Sequential self-assembly of DNA functionalized droplets

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

Zhang, Yin; McMullen, Angus; Pontani, Lea-Laetitia

Complex structures and devices, both natural and manmade, are often constructed sequentially. From crystallization to embryogenesis, a nucleus or seed is formed and built upon. Sequential assembly allows for initiation, signaling, and logical programming, which are necessary for making enclosed, hierarchical structures. Though biology relies on such schemes, they have not been available in materials science. We demonstrate programmed sequential self-assembly of DNA functionalized emulsions. The droplets are initially inert because the grafted DNA strands are pre-hybridized in pairs. Active strands on initiator droplets then displace one of the paired strands and thus release its complement, which in turn activatesmore » the next droplet in the sequence, akin to living polymerization. This strategy provides time and logic control during the self-assembly process, and offers a new perspective on the synthesis of materials.« less

Sequential self-assembly of DNA functionalized droplets

DOE PAGES

Zhang, Yin; McMullen, Angus; Pontani, Lea-Laetitia; ...

2017-06-16

Complex structures and devices, both natural and manmade, are often constructed sequentially. From crystallization to embryogenesis, a nucleus or seed is formed and built upon. Sequential assembly allows for initiation, signaling, and logical programming, which are necessary for making enclosed, hierarchical structures. Though biology relies on such schemes, they have not been available in materials science. We demonstrate programmed sequential self-assembly of DNA functionalized emulsions. The droplets are initially inert because the grafted DNA strands are pre-hybridized in pairs. Active strands on initiator droplets then displace one of the paired strands and thus release its complement, which in turn activatesmore » the next droplet in the sequence, akin to living polymerization. This strategy provides time and logic control during the self-assembly process, and offers a new perspective on the synthesis of materials.« less

Differential proteomic analysis reveals sequential heat stress-responsive regulatory network in radish (Raphanus sativus L.) taproot.

PubMed

Wang, Ronghua; Mei, Yi; Xu, Liang; Zhu, Xianwen; Wang, Yan; Guo, Jun; Liu, Liwang

2018-05-01

Differential abundance protein species (DAPS) involved in reducing damage and enhancing thermotolerance in radish were firstly identified. Proteomic analysis and omics association analysis revealed a HS-responsive regulatory network in radish. Heat stress (HS) is a major destructive factor influencing radish production and supply in summer, for radish is a cool season vegetable crop being susceptible to high temperature. In this study, the proteome changes of radish taproots under 40 °C treatment at 0 h (Control), 12 h (Heat12) and 24 h (Heat24) were analyzed using iTRAQ (Isobaric Tag for Relative and Absolute Quantification) approach. In total, 2258 DAPS representing 1542 differentially accumulated uniprotein species which respond to HS were identified. A total of 604, 910 and 744 DAPS was detected in comparison of Control vs. Heat12, Control vs. Heat24, and Heat12 vs. Heat24, respectively. Gene ontology and pathway analysis showed that annexin, ubiquitin-conjugating enzyme, ATP synthase, heat shock protein (HSP) and other stress-related proteins were predominately enriched in signal transduction, stress and defense pathways, photosynthesis and energy metabolic pathways, working cooperatively to reduce stress-induced damage in radish. Based on iTRAQ combined with the transcriptomics analysis, a schematic model of a sequential HS-responsive regulatory network was proposed. The initial sensing of HS occurred at the plasma membrane, and then key components of stress signal transduction triggered heat-responsive genes in the plant protective metabolism to re-establish homeostasis and enhance thermotolerance. These results provide new insights into characteristics of HS-responsive DAPS and facilitate dissecting the molecular mechanisms underlying heat tolerance in radish and other root crops.

Dynamic Folding Pathway Models of the Trp-Cage Protein

PubMed Central

Kim, Seung-Yeon

2013-01-01

Using action-derived molecular dynamics (ADMD), we study the dynamic folding pathway models of the Trp-cage protein by providing its sequential conformational changes from its initial disordered structure to the final native structure at atomic details. We find that the numbers of native contacts and native hydrogen bonds are highly correlated, implying that the native structure of Trp-cage is achieved through the concurrent formations of native contacts and native hydrogen bonds. In early stage, an unfolded state appears with partially formed native contacts (~40%) and native hydrogen bonds (~30%). Afterward, the folding is initiated by the contact of the side chain of Tyr3 with that of Trp6, together with the formation of the N-terminal α-helix. Then, the C-terminal polyproline structure docks onto the Trp6 and Tyr3 rings, resulting in the formations of the hydrophobic core of Trp-cage and its near-native state. Finally, the slow adjustment processes of the near-native states into the native structure are dominant in later stage. The ADMD results are in agreement with those of the experimental folding studies on Trp-cage and consistent with most of other computational studies. PMID:23865078

Giant morphea-form basal cell carcinoma of the umbilicus: Successful debulking with vismodegib.

PubMed

Orduz Robledo, Mariana; Lebas, Eve; Reginster, Marie-Annick; Baghaie, Mahmoud; Groves, Sabine; Nikkels, Arjen F

2018-01-01

Basal cell carcinoma of the umbilicus is very rare. The nodular subtype is the main representative. Giant basal cell carcinomas represent around 1% of all basal cell carcinomas. The hedgehog pathway inhibitor vismodegib is indicated for advanced basal cell carcinoma and CD56-negative immunostaining seems indicative for successful treatment. A 54-year-old man presented a 10 cm × 14 cm large and 4.5 cm deep morphea-form basal cell carcinoma with faint immunohistochemical CD56 expression arising from the umbilicus. A sequential treatment was initiated with debulking using vismodegib 150 mg per day for 4 months, followed by reconstructive surgery. To the best of our knowledge, this is the first report of a giant basal cell carcinoma of the morphea-form type of the umbilicus. The sequential treatment plan reduces the duration of vismodegib inherent adverse effects and significantly reduces the tumor mass prior to surgery. Besides increasing adherence to vismodegib treatment, this approach facilitates the surgical technique and improves cosmetic outcome.

Sequential and coordinated action of phytochromes A and B during Arabidopsis stem growth revealed by kinetic analysis

NASA Technical Reports Server (NTRS)

Parks, B. M.; Spalding, E. P.; Evans, M. L. (Principal Investigator)

1999-01-01

Photoreceptor proteins of the phytochrome family mediate light-induced inhibition of stem (hypocotyl) elongation during the development of photoautotrophy in seedlings. Analyses of overt mutant phenotypes have established the importance of phytochromes A and B (phyA and phyB) in this developmental process, but kinetic information that would augment emerging molecular models of phytochrome signal transduction is absent. We have addressed this deficiency by genetically dissecting phytochrome-response kinetics, after having solved the technical issues that previously limited growth studies of small Arabidopsis seedlings. We show here, with resolution on the order of minutes, that phyA initiated hypocotyl growth inhibition upon the onset of continuous red light. This primary contribution of phyA began to decrease after 3 hr of irradiation, the same time at which immunochemically detectable phyA disappeared and an exclusively phyB-dependent phase of inhibition began. The sequential and coordinated actions of phyA and phyB in red light were not observed in far-red light, which inhibited growth persistently through an exclusively phyA-mediated pathway.

The effects of autonomy-supportive coaching, need satisfaction, and self-perceptions on initiative and identity in youth swimmers.

PubMed

Coatsworth, J Douglas; Conroy, David E

2009-03-01

This study tested a sequential process model linking youth sport coaching climates (perceived coach behaviors and perceived need satisfaction) to youth self-perceptions (perceived competence and global self-esteem) and youth development outcomes (initiative, identity reflection, identity exploration). A sample of 119 youth between the ages of 10 and 18 who participated in a community-directed summer swim league completed questionnaires over the course of the 7-week season. Results indicated that coaches' autonomy support, particularly via process-focused praise, predicted youth competence need satisfaction and relatedness need satisfaction in the coaching relationship. Youth competence need satisfaction predicted self-esteem indirectly via perceived competence. Finally, self-esteem predicted identity reflection, and perceived competence predicted both identity reflection and initiative. Effects of age, sex, and perceptions of direct contact with the coach were not significant. Findings suggest that the quality of the coaching climate is an important predictor of the developmental benefits of sport participation and that one pathway by which the coaching climate has its effect on initiative and identity reflection is through developing youth self-perceptions.

The Effects of Autonomy-supportive Coaching, Need Satisfaction and Self-Perceptions on Initiative and Identity in Youth Swimmers

PubMed Central

Coatsworth, J. Douglas; Conroy, David E.

2015-01-01

This study tested a sequential process model linking youth sport coaching climates (perceived coach behaviors and perceived need satisfaction) to youth self-perceptions (perceived competence and global self-esteem) and youth development outcomes (initiative, identity reflection, identity exploration). A sample of 119 youth between the ages 10–18 who participated in a community-directed summer swim league completed questionnaires over the course of the seven-week season. Results indicated that coaches’ autonomy support, particularly via process-focused praise, predicted youth competence and relatedness need satisfaction in the coaching relationship. Youth competence need satisfaction predicted self-esteem indirectly via perceived competence. Finally, self-esteem predicted identity reflection and perceived competence predicted both identity reflection and initiative. Effects of age, sex, and perceptions of direct contact with the coach were not significant. Findings suggest that the quality of the coaching climate is an important predictor of the developmental benefits of sport participation and that one pathway by which the coaching climate has its effect on initiative and identity reflection is through developing youth self-perceptions. PMID:19271821

Neuroimaging reveals dual routes to reading in simultaneous proficient readers of two orthographies

PubMed Central

Das, T.; Padakannaya, P.; Pugh, K. R.; Singh, N. C.

2012-01-01

Orthographic differences across languages impose differential weighting on distinct component processes, and consequently on different pathways during word-reading tasks. Readers of transparent orthographies such as Italian and Hindi are thought to rely on spelling-to-sound assembly and show increased activation in phonologically-tuned areas along the dorsal pathway, whereas reading an opaque orthography such as English is thought to rely more on lexically-mediated processing associated with increased activation of semantically-tuned regions along the ventral pathway. To test if biliterate Hindi/English readers exhibit orthography-specific reading pathways, we used behavioural measures and functional neuroimaging. Reaction times and activation patterns of monolingual English and Hindi readers were compared to two groups of adult biliterates; 14 simultaneous readers who learnt to read both languages at age 5 and 10 sequential readers who learnt Hindi at 5 and English at 10. Simultaneous, but not sequential readers demonstrated relative activation differences of dorsal and ventral areas in the two languages. Similar to native counterparts, simultaneous readers preferentially activated the left inferior temporal gyrus for English and left inferior parietal lobule (L-IPL) for Hindi, whereas, sequential readers showed higher activation along the L-IPL for reading both languages. We suggest that early simultaneous exposure to reading distinct orthographies results in orthography-specific plasticity that persists through adulthood. PMID:20854914

Multiple internalization pathways of polyelectrolyte multilayer capsules into mammalian cells.

PubMed

Kastl, Lena; Sasse, Daniel; Wulf, Verena; Hartmann, Raimo; Mircheski, Josif; Ranke, Christiane; Carregal-Romero, Susana; Martínez-López, José Antonio; Fernández-Chacón, Rafael; Parak, Wolfgang J; Elsasser, Hans-Peter; Rivera Gil, Pilar

2013-08-27

Polyelectrolyte multilayer (PEM) capsules are carrier vehicles with great potential for biomedical applications. With the future aim of designing biocompatible, effective therapeutic delivery systems (e.g., for cancer), the pathway of internalization (uptake and fate) of PEM capsules was investigated. In particular the following experiments were performed: (i) the study of capsule co-localization with established endocytic markers, (ii) switching-off endocytotic pathways with pharmaceutical/chemical inhibitors, and (iii) characterization and quantification of capsule uptake with confocal and electron microscopy. As result, capsules co-localized with lipid rafts and with phagolysosomes, but not with other endocytic vesicles. Chemical interference of endocytosis with chemical blockers indicated that PEM capsules enter the investigated cell lines through a mechanism slightly sensitive to electrostatic interactions, independent of clathrin and caveolae, and strongly dependent on cholesterol-rich domains and organelle acidification. Microscopic characterization of cells during capsule uptake showed the formation of phagocytic cups (vesicles) to engulf the capsules, an increased number of mitochondria, and a final localization in the perinuclear cytoplasma. Combining all these indicators we conclude that PEM capsule internalization in general occurs as a combination of different sequential mechanisms. Initially, an adsorptive mechanism due to strong electrostatic interactions governs the stabilization of the capsules at the cell surface. Membrane ruffling and filopodia extensions are responsible for capsule engulfing through the formation of a phagocytic cup. Co-localization with lipid raft domains activates the cell to initiate a lipid-raft-mediated macropinocytosis. Internalization vesicles are very acidic and co-localize only with phagolysosome markers, excluding caveolin-mediated pathways and indicating that upon phagocytosis the capsules are sorted to heterophagolysosomes.

Molecular Characterization of Macrophage-Biomaterial Interactions

PubMed Central

Moore, Laura Beth; Kyriakides, Themis R.

2015-01-01

Implantation of biomaterials in vascularized tissues elicits the sequential engagement of molecular and cellular elements that constitute the foreign body response. Initial events include the non-specific adsorption of proteins to the biomaterial surface that render it adhesive for cells such as neutrophils and macrophages. The latter undergo unique activation and in some cases undergo cell-cell fusion to form foreign body giant cells that contribute to implant damage and fibrotic encapsulation. In this review, we discuss the molecular events that contribute to macrophage activation and fusion with a focus on the role of the inflammasome, signaling pathways such as JAK/STAT and NF-κB, and the putative involvement of micro RNAs in the regulation of these processes. PMID:26306446

Molecular Characterization of Macrophage-Biomaterial Interactions.

PubMed

Moore, Laura Beth; Kyriakides, Themis R

2015-01-01

Implantation of biomaterials in vascularized tissues elicits the sequential engagement of molecular and cellular elements that constitute the foreign body response. Initial events include the non-specific adsorption of proteins to the biomaterial surface that render it adhesive for cells such as neutrophils and macrophages. The latter undergo unique activation and in some cases undergo cell-cell fusion to form foreign body giant cells that contribute to implant damage and fibrotic encapsulation. In this review, we discuss the molecular events that contribute to macrophage activation and fusion with a focus on the role of the inflammasome, signaling pathways such as JAK/STAT and NF-κB, and the putative involvement of micro RNAs in the regulation of these processes.

Theory of C2Hx species on Pt{110} (1×2): Reaction pathways for dehydrogenation

NASA Astrophysics Data System (ADS)

Anghel, A. T.; Wales, D. J.; Jenkins, S. J.; King, D. A.

2007-01-01

A complete reaction sequence for molecular dissociation at a surface has been characterized using density functional theory. The barriers for sequential ethane dehydrogenation on Pt{110} are found to fall into distinct energy sets: very low barriers, with values in the range of 0.29-0.42eV, for the initial ethane dissociation to ethene and ethylidene at the surface; medium barriers, in the range of 0.72-1.10eV, for dehydrogenation of C2H4 fragments to vinylidene and ethyne; and high barriers, requiring more than 1.45eV, for further dehydrogenation. For dissociation processes where more than one pathway has been found, the lowest energetic route links the most stable reactant adsorbed state at the surface to a product state involving the hydrocarbon moiety adsorbed in its most stable configuration at the surface. Hence there is a clear link between surface stability and kinetics for these species.

Towards new therapeutic approaches for malignant melanoma.

PubMed

Pacheco, Ivan; Buzea, Cristina; Tron, Victor

2011-11-01

Recent progress in understanding the molecular mechanisms of the initiation and progression of melanoma has created new opportunities for developing novel therapeutic modalities to manage this potentially lethal disease. Although at first glance, melanoma carcinogenesis appears to be a chaotic system, it is indeed, arguably, a deterministic multistep process involving sequential alterations of proto-oncogenes, tumour suppressors and miRNA genes. The scope of this article is to discuss the most recent and significant advances in melanoma molecular therapeutics. It is apparent that using single agents targeting solely individual melanoma pathways might be insufficient for long-term survival. However, the outstanding results on melanoma survival observed with novel selective inhibitors of B-RAF, such as PLX4032 give hope that melanoma can be cured. The fact that melanoma develops acquired resistance to PLX4032 emphasises the importance of simultaneously targeting several pathways. Because the most striking feature of melanoma is its unsurpassed ability to metastasise, it is important to implement newer systems for drug delivery adapted from research on stem cells and nanotechnology.

