru; Sano, Hikaru; Ando, Hisanori; Kiyobayashi, Tetsu

    2015-06-01

    Is it possible to exceed the lithium redox potential in electrochemical systems? It seems impossible to exceed the lithium potential because the redox potential of the elemental lithium is the lowest among all the elements, which contributes to the high voltage characteristics of the widely used lithium ion battery. However, it should be possible when we use a molecule-based ion which is not reduced even at the lithium potential in principle. Here we propose a new model system using a molecular electrolyte salt with polymer-based active materials in order to verify whether a molecular ion species serves as a charge carrier. Although the potential of the negative-electrode is not yet lower than that of lithium at present, this study reveals that a molecular ion can work as a charge carrier in a battery and the system is certainly a molecular ion-based “rocking chair” type battery.

  18. Maternal obesity alters the apelinergic system at the feto-maternal interface.

    PubMed

    Hanssens, Sandy; Marx-Deseure, Aurore; Lecoutre, Simon; Butruille, Laura; Fournel, Audren; Knauf, Claude; Besengez, Capucine; Breton, Christophe; Storme, Laurent; Deruelle, Philippe; Lesage, Jean

    2016-03-01

    Apelin and its receptor APJ have been implicated in pathologies including cardiovascular disease, diabetes and obesity. Little is known about the function of the apelinergic system during gestation. We evaluated in mice this system at the feto-maternal interface in insulin-resistant obese female (HF) mice. Maternal apelinemia was decreased at term and fetal apelinemia was sixfold higher than maternal level. Ex-vivo, the placenta releases apelin at E12.5 and E18.5. In HF pregnant mice at term, apelinemia as well as placental apelin and APJ mRNA levels were increased whereas placental release of apelin was drastically reduced compared to controls. PMID:26992673

  19. System among the corticosteroids: specificity and molecular dynamics

    PubMed Central

    Brookes, Jennifer C.; Galigniana, Mario D.; Harker, Anthony H.; Stoneham, A. Marshall; Vinson, Gavin P.

    2012-01-01

    Understanding how structural features determine specific biological activities has often proved elusive. With over 161 000 steroid structures described, an algorithm able to predict activity from structural attributes would provide manifest benefits. Molecular simulations of a range of 35 corticosteroids show striking correlations between conformational mobility and biological specificity. Thus steroid ring A is important for glucocorticoid action, and is rigid in the most specific (and potent) examples, such as dexamethasone. By contrast, ring C conformation is important for the mineralocorticoids, and is rigid in aldosterone. Other steroids that are less specific, or have mixed functions, or none at all, are more flexible. One unexpected example is 11-deoxycorticosterone, which the methods predict (and our activity studies confirm) is not only a specific mineralocorticoid, but also has significant glucocorticoid activity. These methods may guide the design of new corticosteroid agonists and antagonists. They will also have application in other examples of ligand–receptor interactions. PMID:21613285

  20. Two Molecular Information Processing Systems Based on Catalytic Nucleic Acids

    NASA Astrophysics Data System (ADS)

    Stojanovic, Milan

    Mixtures of molecules are capable of powerful information processing [1]. This statement is in the following way self-evident: it is a hierarchically organized complex mixture of molecules that is formulating it to other similarly organized mixtures of molecules. By making such a statement I am not endorsing the extreme forms of reductionism; rather, I am making what I think is a small first step towards harnessing information processing prowess of molecules and, hopefully, overcoming some limitations of more traditional computing paradigms. There are different ideas on how to understand and use molecular information processing abilities and I will list some below. My list is far from inclusive, and delineations are far from clear-cut; whenever available, I will provide examples from our research efforts. I should stress, for a computer science audience that I am a chemist. Thus, my approach may have much different focus and mathematical rigor, then if it would be taken by a computer scientist.

  1. Including Quantum Effects in the Dynamics of Complex (i.e., Large)Molecular Systems

    SciTech Connect

    Miller, William H.

    2006-04-27

    The development in the 1950's and 60's of crossed molecular beam methods for studying chemical reactions at the single-collision molecular level stimulated the need and desire for theoretical methods to describe these and other dynamical processes in molecular systems. Chemical dynamics theory has made great strides in the ensuing decades, so that methods are now available for treating the quantum dynamics of small molecular systems essentially completely. For the large molecular systems that are of so much interest nowadays (e.g. chemical reactions in solution, in clusters, in nano-structures, in biological systems, etc.), however, the only generally available theoretical approach is classical molecular dynamics (MD) simulations. Much effort is currently being devoted to the development of approaches for describing the quantum dynamics of these complex systems. This paper reviews some of these approaches, especially the use of semiclassical approximations for adding quantum effects to classical MD simulations, also showing some new versions that should make these semiclassical approaches even more practical and accurate.

  2. 75 FR 34755 - Privacy Act; Proposed Alteration to Existing Systems of Records, Single Family Mortgage Asset...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-18

    ..., this notice supersedes previous notice published at 73 FR 41105 on July 17, 2008. DATES: Effective Date... Responsibilities for Maintaining Records About Individuals,'' July 25, 1994; 59 FR 37914. Authority: 5 U.S.C. 552a... Citrix Server). CATEGORIES OF INDIVIDUALS COVERED BY THE SYSTEM: Mortgagors (Secretary-Held First,...