Visualizing non-equilibrium lithiation of spinel oxide via in situ transmission electron microscopy

PubMed Central

He, Kai; Zhang, Sen; Li, Jing; Yu, Xiqian; Meng, Qingping; Zhu, Yizhou; Hu, Enyuan; Sun, Ke; Yun, Hongseok; Yang, Xiao-Qing; Zhu, Yimei; Gan, Hong; Mo, Yifei; Stach, Eric A.; Murray, Christopher B.; Su, Dong

2016-01-01

Spinel transition metal oxides are important electrode materials for lithium-ion batteries, whose lithiation undergoes a two-step reaction, whereby intercalation and conversion occur in a sequential manner. These two reactions are known to have distinct reaction dynamics, but it is unclear how their kinetics affects the overall electrochemical response. Here we explore the lithiation of nanosized magnetite by employing a strain-sensitive, bright-field scanning transmission electron microscopy approach. This method allows direct, real-time, high-resolution visualization of how lithiation proceeds along specific reaction pathways. We find that the initial intercalation process follows a two-phase reaction sequence, whereas further lithiation leads to the coexistence of three distinct phases within single nanoparticles, which has not been previously reported to the best of our knowledge. We use phase-field theory to model and describe these non-equilibrium reaction pathways, and to directly correlate the observed phase evolution with the battery's discharge performance. PMID:27157119

Simultaneous activation of parallel sensory pathways promotes a grooming sequence in Drosophila

PubMed Central

Hampel, Stefanie; McKellar, Claire E

2017-01-01

A central model that describes how behavioral sequences are produced features a neural architecture that readies different movements simultaneously, and a mechanism where prioritized suppression between the movements determines their sequential performance. We previously described a model whereby suppression drives a Drosophila grooming sequence that is induced by simultaneous activation of different sensory pathways that each elicit a distinct movement (Seeds et al., 2014). Here, we confirm this model using transgenic expression to identify and optogenetically activate sensory neurons that elicit specific grooming movements. Simultaneous activation of different sensory pathways elicits a grooming sequence that resembles the naturally induced sequence. Moreover, the sequence proceeds after the sensory excitation is terminated, indicating that a persistent trace of this excitation induces the next grooming movement once the previous one is performed. This reveals a mechanism whereby parallel sensory inputs can be integrated and stored to elicit a delayed and sequential grooming response. PMID:28887878

S/He's a Rebel: Toward a Sequential Stress Theory of Delinquency and Gendered Pathways to Disadvantage in Emerging Adulthood.

ERIC Educational Resources Information Center

Hagan, John; Foster, Holly

2003-01-01

Data from the National Longitudinal Study of Adolescent Health on 11,506 high school students were used to test a gendered and age-graded sequential stress theory in which delinquency can play an additive and intervening role in adolescents' movement from early anger through rebellious or aggressive forms of behavior to later depressive symptoms…

Practical approaches to adverse outcome pathway development and weight‐of‐evidence evaluation as illustrated by ecotoxicological case studies

EPA Science Inventory

Adverse Outcome Pathways (AOPs) describe toxicant effects as a sequential chain of causally linked events beginning with a molecular perturbation and culminating in an adverse outcome at an individual or population level. Strategies for developing AOPs are still evolving and dep...

Ecdysteroid biosynthesis in varroa mites: identification of halloween genes from the biosynthetic pathway and their regulation during reproduction

USDA-ARS?s Scientific Manuscript database

Biosynthesis of ecdysteroids involves sequential enzymatic hydroxylations by microsomal enzymes and mitochondrial cytochrome P450’s. Enzymes of the pathway are collectively known as Halloween genes. Complete sequences for three Halloween genes, spook (Vdspo), disembodied (Vddib) and shade (Vdshd), w...

The impact of comorbid body dysmorphic disorder on the response to sequential pharmacological trials for obsessive-compulsive disorder.

PubMed

Diniz, Juliana B; Costa, Daniel Lc; Cassab, Raony Cc; Pereira, Carlos Ab; Miguel, Euripedes C; Shavitt, Roseli G

2014-06-01

Our aim was to investigate the impact of comorbid body dysmorphic disorder (BDD) on the response to sequential pharmacological trials in adult obsessive-compulsive disorder (OCD) patients. The sequential trial initially involved fluoxetine monotherapy followed by one of three randomized, add-on strategies: placebo, clomipramine or quetiapine. We included 138 patients in the initial phase of fluoxetine, up to 80 mg or the maximum tolerated dosage, for 12 weeks. We invited 70 non-responders to participate in the add-on trial; as 54 accepted, we allocated 18 to each treatment group and followed them for an additional 12 weeks. To evaluate the combined effects of sex, age, age at onset, initial severity, type of augmentation and BDD on the response to sequential treatments, we constructed a model using generalized estimating equations (GEE). Of the 39 patients who completed the study (OCD-BDD, n = 13; OCD-non-BDD, n = 26), the OCD-BDD patients were less likely to be classified as responders than the OCD-non-BDD patients (Pearson Chi-Square = 4.4; p = 0.036). In the GEE model, BDD was not significantly associated with a worse response to sequential treatments (z-robust = 1.77; p = 0.07). The predictive potential of BDD regarding sequential treatment strategies for OCD did not survive when the analyses were controlled for other clinical characteristics. © The Author(s) 2013.

Speech Perception and Production by Sequential Bilingual Children: A Longitudinal Study of Voice Onset Time Acquisition

PubMed Central

McCarthy, Kathleen M; Mahon, Merle; Rosen, Stuart; Evans, Bronwen G

2014-01-01

The majority of bilingual speech research has focused on simultaneous bilinguals. Yet, in immigrant communities, children are often initially exposed to their family language (L1), before becoming gradually immersed in the host country's language (L2). This is typically referred to as sequential bilingualism. Using a longitudinal design, this study explored the perception and production of the English voicing contrast in 55 children (40 Sylheti-English sequential bilinguals and 15 English monolinguals). Children were tested twice: when they were in nursery (52-month-olds) and 1 year later. Sequential bilinguals' perception and production of English plosives were initially driven by their experience with their L1, but after starting school, changed to match that of their monolingual peers. PMID:25123987

The Ames dwarf gene, df, is required early in pituitary ontogeny for the extinction of Rpx transcription and initiation of lineage-specific cell proliferation.

PubMed

Gage, P J; Brinkmeier, M L; Scarlett, L M; Knapp, L T; Camper, S A; Mahon, K A

1996-12-01

Two nonallelic dwarfing mutations in mice define genes important for pituitary development and function. Mice homozygous for either the Ames (df) or Snell (Pit 1dw) dwarf mutations exhibit severe proportional dwarfism, hypothyroidism, and infertility due to the cytodifferentiation failure of three anterior pituitary cell types: thyrotropes, somatotropes, and lactotropes. Analysis of double heterozygotes and double mutants has provided evidence that the df and dw genes act sequentially in the same genetic pathway. Double heterozygotes had no reduction in growth rate or final adult size. Double homozygotes had essentially the same phenotype as the single mutants and were recovered at the predicted frequency, indicating that there are no previously unrecognized, redundant functions of the two genes. Several lines of evidence demonstrate that df acts earlier in the differentiation pathway than Pit1. The df mutants fail to extinguish expression of the homeobox gene Rpx on embryonic day 13.5 (e13.5), and the size of their nascent pituitary glands is reduced by e14.5. In contrast, Pit1dw mutants down-regulate Rpx appropriately and exhibit normal cell proliferation up to e14.5. The failure to extinguish Rpx and the concomitant hypocellularity of df pituitaries suggest the importance of Rpx repression in lineage-specific cell proliferation before the appearance of lineage-specific markers. Later, Pit-1 and hypothalamic neuropeptides act sequentially to regulate marker gene transcription and cell proliferation. These results establish the time of df action in a cascade of genes that regulate pituitary ontogeny.

Three-body dissociation of OCS3+: Separating sequential and concerted pathways

NASA Astrophysics Data System (ADS)

Kumar, Herendra; Bhatt, Pragya; Safvan, C. P.; Rajput, Jyoti

2018-02-01

Events from the sequential and concerted modes of the fragmentation of OCS3+ that result in coincident detection of fragments C+, O+, and S+ have been separated using a newly proposed representation. An ion beam of 1.8 MeV Xe9+ is used to make the triply charged molecular ion, with the fragments being detected by a recoil ion momentum spectrometer. By separating events belonging exclusively to the sequential mode of breakup, the electronic states of the intermediate molecular ion (CO2+ or CS2+) involved are determined, and from the kinetic energy release spectra, it is shown that the low lying excited states of the parent OCS3+ are responsible for this mechanism. An estimate of branching ratios of events coming from sequential versus concerted mode is presented.

PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways

PubMed Central

Wang, Minli; Wu, Weizhong; Wu, Wenqi; Rosidi, Bustanur; Zhang, Lihua; Wang, Huichen; Iliakis, George

2006-01-01

Poly(ADP-ribose)polymerase 1 (PARP-1) recognizes DNA strand interruptions in vivo and triggers its own modification as well as that of other proteins by the sequential addition of ADP-ribose to form polymers. This modification causes a release of PARP-1 from DNA ends and initiates a variety of responses including DNA repair. While PARP-1 has been firmly implicated in base excision and single strand break repair, its role in the repair of DNA double strand breaks (DSBs) remains unclear. Here, we show that PARP-1, probably together with DNA ligase III, operates in an alternative pathway of non-homologous end joining (NHEJ) that functions as backup to the classical pathway of NHEJ that utilizes DNA-PKcs, Ku, DNA ligase IV, XRCC4, XLF/Cernunnos and Artemis. PARP-1 binds to DNA ends in direct competition with Ku. However, in irradiated cells the higher affinity of Ku for DSBs and an excessive number of other forms of competing DNA lesions limit its contribution to DSB repair. When essential components of the classical pathway of NHEJ are absent, PARP-1 is recruited for DSB repair, particularly in the absence of Ku and non-DSB lesions. This form of DSB repair is sensitive to PARP-1 inhibitors. The results define the function of PARP-1 in DSB repair and characterize a candidate pathway responsible for joining errors causing genomic instability and cancer. PMID:17088286

[The use of local vibration and ultrasound in the rehabilitation of urolithiasis patients with the "stone pathway" syndrome of the distal ureter].

PubMed

Li, A A; Nesterov, N I; Avilov, V Ia

1996-01-01

Sequential intrarectal impacts with local vibration and ultrasound on distal part of ureter in 60 patients with "stone pathway" promoted elimination of the stone fragments in 58 (96.7%) patients. The size of the urolith fragments varied from 1 to 5 mm.

Pathways for learning two languages: lexical and grammatical associations within and across languages in sequential bilingual children*

PubMed Central

PHAM, GIANG

2018-01-01

This study examines the strength and direction of lexical-grammatical associations within and between first and second languages (L1 and L2) in a longitudinal sample of sequential bilinguals. Thirty-three children who spoke Vietnamese (L1) and English (L2) completed picture-naming and story-telling tasks in each language at four yearly intervals. Hierarchical linear modeling across Years 1–4 revealed bidirectional within-language associations and a unidirectional cross-language association from the L1 to L2. Results suggest a conditional relationship between languages in which the L1 supports L2 growth, but not vice versa. Findings contribute to defining pathways for L1 and L2 learning across domains and languages. PMID:29670455

Observation of non-classical correlations in sequential measurements of photon polarization

NASA Astrophysics Data System (ADS)

Suzuki, Yutaro; Iinuma, Masataka; Hofmann, Holger F.

2016-10-01

A sequential measurement of two non-commuting quantum observables results in a joint probability distribution for all output combinations that can be explained in terms of an initial joint quasi-probability of the non-commuting observables, modified by the resolution errors and back-action of the initial measurement. Here, we show that the error statistics of a sequential measurement of photon polarization performed at different measurement strengths can be described consistently by an imaginary correlation between the statistics of resolution and back-action. The experimental setup was designed to realize variable strength measurements with well-controlled imaginary correlation between the statistical errors caused by the initial measurement of diagonal polarizations, followed by a precise measurement of the horizontal/vertical polarization. We perform the experimental characterization of an elliptically polarized input state and show that the same complex joint probability distribution is obtained at any measurement strength.

Ultraviolet Absorption Induces Hydrogen-Atom Transfer in G⋅C Watson-Crick DNA Base Pairs in Solution.

PubMed

Röttger, Katharina; Marroux, Hugo J B; Grubb, Michael P; Coulter, Philip M; Böhnke, Hendrik; Henderson, Alexander S; Galan, M Carmen; Temps, Friedrich; Orr-Ewing, Andrew J; Roberts, Gareth M

2015-12-01

Ultrafast deactivation pathways bestow photostability on nucleobases and hence preserve the structural integrity of DNA following absorption of ultraviolet (UV) radiation. One controversial recovery mechanism proposed to account for this photostability involves electron-driven proton transfer (EDPT) in Watson-Crick base pairs. The first direct observation is reported of the EDPT process after UV excitation of individual guanine-cytosine (G⋅C) Watson-Crick base pairs by ultrafast time-resolved UV/visible and mid-infrared spectroscopy. The formation of an intermediate biradical species (G[-H]⋅C[+H]) with a lifetime of 2.9 ps was tracked. The majority of these biradicals return to the original G⋅C Watson-Crick pairs, but up to 10% of the initially excited molecules instead form a stable photoproduct G*⋅C* that has undergone double hydrogen-atom transfer. The observation of these sequential EDPT mechanisms across intermolecular hydrogen bonds confirms an important and long debated pathway for the deactivation of photoexcited base pairs, with possible implications for the UV photochemistry of DNA. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Surface Structure Characterization of Aspergillus fumigatus Conidia Mutated in the Melanin Synthesis Pathway and Their Human Cellular Immune Response

PubMed Central

Bayry, Jagadeesh; Beaussart, Audrey; Dufrêne, Yves F.; Sharma, Meenu; Bansal, Kushagra; Kniemeyer, Olaf; Aimanianda, Vishukumar; Brakhage, Axel A.; Kaveri, Srini V.; Kwon-Chung, Kyung J.

2014-01-01

In Aspergillus fumigatus, the conidial surface contains dihydroxynaphthalene (DHN)-melanin. Six-clustered gene products have been identified that mediate sequential catalysis of DHN-melanin biosynthesis. Melanin thus produced is known to be a virulence factor, protecting the fungus from the host defense mechanisms. In the present study, individual deletion of the genes involved in the initial three steps of melanin biosynthesis resulted in an altered conidial surface with masked surface rodlet layer, leaky cell wall allowing the deposition of proteins on the cell surface and exposing the otherwise-masked cell wall polysaccharides at the surface. Melanin as such was immunologically inert; however, deletion mutant conidia with modified surfaces could activate human dendritic cells and the subsequent cytokine production in contrast to the wild-type conidia. Cell surface defects were rectified in the conidia mutated in downstream melanin biosynthetic pathway, and maximum immune inertness was observed upon synthesis of vermelone onward. These observations suggest that although melanin as such is an immunologically inert material, it confers virulence by facilitating proper formation of the A. fumigatus conidial surface. PMID:24818666

Genome-wide expression analysis of human in vivo irritated epidermis: differential profiles induced by sodium lauryl sulfate and nonanoic acid.

PubMed

Clemmensen, Anders; Andersen, Klaus E; Clemmensen, Ole; Tan, Qihua; Petersen, Thomas K; Kruse, Torben A; Thomassen, Mads

2010-09-01

The pathogenesis of irritant contact dermatitis (ICD) is poorly understood, and genes participating in the epidermal response to chemical irritants are only partly known. It is commonly accepted that different irritants have different mechanisms of action in the development of ICD. To define the differential molecular events induced in the epidermis by different irritants, we collected sequential biopsies ((1/2), 4, and 24 hours after a single exposure and at day 11 after repeated exposure) from human volunteers exposed to either sodium lauryl sulfate (SLS) or nonanoic acid (NON). Gene expression analysis using high-density oligonucleotide microarrays (representing 47,000 transcripts) revealed essentially different pathway responses (1/2)hours after exposure: NON transiently induced the IL-6 pathway as well as a number of mitogen-activated signaling cascades including extracellular signal-regulated kinase and growth factor receptor signaling, whereas SLS transiently downregulated cellular energy metabolism pathways. Differential expression of the cyclooxygenase-2 and matrix metalloproteinase 3 transcripts was confirmed immunohistochemically. After cumulative exposure, 883 genes were differentially expressed, whereas we identified 23 suggested common biomarkers for ICD. In conclusion, we bring new insights into two hitherto less well-elucidated phases of skin irritancy: the very initial as well as the late phase after single and cumulative mild exposures, respectively.

Folding mechanism of an extremely thermostable (βα)(8)-barrel enzyme: a high kinetic barrier protects the protein from denaturation.

PubMed

Carstensen, Linn; Zoldák, Gabriel; Schmid, Franz-Xaver; Sterner, Reinhard

2012-04-24

HisF, the cyclase subunit of imidazole glycerol phosphate synthase (ImGPS) from Thermotoga maritima, is an extremely thermostable (βα)(8)-barrel protein. We elucidated the unfolding and refolding mechanism of HisF. Its unfolding transition is reversible and adequately described by the two-state model, but 6 weeks is necessary to reach equilibrium (at 25 °C). During refolding, initially a burst-phase off-pathway intermediate is formed. The subsequent productive folding occurs in two kinetic phases with time constants of ~3 and ~20 s. They reflect a sequential process via an on-pathway intermediate, as revealed by stopped-flow double-mixing experiments. The final step leads to native HisF, which associates with the glutaminase subunit HisH to form the functional ImGPS complex. The conversion of the on-pathway intermediate to the native protein results in a 10(6)-fold increase of the time constant for unfolding from 89 ms to 35 h (at 4.0 M GdmCl) and thus establishes a high energy barrier to denaturation. We conclude that the extra stability of HisF is used for kinetic protection against unfolding. In its refolding mechanism, HisF resembles other (βα)(8)-barrel proteins.

Outside-in assembly pathway of the type IV pilus system in Myxococcus xanthus.

PubMed

Friedrich, Carmen; Bulyha, Iryna; Søgaard-Andersen, Lotte

2014-01-01

Type IV pili (T4P) are ubiquitous bacterial cell surface structures that undergo cycles of extension, adhesion, and retraction. T4P function depends on a highly conserved envelope-spanning macromolecular machinery consisting of 10 proteins that localizes polarly in Myxococcus xanthus. Using this localization, we investigated the entire T4P machinery assembly pathway by systematically profiling the stability of all and the localization of eight of these proteins in the absence of other T4P machinery proteins as well as by mapping direct protein-protein interactions. Our experiments uncovered a sequential, outside-in pathway starting with the outer membrane (OM) PilQ secretin ring. PilQ recruits a subcomplex consisting of the inner membrane (IM) lipoprotein PilP and the integral IM proteins PilN and PilO by direct interaction with the periplasmic domain of PilP. The PilP/PilN/PilO subcomplex recruits the cytoplasmic PilM protein, by direct interaction between PilN and PilM, and the integral IM protein PilC. The PilB/PilT ATPases that power extension/retraction localize independently of other T4P machinery proteins. Thus, assembly of the T4P machinery initiates with formation of the OM secretin ring and continues inwards over the periplasm and IM to the cytoplasm.

"Plate cherry picking": a novel semi-sequential screening paradigm for cheaper, faster, information-rich compound selection.

PubMed

Crisman, Thomas J; Jenkins, Jeremy L; Parker, Christian N; Hill, W Adam G; Bender, Andreas; Deng, Zhan; Nettles, James H; Davies, John W; Glick, Meir

2007-04-01

This work describes a novel semi-sequential technique for in silico enhancement of high-throughput screening (HTS) experiments now employed at Novartis. It is used in situations in which the size of the screen is limited by the readout (e.g., high-content screens) or the amount of reagents or tools (proteins or cells) available. By performing computational chemical diversity selection on a per plate basis (instead of a per compound basis), 25% of the 1,000,000-compound screening was optimized for general initial HTS. Statistical models are then generated from target-specific primary results (percentage inhibition data) to drive the cherry picking and testing from the entire collection. Using retrospective analysis of 11 HTS campaigns, the authors show that this method would have captured on average two thirds of the active compounds (IC(50) < 10 microM) and three fourths of the active Murcko scaffolds while decreasing screening expenditure by nearly 75%. This result is true for a wide variety of targets, including G-protein-coupled receptors, chemokine receptors, kinases, metalloproteinases, pathway screens, and protein-protein interactions. Unlike time-consuming "classic" sequential approaches that require multiple iterations of cherry picking, testing, and building statistical models, here individual compounds are cherry picked just once, based directly on primary screening data. Strikingly, the authors demonstrate that models built from primary data are as robust as models built from IC(50) data. This is true for all HTS campaigns analyzed, which represent a wide variety of target classes and assay types.

On the Lulejian-I Combat Model

DTIC Science & Technology

1976-08-01

possible initial massing of the attacking side’s resources, the model tries to represent in a game -theoretic context the adversary nature of the...sequential game , as outlined in [A]. In principle, it is necessary to run the combat simulation once for each possible set of sequentially chosen...sequential game , in which the evaluative portion of the model (i.e., the combat assessment) serves to compute intermediate and terminal payoffs for the

Distinct regions of the interleukin-7 receptor regulate different Bcl2 family members.

PubMed

Jiang, Qiong; Li, Wen Qing; Hofmeister, Robert R; Young, Howard A; Hodge, David R; Keller, Jonathan R; Khaled, Annette R; Durum, Scott K

2004-07-01

The antiapoptotic function of the interleukin-7 (IL-7) receptor is related to regulation of three members of the Bcl2 family: synthesis of Bcl2, phosphorylation of Bad, and cytosolic retention of Bax. Here we show that, in an IL-7-dependent murine T-cell line, different regions of the IL-7 receptor initiate the signal transduction pathways that regulate these proteins. Both Box1 and Y449 are required to signal Bcl2 synthesis and Bax cytosolic retention. This suggests a sequential model in which Jak1, which binds to Box1, is first activated and then phosphorylates Y449, leading to Bcl2 and Bax regulation, accounting for approximately 90% of the survival function. Phosphorylation of Bad required Box1 but not Y449, suggesting that Jak1 also initiates an additional signaling cascade that accounts for approximately 10% of the survival function. Stat5 was activated from the Y449 site but only partially accounted for the survival signal. Proliferation required both Y449 and Box1. Thymocyte development in vivo showed that deletion of Y449 eliminated 90% of alphabeta T-cell development and completely eliminated gammadelta T-cell development, whereas deleting Box 1 completely eliminated both alphabeta and gammadelta T-cell development. Thus the IL-7 receptor controls at least two distinct pathways, in addition to Stat5, that are required for cell survival.

Heterogeneous photo-Fenton decolorization of Orange II over Al-pillared Fe-smectite: response surface approach, degradation pathway, and toxicity evaluation.

PubMed

Li, Huiyuan; Li, Yanli; Xiang, Luojing; Huang, Qianqian; Qiu, Juanjuan; Zhang, Hui; Sivaiah, Matte Venkata; Baron, Fabien; Barrault, Joel; Petit, Sabine; Valange, Sabine

2015-04-28

A ferric smectite clay material was synthesized and further intercalated with Al2O3 pillars for the first time with the aim of evaluating its ability to be used as heterogeneous catalyst for the photo-Fenton decolorization of azo dye Orange II. UV irradiation was found to enhance the activity of the catalyst in the heterogeneous photo-Fenton process. Catalyst loading of 0.5g/L and hydrogen peroxide concentration of 13.5mM yielded a remarkable color removal, accompanied by excellent catalyst stability. The decolorization of Orange II followed the pseudo-first-order kinetics for initial dye concentrations from 20 to 160mg/L. The central composite design (CCD) based on the response surface methodology (RSM) was applied to evaluate the effects of several operating parameters, namely initial pH, catalyst loading and hydrogen peroxide concentration, on the decolorization efficiency. The RSM model was derived and the response surface plots were developed based on the results. Moreover, the main intermediate products were separated and identified using gas chromatography-mass spectrometry (GC-MS) and a possible degradation pathway was proposed accordingly. The acute toxicity experiments illustrated that the Daphniamagna immobilization rate continuously decreased during 150min reaction, indicating that the effluent was suitable for sequential biological treatment. Copyright © 2015 Elsevier B.V. All rights reserved.

Rise and fall of political complexity in island South-East Asia and the Pacific.

PubMed

Currie, Thomas E; Greenhill, Simon J; Gray, Russell D; Hasegawa, Toshikazu; Mace, Ruth

2010-10-14

There is disagreement about whether human political evolution has proceeded through a sequence of incremental increases in complexity, or whether larger, non-sequential increases have occurred. The extent to which societies have decreased in complexity is also unclear. These debates have continued largely in the absence of rigorous, quantitative tests. We evaluated six competing models of political evolution in Austronesian-speaking societies using phylogenetic methods. Here we show that in the best-fitting model political complexity rises and falls in a sequence of small steps. This is closely followed by another model in which increases are sequential but decreases can be either sequential or in bigger drops. The results indicate that large, non-sequential jumps in political complexity have not occurred during the evolutionary history of these societies. This suggests that, despite the numerous contingent pathways of human history, there are regularities in cultural evolution that can be detected using computational phylogenetic methods.

Protein folding and misfolding: mechanism and principles

PubMed Central

Englander, S. Walter; Mayne, Leland; Krishna, Mallela M. G.

2012-01-01

Two fundamentally different views of how proteins fold are now being debated. Do proteins fold through multiple unpredictable routes directed only by the energetically downhill nature of the folding landscape or do they fold through specific intermediates in a defined pathway that systematically puts predetermined pieces of the target native protein into place? It has now become possible to determine the structure of protein folding intermediates, evaluate their equilibrium and kinetic parameters, and establish their pathway relationships. Results obtained for many proteins have serendipitously revealed a new dimension of protein structure. Cooperative structural units of the native protein, called foldons, unfold and refold repeatedly even under native conditions. Much evidence obtained by hydrogen exchange and other methods now indicates that cooperative foldon units and not individual amino acids account for the unit steps in protein folding pathways. The formation of foldons and their ordered pathway assembly systematically puts native-like foldon building blocks into place, guided by a sequential stabilization mechanism in which prior native-like structure templates the formation of incoming foldons with complementary structure. Thus the same propensities and interactions that specify the final native state, encoded in the amino-acid sequence of every protein, determine the pathway for getting there. Experimental observations that have been interpreted differently, in terms of multiple independent pathways, appear to be due to chance misfolding errors that cause different population fractions to block at different pathway points, populate different pathway intermediates, and fold at different rates. This paper summarizes the experimental basis for these three determining principles and their consequences. Cooperative native-like foldon units and the sequential stabilization process together generate predetermined stepwise pathways. Optional misfolding errors are responsible for 3-state and heterogeneous kinetic folding. PMID:18405419

Matriptase activation connects tissue factor-dependent coagulation initiation to epithelial proteolysis and signaling.

PubMed

Le Gall, Sylvain M; Szabo, Roman; Lee, Melody; Kirchhofer, Daniel; Craik, Charles S; Bugge, Thomas H; Camerer, Eric

2016-06-23

The coagulation cascade is designed to sense tissue injury by physical separation of the membrane-anchored cofactor tissue factor (TF) from inactive precursors of coagulation proteases circulating in plasma. Once TF on epithelial and other extravascular cells is exposed to plasma, sequential activation of coagulation proteases coordinates hemostasis and contributes to host defense and tissue repair. Membrane-anchored serine proteases (MASPs) play critical roles in the development and homeostasis of epithelial barrier tissues; how MASPs are activated in mature epithelia is unknown. We here report that proteases of the extrinsic pathway of blood coagulation transactivate the MASP matriptase, thus connecting coagulation initiation to epithelial proteolysis and signaling. Exposure of TF-expressing cells to factors (F) VIIa and Xa triggered the conversion of latent pro-matriptase to an active protease, which in turn cleaved the pericellular substrates protease-activated receptor-2 (PAR2) and pro-urokinase. An activation pathway-selective PAR2 mutant resistant to direct cleavage by TF:FVIIa and FXa was activated by these proteases when cells co-expressed pro-matriptase, and matriptase transactivation was necessary for efficient cleavage and activation of wild-type PAR2 by physiological concentrations of TF:FVIIa and FXa. The coagulation initiation complex induced rapid and prolonged enhancement of the barrier function of epithelial monolayers that was dependent on matriptase transactivation and PAR2 signaling. These observations suggest that the coagulation cascade engages matriptase to help coordinate epithelial defense and repair programs after injury or infection, and that matriptase may contribute to TF-driven pathogenesis in cancer and inflammation.

A Two-Component Monooxygenase Catalyzes Both the Hydroxylation of p-Nitrophenol and the Oxidative Release of Nitrite from 4-Nitrocatechol in Bacillus sphaericus JS905

PubMed Central

Kadiyala, Venkateswarlu; Spain, Jim C.

1998-01-01

Bacteria that metabolize p-nitrophenol (PNP) oxidize the substrate to 3-ketoadipic acid via either hydroquinone or 1,2,4-trihydroxybenzene (THB); however, initial steps in the pathway for PNP biodegradation via THB are unclear. The product of initial hydroxylation of PNP could be either 4-nitrocatechol or 4-nitroresorcinol. Here we describe the complete pathway for aerobic PNP degradation by Bacillus sphaericus JS905 that was isolated by selective enrichment from an agricultural soil in India. Washed cells of PNP-grown JS905 released nitrite in stoichiometric amounts from PNP and 4-nitrocatechol. Experiments with extracts obtained from PNP-grown cells revealed that the initial reaction is a hydroxylation of PNP to yield 4-nitrocatechol. 4-Nitrocatechol is subsequently oxidized to THB with the concomitant removal of the nitro group as nitrite. The enzyme that catalyzed the two sequential monooxygenations of PNP was partially purified and separated into two components by anion-exchange chromatography and size exclusion chromatography. Both components were required for NADH-dependent oxidative release of nitrite from PNP or 4-nitrocatechol. One of the components was identified as a reductase based on its ability to catalyze the NAD(P)H-dependent reduction of 2,6-dichlorophenolindophenol and nitroblue tetrazolium. Nitrite release from either PNP or 4-nitrocatechol was inhibited by the flavoprotein inhibitor methimazole. Our results indicate that the two monooxygenations of PNP to THB are catalyzed by a single two-component enzyme system comprising a flavoprotein reductase and an oxygenase. PMID:9647818

Durability of Adherence to Antiretroviral Therapy on Initial and Subsequent Regimens

PubMed Central

GARDNER, EDWARD M.; BURMAN, WILLIAM J.; MARAVI, MOISES E.; DAVIDSON, ARTHUR J.

2007-01-01

There is uncertainty regarding the durability of adherence to antiretroviral therapy. This study is a retrospective review of previously antiretroviral naïve patients initiating therapy between 1997 and 2002. Antiretroviral adherence was calculated using prescription refill data and was analyzed over time on an initial regimen and on sequential antiretroviral regimens. Three hundred forty-four patients were included. The median lengths of the first, second, and third regimens were stable at 1.7 years, 1.2 years, and 1.5 years, respectively (p = 0.10). In multivariate analysis the factor most significantly associated with earlier initial regimen termination was poor adherence. On an initial regimen, adherence decreased over time and declined most rapidly in patients with the shortest regimens (4 to <16 months, −43% per year), followed by patients with intermediate regimen duration (16 to <28 months, −19% per year), and then patients with longer regimens (≥28 months, −5% per year). In patients progressing to a third regimen, there was a trend toward decreasing adherence over successive regimens. In conclusion, sequential antiretroviral regimens are of similar lengths, with adherence being highly associated with first regimen duration. Adherence decreases during an initial regimen and on sequential antiretroviral regimens. Effective and durable interventions to prevent declining adherence are needed. PMID:16987049

SWATH label-free proteomics analyses revealed the roles of oxidative stress and antioxidant defensing system in sclerotia formation of Polyporus umbellatus

NASA Astrophysics Data System (ADS)

Li, Bing; Tian, Xiaofang; Wang, Chunlan; Zeng, Xu; Xing, Yongmei; Ling, Hong; Yin, Wanqiang; Tian, Lixia; Meng, Zhixia; Zhang, Jihui; Guo, Shunxing

2017-01-01

Understanding the initiation and maturing mechanisms is important for rational manipulating sclerotia differentiation and growth from hypha of Polyporus umbellatus. Proteomes in P. umbellatus sclerotia and hyphae at initial, developmental and mature phases were studied. 1391 proteins were identified by nano-liquid chromatograph-mass spectrometry (LC-MS) in Data Dependant Acquisition mode, and 1234 proteins were quantified successfully by Sequential Window Acquisition of all THeoretical fragment ion spectra-MS (SWATH-MS) technology. There were 347 differentially expressed proteins (DEPs) in sclerotia at initial phase compared with those in hypha, and the DEP profiles were dynamically changing with sclerotia growth. Oxidative stress (OS) in sclerotia at initial phase was indicated by the repressed proteins of respiratory chain, tricarboxylic acid cycle and the activation of glycolysis/gluconeogenesis pathways were determined based on DEPs. The impact of glycolysis/gluconeogenesis on sclerotium induction was further verified by glycerol addition assays, in which 5% glycerol significantly increased sclerotial differentiation rate and biomass. It can be speculated that OS played essential roles in triggering sclerotia differentiation from hypha of P. umbellatus, whereas antioxidant activity associated with glycolysis is critical for sclerotia growth. These findings reveal a mechanism for sclerotial differentiation in P. umbellatus, which may also be applicable for other fungi.