  3. Windblown soil surface characteristics altered by oilseeds in a wheat-fallow cropping system

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Oilseeds are integral to the production of biofuels and diversifying rainfed cropping systems in the Pacific Northwest United States (PNW). However, there is evidence to suggest greater potential for wind erosion when growing oilseeds in wheat rotations. Little is known concerning the impact of grow...

  4. 76 FR 77575 - Privacy Act of 1974; Report of an Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-13

    ....C. 552a), PC-21-- Peace Corps Response Database. The first revision modifies the individuals covered... to PC-21. DATES: This proposed action will be effective without further notice January 27, 2012... know. System name: PC-21--Peace Corps Response Database. Changes: * * * * * Category of...

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    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-30

    ... 1974, (5 U.S.C. 552a), PC-17--Volunteer Applicant and Service Records System, and PC-18-- Former Peace Corps Volunteers Database. The first revision adds a specific routine use to both PC-17 and PC-18. This... adds another specific routine use to both PC-17 and PC- 18 indicating that the Peace Corps may...

  6. 76 FR 4476 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... knowledge to the health community for the implementation of such programs. ] This System of Record Notice is... to communicate new knowledge to the health community for the implementation of such programs. II... that the knowing and willful request for or acquisition of a record pertaining to an individual...

  7. Phosphate availability alters architecture and causes changes in hormone sensitivity in the Arabidopsis root system.

    PubMed

    López-Bucio, José; Hernández-Abreu, Esmeralda; Sánchez-Calderón, Lenin; Nieto-Jacobo, María Fernanda; Simpson, June; Herrera-Estrella, Luis

    2002-05-01

    The postembryonic developmental program of the plant root system is plastic and allows changes in root architecture to adapt to environmental conditions such as water and nutrient availability. Among essential nutrients, phosphorus (P) often limits plant productivity because of its low mobility in soil. Therefore, the architecture of the root system may determine the capacity of the plant to acquire this nutrient. We studied the effect of P availability on the development of the root system in Arabidopsis. We found that at P-limiting conditions (<50 microM), the Arabidopsis root system undergoes major architectural changes in terms of lateral root number, lateral root density, and primary root length. Treatment with auxins and auxin antagonists indicate that these changes are related to an increase in auxin sensitivity in the roots of P-deprived Arabidopsis seedlings. It was also found that the axr1-3, axr2-1, and axr4-1 Arabidopsis mutants have normal responses to low P availability conditions, whereas the iaa28-1 mutant shows resistance to the stimulatory effects of low P on root hair and lateral root formation. Analysis of ethylene signaling mutants and treatments with 1-aminocyclopropane-1-carboxylic acid showed that ethylene does not promote lateral root formation under P deprivation. These results suggest that in Arabidopsis, auxin sensitivity may play a fundamental role in the modifications of root architecture by P availability. PMID:12011355

  8. Cover crops alter phosphorus soil fractions and organic matter accumulation in a Peruvian cacao agroforestry system

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In many tropical soils, excessive weathering of primary minerals confounded by intense agricultural production has resulted in the depletion of organic matter and plant available forms of phosphorus (P). Long-term growth of cover crops in tropical agroforestry systems have been shown to influence nu...

  9. 77 FR 4004 - Privacy Act of 1974; Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-26

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF COMMERCE RIN... Commerce. ACTION: Notice of Amendment, Privacy Act System of Records; COMMERCE/ CENSUS-4, Minority-Owned... 5 United States Code (U.S.C.) 552a(e)(4) and (11); and Office of Management and Budget...

  10. 77 FR 4000 - Privacy Act of 1974; Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-26

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  11. 76 FR 4483 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

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    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... control unauthorized access to the system. Attempts to gain access by unauthorized individuals are... limited access rights to files and directories at varying levels to control file sharing. There are... HUMAN SERVICES Centers for Disease Control and Prevention Privacy Act of 1974; Report of Modified...

  13. 76 FR 4458 - Privacy Act of 1974; Report of Modified or Altered System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... security package is implemented on CDC's mainframe computer to control unauthorized access to the system... user name is assigned limited access rights to files and directories at varying levels to control file... HUMAN SERVICES Centers for Disease Control and Prevention Privacy Act of 1974; Report of Modified...

  14. Cocaine Self-Administration Alters the Relative Effectiveness of Multiple Memory Systems during Extinction

    ERIC Educational Resources Information Center

    Gabriele, Amanda; Setlow, Barry; Packard, Mark G.

    2009-01-01

    Rats were trained to run a straight-alley maze for an oral cocaine or sucrose vehicle solution reward, followed by either response or latent extinction training procedures that engage neuroanatomically dissociable "habit" and "cognitive" memory systems, respectively. In the response extinction condition, rats performed a runway approach response…

  15. Targeting the-Dopaminergic Nervous System: Altering Behavior in Larval Zebrafish

    EPA Science Inventory

    Zebrafish (Dania rerio) are becoming an important model system in studying the effects of environmental chemicals on behavior. In order to develop a rapid in vivo screen to prioritize toxic chemicals, we have begun assessing the acute locomotor effects of drugs that act on the do...