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats.

PubMed

Qin, Liyan; Dai, Xufang; Yin, Yunhou

2016-09-01

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, limited verbal communication and repetitive behaviors. Recent studies have demonstrated that Wnt signaling and mTOR signaling play important roles in the pathogenesis of ASD. However, the relationship of these two signaling pathways in ASD remains unclear. We assessed this question using the valproic acid (VPA) rat model of autism. Our results demonstrated that VPA exposure activated mTOR signaling and suppressed autophagy in the prefrontal cortex, hippocampus and cerebellum of autistic model rats, characterized by enhanced phospho-mTOR and phospho-S6 and decreased Beclin1, Atg5, Atg10, LC3-II and autophagosome formation. Rapamycin treatment suppressed the effect of VPA on mTOR signaling and ameliorated the autistic-like behaviors of rats in our autism model. The administration of VPA also activated Wnt signaling through up-regulating beta-catenin and phospho-GSK3beta. Suppression of the Wnt pathway by sulindac relieved autistic-like behaviors and attenuated VPA-induced mTOR signaling activation in autistic model rats. Our results demonstrate that VPA exposure sequentially activates Wnt signaling and mTOR signaling in rats. Suppression of the Wnt signaling pathway relieves autistic-like behaviors partially by deactivating the mTOR signaling pathway in VPA-exposed rats. Copyright © 2016 Elsevier Inc. All rights reserved.

Communication: Direct evidence for sequential dissociation of gas-phase Fe(CO)5 via a singlet pathway upon excitation at 266 nm

PubMed Central

Leitner, T.; Mazza, T.; Schröder, H.; Kunnus, K.; Schreck, S.; Radcliffe, P.; Düsterer, S.; Meyer, M.; Föhlisch, A.

2017-01-01

We prove the hitherto hypothesized sequential dissociation of Fe(CO)5 in the gas phase upon photoexcitation at 266 nm via a singlet pathway with time-resolved valence and core-level photoelectron spectroscopy with an x-ray free-electron laser. Valence photoelectron spectra are used to identify free CO molecules and to determine the time constants of stepwise dissociation to Fe(CO)4 within the temporal resolution of the experiment and further to Fe(CO)3 within 3 ps. Fe 3p core-level photoelectron spectra directly reflect the singlet spin state of the Fe center in Fe(CO)5, Fe(CO)4, and Fe(CO)3 showing that the dissociation exclusively occurs along a singlet pathway without triplet-state contribution. Our results are important for assessing intra- and intermolecular relaxation processes in the photodissociation dynamics of the prototypical Fe(CO)5 complex in the gas phase and in solution, and they establish time-resolved core-level photoelectron spectroscopy as a powerful tool for determining the multiplicity of transition metals in photochemical reactions of coordination complexes. PMID:28595420

Putative adverse outcome pathways relevant to neurotoxicity

PubMed Central

Bal-Price, Anna; Crofton, Kevin M.; Sachana, Magdalini; Shafer, Timothy J.; Behl, Mamta; Forsby, Anna; Hargreaves, Alan; Landesmann, Brigitte; Lein, Pamela J.; Louisse, Jochem; Monnet-Tschudi, Florianne; Paini, Alicia; Rolaki, Alexandra; Schrattenholz, André; Suñol, Cristina; van Thriel, Christoph; Whelan, Maurice; Fritsche, Ellen

2016-01-01

The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways. PMID:25605028

Substitutions at Amino Acid Positions 143, 148, and 155 of HIV-1 Integrase Define Distinct Genetic Barriers to Raltegravir Resistance In Vivo

PubMed Central

Fransen, Signe; Gupta, Soumi; Frantzell, Arne; Petropoulos, Christos J.

2012-01-01

Mutations at amino acids 143, 148, and 155 in HIV-1 integrase (IN) define primary resistance pathways in subjects failing raltegravir (RAL)-containing treatments. Although each pathway appears to be genetically distinct, shifts in the predominant resistant virus population have been reported under continued drug pressure. To better understand this dynamic, we characterized the RAL susceptibility of 200 resistant viruses, and we performed sequential clonal analysis for selected cases. Patient viruses containing Y143R, Q148R, or Q148H mutations consistently exhibited larger reductions in RAL susceptibility than patient viruses containing N155H mutations. Sequential analyses of virus populations from three subjects revealed temporal shifts in subpopulations representing N155H, Y143R, or Q148H escape pathways. Evaluation of molecular clones isolated from different time points demonstrated that Y143R and Q148H variants exhibited larger reductions in RAL susceptibility and higher IN-mediated replication capacity (RC) than N155H variants within the same subject. Furthermore, shifts from the N155H pathway to either the Q148R or H pathway or the Y143R pathway were dependent on the amino acid substitution at position 148 and the secondary mutations in Y143R- or Q148R- or H-containing variants and correlated with reductions in RAL susceptibility and restorations in RC. Our observations in patient viruses were confirmed by analyzing site-directed mutations. In summary, viruses that acquire mutations defining the 143 or 148 escape pathways are less susceptible to RAL and exhibit greater RC than viruses containing 155 pathway mutations. These selective pressures result in the displacement of N155H variants by 143 or 148 variants under continued drug exposure. PMID:22553340

The Nature of Phonological Encoding During Spoken Word Retrieval.

ERIC Educational Resources Information Center

Sullivan, Michael P.; Riffel, Brian

1999-01-01

Examined whether phonological selection occurs sequentially or in parallel. College students named picture primes and targets, with varied response stimulus intervals between primes and targets. Results were consistent with Dell's (1988) two-stage sequential model of encoding, which shows an initial parallel activation within a lexical network…

COMPARISON OF HYDROGEN CONCENTRATIONS IN PCE-DEHALOGENATING AND SULFATE-REDUCING ESTUARINE SEDIMENTS

EPA Science Inventory

The primary transformation pathway for PCE in anoxic environments is through sequential reductive dehalogenation, and information concerning dehalogenation processes that occur in environments containing alternative electron acceptors (sulfate) is limited. Hydrogen is postulated ...

Protein-protein interactions and metabolite channelling in the plant tricarboxylic acid cycle

PubMed Central

Zhang, Youjun; Beard, Katherine F. M.; Swart, Corné; Bergmann, Susan; Krahnert, Ina; Nikoloski, Zoran; Graf, Alexander; Ratcliffe, R. George; Sweetlove, Lee J.; Fernie, Alisdair R.; Obata, Toshihiro

2017-01-01

Protein complexes of sequential metabolic enzymes, often termed metabolons, may permit direct channelling of metabolites between the enzymes, providing increased control over metabolic pathway fluxes. Experimental evidence supporting their existence in vivo remains fragmentary. In the present study, we test binary interactions of the proteins constituting the plant tricarboxylic acid (TCA) cycle. We integrate (semi-)quantitative results from affinity purification-mass spectrometry, split-luciferase and yeast-two-hybrid assays to generate a single reliability score for assessing protein–protein interactions. By this approach, we identify 158 interactions including those between catalytic subunits of sequential enzymes and between subunits of enzymes mediating non-adjacent reactions. We reveal channelling of citrate and fumarate in isolated potato mitochondria by isotope dilution experiments. These results provide evidence for a functional TCA cycle metabolon in plants, which we discuss in the context of contemporary understanding of this pathway in other kingdoms. PMID:28508886

General mechanism of two-state protein folding kinetics.

PubMed

Rollins, Geoffrey C; Dill, Ken A

2014-08-13

We describe here a general model of the kinetic mechanism of protein folding. In the Foldon Funnel Model, proteins fold in units of secondary structures, which form sequentially along the folding pathway, stabilized by tertiary interactions. The model predicts that the free energy landscape has a volcano shape, rather than a simple funnel, that folding is two-state (single-exponential) when secondary structures are intrinsically unstable, and that each structure along the folding path is a transition state for the previous structure. It shows how sequential pathways are consistent with multiple stochastic routes on funnel landscapes, and it gives good agreement with the 9 order of magnitude dependence of folding rates on protein size for a set of 93 proteins, at the same time it is consistent with the near independence of folding equilibrium constant on size. This model gives estimates of folding rates of proteomes, leading to a median folding time in Escherichia coli of about 5 s.

A Sequential Multiplicative Extended Kalman Filter for Attitude Estimation Using Vector Observations.

PubMed

Qin, Fangjun; Chang, Lubin; Jiang, Sai; Zha, Feng

2018-05-03

In this paper, a sequential multiplicative extended Kalman filter (SMEKF) is proposed for attitude estimation using vector observations. In the proposed SMEKF, each of the vector observations is processed sequentially to update the attitude, which can make the measurement model linearization more accurate for the next vector observation. This is the main difference to Murrell’s variation of the MEKF, which does not update the attitude estimate during the sequential procedure. Meanwhile, the covariance is updated after all the vector observations have been processed, which is used to account for the special characteristics of the reset operation necessary for the attitude update. This is the main difference to the traditional sequential EKF, which updates the state covariance at each step of the sequential procedure. The numerical simulation study demonstrates that the proposed SMEKF has more consistent and accurate performance in a wide range of initial estimate errors compared to the MEKF and its traditional sequential forms.

A Sequential Multiplicative Extended Kalman Filter for Attitude Estimation Using Vector Observations

PubMed Central

Qin, Fangjun; Jiang, Sai; Zha, Feng

2018-01-01

In this paper, a sequential multiplicative extended Kalman filter (SMEKF) is proposed for attitude estimation using vector observations. In the proposed SMEKF, each of the vector observations is processed sequentially to update the attitude, which can make the measurement model linearization more accurate for the next vector observation. This is the main difference to Murrell’s variation of the MEKF, which does not update the attitude estimate during the sequential procedure. Meanwhile, the covariance is updated after all the vector observations have been processed, which is used to account for the special characteristics of the reset operation necessary for the attitude update. This is the main difference to the traditional sequential EKF, which updates the state covariance at each step of the sequential procedure. The numerical simulation study demonstrates that the proposed SMEKF has more consistent and accurate performance in a wide range of initial estimate errors compared to the MEKF and its traditional sequential forms. PMID:29751538

A Sequential Model of Host Cell Killing and Phagocytosis by Entamoeba histolytica

PubMed Central

Sateriale, Adam; Huston, Christopher D.

2011-01-01

The protozoan parasite Entamoeba histolytica is responsible for invasive intestinal and extraintestinal amebiasis. The virulence of Entamoeba histolytica is strongly correlated with the parasite's capacity to effectively kill and phagocytose host cells. The process by which host cells are killed and phagocytosed follows a sequential model of adherence, cell killing, initiation of phagocytosis, and engulfment. This paper presents recent advances in the cytolytic and phagocytic processes of Entamoeba histolytica in context of the sequential model. PMID:21331284

Accurate means of detecting and characterizing abnormal patterns of ventricular activation by phase image analysis

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

Botvinick, E.H.; Frais, M.A.; Shosa, D.W.

1982-08-01

The ability of scintigraphic phase image analysis to characterize patterns of abnormal ventricular activation was investigated. The pattern of phase distribution and sequential phase changes over both right and left ventricular regions of interest were evaluated in 16 patients with normal electrical activation and wall motion and compared with those in 8 patients with an artificial pacemaker and 4 patients with sinus rhythm with the Wolff-Parkinson-White syndrome and delta waves. Normally, the site of earliest phase angle was seen at the base of the interventricular septum, with sequential change affecting the body of the septum and the cardiac apex andmore » then spreading laterally to involve the body of both ventricles. The site of earliest phase angle was located at the apex of the right ventricle in seven patients with a right ventricular endocardial pacemaker and on the lateral left ventricular wall in one patient with a left ventricular epicardial pacemaker. In each case the site corresponded exactly to the position of the pacing electrode as seen on posteroanterior and left lateral chest X-ray films, and sequential phase changes spread from the initial focus to affect both ventricles. In each of the patients with the Wolff-Parkinson-White syndrome, the site of earliest ventricular phase angle was located, and it corresponded exactly to the site of the bypass tract as determined by endocardial mapping. In this way, four bypass pathways, two posterior left paraseptal, one left lateral and one right lateral, were correctly localized scintigraphically. On the basis of the sequence of mechanical contraction, phase image analysis provides an accurate noninvasive method of detecting abnormal foci of ventricular activation.« less

Methods of sequential estimation for determining initial data in numerical weather prediction. Ph.D. Thesis

NASA Technical Reports Server (NTRS)

Cohn, S. E.

1982-01-01

Numerical weather prediction (NWP) is an initial-value problem for a system of nonlinear differential equations, in which initial values are known incompletely and inaccurately. Observational data available at the initial time must therefore be supplemented by data available prior to the initial time, a problem known as meteorological data assimilation. A further complication in NWP is that solutions of the governing equations evolve on two different time scales, a fast one and a slow one, whereas fast scale motions in the atmosphere are not reliably observed. This leads to the so called initialization problem: initial values must be constrained to result in a slowly evolving forecast. The theory of estimation of stochastic dynamic systems provides a natural approach to such problems. For linear stochastic dynamic models, the Kalman-Bucy (KB) sequential filter is the optimal data assimilation method, for linear models, the optimal combined data assimilation-initialization method is a modified version of the KB filter.

Decomposition of the polycyclic nitramine explosive, CL-20, by Fe(0).

PubMed

Balakrishnan, Vimal K; Monteil-Rivera, Fanny; Halasz, Annamaria; Corbeanu, Aurelian; Hawari, Jalal

2004-12-15

CL-20 (2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane), C6H6N12O12, is an emerging energetic chemical that may replace RDX, but its degradation pathways are not well-known. In the present study, zerovalent iron was used to degrade CL-20 with the aim of determining its products and degradation pathways. In the absence of O2, CL-20 underwent a rapid decomposition with the concurrent formation of nitrite to ultimately produce nitrous oxide, ammonium, formate, glyoxal, and glycolate. LC/MS (ES-) showed the presence of several key products carrying important information on the initial reactions involved in the degradation of CL-20. For instance, a doubly denitrated intermediate of CL-20 was detected together with the mono- and dinitroso derivatives of the energetic chemical. Two other intermediates with [M-H]- at 392 and 376 Da, matching empirical formulas of C6H7N11O10 and C6H7N11O9, respectively, were detected. Using 15N-labeled CL-20, the two intermediates were tentatively identified as the denitrohydrogenated products of CL-20 and its mononitroso derivative, respectively. The present experimental findings suggest that CL-20 degraded via at least two initial routes: one involving denitration and the second involving sequential reduction of the N-NO2 to the corresponding nitroso (N-NO) derivatives prior to denitration and ring cleavage.

Surface structure characterization of Aspergillus fumigatus conidia mutated in the melanin synthesis pathway and their human cellular immune response.

PubMed

Bayry, Jagadeesh; Beaussart, Audrey; Dufrêne, Yves F; Sharma, Meenu; Bansal, Kushagra; Kniemeyer, Olaf; Aimanianda, Vishukumar; Brakhage, Axel A; Kaveri, Srini V; Kwon-Chung, Kyung J; Latgé, Jean-Paul; Beauvais, Anne

2014-08-01

In Aspergillus fumigatus, the conidial surface contains dihydroxynaphthalene (DHN)-melanin. Six-clustered gene products have been identified that mediate sequential catalysis of DHN-melanin biosynthesis. Melanin thus produced is known to be a virulence factor, protecting the fungus from the host defense mechanisms. In the present study, individual deletion of the genes involved in the initial three steps of melanin biosynthesis resulted in an altered conidial surface with masked surface rodlet layer, leaky cell wall allowing the deposition of proteins on the cell surface and exposing the otherwise-masked cell wall polysaccharides at the surface. Melanin as such was immunologically inert; however, deletion mutant conidia with modified surfaces could activate human dendritic cells and the subsequent cytokine production in contrast to the wild-type conidia. Cell surface defects were rectified in the conidia mutated in downstream melanin biosynthetic pathway, and maximum immune inertness was observed upon synthesis of vermelone onward. These observations suggest that although melanin as such is an immunologically inert material, it confers virulence by facilitating proper formation of the A. fumigatus conidial surface. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Dynamic DNA methylation reconfiguration during seed development and germination.