  16. Selective alterations in cerebral metabolism within the mesocorticolimbic dopaminergic system produced by acute cocaine administration in rats

    SciTech Connect

    Porrino, L.J.; Domer, F.R.; Crane, A.M.; Sokoloff, L.

    1988-05-01

    The 2-(/sup 14/C)deoxyglucose method was used to examine the effects of acute intravenous administration of cocaine on local cerebral glucose utilization in rats. These effects were correlated with the effects of cocaine on locomotor activity assessed simultaneously in the same animals. At the lowest dose of cocaine, 0.5 mg/kg (1.47 mumol/kg), alterations in glucose utilization were restricted to the medial prefrontal cortex and nucleus accumbens. Metabolic activity at 1.0 mg/kg (2.9 mumol/kg) was altered in these structures, but in the substantia nigra reticulata and lateral habenula as well. The selectivity of cocaine's effects at low doses demonstrates the particular sensitivity of these structures to cocaine's actions in the brain. In contrast, 5.0 mg/kg (14.7 mumol/kg) produced widespread changes in glucose utilization, particularly in the extrapyramidal system. Only this dose significantly increased locomotor activity above levels in vehicle-treated controls. Rates of glucose utilization were positively correlated with locomotor activity in the globus pallidus, substantia nigra reticulata, and subthalamic nucleus, and negatively correlated in the lateral habenula.

  17. Metazoan endoparasites diversity of Pseudoplatystoma corruscans (Siluriformes: Pimelodidae) as an indicator of environmental alterations on a tropical aquatic system.

    PubMed

    Ribeiro, Thamy S; Lizama, Maria A P; Takemoto, Ricardo M

    2014-09-01

    The aim of the present study was to detect the alterations of Pseudoplatystoma corruscans parasite infracommunity structure, after the construction of the Porto Primavera dam on the high Paraná River floodplain. The execution of this research was based on 119 host specimens collected between March 2011 and September 2012, and the results were compared to studies performed on periods before the reservoir's construction, when 110 fishes were collected between March 1992 and February 1993. Five parasite species still remain on the environment, despite the environmental modifications: Choanoscolex abscissus, Spasskyelina spinulifera, Nomimoscolex pertierrae, Harriscolex kaparari and Contracaecum sp 2. The Berger-Parker dominance index, calculated to the parasite fauna of 1992, did not show the dominance of any species, while, on the present days, this same index accused the dominance of Nomimoscolex pertierrae (49%) and Choanoscolex abscissus (50%). The present study reports the disappearance of Megathylacus travassosi, Contracaecum sp. 1, Contracaecum sp. 3, Procamallanus (Spirocamallanus) sp. and Cucullanus pseudoplatystomae, suggesting the possibility of a local extinction or a host switch of these species. It has also been registered an Acanthocephala specimen, a genus not observed on this host yet. The results here presented show that the antropic influences on natural systems alter the environmental conditions, what is reflected on the richness and diversity parasite levels. PMID:25119352

  18. Prenatal diazepam exposure alters respiratory control system and GABAA and adenosine receptor gene expression in newborn rats.

    PubMed

    Picard, Nathalie; Guénin, Stéphanie; Perrin, Yolande; Hilaire, Gérard; Larnicol, Nicole

    2008-07-01

    In experimental animals, prenatal diazepam exposure has clearly been associated with behavioral disturbances. Its impact on newborn breathing has not been documented despite potential deleterious consequences for later brain development. We addressed this issue in neonatal rats (0-2 d) born from dams, which consumed 2 mg/kg/d diazepam via drinking fluid throughout gestation. In vivo, prenatal diazepam exposure significantly altered the normoxic-breathing pattern, lowering breathing frequency (105 vs. 125 breaths/min) and increasing tidal volume (16.2 vs. 12.7 mL/kg), and the ventilatory response to hypoxia, inducing an immediate and marked decrease in tidal volume (-30%) absent in controls. In vitro, prenatal diazepam exposure significantly increased the respiratory-like frequency produced by pontomedullary and medullary preparations (+38% and +19%, respectively) and altered the respiratory-like response to application of nonoxygenated superfusate. Both in vivo and in vitro, the recovery from oxygen deprivation challenges was delayed by prenatal diazepam exposure. Finally, real-time PCR showed that prenatal diazepam exposure affected mRNA levels of alpha1 and alpha2 GABAA receptor subunits and of A1 and A2A adenosine receptors in the brainstem. These mRNA changes, which are region-specific, suggest that prenatal diazepam exposure interferes with developmental events whose impact on the respiratory system maturation deserves further studies. PMID:18360306

  19. Studies of Complex Biological Systems with Applications to Molecular Medicine: The Need to Integrate Transcriptomic and Proteomic Approaches

    PubMed Central

    Silvestri, Elena; Lombardi, Assunta; de Lange, Pieter; Glinni, Daniela; Senese, Rosalba; Cioffi, Federica; Lanni, Antonia; Goglia, Fernando; Moreno, Maria