PubMed

Kawakatsu, Taiji; Nery, Joseph R; Castanon, Rosa; Ecker, Joseph R

2017-09-15

Unlike animals, plants can pause their life cycle as dormant seeds. In both plants and animals, DNA methylation is involved in the regulation of gene expression and genome integrity. In animals, reprogramming erases and re-establishes DNA methylation during development. However, knowledge of reprogramming or reconfiguration in plants has been limited to pollen and the central cell. To better understand epigenetic reconfiguration in the embryo, which forms the plant body, we compared time-series methylomes of dry and germinating seeds to publicly available seed development methylomes. Time-series whole genome bisulfite sequencing reveals extensive gain of CHH methylation during seed development and drastic loss of CHH methylation during germination. These dynamic changes in methylation mainly occur within transposable elements. Active DNA methylation during seed development depends on both RNA-directed DNA methylation and heterochromatin formation pathways, whereas global demethylation during germination occurs in a passive manner. However, an active DNA demethylation pathway is initiated during late seed development. This study provides new insights into dynamic DNA methylation reprogramming events during seed development and germination and suggests possible mechanisms of regulation. The observed sequential methylation/demethylation cycle suggests an important role of DNA methylation in seed dormancy.

Ru–protein–Co biohybrids designed for solar hydrogen production: understanding electron transfer pathways related to photocatalytic function† †Electronic supplementary information (ESI) available: Time traces of photocatalysis, additional EPR spectra and parameters, UV-visible spectroscopy data, and kinetic fits of TA traces. See DOI: 10.1039/c6sc03121h Click here for additional data file.

PubMed Central

Soltau, Sarah R.; Dahlberg, Peter D.; Niklas, Jens; Poluektov, Oleg G.; Mulfort, Karen L.

2016-01-01

A series of Ru–protein–Co biohybrids have been prepared using the electron transfer proteins ferredoxin (Fd) and flavodoxin (Fld) as scaffolds for photocatalytic hydrogen production. The light-generated charge separation within these hybrids has been monitored by transient optical and electron paramagnetic resonance spectroscopies. Two distinct electron transfer pathways are observed. The Ru–Fd–Co biohybrid produces up to 650 turnovers of H2 utilizing an oxidative quenching mechanism for Ru(ii)* and a sequential electron transfer pathway via the native [2Fe–2S] cluster to generate a Ru(iii)–Fd–Co(i) charge separated state that lasts for ∼6 ms. In contrast, a direct electron transfer pathway occurs for the Ru–ApoFld–Co biohybrid, which lacks an internal electron relay, generating Ru(i)–ApoFld–Co(i) charge separated state that persists for ∼800 μs and produces 85 turnovers of H2 by a reductive quenching mechanism for Ru(ii)*. This work demonstrates the utility of protein architectures for linking donor and catalytic function via direct or sequential electron transfer pathways to enable stabilized charge separation which facilitates photocatalysis for solar fuel production. PMID:28451142

The composite sequential clustering technique for analysis of multispectral scanner data

NASA Technical Reports Server (NTRS)

Su, M. Y.

1972-01-01

The clustering technique consists of two parts: (1) a sequential statistical clustering which is essentially a sequential variance analysis, and (2) a generalized K-means clustering. In this composite clustering technique, the output of (1) is a set of initial clusters which are input to (2) for further improvement by an iterative scheme. This unsupervised composite technique was employed for automatic classification of two sets of remote multispectral earth resource observations. The classification accuracy by the unsupervised technique is found to be comparable to that by traditional supervised maximum likelihood classification techniques. The mathematical algorithms for the composite sequential clustering program and a detailed computer program description with job setup are given.

Ultrafast fragmentation dynamics of triply charged carbon dioxide: Vibrational-mode-dependent molecular bond breakage

NASA Astrophysics Data System (ADS)

Yang, HongJiang; Wang, Enliang; Dong, WenXiu; Gong, Maomao; Shen, Zhenjie; Tang, Yaguo; Shan, Xu; Chen, Xiangjun

2018-05-01

The a b i n i t i o molecular dynamics (MD) simulations using an atom-centered density matrix propagation method have been carried out to investigate the fragmentation of the ground-state triply charged carbon dioxide, CO23 +→C+ + Oa+ + Ob+ . Ten thousands of trajectories have been simulated. By analyzing the momentum correlation of the final fragments, it is demonstrated that the sequential fragmentation dominates in the three-body dissociation, consistent with our experimental observations which were performed by electron collision at impact energy of 1500 eV. Furthermore, the MD simulations allow us to have detailed insight into the ultrafast evolution of the molecular bond breakage at a very early stage, within several tens of femtoseconds, and the result shows that the initial nuclear vibrational mode plays a decisive role in switching the dissociation pathways.

Bayesian parameter estimation for the Wnt pathway: an infinite mixture models approach.

PubMed

Koutroumpas, Konstantinos; Ballarini, Paolo; Votsi, Irene; Cournède, Paul-Henry

2016-09-01

Likelihood-free methods, like Approximate Bayesian Computation (ABC), have been extensively used in model-based statistical inference with intractable likelihood functions. When combined with Sequential Monte Carlo (SMC) algorithms they constitute a powerful approach for parameter estimation and model selection of mathematical models of complex biological systems. A crucial step in the ABC-SMC algorithms, significantly affecting their performance, is the propagation of a set of parameter vectors through a sequence of intermediate distributions using Markov kernels. In this article, we employ Dirichlet process mixtures (DPMs) to design optimal transition kernels and we present an ABC-SMC algorithm with DPM kernels. We illustrate the use of the proposed methodology using real data for the canonical Wnt signaling pathway. A multi-compartment model of the pathway is developed and it is compared to an existing model. The results indicate that DPMs are more efficient in the exploration of the parameter space and can significantly improve ABC-SMC performance. In comparison to alternative sampling schemes that are commonly used, the proposed approach can bring potential benefits in the estimation of complex multimodal distributions. The method is used to estimate the parameters and the initial state of two models of the Wnt pathway and it is shown that the multi-compartment model fits better the experimental data. Python scripts for the Dirichlet Process Gaussian Mixture model and the Gibbs sampler are available at https://sites.google.com/site/kkoutroumpas/software konstantinos.koutroumpas@ecp.fr. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Sequential Reactions of Surface-Tethered Glycolytic Enzymes

PubMed Central

Mukai, Chinatsu; Bergkvist, Magnus; Nelson, Jacquelyn L.; Travis, Alexander J.

2014-01-01

SUMMARY The development of complex hybrid organic-inorganic devices faces several challenges, including how they can generate energy. Cells face similar challenges regarding local energy production. Mammalian sperm solve this problem by generating ATP down the flagellar principal piece by means of glycolytic enzymes, several of which are tethered to a cytoskeletal support via germ cell-specific targeting domains. Inspired by this design, we have produced recombinant hexokinase type 1 and glucose-6-phosphate isomerase capable of oriented immobilization on a nickel-nitrilotriacetic acid modified surface. Specific activities of enzymes tethered via this strategy were substantially higher than when randomly adsorbed. Furthermore, these enzymes showed sequential activities when tethered onto the same surface. This is the first demonstration of surface-tethered pathway components showing sequential enzymatic activities, and it provides a first step toward reconstitution of glycolysis on engineered hybrid devices. PMID:19778729

ROC and Loss Function Analysis in Sequential Testing

ERIC Educational Resources Information Center

Muijtjens, Arno M. M.; Van Luijk, Scheltus J.; Van Der Vleuten, Cees P. M.

2006-01-01

Sequential testing is applied to reduce costs in SP-based tests (OSCEs). Initially, all candidates take a screening test consisting of a part of the OSCE. Candidates who fail the screen sit the complete test, whereas those who pass the screen are qualified as a pass of the complete test. The procedure may result in a reduction of testing…

Discovering the route from inflammation to pancreatic cancer

PubMed Central

MOMI, N.; KAUR, S.; KRISHN, S. R.; BATRA, S. K.

2013-01-01

Pancreatic cancer (PC) remains a complex malignancy with the worst prognosis, lack of early diagnostic symptoms and resistance to conventional chemo- and radiotherapies. A better understanding of the etiology and early developmental events of PC requires profound attention. The evolution of fully blown PC from initial pancreatic injury is a multi-factorial phenomenon with a series of sequential events. The initial acute infection or tissue damage triggers inflammation that, in conjunction with innate immunity, establishes a state of homeostasis to limit harm to the body. Recurrent pancreatic injuries due to genetic susceptibility, smoking, unhealthy diet, and alcohol abuse induces a pro-inflammatory milieu, consisting of various types of immune cells, cytokines, chemokines, growth factors and restructured extracellular matrix, leading to prolonged inflammatory/chronic conditions. Cells having sustained DNA damage and/or mutagenic assault take advantage of this prolonged inflammatory response and aid in the initiation and development of neoplastic/fibrotic events. Eventually, many tumor-stromal interactions result in a chaotic environment accompanied by a loss of immune surveillance and repair response, thereby leading to PC. A better understanding of the inflammatory markers defining this “injury-inflammation-cancer” pathway would help to identify novel molecular targets for early screening and therapeutic intervention for this lethal malignancy. PMID:23207606

Losing a dime with a satisfied mind: positive affect predicts less search in sequential decision making.

PubMed

von Helversen, Bettina; Mata, Rui

2012-12-01

We investigated the contribution of cognitive ability and affect to age differences in sequential decision making by asking younger and older adults to shop for items in a computerized sequential decision-making task. Older adults performed poorly compared to younger adults partly due to searching too few options. An analysis of the decision process with a formal model suggested that older adults set lower thresholds for accepting an option than younger participants. Further analyses suggested that positive affect, but not fluid abilities, was related to search in the sequential decision task. A second study that manipulated affect in younger adults supported the causal role of affect: Increased positive affect lowered the initial threshold for accepting an attractive option. In sum, our results suggest that positive affect is a key factor determining search in sequential decision making. Consequently, increased positive affect in older age may contribute to poorer sequential decisions by leading to insufficient search. 2013 APA, all rights reserved

Unsteady, one-dimensional gas dynamics computations using a TVD type sequential solver

NASA Technical Reports Server (NTRS)

Thakur, Siddharth; Shyy, Wei

1992-01-01

The efficacy of high resolution convection schemes to resolve sharp gradient in unsteady, 1D flows is examined using the TVD concept based on a sequential solution algorithm. Two unsteady flow problems are considered which include the problem involving the interaction of the various waves in a shock tube with closed reflecting ends and the problem involving the unsteady gas dynamics in a tube with closed ends subject to an initial pressure perturbation. It is concluded that high accuracy convection schemes in a sequential solution framework are capable of resolving discontinuities in unsteady flows involving complex gas dynamics. However, a sufficient amount of dissipation is required to suppress oscillations near discontinuities in the sequential approach, which leads to smearing of the solution profiles.

Modeling non-homologous end joining.

PubMed

Li, Yongfeng; Cucinotta, Francis A

2011-08-21

Non-homologous end joining (NHEJ) is an important DNA repair pathway for DNA double-strand breaks. Several proteins, including Ku, DNA-PKcs, Artemis, XRCC4/Ligase IV and XLF, are involved in the NHEJ for the DNA damage detection, DNA free end processing and ligation. The classical model of NHEJ is a sequential model in which DNA-PKcs is first recruited by the Ku bound DNA prior to any other repair proteins. Recent experimental study (McElhinny et al., 2000; Costantini et al., 2007; Mari et al., 2006; Yano and Chen, 2008) suggested that the recruitment ordering is not crucial. In this work, by proposing a mathematical model in terms of biochemical reaction network and performing stability and related analysis, we demonstrate theoretically that if DSB repair pathway independent of DNA-PKcs exists, then the classical sequential model and new two-phase model are essentially indistinguishable in the sense that DSB can be repaired thoroughly in both models when the repair proteins are sufficient. Published by Elsevier Ltd.

General Mechanism of Two-State Protein Folding Kinetics

PubMed Central

Rollins, Geoffrey C.; Dill, Ken A.

2016-01-01

We describe here a general model of the kinetic mechanism of protein folding. In the Foldon Funnel Model, proteins fold in units of secondary structures, which form sequentially along the folding pathway, stabilized by tertiary interactions. The model predicts that the free energy landscape has a volcano shape, rather than a simple funnel, that folding is two-state (single-exponential) when secondary structures are intrinsically unstable, and that each structure along the folding path is a transition state for the previous structure. It shows how sequential pathways are consistent with multiple stochastic routes on funnel landscapes, and it gives good agreement with the 9 order of magnitude dependence of folding rates on protein size for a set of 93 proteins, at the same time it is consistent with the near independence of folding equilibrium constant on size. This model gives estimates of folding rates of proteomes, leading to a median folding time in Escherichia coli of about 5 s. PMID:25056406

Disentangling the photodissociation pathways of small lead clusters by time-resolved monitoring of their delayed decays: the case of {{{\\rm{P}}{\\rm{b}}}_{31}}^{+}

NASA Astrophysics Data System (ADS)

Wolfram, Markus; König, Stephan; Bandelow, Steffi; Fischer, Paul; Jankowski, Alexander; Marx, Gerrit; Schweikhard, Lutz

2018-02-01

Lead clusters {{{{Pb}}}{n}}+/- in the size range between about n = 15 and 40 have recently shown to exhibit complex dissociation spectra due to sequential and competing decays. In order to disentangle the pathways the exemplary {{{{Pb}}}31}+ clusters have been stored and size selected in a Penning trap and irradiated by nanosecond laser pulses. We present time-resolved measurements at time scales from several tens of microseconds to several hundreds of milliseconds. The study results in strong evidence that {{{{Pb}}}31}+ decays not only by neutral monomer evaporation but also by neutral heptamers breaking off. In addition, the decays are further followed to smaller products. The corresponding decay and growth times show that {{{{Pb}}}30}+ also dissociates by either monomer evaporation or heptamer break-off. Furthermore, the product {{{{Pb}}}17}+ may well be a result of heptamer break-off from {{{{Pb}}}24}+—as the second step of a sequential heptamer decay.

Biomimicry Promotes the Efficiency of a 10-Step Sequential Enzymatic Reaction on Nanoparticles, Converting Glucose to Lactate.

PubMed

Mukai, Chinatsu; Gao, Lizeng; Nelson, Jacquelyn L; Lata, James P; Cohen, Roy; Wu, Lauren; Hinchman, Meleana M; Bergkvist, Magnus; Sherwood, Robert W; Zhang, Sheng; Travis, Alexander J

2017-01-02

For nanobiotechnology to achieve its potential, complex organic-inorganic systems must grow to utilize the sequential functions of multiple biological components. Critical challenges exist: immobilizing enzymes can block substrate-binding sites or prohibit conformational changes, substrate composition can interfere with activity, and multistep reactions risk diffusion of intermediates. As a result, the most complex tethered reaction reported involves only 3 enzymes. Inspired by the oriented immobilization of glycolytic enzymes on the fibrous sheath of mammalian sperm, here we show a complex reaction of 10 enzymes tethered to nanoparticles. Although individual enzyme efficiency was higher in solution, the efficacy of the 10-step pathway measured by conversion of glucose to lactate was significantly higher when tethered. To our knowledge, this is the most complex organic-inorganic system described, and it shows that tethered, multi-step biological pathways can be reconstituted in hybrid systems to carry out functions such as energy production or delivery of molecular cargo. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biomimicry promotes the efficiency of a 10-step sequential enzymatic reaction on nanoparticles, converting glucose to lactate

PubMed Central

Mukai, Chinatsu; Gao, Lizeng; Nelson, Jacquelyn L.; Lata, James P.; Cohen, Roy; Wu, Lauren; Hinchman, Meleana M.; Bergkvist, Magnus; Sherwood, Robert W.; Zhang, Sheng; Travis, Alexander J.

2016-01-01

For nanobiotechnology to achieve its potential, complex organic-inorganic systems must grow to utilize the sequential functions of multiple biological components. Critical challenges exist: immobilizing enzymes can block substrate-binding sites or prohibit conformational changes, substrate composition can interfere with activity, and multistep reactions risk diffusion of intermediates. As a result, the most complex tethered reaction reported involves only 3 enzymes. Inspired by the oriented immobilization of glycolytic enzymes on the fibrous sheath of mammalian sperm, here we show a complex reaction of 10 enzymes tethered to nanoparticles. Although individual enzyme efficiency was higher in solution, the efficacy of the 10-step pathway measured by conversion of glucose to lactate was significantly higher when tethered. To our knowledge, this is the most complex organic-inorganic system described, and it shows that tethered, multi-step biological pathways can be reconstituted in hybrid systems to carry out functions such as energy production or delivery of molecular cargo. PMID:27901298

The Integration of Study and Work-Integrated Learning Experience through the Sequential, Embedded Completion of Tertiary Qualifications

ERIC Educational Resources Information Center

Whannell, Patricia; Humphries, Judy; Whannell, Robert; Usher, Kim

2015-01-01

A number of different models have been developed to integrate both Vocational Education and Training (VET) and university study with a view to producing work-ready graduates. This paper describes one joint initiative which allows students to integrate their theoretical study and work-integrated learning (WIL) experience by supporting a sequential,…

Speech Perception and Production by Sequential Bilingual Children: A Longitudinal Study of Voice Onset Time Acquisition

ERIC Educational Resources Information Center

McCarthy, Kathleen M.; Mahon, Merle; Rosen, Stuart; Evans, Bronwen G.

2014-01-01

The majority of bilingual speech research has focused on simultaneous bilinguals. Yet, in immigrant communities, children are often initially exposed to their family language (L1), before becoming gradually immersed in the host country's language (L2). This is typically referred to as sequential bilingualism. Using a longitudinal design, this…

Sequential mediating effects of provided and received social support on trait emotional intelligence and subjective happiness: A longitudinal examination in Hong Kong Chinese university students.

PubMed

Ye, Jiawen; Yeung, Dannii Y; Liu, Elaine S C; Rochelle, Tina L

2018-04-03

Past research has often focused on the effects of emotional intelligence and received social support on subjective well-being yet paid limited attention to the effects of provided social support. This study adopted a longitudinal design to examine the sequential mediating effects of provided and received social support on the relationship between trait emotional intelligence and subjective happiness. A total of 214 Hong Kong Chinese undergraduates were asked to complete two assessments with a 6-month interval in between. The results of the sequential mediation analysis indicated that the trait emotional intelligence measured in Time 1 indirectly influenced the level of subjective happiness in Time 2 through a sequential pathway of social support provided for others in Time 1 and social support received from others in Time 2. These findings highlight the importance of trait emotional intelligence and the reciprocal exchanges of social support in the subjective well-being of university students. © 2018 International Union of Psychological Science.

Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells.

PubMed

Wang, Guansong; Qian, Pin; Jackson, Fannie R; Qian, Guisheng; Wu, Guangyu

2008-01-01

Xanthine dehydrogenase/oxidase (XDH/XO) is associated with various pathological conditions related to the endothelial injury. However, the molecular mechanism underlying the activation of XDH/XO by hypoxia remains largely unknown. In this report, we determined whether the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling pathway is involved in hypoxia-induced activation of XDH/XO in primary cultures of lung microvascular endothelial cells (LMVEC). We found that hypoxia significantly increased interleukin 6 (IL6) production in a time-dependent manner in LMVEC. Hypoxia also markedly augmented phosphorylation/activation of JAKs (JAK1, JAK2 and JAK3) and the JAK downstream effectors STATs (STAT3 and STAT5). Hypoxia-induced activation of STAT3 was blocked by IL6 antibodies, the JAK inhibitor AG490 and the suppressor of cytokine signaling 3 (SOCS3), implying that hypoxia-promoted IL6 secretion activates the JAK/STAT pathway in LMVEC. Phosphorylation and DNA-binding activity of STAT3 were also inhibited by the p38 MAPK inhibitor SB203580 and the phosphatidylinositol 3-kinase inhibitor LY294002, suggesting that multiple signaling pathways involved in STAT activation by hypoxia. Importantly, hypoxia promoted XDH/XO activation in LMVEC, which was markedly reversed by inhibiting the JAK-STAT pathway using IL6 antibodies, AG490 and SOCS3. These data demonstrated that JAKs, STATs and XDH/XO were sequentially activated by hypoxia. These data provide the first evidence indicating that the JAK-STAT pathway is involved in hypoxia-mediated XDH/XO activation in LMVEC.

Sequential Modelling of Building Rooftops by Integrating Airborne LIDAR Data and Optical Imagery: Preliminary Results

NASA Astrophysics Data System (ADS)

Sohn, G.; Jung, J.; Jwa, Y.; Armenakis, C.

2013-05-01

This paper presents a sequential rooftop modelling method to refine initial rooftop models derived from airborne LiDAR data by integrating it with linear cues retrieved from single imagery. A cue integration between two datasets is facilitated by creating new topological features connecting between the initial model and image lines, with which new model hypotheses (variances to the initial model) are produced. We adopt Minimum Description Length (MDL) principle for competing the model candidates and selecting the optimal model by considering the balanced trade-off between the model closeness and the model complexity. Our preliminary results, combined with the Vaihingen data provided by ISPRS WGIII/4 demonstrate the image-driven modelling cues can compensate the limitations posed by LiDAR data in rooftop modelling.

Mevalonate 5-diphosphate mediates ATP binding to the mevalonate diphosphate decarboxylase from the bacterial pathogen Enterococcus faecalis

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

Chen, Chun-Liang; Mermoud, James C.; Paul, Lake N.

The mevalonate pathway produces isopentenyl diphosphate (IPP), a building block for polyisoprenoid synthesis, and is a crucial pathway for growth of the human bacterial pathogen Enterococcus faecalis. The final enzyme in this pathway, mevalonate diphosphate decarboxylase (MDD), acts on mevalonate diphosphate (MVAPP) to produce IPP while consuming ATP. This essential enzyme has been suggested as a therapeutic target for the treatment of drug-resistant bacterial infections. Here, we report functional and structural studies on the mevalonate diphosphate decarboxylase from E. faecalis (MDDEF). The MDDEF crystal structure in complex with ATP (MDDEF–ATP) revealed that the phosphate-binding loop (amino acids 97–105) is notmore » involved in ATP binding and that the phosphate tail of ATP in this structure is in an outward-facing position pointing away from the active site. This suggested that binding of MDDEF to MVAPP is necessary to guide ATP into a catalytically favorable position. Enzymology experiments show that the MDDEF performs a sequential ordered bi-substrate reaction with MVAPP as the first substrate, consistent with the isothermal titration calorimetry (ITC) experiments. On the basis of ITC results, we propose that this initial prerequisite binding of MVAPP enhances ATP binding. In summary, our findings reveal a substrate-induced substrate-binding event that occurs during the MDDEF-catalyzed reaction. The disengagement of the phosphate-binding loop concomitant with the alternative ATP-binding configuration may provide the structural basis for antimicrobial design against these pathogenic enterococci.« less

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells.

PubMed

Testa, Ugo; Castelli, Germana; Pelosi, Elvira

2017-11-20

Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells.

Distinct roles for multiple Src family kinases at fertilization.

PubMed

O'Neill, Forest J; Gillett, Jessica; Foltz, Kathy R

2004-12-01

Egg activation at fertilization requires the release of Ca2+ from the endoplasmic reticulum of the egg. Recent evidence indicates that Src family kinases (SFKs) function in the signaling pathway that initiates this Ca2+ release in the eggs of many deuterostomes. We have identified three SFKs expressed in starfish (Asterina miniata) eggs, designated AmSFK1, AmSFK2 and AmSFK3. Antibodies made against the unique domains of each AmSFK protein revealed that all three are expressed in eggs and localized primarily to the membrane fraction. Both AmSFK1 and AmSFK3 (but not AmSFK2) are necessary for egg activation, as determined by injection of starfish oocytes with dominant-interfering Src homology 2 (SH2) domains, which specifically delay and reduce the initial release of Ca2+ at fertilization. AmSFK3 exhibits a very rapid and transient kinase activity in response to fertilization, peaking at 30 seconds post sperm addition. AmSFK1 kinase activity also increases transiently at fertilization, but peaks later, at 2 minutes. These results indicate that there are multiple SFKs present in starfish eggs with distinct, perhaps sequential, signaling roles.

Biotransformation of tetracycline by a novel bacterial strain Stenotrophomonas maltophilia DT1.

PubMed

Leng, Yifei; Bao, Jianguo; Chang, Gaofeng; Zheng, Han; Li, Xingxing; Du, Jiangkun; Snow, Daniel; Li, Xu

2016-11-15

Although several abiotic processes have been reported that can transform antibiotics, little is known about whether and how microbiological processes may degrade antibiotics in the environment. This work isolated one tetracycline degrading bacterial strain, Stenotrophomonas maltophilia strain DT1, and characterized the biotransformation of tetracycline by DT1 under various environmental conditions. The biotransformation rate was the highest when the initial pH was 9 and the reaction temperature was at 30°C, and can be described using the Michaelis-Menten model under different initial tetracycline concentrations. When additional substrate was present, the substrate that caused increased biomass resulted in a decreased biotransformation rate of tetracycline. According to disk diffusion tests, the biotransformation products of tetracycline had lower antibiotic potency than the parent compound. Six possible biotransformation products were identified, and a potential biotransformation pathway was proposed that included sequential removal of N-methyl, carbonyl, and amine function groups. Results from this study can lead to better estimation of the fate and transport of antibiotics in the environment and has the potential to be utilized in designing engineering processes to remove tetracycline from water and soil. Copyright © 2016 Elsevier B.V. All rights reserved.

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells

PubMed Central

Castelli, Germana; Pelosi, Elvira

2017-01-01

Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells. PMID:29156643

Pathways of proton transfer in the light-driven pump bacteriorhodopsin

NASA Technical Reports Server (NTRS)

Lanyi, J. K.

1993-01-01

The mechanism of proton transport in the light-driven pump bacteriorhodopsin is beginning to be understood. Light causes the all-trans to 13-cis isomerization of the retinal chromophore. This sets off a sequential and directed series of transient decreases in the pKa's of a) the retinal Schiff base, b) an extracellular proton release complex which includes asp-85, and c) a cytoplasmic proton uptake complex which includes asp-96. The timing of these pKa changes during the photoreaction cycle causes sequential proton transfers which result in the net movement of a proton across the protein, from the cytoplasmic to the extracellular surface.

Sequential Transition Patterns of Preschoolers' Social Interactions during Child-Initiated Play: Is Parallel-Aware Play a Bidirectional Bridge to Other Play States?

ERIC Educational Resources Information Center

Robinson, Clyde C.; Anderson, Genan T.; Porter, Christin L.; Hart, Craig, H.; Wouden-Miller, Melissa

2003-01-01

Explored the simultaneous sequential transition patterns of preschoolers' social play within classroom settings. Found that the proportion of social-play states did not vary during play episodes even when accounting for type of activity center, gender, and SES. Found a reciprocal relationship between parallel-aware and other social-play states…

Carbonate mineralization via an amorphous calcium carbonate (ACC) pathway: Tuning polymorph selection by Mg, pH, and mixing environment

NASA Astrophysics Data System (ADS)

Dove, P. M.; Blue, C.; Mergelsberg, S. T.; Giuffre, A. J.; Han, N.; De Yoreo, J. J.

2017-12-01

Mineral formation by nonclassical processes is widespread with many pathways that include aggregation of nanoparticles, oriented attachment of fully formed crystals, and sequential nucleation/transformation of amorphous phases (De Yoreo et al., 2015, Science). Field observations indicate amorphous calcium carbonate (ACC) can be the initial precipitate when local conditions promote high supersaturations for short time periods. Examples include microbial mats, marine porewaters that undergo pulses of increased alkalinity, closed basin lakes, and sabkhas. The crystalline products exhibit diverse morphologies and complex elemental and isotopic signatures. This study quantifies relationships between solution composition and the crystalline polymorphs that transform from ACC (Blue et al., GCA, 2017). Our experimental design synthesized ACC under controlled conditions for a suite of compositions by tuning input pH, Mg/Ca, and total carbonate concentration. ACC products were allowed to transform within output suspensions under stirred or quiescent mixing while characterizing the polymorph and composition of evolving solutions and solids. We find that ACC transforms to crystalline polymorphs with a systematic relationship to solution composition to give a quantitative framework based upon solution aMg2+/aCa2+ and aCO32-/aCa2+. We also measure a polymorph-specific evolution of pH and Mg/Ca during the transformation that indicates the initial polymorph to form. Pathway is further modulated by stirring versus quiescent conditions. The findings reconcile discrepancies among previous studies of ACC to crystalline products and supports claims that monohydrocalcite may be an overlooked, transient phase during formation of some aragonite and calcite deposits. Organic additives and extreme pH are not required to tune composition and polymorph. Insights from this study reiterate the need to revisit long-standing dogmas regarding controls on CaCO3 polymorph selection. Classical models assume thermodynamic equilibria but cannot provide a reliable predictor of compositions when kinetic factors are driving mineralization. Nonclassical pathways to mineralization may be the missing link to interpreting unusual CaCO3 polymorphs, compositions and textures in modern and ancient carbonates.

Pathways to Hazardous Drinking Among Racially and Socioeconomically Diverse Lesbian Women: Sexual Minority Stress, Rumination, Social Isolation, and Drinking to Cope

PubMed Central

Lewis, Robin J.; Mason, Tyler B.; Winstead, Barbara A.; Gaskins, Melissa; Irons, Lance B.

2016-01-01

Lesbian women engage in more hazardous drinking than heterosexual women yet we know relatively little about what explains this disparity. In the present study, race, socioeconomic status, minority stress, general psychological processes and distress were examined as pathways to hazardous drinking among young (18-35 years) Black and non-Hispanic White lesbian women. We used the psychological mediation framework adaptation of minority stress theory and the reserve capacity model as theoretical underpinnings of the conceptual model in the current study. Self-identified lesbian participants (N= 867) completed a one-time online survey that assessed race, socioeconomic status, perceived sexual minority discrimination, proximal minority stress (concealment, internalized homophobia, lack of connection to lesbian community), rumination, social isolation, psychological distress, drinking to cope, and hazardous drinking. Cross-sectional results demonstrated that being Black was associated with hazardous drinking via sequential mediators of rumination, psychological distress, and drinking to cope. Socioeconomic status was associated with hazardous drinking via sequential mediators of sexual minority discrimination, proximal minority stress, rumination, social isolation, psychological distress, and drinking to cope. Understanding these pathways can aid researchers and clinicians studying and working with lesbians who are at risk for hazardous drinking. PMID:28138208

Understanding the fate of the oxyallyl cation following Nazarov electrocyclization: sequential Wagner-Meerwein migrations and the synthesis of spirocyclic cyclopentenones

PubMed Central

Huang, Jie; Lebœuf, David; Frontier, Alison J.

2011-01-01

A general reaction sequence is described that involves Nazarov cyclization followed by two sequential Wagner Meerwein migrations, to afford spirocyclic compounds from divinyl ketones in the presence of one equivalent of copper(II) complexes. A detailed investigation of this sequence is described including a study of substrate scope and limitations. It was found that after 4π electrocyclization, two different pathways are available to the oxyallyl cation intermediate: elimination of a proton can give the usual Nazarov cycloadduct, or ring contraction can give an alternative tertiary carbocation. After ring contraction, either [1,2]-hydride or carbon migration can occur, depending upon the substitution pattern of the substrate, to furnish spirocyclic products. The rearrangement pathway is favored over the elimination pathway when catalyst loading was high and the copper(II) counterion is noncoordinating. Several ligands were found to be effective for the reaction. Thus, the reaction sequence can be controlled by judicious choice of reaction conditions to allow selective generation of richly functionalized spirocycles. The three steps of the sequence are stereospecific: electrocyclization followed by two [1,2]-suprafacial Wagner-Meerwein shifts: the ring contraction and then an hydride, alkenyl or aryl shift. The method allows stereospecific installation of adjacent stereocenters or adjacent quaternary centers arrayed around a cyclopentenone ring. PMID:21466152

Pathways between Ecstasy Initiation and Other Drug Use

PubMed Central

Martins, Silvia S.; Ghandour, Lilian A.; Chilcoat, Howard D.

2007-01-01

This study aims to shed light on drug use pathways associated with ecstasy use initiation. Data from 54,573 respondents aged 12-21 years old from the 2002-2003 National Survey on Drug Use and Health (NSDUH) public use data files were analyzed via Cox proportional hazards models with time-dependent covariates. Our findings showed that marijuana, cocaine, and heroin were significant independent predictors of subsequent ecstasy use. Earlier ecstasy initiation was significantly associated with subsequent other illegal drug initiation (marijuana, cocaine and heroin). The strength of the association was greater for the pathway from earlier marijuana initiation to subsequent ecstasy initiation as compared to the pathway in the opposite direction. The pathway from earlier ecstasy initiation to subsequent cocaine and heroin initiation was also stronger as compared to pathways in the opposite directions. Pathways between ecstasy initiation and marijuana, cocaine and heroin initiation seem to be independent of the association between drug use and psychiatric symptoms/deviant behaviors. Ecstasy initiation seems to play a role in the subsequent initiation of cocaine and heroin. PMID:17174036

Step-wise refolding of recombinant proteins.

PubMed

Tsumoto, Kouhei; Arakawa, Tsutomu; Chen, Linda

2010-04-01

Protein refolding is still on trial-and-error basis. Here we describe step-wise dialysis refolding, in which denaturant concentration is altered in step-wise fashion. This technology controls the folding pathway by adjusting the concentrations of the denaturant and other solvent additives to induce sequential folding or disulfide formation.