    2011-01-01

    Omics approaches to the study of complex biological systems with potential applications to molecular medicine are attracting great interest in clinical as well as in basic biological research. Genomics, transcriptomics and proteomics are characterized by the lack of an a priori definition of scope, and this gives sufficient leeway for investigators (a) to discern all at once a globally altered pattern of gene/protein expression and (b) to examine the complex interactions that regulate entire biological processes. Two popular platforms in “omics” are DNA microarrays, which measure messenger RNA transcript levels, and proteomic analyses, which identify and quantify proteins. Because of their intrinsic strengths and weaknesses, no single approach can fully unravel the complexities of fundamental biological events. However, an appropriate combination of different tools could lead to integrative analyses that would furnish new insights not accessible through one-dimensional datasets. In this review, we will outline some of the challenges associated with integrative analyses relating to the changes in metabolic pathways that occur in complex pathophysiological conditions (viz. ageing and altered thyroid state) in relevant metabolically active tissues. In addition, we discuss several new applications of proteomic analysis to the investigation of mitochondrial activity. PMID:20981256

  20. It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease

    PubMed Central

    Tramutola, Antonella; Di Domenico, Fabio; Barone, Eugenio; Perluigi, Marzia; Butterfield, D. Allan

    2016-01-01

    Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of “aberrant” proteins results from both the increased occurrence of damage and the decreased efficiency of degradative systems. One of the most important cellular proteolytic systems responsible for the removal of oxidized proteins in the cytosol and in the nucleus is the proteasomal system. Several studies have demonstrated the impairment of the proteasome in AD thus suggesting a direct link between accumulation of oxidized/misfolded proteins and reduction of this clearance system. In this review we discuss the impairment of the proteasome system as a consequence of oxidative stress and how this contributes to AD neuropathology. Further, we focus the attention on the oxidative modifications of a key component of the ubiquitin-proteasome pathway, UCHL1, which lead to the impairment of its activity. PMID:26881020

  1. The quantified NTO analysis for the electronic excitations of molecular many-body systems

    NASA Astrophysics Data System (ADS)

    Li, Jian-Hao; Chai, Jeng-Da; Guo, Guang-Yu; Hayashi, Michitoshi

    2011-10-01

    We show that the origin of electronic transitions of molecular many-body systems can be investigated by a quantified natural transition orbitals (QNTO) analysis and the electronic excitations of the total system can be mapped onto a standard orbitals set of a reference system. We further illustrate QNTO on molecular systems by studying the origin of electronic transitions of DNA moiety, thymine and thymidine. This QNTO analysis also allows us to assess the performance of various functionals used in time-dependent density functional response theory.

  2. Molecular cooperativity in the dynamics of glass-forming systems: A new insight

    NASA Astrophysics Data System (ADS)

    Hong, L.; Gujrati, P. D.; Novikov, V. N.; Sokolov, A. P.

    2009-11-01

    The mechanism behind the steep slowing down of molecular motions upon approaching the glass transition remains a great puzzle. Most of the theories relate this mechanism to the cooperativity in molecular motion. In this work, we estimate the length scale of molecular cooperativity ξ for many glass-forming systems from the collective vibrations (the so-called boson peak). The obtained values agree well with the dynamic heterogeneity length scale estimated using four-dimensional NMR. We demonstrate that ξ directly correlates to the dependence of the structural relaxation on volume. This dependence presents only one part of the mechanism of slowing down the structural relaxation. Our analysis reveals that another part, the purely thermal variation in the structural relaxation (at constant volume), does not have a direct correlation with molecular cooperativity. These results call for a conceptually new approach to the analysis of the mechanism of the glass transition and to the role of molecular cooperativity.

  3. Climate change impacts in multispecies systems: drought alters food web size structure in a field experiment

    PubMed Central

    Woodward, Guy; Brown, Lee E.; Edwards, Francois K.; Hudson, Lawrence N.; Milner, Alexander M.; Reuman, Daniel C.; Ledger, Mark E.

    2012-01-01

    Experimental data from intergenerational field manipulations of entire food webs are scarce, yet such approaches are essential for gauging impacts of environmental change in natural systems. We imposed 2 years of intermittent drought on stream channels in a replicated field trial, to measure food web responses to simulated climate change. Drought triggered widespread losses of species and links, with larger taxa and those that were rare for their size, many of which were predatory, being especially vulnerable. Many network properties, including size–scaling relationships within food chains, changed in response to drought. Other properties, such as connectance, were unaffected. These findings highlight the need for detailed experimental data from different organizational levels, from pairwise links to the entire food web. The loss of not only large species, but also those that were rare for their size, provides a newly refined way to gauge likely impacts that may be applied more generally to other systems and/or impacts. PMID:23007087

  4. Climate change impacts in multispecies systems: drought alters food web size structure in a field experiment.

    PubMed

    Woodward, Guy; Brown, Lee E; Edwards, Francois K; Hudson, Lawrence N; Milner, Alexander M; Reuman, Daniel C; Ledger, Mark E

    2012-11-01

    Experimental data from intergenerational field manipulations of entire food webs are scarce, yet such approaches are essential for gauging impacts of environmental change in natural systems. We imposed 2 years of intermittent drought on stream channels in a replicated field trial, to measure food web responses to simulated climate change. Drought triggered widespread losses of species and links, with larger taxa and those that were rare for their size, many of which were predatory, being especially vulnerable. Many network properties, including size-scaling relationships within food chains, changed in response to drought. Other properties, such as connectance, were unaffected. These findings highlight the need for detailed experimental data from different organizational levels, from pairwise links to the entire food web. The loss of not only large species, but also those that were rare for their size, provides a newly refined way to gauge likely impacts that may be applied more generally to other systems and/or impacts. PMID:23007087