Cytochromes P450 and Skin Cancer: Role of Local Endocrine Pathways

PubMed Central

Slominski, Andrzej T.; Zmijewski, Michal A.; Semak, Igor; Zbytek, Blazej; Pisarchik, Alexander; Li, Wei; Zjawiony, Jordan; Tuckey, Robert C.

2013-01-01

Skin is the largest body organ forming a metabolically active barrier between external and internal environments. The metabolic barrier is composed of cytochromes P450 (CYPs) that regulate its homeostasis through activation or inactivation of biologically relevant molecules. In this review we focus our attention on local steroidogenic and secosteroidogenic systems in relation to skin cancer, e.g., prevention, attenuation of tumor progression and therapy. The local steroidogenic system is composed of locally expressed CYPs involved in local production of androgens, estrogens, gluco- and mineralo-corticosteroids from cholesterol (initiated by CYP11A1) or from steroid precursors delivered to the skin, and of their metabolism and/or inactivation. Cutaneous 7-hydroxylases (CYP7A1, CYP7B1 and CYP39) potentially can produce 7-hydroxy/oxy-steroids/sterols with modifying effects on local tumorigenesis. CYP11A1 also transforms 7-dehydrocholesterol (7DHC)→22(OH)7DHC→20,22(OH)2-7DHC→7-dehydropregnenolone, which can be further metabolized to other 5,7-steroidal dienes. These 5,7-dienal intermediates are converted by ultraviolet radiation B (UVB) into secosteroids which show pro-differentiation and anti-cancer properties. Finally, the skin is the site of activation of vitamin D3 through two alternative pathways. The classical one involves sequential hydroxylation at positions 25 and 1 to produce active 1,25(OH)2D3, which is further inactivated through hydroxylation at C24. The novel pathway is initiated by CYP11A1 with predominant production of 20(OH)D3 which is further metabolized to biologically active but non-calcemic D3-hydroxyderivatives. Classical and non-classical (novel) vitamin D analogs show pro-differentiation, anti-proliferative and anticancer properties. In addition, melatonin is metabolized by local CYPs. In conclusion cutaneously expressed CYPs have significant effects on skin physiology and pathology trough regulation of its chemical milieu. PMID:23869782

Computational aspects of helicopter trim analysis and damping levels from Floquet theory

NASA Technical Reports Server (NTRS)

Gaonkar, Gopal H.; Achar, N. S.

1992-01-01

Helicopter trim settings of periodic initial state and control inputs are investigated for convergence of Newton iteration in computing the settings sequentially and in parallel. The trim analysis uses a shooting method and a weak version of two temporal finite element methods with displacement formulation and with mixed formulation of displacements and momenta. These three methods broadly represent two main approaches of trim analysis: adaptation of initial-value and finite element boundary-value codes to periodic boundary conditions, particularly for unstable and marginally stable systems. In each method, both the sequential and in-parallel schemes are used and the resulting nonlinear algebraic equations are solved by damped Newton iteration with an optimally selected damping parameter. The impact of damped Newton iteration, including earlier-observed divergence problems in trim analysis, is demonstrated by the maximum condition number of the Jacobian matrices of the iterative scheme and by virtual elimination of divergence. The advantages of the in-parallel scheme over the conventional sequential scheme are also demonstrated.

Sequential bearings-only-tracking initiation with particle filtering method.

PubMed

Liu, Bin; Hao, Chengpeng

2013-01-01

The tracking initiation problem is examined in the context of autonomous bearings-only-tracking (BOT) of a single appearing/disappearing target in the presence of clutter measurements. In general, this problem suffers from a combinatorial explosion in the number of potential tracks resulted from the uncertainty in the linkage between the target and the measurement (a.k.a the data association problem). In addition, the nonlinear measurements lead to a non-Gaussian posterior probability density function (pdf) in the optimal Bayesian sequential estimation framework. The consequence of this nonlinear/non-Gaussian context is the absence of a closed-form solution. This paper models the linkage uncertainty and the nonlinear/non-Gaussian estimation problem jointly with solid Bayesian formalism. A particle filtering (PF) algorithm is derived for estimating the model's parameters in a sequential manner. Numerical results show that the proposed solution provides a significant benefit over the most commonly used methods, IPDA and IMMPDA. The posterior Cramér-Rao bounds are also involved for performance evaluation.

Infiltration Processes and Flow Velocities Across the Landscape: When and Where is Macropore Flow Relevant?

NASA Astrophysics Data System (ADS)

Demand, D.; Blume, T.; Weiler, M.

2017-12-01

Preferential flow in macropores significantly affects the distributions of water and solutes in soil and many studies showed its relevance worldwide. Although some models include this process as a second pore domain, little is known about the spatial patterns and temporal dynamics. For example, while flow in the matrix is usually modeled and parameterized based on soil texture, an influence of texture on non-capillary flow for a given land-use class is poorly understood. To investigate the temporal and spatial dynamics on preferential flow we used a four-year soil moisture dataset from the mesoscale Attert catchment (288 km²) in Luxembourg. This dataset contains time series from 126 soil profiles in different textures and two land-use classes (forest, grassland). The soil moisture probes were installed in 10, 30 and 50 cm depth and measured in a 5-minute temporal resolution. Events were defined by a soil moisture increase higher than the instrument noise after a precipitation sum of more than 1 mm. Precipitation was measured next to the profiles so that each location could be associated to its unique precipitation characteristics. For every event and profile the soil moisture reaction was classified in sequential (ordered by depth) and non-sequential response. A non-sequential soil moisture reaction was used as an indicator of preferential flow. For sequential flow, the velocity was determined by the first reaction between two vertically adjacent sensors. The sensor reaction and wetting front velocity was analyzed in the context of precipitation characteristics and initial soil water content. Grassland sites showed a lower proportion of non-sequential flow than forest sites. For forest, non-sequential response is dependent on texture, rainfall intensity and initial water content. This is less distinct for the grassland sites. Furthermore, sequential reactions show higher flow velocities at sites, which also have high percentage of non-sequential response. In contrast, grassland sites show a more homogenous wetting front independent of soil texture. Compared against common modelling approaches of soil water flow, measured velocities show clear evidence of preferential flow, especially for forest soils. The analysis also shows that vegetation can alter the soil properties above the textural properties alone.

Enhanced Hydrodeoxygenation of m -Cresol over Bimetallic Pt–Mo Catalysts through an Oxophilic Metal-Induced Tautomerization Pathway

DOE PAGES

Robinson, Allison; Ferguson, Glen Allen; Gallagher, James R.; ...

2016-05-26

Supported bimetallic catalysts consisting of a noble metal (e.g., Pt) and an oxophilic metal (e.g., Mo) have received considerable attention for the hydrodeoxygenation of oxygenated aromatic compounds produced from biomass fast pyrolysis. Here, we report that PtMo can catalyze m-cresol deoxygenation via a pathway involving an initial tautomerization step. In contrast, the dominant mechanism on monometallic Pt/Al 2O 3 was found to be sequential Pt-catalyzed ring hydrogenation followed by dehydration on the support. Bimetallic Pt 10Mo 1 and Pt 1Mo 1 catalysts were found to produce the completely hydrogenated and deoxygenated product, methylcyclohexane (MCH), with much higher yields than monometallicmore » Pt catalysts with comparable metal loadings and surface areas. Over an inert carbon support, MCH formation was found to be slow over monometallic Pt catalysts, while deoxygenation was significant for PtMo catalysts even in the absence of an acidic support material. Experimental studies of m-cresol deoxygenation together with density functional theory calculations indicated that Mo sites on the PtMo bimetallic surface dramatically lower the barrier for m-cresol tautomerization and subsequent deoxygenation. The accessibility of this pathway arises from the increased interaction between the oxygen of m-cresol and the Mo sites in the Pt surface. This interaction significantly alters the configuration of the precursor and transition states for tautomerization. Lastly, a suite of catalyst characterization techniques including X-ray absorption spectroscopy (XAS) and temperature-programmed reduction (TPR) indicate that Mo was present in a reduced state on the bimetallic surface under conditions relevant for reaction. Overall, these results suggest that the use of bifunctional metal catalysts can result in new reaction pathways that are unfavorable on monometallic noble metal catalysts.« less

Active and Inactive Leg Hemodynamics during Sequential Single-Leg Interval Cycling.

PubMed

Gordon, Nicole; Abbiss, Chris R; Ihsan, Mohammed; Maiorana, Andrew J; Peiffer, Jeremiah J

2018-06-01

Leg order during sequential single-leg cycling (i.e., exercising both legs independently within a single session) may affect local muscular responses potentially influencing adaptations. This study examined the cardiovascular and skeletal muscle hemodynamic responses during double-leg and sequential single-leg cycling. Ten young healthy adults (28 ± 6 yr) completed six 1-min double-leg intervals interspersed with 1 min of passive recovery and, on a separate occasion, 12 (six with one leg followed by six with the other leg) 1-min single-leg intervals interspersed with 1 min of passive recovery. Oxygen consumption, heart rate, blood pressure, muscle oxygenation, muscle blood volume, and power output were measured throughout each session. Oxygen consumption, heart rate, and power output were not different between sets of single-leg intervals, but the average of both sets was lower than the double-leg intervals. Mean arterial pressure was higher during double-leg compared with sequential single-leg intervals (115 ± 9 vs 104 ± 9 mm Hg, P < 0.05) and higher during the initial compared with second set of single-leg intervals (108 ± 10 vs 101 ± 10 mm Hg, P < 0.05). The increase in muscle blood volume from baseline was similar between the active single leg and the double leg (267 ± 150 vs 214 ± 169 μM·cm, P = 0.26). The pattern of change in muscle blood volume from the initial to second set of intervals was significantly different (P < 0.05) when the leg was active in the initial (-52.3% ± 111.6%) compared with second set (65.1% ± 152.9%). These data indicate that the order in which each leg performs sequential single-leg cycling influences the local hemodynamic responses, with the inactive muscle influencing the stimulus experienced by the contralateral leg.

Communication latencies of wireless devices suitable for time-critical messaging to anesthesia providers.

PubMed

Epstein, Richard H; Dexter, Franklin; Rothman, Brian

2013-04-01

Rapid and reliable methods of text communication to mobile anesthesia care providers are important to patient care and to efficient operating room management. Anesthesia departments are implementing automated methods to send text messages to mobile devices for abnormal vital signs, clinical recommendations, quality of care, and compliance or billing issues. The most time-critical communications determine maximum acceptable latencies. We studied the reliability of several alphanumeric messaging systems to identify an appropriate technology for such use. Latencies between message initiation and delivery to 3 alphanumeric paging devices were measured over weeks. Two devices used Internet pathways outside the hospital's local network with an external paging vendor (SkyTel). The third device used only the internal hospital network (Zetron). Sequential cell phone text page latencies were examined for lag-1 autocorrelation using the runs test, with results binned by hour and by day. Message latencies subsequently were batched in successive 1-week bins for calculation of the mean and 99th percentiles of latencies. We defined acceptance criteria as a mean latency <30 seconds and no more than 1 in 200 pages (0.5%) having a latency longer than 100 seconds. Cell phone texting was used as a positive control to assure that the analysis was appropriate, because such devices have (known) poor reliability during high network activity. There was substantial correlation among latencies for sequential cell phone text messages when binned by hours (P < 0.0001), but not by days (P = 0.61). The 2 devices using Internet pathways outside the hospital's network demonstrated unacceptable performance, with 1.3% and 33% of latencies exceeding 100 seconds, respectively. The device dependent only on the internal network had a mean latency of 8 seconds, with 100% of 40,200 pages having latencies <100 seconds. The findings suggest that the network used was the deciding factor. Developers of anesthesia communication systems need to measure latencies of proposed communication pathways and devices used to deliver urgent messages to mobile users. Similar evaluation is relevant for text pagers used on an ad hoc basis for delivery of time-critical notifications. Testing over a period of hours to days is adequate only for disqualification of a candidate paging system, because acceptable results are not necessarily indicative of long-term performance. Rather, weeks of testing are required, with appropriate batching of pages for analysis.

MSFC Skylab airlock module, volume 1. [systems design and performance

NASA Technical Reports Server (NTRS)

1974-01-01

The history and development of the Skylab Airlock Module and Payload Shroud is presented from initial concept through final design. A summary is given of the Airlock features and systems. System design and performance are presented for the Spent Stage Experiment Support Module, structure and mechanical systems, mass properties, thermal and environmental control systems, EVA/IVA suite system, electrical power system, sequential system, sequential system, and instrumentation system.

Lithospheric structure of Taiwan from gravity modelling and sequential inversion of seismological and gravity data

NASA Astrophysics Data System (ADS)

Masson, F.; Mouyen, M.; Hwang, C.; Wu, Y.-M.; Ponton, F.; Lehujeur, M.; Dorbath, C.

2012-11-01

Using a Bouguer anomaly map and a dense seismic data set, we have performed two studies in order to improve our knowledge of the deep structure of Taiwan. First, we model the Bouguer anomaly along a profile crossing the island using simple forward modelling. The modelling is 2D, with the hypothesis of cylindrical symmetry. Second we present a joint analysis of gravity anomaly and seismic arrival time data recorded in Taiwan. An initial velocity model has been obtained by local earthquake tomography (LET) of the seismological data. The LET velocity model was used to construct an initial 3D gravity model, using a linear velocity-density relationship (Birch's law). The synthetic Bouguer anomaly calculated for this model has the same shape and wavelength as the observed anomaly. However some characteristics of the anomaly map are not retrieved. To derive a crustal velocity/density model which accounts for both types of observations, we performed a sequential inversion of seismological and gravity data. The variance reduction of the arrival time data for the final sequential model was comparable to the variance reduction obtained by simple LET. Moreover, the sequential model explained about 80% of the observed gravity anomaly. New 3D model of Taiwan lithosphere is presented.

The ‘when’ parietal pathway explored by lesion studies

PubMed Central

Battelli, Lorella; Walsh, Vincent; Pascual-Leone, Alvaro; Cavanagh, Patrick

2016-01-01

Summary The perception of events in space and time is at the root of our interactions with the environment. The precision with which we perceive visual events in time enables us to act upon objects with great accuracy and the loss of such functions, due to brain lesions can be catastrophic. We outline a visual timing mechanism that deals with the trajectory of an object’s existence across time, a critical function when keeping track of multiple objects that temporally overlap or occur sequentially. Recent evidence suggests these functions are served by an extended network of areas which we call the ‘when’ pathway. Here we show that the when pathway is distinct from and interacts with, the well established ‘where’ and ‘what’ pathways. PMID:18708141

Sequential events in the irreversible thermal denaturation of human brain-type creatine kinase by spectroscopic methods.

PubMed

Gao, Yan-Song; Su, Jing-Tan; Yan, Yong-Bin

2010-06-25

The non-cooperative or sequential events which occur during protein thermal denaturation are closely correlated with protein folding, stability, and physiological functions. In this research, the sequential events of human brain-type creatine kinase (hBBCK) thermal denaturation were studied by differential scanning calorimetry (DSC), CD, and intrinsic fluorescence spectroscopy. DSC experiments revealed that the thermal denaturation of hBBCK was calorimetrically irreversible. The existence of several endothermic peaks suggested that the denaturation involved stepwise conformational changes, which were further verified by the discrepancy in the transition curves obtained from various spectroscopic probes. During heating, the disruption of the active site structure occurred prior to the secondary and tertiary structural changes. The thermal unfolding and aggregation of hBBCK was found to occur through sequential events. This is quite different from that of muscle-type CK (MMCK). The results herein suggest that BBCK and MMCK undergo quite dissimilar thermal unfolding pathways, although they are highly conserved in the primary and tertiary structures. A minor difference in structure might endow the isoenzymes dissimilar local stabilities in structure, which further contribute to isoenzyme-specific thermal stabilities.

Impacts of climate change on cropping patterns in a tropical, sub-humid watershed

PubMed Central

Zwart, Sander J.; Hein, Lars

2018-01-01

In recent decades, there have been substantial increases in crop production in sub-Saharan Africa (SSA) as a result of higher yields, increased cropping intensity, expansion of irrigated cropping systems, and rainfed cropland expansion. Yet, to date much of the research focus of the impact of climate change on crop production in the coming decades has been on crop yield responses. In this study, we analyse the impact of climate change on the potential for increasing rainfed cropping intensity through sequential cropping and irrigation expansion in central Benin. Our approach combines hydrological modelling and scenario analysis involving two Representative Concentration Pathways (RCPs), two water-use scenarios for the watershed based on the Shared Socioeconomic Pathways (SSPs), and environmental water requirements leading to sustained streamflow. Our analyses show that in Benin, warmer temperatures will severely limit crop production increases achieved through the expansion of sequential cropping. Depending on the climate change scenario, between 50% and 95% of cultivated areas that can currently support sequential cropping or will need to revert to single cropping. The results also show that the irrigation potential of the watershed will be at least halved by mid-century in all scenario combinations. Given the urgent need to increase crop production to meet the demands of a growing population in SSA, our study outlines challenges and the need for planned development that need to be overcome to improve food security in the coming decades. PMID:29513753

Hospitalist management of vaso-occlusive pain crisis in patients with sickle cell disease using a pathway of care.