  5. Exploring the envelope. Systematic alteration in the sex-determination system of the nematode caenorhabditis elegans.

    PubMed Central

    Hodgkin, Jonathan

    2002-01-01

    The natural sexes of the nematode Caenorhabditis elegans are the self-fertilizing hermaphrodite (XX) and the male (XO). The underlying genetic pathway controlling sexual phenotype has been extensively investigated. Mutations in key regulatory genes have been used to create a series of stable populations in which sex is determined not by X chromosome dosage, but in a variety of other ways, many of which mimic the diverse sex-determination systems found in different animal species. Most of these artificial strains have male and female sexes. Each of seven autosomal genes can be made to adopt a role as the primary determinant of sex, and each of the five autosomes can carry the primary determinant, thereby becoming a sex chromosome. Strains with sex determination by fragment chromosomes, episomes, compound chromosomes, or environmental factors have also been constructed. The creation of these strains demonstrates the ease with which one sex-determination system can be transformed into another. PMID:12399387

  6. Design and testing of alterable preload running-in system of solid lubricated bearings

    NASA Astrophysics Data System (ADS)

    Wu, Jianwei; Zhao, Hefan; Cui, Jiwen

    2013-01-01

    The lubricating mechanism and improved performances of MoS2 film in bearings is analyzed in this paper. In order to improve the performance of solid lubricated bearings, the running-in is necssary. The design of the running-in system which can change the bearing preload during the process of running-in is introduced in detail. The results of the running-in experiments are analyzed.

  7. Altered dynamics between neural systems sub-serving decisions for unhealthy food.

    PubMed

    He, Qinghua; Xiao, Lin; Xue, Gui; Wong, Savio; Ames, Susan L; Xie, Bin; Bechara, Antoine

    2014-01-01

    Using BOLD functional magnetic resonance imaging (fMRI) techniques, we examined the relationships between activities in the neural systems elicited by the decision stage of the Iowa Gambling Task (IGT), and food choices of either vegetables or snacks high in fat and sugar. Twenty-three healthy normal weight adolescents and young adults, ranging in age from 14 to 21, were studied. Neural systems implicated in decision-making and inhibitory control were engaged by having participants perform the IGT during fMRI scanning. The Youth/Adolescent Questionnaire, a food frequency questionnaire, was used to obtain daily food choices. Higher consumption of vegetables correlated with higher activity in prefrontal cortical regions, namely the left superior frontal gyrus (SFG), and lower activity in sub-cortical regions, namely the right insular cortex. In contrast, higher consumption of fatty and sugary snacks correlated with lower activity in the prefrontal regions, combined with higher activity in the sub-cortical, insular cortex. These results provide preliminary support for our hypotheses that unhealthy food choices in real life are reflected by neuronal changes in key neural systems involved in habits, decision-making and self-control processes. These findings have implications for the creation of decision-making based intervention strategies that promote healthier eating. PMID:25414630

  8. Altered dynamics between neural systems sub-serving decisions for unhealthy food

    PubMed Central

    He, Qinghua; Xiao, Lin; Xue, Gui; Wong, Savio; Ames, Susan L.; Xie, Bin; Bechara, Antoine

    2014-01-01

    Using BOLD functional magnetic resonance imaging (fMRI) techniques, we examined the relationships between activities in the neural systems elicited by the decision stage of the Iowa Gambling Task (IGT), and food choices of either vegetables or snacks high in fat and sugar. Twenty-three healthy normal weight adolescents and young adults, ranging in age from 14 to 21, were studied. Neural systems implicated in decision-making and inhibitory control were engaged by having participants perform the IGT during fMRI scanning. The Youth/Adolescent Questionnaire, a food frequency questionnaire, was used to obtain daily food choices. Higher consumption of vegetables correlated with higher activity in prefrontal cortical regions, namely the left superior frontal gyrus (SFG), and lower activity in sub-cortical regions, namely the right insular cortex. In contrast, higher consumption of fatty and sugary snacks correlated with lower activity in the prefrontal regions, combined with higher activity in the sub-cortical, insular cortex. These results provide preliminary support for our hypotheses that unhealthy food choices in real life are reflected by neuronal changes in key neural systems involved in habits, decision-making and self-control processes. These findings have implications for the creation of decision-making based intervention strategies that promote healthier eating. PMID:25414630

  9. Systems biology of cancer: moving toward the integrative study of the metabolic alterations in cancer cells

    PubMed Central

    Hernández Patiño, Claudia E.; Jaime-Muñoz, Gustavo; Resendis-Antonio, Osbaldo

    2013-01-01

    One of the main objectives in systems biology is to understand the biological mechanisms that give rise to the phenotype of a microorganism by using high-throughput technologies (HTs) and genome-scale mathematical modeling. The computational modeling of genome-scale metabolic reconstructions is one systemic and quantitative strategy for characterizing the metabolic phenotype associated with human diseases and potentially for designing drugs with optimal clinical effects. The purpose of this short review is to describe how computational modeling, including the specific case of constraint-based modeling, can be used to explore, characterize, and predict the metabolic capacities that distinguish the metabolic phenotype of cancer cell lines. As we show herein, this computational framework is far from a pure theoretical description, and to ensure proper biological interpretation, it is necessary to integrate high-throughput data and generate predictions for later experimental assessment. Hence, genome-scale modeling serves as a platform for the following: (1) the integration of data from HTs, (2) the assessment of how metabolic activity is related to phenotype in cancer cell lines, and (3) the design of new experiments to evaluate the outcomes of the in silico analysis. By combining the functions described above, we show that computational modeling is a useful methodology to construct an integrative, systemic, and quantitative scheme for understanding the metabolic profiles of cancer cell lines, a first step to determine the metabolic mechanism by which cancer cells maintain and support their malignant phenotype in human tissues. PMID:23316163

  10. A grass molecular identification system for forensic botany: a critical evaluation of the strengths and limitations.

    PubMed

    Ward, Jodie; Gilmore, Simon R; Robertson, James; Peakall, Rod

    2009-11-01

    Plant material is frequently encountered in criminal investigations but often overlooked as potential evidence. We designed a DNA-based molecular identification system for 100 Australian grasses that consisted of a series of polymerase chain reaction assays that enabled the progressive identification of grasses to different taxonomic levels. The identification system was based on DNA sequence variation at four chloroplast and two mitochondrial loci. Seventeen informative indels and 68 single-nucleotide polymorphisms were utilized as molecular markers for subfamily to species-level identification. To identify an unknown sample to subfamily level required a minimum of four markers or nine markers for species identification. The accuracy of the system was confirmed by blind tests. We have demonstrated "proof of concept" of a molecular identification system for trace botanical samples. Our evaluation suggests that the adoption of a system that combines this approach with DNA sequencing could assist the morphological identification of grasses found as forensic evidence. PMID:19818109

  11. Carbon nanotube–liposome supramolecular nanotrains for intelligent molecular-transport systems

    PubMed Central

    Miyako, Eijiro; Kono, Kenji; Yuba, Eiji; Hosokawa, Chie; Nagai, Hidenori; Hagihara, Yoshihisa

    2012-01-01

    Biological network systems, such as inter- and intra-cellular signalling systems, are handled in a sophisticated manner by the transport of molecular information. Over the past few decades, there has been a growing interest in the development of synthetic molecular-transport systems. However, several key technologies have not been sufficiently realized to achieve optimum performance of transportation methods. Here we show that a new type of supramolecular system comprising of carbon nanotubes and liposomes enables the directional transport and controlled release of carrier molecules, and allows an enzymatic reaction at a desired area. The study highlights important progress that has been made towards the development of biomimetic molecular-transport systems and various lab-on-a-chip applications, such as medical diagnosis, sensors, bionic computers and artificial biological networks. PMID:23187626

  12. Caffeine exposure alters adenosine system and neurochemical markers during retinal development.

    PubMed

    Brito, Rafael; Pereira-Figueiredo, Danniel; Socodato, Renato; Paes-de-Carvalho, Roberto; Calaza, Karin C

    2016-08-01

    Evidence points to beneficial properties of caffeine in the adult central nervous system, but teratogenic effects have also been reported. Caffeine exerts most of its effects by antagonizing adenosine receptors, especially A1 and A2A subtypes. In this study, we evaluated the role of caffeine on the expression of components of the adenosinergic system in the developing avian retina and the impact of caffeine exposure upon specific markers for classical neurotransmitter systems. Caffeine exposure (5-30 mg/kg by in ovo injection) to 14-day-old chick embryos increased the expression of A1 receptors and concomitantly decreased A2A adenosine receptors expression after 48 h. Accordingly, caffeine (30 mg/kg) increased [(3) H]-8-cyclopentyl-1,3-dipropylxanthine (A1 antagonist) binding and reduced [(3) H]-ZM241385 (A2A antagonist) binding. The caffeine time-response curve demonstrated a reduction in A1 receptors 6 h after injection, but an increase after 18 and 24 h. In contrast, caffeine exposure increased the expression of A2A receptors from 18 and 24 h. Kinetic assays of [(3) H]-S-(4-nitrobenzyl)-6-thioinosine binding to the equilibrative adenosine transporter ENT1 revealed an increase in Bmax with no changes in Kd , an effect accompanied by an increase in adenosine uptake. Immunohistochemical analysis showed a decrease in retinal content of tyrosine hydroxylase, calbindin and choline acetyltransferase, but not Brn3a, after 48 h of caffeine injection. Furthermore, retinas exposed to caffeine had increased levels of phosphorylated extracellular signal-regulated kinase and cAMP-response element binding protein. Overall, we show an in vivo regulation of the adenosine system, extracellular signal-regulated kinase and cAMP-response element binding protein function and protein expression of specific neurotransmitter systems by caffeine in the developing retina. The beneficial or maleficent effects of caffeine have been demonstrated by the work of different studies. It

  13. Molecular and Functional Diversity of GABA-A Receptors in the Enteric Nervous System of the Mouse Colon

    PubMed Central

    Seifi, Mohsen; Brown, James F.; Mills, Jeremy; Bhandari, Pradeep; Belelli, Delia; Lambert, Jeremy J.; Rudolph, Uwe

    2014-01-01

    The enteric nervous system (ENS) provides the intrinsic neural control of the gastrointestinal tract (GIT) and regulates virtually all GI functions. Altered neuronal activity within the ENS underlies various GI disorders with stress being a key contributing factor. Thus, elucidating the expression and function of the neurotransmitter systems, which determine neuronal excitability within the ENS, such as the GABA-GABAA receptor (GABAAR) system, could reveal novel therapeutic targets for such GI disorders. Molecular and functionally diverse GABAARs modulate rapid GABAergic-mediated regulation of neuronal excitability throughout the nervous system. However, the cellular and subcellular GABAAR subunit expression patterns within neurochemically defined cellular circuits of the mouse ENS, together with the functional contribution of GABAAR subtypes to GI contractility remains to be determined. Immunohistochemical analyses revealed that immunoreactivity for the GABAAR gamma (γ) 2 and alphas (α) 1, 2, 3 subunits was located on somatodendritic surfaces of neurochemically distinct myenteric plexus neurons, while being on axonal compartments of submucosal plexus neurons. In contrast, immunoreactivity for the α4–5 subunits was only detected in myenteric plexus neurons. Furthermore, α-γ2 subunit immunoreactivity was located on non-neuronal interstitial cells of Cajal. In organ bath studies, GABAAR subtype-specific ligands had contrasting effects on the force and frequency of spontaneous colonic longitudinal smooth muscle contractions. Finally, enhancement of γ2-GABAAR function with alprazolam reversed the stress-induced increase in the force of spontaneous colonic contractions. The study demonstrates the molecular and functional diversity of the GABAAR system within the mouse colon providing a framework for developing GABAAR-based therapeutics in GI disorders. PMID:25080596

  14. Foliar application of glyphosate affects molecular mechanisms in underground adventitious buds of leafy spurge (Euphorbia esula) and alters their vegetative growth patterns

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long term control of leafy spurge with glyphosate requires multiple applications because the plant reproduces vegetatively from abundant underground adventitious buds (UABs). Determining the molecular mechanisms involved in controlling vegetative reproduction in leafy spurge following foliar glyphos...

  15. Alterations in the hippocampal glycinergic system in an animal model of posttraumatic stress disorder.

    PubMed

    Yamamoto, Shigeto; Morinobu, Shigeru; Iwamoto, Yasuyuki; Ueda, Yuto; Takei, Shiro; Fujita, Yosuke; Yamawaki, Shigeto

    2010-11-01

    Previous studies have demonstrated that rats subjected to single prolonged stress (SPS) exhibit posttraumatic stress disorder (PTSD)-like symptoms, such as enhanced contextual fear in response to trauma-related and trauma-unrelated events. Furthermore, we previously reported that upregulation of hippocampal glycine transporter 1 (GlyT-1) mRNA after context exposure could be the initial mechanism underlying impaired fear extinction in SPS rats. To clarify the involvement of the hippocampal glycinergic system in impaired fear extinction in SPS rats, we measured the time course of changes in the duration of freezing and the hippocampal levels of Gly-T1 mRNA using contextual fear conditioning (FC) and extinction training. We also used in vivo microdialysis to measure the concentration of extracellular glycine in the hippocampus during the time interval between FC and the first context exposure. SPS rats exhibited increased and sustained contextual fear responses. The enhanced contextual fear response in SPS rats was associated with a sustained increase in hippocampal levels of Gly-T1 mRNA after FC relative to sham rats, and by a decrease in the extracellular glycine concentration. GlyT-1 mRNA levels in rats that underwent repeated extinction training were significantly lower than in rats that did not undergo extinction training. These findings indicate that reduced activity of the hippocampal glycinergic system could be closely involved in impaired fear extinction in SPS rats, suggesting that activation of the glycinergic system by d-cycloserine or GlyT-1 inhibitors may ameliorate the impairment of fear extinction. PMID:20427053

  16. [Alterations of prooxidant-antioxidant system of rat liver at ethanol and tetracycline action].

    PubMed

    Nedoshytko, Kh Iu

    2013-01-01

    The state of antioxidant system and fatty acid composition of lipids in the liver tissues of rats of different sex at the ethanol and tetracycline action and at the influence of biologically active additives (BAA) "Alpha + Omega" at a dose of 0.5 mg/kg b.w. per os was investigated. It was found that the contet of lipid peroxidation products in the liver was increased at the action of 40% ethanol at a dose of 7 ml/kg b.w. per os and tetracycline--500 mg/kg and more profound at their joint using. However, the content of diene conjugates was stronger increased in the liver of females at the action of ethanol, while in the liver of males at the action of tetracycline (P < 0.05). It was shown that the application of the investigated compounds led to the reduction of an antioxidant defense system activity of males and females liver, as evidenced by the decrease of superoxide dismutase activity by 46 and 43% and reduction of glutathione content by 39 and 38% (P < 0.05). The activity of alanineaminotransferase, aspartateaminotransferase and alkalinephosphatase was increased in the liver of males and females under the influence of ethanol and tetracycline and more profound at their joint usage (P < 0.05). It was established that ethanol and tetracycline unidirectionally changed fatty acid composition of total lipids of rat liver, but at the ethanol action the changes were more expressed in females while at the tetracycline action in males. The application during 14 days of BAA "Alpha + Omega" to male and female rats with an acute tetracycline damage at subacute ethanol action led to partial normalization of prooxidant-antioxidant system and the relative content of total lipids fatty acids of the liver of both sexes animals. PMID:24479333

  17. Algorithms for computer detection of symmetry elements in molecular systems.

    PubMed

    Beruski, Otávio; Vidal, Luciano N

    2014-02-01

    Simple procedures for the location of proper and improper rotations and reflexion planes are presented. The search is performed with a molecule divided into subsets of symmetrically equivalent atoms (SEA) which are analyzed separately as if they were a single molecule. This approach is advantageous in many aspects. For instance, in those molecules that are symmetric rotors, the number of atoms and the inertia tensor of the SEA provide one straight way to find proper rotations of any order. The algorithms are invariant to the molecular orientation and their computational cost is low, because the main information required to find symmetry elements is interatomic distances and the principal moments of the SEA. For example, our Fortran implementation, running on a single processor, took only a few seconds to locate all 120 symmetry operations of the large and highly symmetrical fullerene C720, belonging to the Ih point group. Finally, we show how the interatomic distances matrix of a slightly unsymmetrical molecule is used to symmetrize its geometry. PMID:24403016

  18. Flexibility and molecular recognition in the immune system

    PubMed Central

    Jimenez, Ralph; Salazar, Georgina; Baldridge, Kim K.; Romesberg, Floyd E.

    2003-01-01

    Photon echo spectroscopy has been used to measure the response of three antibody-binding sites to perturbation from electronic excitation of a bound antigen, fluorescein. The three antibodies show motions that range in time scale from tens of femtoseconds to nanoseconds. Relative to the others, one antibody, 4-4-20, possesses a rigid binding site that likely results from a short and inflexible heavy chain complementarity-determining region 3 (HCDR3) loop and a critical Tyr that acts as a “molecular splint,” rigidifying the antigen across its most flexible internal degree of freedom. The remaining two antibodies, 34F10 and 40G4, despite being generated against the same antigen, possess binding sites that are considerably more flexible. The more flexible combining sites likely result from longer HCDR3 loops and a deletion in the light chain complementarity-determining region 1 (LCDR1) that removes the critical Tyr residue. The binding site flexibilities may result in varying mechanisms of antigen recognition including lock-and-key, induced-fit, and conformational selection. PMID:12518056

  19. Intramolecular electronic energy transfer in bichromophoric molecular macrocyclic systems

    NASA Astrophysics Data System (ADS)

    Speiser, Shammai

    1993-01-01

    The structures and spectral properties of several bichromophoric molecules, suitable for optical data processing, are presented. The bichromophoric molecules are composed of an aromatic ring connected by two methylene chains to an (alpha) -diketone moiety. Both the absorption and emission spectra of these compounds can be attributed to a superposition of the individual spectra of the separate chromophores. The critical transfer radia for electronic energy transfer from the aromatic (donor) chromophore to the (alpha) -diketone (acceptor) chromophore was calculated from the spectral overlap between the fluorescence spectrum of the aromatic ring with the absorption spectrum of the (alpha) -diketone chromophore. The results show that this series of molecules is well suited for a mechanistic study of short-range intramolecular electronic energy transfer (intra-EET). The temperature and the molecular structure dependence of the intra-EET efficiency in this series was measured and analyzed for both singlet-singlet and triplet-triplet routes. The results show that the transfer efficiency is strongly temperature and structure dependent, indicating that exchange interaction is responsible for intra-EET between close chromophores in a bichromophoric molecule. The relative contributions of interchromophoric distance and that of the relative orientation of the two chromophores to exchange interaction are discussed.

  20. Hesr1 knockout mice exhibit behavioral alterations through the dopaminergic nervous system.

    PubMed

    Fuke, Satoshi; Minami, Natsumi; Kokubo, Hiroki; Yoshikawa, Ayumu; Yasumatsu, Hiroshi; Sasagawa, Noboru; Saga, Yumiko; Tsukahara, Toshifumi; Ishiura, Shoichi

    2006-11-15

    The basic helix-loop-helix (bHLH) transcriptional factor Hesr1 gene (hairy and enhancer of split-related 1, also called Hey1/HRT1/CHF2/HERP2) has been identified and characterized as a member of the subfamily of hairy/Enhancer of split, and shown to be involved in cardiovascular and neural development. We report that HESR1 binds directly to a part of the 3' non-coding region of the human dopamine transporter (DAT1) gene and represses the endogenous DAT1 gene in HEK293 cells. To investigate functions of the HESR1 gene in the dopaminergic nervous system in vivo, we analyzed the expressions of dopamine-related genes in the postnatal day 0 whole brains of Hesr1 knockout mice by real-time RT-PCR analysis. Several dopamine-related genes, such as DAT, dopamine receptors D1, D2, D4, and D5, were significantly upregulated. Moreover, young adults of Hesr1 knockout mice showed a decrease in spontaneous locomotor activity and a reduction in exploratory behavior or behavioral responses to novelty in the open-field, and elevated plus-maze tests. These results indicate that the HESR1 gene is related to neuropsychiatric disorders and behavioral traits through the dopaminergic nervous system. PMID:16998899