PubMed

Allen Liles, Edmund; Kirsch, Jonathan; Gilchrist, Michael; Adem, Mukhtar

2014-04-01

Patients with sickle cell disease (SCD) suffer from intermittent vaso-occlusive pain crises (VOCs). These crises lead to frequent hospitalizations, significant morbidity, and increased mortality risk. Care pathways can enhance efficiency and quality of care. Our study sought to evaluate the development and implementation of a care pathway for patients with SCD experiencing VOCs. The University of North Carolina (UNC) Comprehensive Sickle Cell Program provides all levels of care for a large population of patients with sickle cell anemia. All patients admitted to UNC Hospitals with SCD VOCs from January 2009 through June 2011 were evaluated. During this time period, we also assessed sequential prospective cohorts during progressive phases of developing and implementing a quality improvement and pathway of care program for this patient population in our study. The developed pathway entailed geographic localization for VOC patients, a single group of faculty physicians caring for these patients, and early use of patient-controlled analgesia (PCA) to achieve pain control. Physicians from the UNC Hospital Medicine Program were responsible for the initiatives. Cohorts were compared to a baseline historical control. Outcomes of interest included patient length of stay (LOS) in the hospital, 30-day readmission rate, need for transfusion, incidence of acute chest syndrome, use of naloxone, and use of PCA. Compared with an historical baseline cohort, the development and implementation of a VOC care pathway for patients with SCD led to reduction in average hospital LOS by 1.44 days (P < 0.05) and an increase in use of PCAs (P < 0.05). Patient readmission rates, number of transfusions, incidence of acute chest syndrome, and use of naloxone did not significantly change. Hospitalist-led management of patients with SCD VOCs using a care pathway that emphasizes early, aggressive PCA-based pain control is associated with reduced hospital LOS. The LOS reduction seen in our study is clinically meaningful. Notably, other measures of patient outcomes and quality of care metrics did not change significantly, and some trended towards improvement.

Sequential Changes in Alanine Metabolism Following Partial Hepatectomy in the Rat

DTIC Science & Technology

1990-11-01

complete semipurified diet for 10 days be- libitum and the second subgroup was pair-fed with HX fore and after experimentation. 5 Food was removed rats. Nine...amino acid to form ing the ketogenic pathway. Indeed, reduced ketogene - pyruvate which can enter the tricarboxylic acid (TCA) sis after partial

Arsenic release from arsenopyrite weathering: insights from sequential extraction and microscopic studies.

PubMed

Basu, Ankan; Schreiber, Madeline E

2013-11-15

At a former As mine site, arsenopyrite oxidation has resulted in formation of scorodite and As-bearing iron hydroxide, both in host rock and mine tailings. Electron microprobe analysis documents that arsenopyrite weathers along two pathways: one that involves formation of sulfur, and one that does not. In both pathways, arsenopyrite oxidizes to form scorodite, which dissolves incongruently to form As-bearing iron hydroxides. From a mass balance perspective, arsenopyrite oxidation to scorodite conserves As, but as scorodite dissolves incongruently to iron hydroxides, As is released to solution, resulting in elevated As concentrations in the headwater stream adjacent to the site. The As-bearing iron hydroxide is the dominant solid phase reservoir of As in mine tailings and stream sediment, as suggested by sequential extraction. This As-bearing iron hydroxide is stable under the aerobic and pH 4-6 conditions at the site; however, changes in biogeochemical conditions resulting from sediment burial or future remedial efforts, which could promote As release from this reservoir due to reductive dissolution, should be avoided. Copyright © 2012 Elsevier B.V. All rights reserved.

Sequential analysis as a tool for detection of amikacin ototoxicity in the treatment of multidrug-resistant tuberculosis.

PubMed

Vasconcelos, Karla Anacleto de; Frota, Silvana Maria Monte Coelho; Ruffino-Netto, Antonio; Kritski, Afrânio Lineu

2018-04-01

To investigate early detection of amikacin-induced ototoxicity in a population treated for multidrug-resistant tuberculosis (MDR-TB), by means of three different tests: pure-tone audiometry (PTA); high-frequency audiometry (HFA); and distortion-product otoacoustic emission (DPOAE) testing. This was a longitudinal prospective cohort study involving patients aged 18-69 years with a diagnosis of MDR-TB who had to receive amikacin for six months as part of their antituberculosis drug regimen for the first time. Hearing was assessed before treatment initiation and at two and six months after treatment initiation. Sequential statistics were used to analyze the results. We included 61 patients, but the final population consisted of 10 patients (7 men and 3 women) because of sequential analysis. Comparison of the test results obtained at two and six months after treatment initiation with those obtained at baseline revealed that HFA at two months and PTA at six months detected hearing threshold shifts consistent with ototoxicity. However, DPOAE testing did not detect such shifts. The statistical method used in this study makes it possible to conclude that, over the six-month period, amikacin-associated hearing threshold shifts were detected by HFA and PTA, and that DPOAE testing was not efficient in detecting such shifts.

Alcohol and the pancreas. II. Pancreatic morphology of advanced alcoholic pancreatitis.

PubMed

Noronha, M; Bordalo, O; Dreiling, D A

1981-08-01

The histopathology of advanced chronic alcoholic pancreatitis is dominated by cellular degeneration, atrophy and fibrosis. Sequential changes in the histopathology of alcoholic pancreatic disease has been defined and traced from initial injury to end-stage disease. These sequential histopathologies have been correlated with clinical syndrome and secretory patterns. The data are more consistent with a toxic-metabolic pathogenesis of alcoholic pancreatitis than the previous Big Duct and Small Duct hypotheses.

Electrospray ionization study of tricarbonyl fac-[Re(CO)3 (PO)(X)]-type complexes: influence of ancillary co-ligands in the release of carbon monoxide.

PubMed

Tisato, Francesco; Porchia, Marina; Shegani, Antoni; Maina, Theodosia; Papadopoulos, Minas S; Seraglia, Roberta; Traldi, Pietro

2018-05-08

fac-[Re(CO) 3 (PO)(X)]-type complexes (PO = chelated bidentate tertiary phosphine(1-), X = various neutral, mono-dentate ligands) represent a class of compounds that meets the synthetic criteria for the preparation of potential carbon monoxide (CO) release molecules (CORMs) for medicinal application. The aim of our investigation was to achieve qualitative information whether the nature of the ancillary X ligand might influence the release of CO. The release of CO has been investigated by means of product ion spectrometry of electrospray ionization-generated [M + H] + species, produced by multiple collisional experiments, using an ion trap mass spectrometer. Tandem mass spectrometry applied to the protonated species [Re(CO) 3 (PO)(X) + H] + of seven complexes (those including X = OH 2 (1), isonitrile (2, 3), imidazole (4), pyridine (5) and phosphine (6, 7) show initial loss of coordinated water (1) or pyridine (5), whereas the majority of investigated entries display initial, sequential release of CO groups. The energetics of CO release have been investigated by breakdown curves for selected collisionally-activated decomposition processes involving CO, and compared with those involving X groups. The nature of the co-ligand X drives the primary loss in the MS n processes of [Re(CO) 3 (PO)(X) + H] + compounds. When X = solvent, the energetics of these decompositions follow the trend H 2 O < MeOH < CO. In each case, loss of CO is a favored fragmentation route with associated energies following the trend: N-py ≤ P-phosphine < C-isonitrile. Overall, MS n pathways indicate that [Re(PO)] (Re with chelated PO phosphine) constitutes the residual moiety. This behavior indicates that the presence of a functionalized phosphine is essential for a sequential, controlled release of CO. This article is protected by copyright. All rights reserved.

Spatiotemporal expression dynamics of selectins govern the sequential extravasation of neutrophils and monocytes in the acute inflammatory response.

PubMed

Zuchtriegel, Gabriele; Uhl, Bernd; Hessenauer, Maximilian E T; Kurz, Angela R M; Rehberg, Markus; Lauber, Kirsten; Krombach, Fritz; Reichel, Christoph A

2015-04-01

Leukocyte recruitment to the site of inflammation is a key event in a variety of cardiovascular pathologies. Infiltrating neutrophils constitute the first line of defense that precedes a second wave of emigrating monocytes reinforcing the inflammatory reaction. The mechanisms initiating this sequential process remained largely obscure. Using advanced in vivo microscopy and in vitro/ex vivo techniques, we identified individual spatiotemporal expression patterns of selectins and their principal interaction partners on neutrophils, resident/inflammatory monocytes, and endothelial cells. Coordinating the intraluminal trafficking of neutrophils and inflammatory monocytes to common sites of extravasation, selectins assign different sites to these immune cells for their initial interactions with the microvascular endothelium. Whereas constitutively expressed leukocyte L-selectin/CD62L and endothelial P-selectin/CD62P together with CD44 and P-selectin glycoprotein ligand-1/CD162 initiate the emigration of neutrophils, de novo synthesis of endothelial E-selectin/CD62E launches the delayed secondary recruitment of inflammatory monocytes. In this context, P-selectin/CD62P and L-selectin/CD62L together with P-selectin glycoprotein ligand-1/CD162 and CD44 were found to regulate the flux of rolling neutrophils and inflammatory monocytes, whereas E-selectin/CD62E selectively adjusts the rolling velocity of inflammatory monocytes. Moreover, selectins and their interaction partners P-selectin glycoprotein ligand-1/CD162 and CD44 differentially control the intraluminal crawling behavior of neutrophils and inflammatory monocytes collectively enabling the sequential extravasation of these immune cells to inflamed tissue. Our findings provide novel insights into the mechanisms initiating the sequential infiltration of the perivascular tissue by neutrophils and monocytes in the acute inflammatory response and might thereby contribute to the development of targeted therapeutic strategies for prevention and treatment of cardiovascular diseases. © 2015 American Heart Association, Inc.

Sequential simulation (SqS) of clinical pathways: a tool for public and patient engagement in point-of-care diagnostics

PubMed Central

Huddy, Jeremy R; Weldon, Sharon-Marie; Ralhan, Shvaita; Painter, Tim; Hanna, George B; Kneebone, Roger; Bello, Fernando

2016-01-01

Objectives Public and patient engagement (PPE) is fundamental to healthcare research. To facilitate effective engagement in novel point-of-care tests (POCTs), the test and downstream consequences of the result need to be considered. Sequential simulation (SqS) is a tool to represent patient journeys and the effects of intervention at each and subsequent stages. This case study presents a process evaluation of SqS as a tool for PPE in the development of a volatile organic compound-based breath test POCT for the diagnosis of oesophagogastric (OG) cancer. Setting Three 3-hour workshops in central London. Participants 38 members of public attended a workshop, 26 (68%) had no prior experience of the OG cancer diagnostic pathway. Interventions Clinical pathway SqS was developed from a storyboard of a patient, played by an actor, noticing symptoms of oesophageal cancer and following a typical diagnostic pathway. The proposed breath testing strategy was then introduced and incorporated into a second SqS to demonstrate pathway impact. Facilitated group discussions followed each SqS. Primary and secondary outcome measures Evaluation was conducted through pre-event and postevent questionnaires, field notes and analysis of audiovisual recordings. Results 38 participants attended a workshop. All participants agreed they were able to contribute to discussions and like the idea of an OG cancer breath test. Five themes emerged related to the proposed new breath test including awareness of OG cancer, barriers to testing and diagnosis, design of new test device, new clinical pathway and placement of test device. 3 themes emerged related to the use of SqS: participatory engagement, simulation and empathetic engagement, and why participants attended. Conclusions SqS facilitated a shared immersive experience for participants and researchers that led to the coconstruction of knowledge that will guide future research activities and be of value to stakeholders concerned with the invention and adoption of POCT. PMID:27625053

[Sequential degradation of p-cresol by photochemical and biological methods].

PubMed

Karetnikova, E A; Chaĭkovskaia, O N; Sokolova, I V; Nikitina, L I

2008-01-01

Sequential photo- and biodegradation of p-cresol was studied using a mercury lamp, as well as KrCl and XeCl excilamps. Preirradiation of p-cresol at a concentration of 10(-4) M did not affect the rate of its subsequent biodegradation. An increase in the concentration of p-cresol to 10(-3) M and in the duration preliminary UV irradiation inhibited subsequent biodegradation. Biodegradation of p-cresol was accompanied by the formation of a product with a fluorescence maximum at 365 nm (lambdaex 280 nm), and photodegradation yielded a compound fluorescing at 400 nm (lambdaex 330 nm). Sequential UV and biodegradation led to the appearance of bands in the fluorescence spectra that were ascribed to p-cresol and its photolysis products. It was shown that sequential use of biological and photochemical degradation results in degradation of not only the initial toxicant but also the metabolites formed during its biodegradation.

Iterative non-sequential protein structural alignment.

PubMed

Salem, Saeed; Zaki, Mohammed J; Bystroff, Christopher

2009-06-01

Structural similarity between proteins gives us insights into their evolutionary relationships when there is low sequence similarity. In this paper, we present a novel approach called SNAP for non-sequential pair-wise structural alignment. Starting from an initial alignment, our approach iterates over a two-step process consisting of a superposition step and an alignment step, until convergence. We propose a novel greedy algorithm to construct both sequential and non-sequential alignments. The quality of SNAP alignments were assessed by comparing against the manually curated reference alignments in the challenging SISY and RIPC datasets. Moreover, when applied to a dataset of 4410 protein pairs selected from the CATH database, SNAP produced longer alignments with lower rmsd than several state-of-the-art alignment methods. Classification of folds using SNAP alignments was both highly sensitive and highly selective. The SNAP software along with the datasets are available online at http://www.cs.rpi.edu/~zaki/software/SNAP.

Multiple acquisitions via sequential transfer of orphan spin polarization (MAeSTOSO): How far can we push residual spin polarization in solid-state NMR?

NASA Astrophysics Data System (ADS)

Gopinath, T.; Veglia, Gianluigi

2016-06-01

Conventional multidimensional magic angle spinning (MAS) solid-state NMR (ssNMR) experiments detect the signal arising from the decay of a single coherence transfer pathway (FID), resulting in one spectrum per acquisition time. Recently, we introduced two new strategies, namely DUMAS (DUal acquisition Magic Angle Spinning) and MEIOSIS (Multiple ExperIments via Orphan SpIn operatorS), that enable the simultaneous acquisitions of multidimensional ssNMR experiments using multiple coherence transfer pathways. Here, we combined the main elements of DUMAS and MEIOSIS to harness both orphan spin operators and residual polarization and increase the number of simultaneous acquisitions. We show that it is possible to acquire up to eight two-dimensional experiments using four acquisition periods per each scan. This new suite of pulse sequences, called MAeSTOSO for Multiple Acquisitions via Sequential Transfer of Orphan Spin pOlarization, relies on residual polarization of both 13C and 15N pathways and combines low- and high-sensitivity experiments into a single pulse sequence using one receiver and commercial ssNMR probes. The acquisition of multiple experiments does not affect the sensitivity of the main experiment; rather it recovers the lost coherences that are discarded, resulting in a significant gain in experimental time. Both merits and limitations of this approach are discussed.

Energetics, kinetics, and pathway of SNARE folding and assembly revealed by optical tweezers.

PubMed

Zhang, Yongli

2017-07-01

Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are universal molecular engines that drive membrane fusion. Particularly, synaptic SNAREs mediate fast calcium-triggered fusion of neurotransmitter-containing vesicles with plasma membranes for synaptic transmission, the basis of all thought and action. During membrane fusion, complementary SNAREs located on two apposed membranes (often called t- and v-SNAREs) join together to assemble into a parallel four-helix bundle, releasing the energy to overcome the energy barrier for fusion. A long-standing hypothesis suggests that SNAREs act like a zipper to draw the two membranes into proximity and thereby force them to fuse. However, a quantitative test of this SNARE zippering hypothesis was hindered by difficulties to determine the energetics and kinetics of SNARE assembly and to identify the relevant folding intermediates. Here, we first review different approaches that have been applied to study SNARE assembly and then focus on high-resolution optical tweezers. We summarize the folding energies, kinetics, and pathways of both wild-type and mutant SNARE complexes derived from this new approach. These results show that synaptic SNAREs assemble in four distinct stages with different functions: slow N-terminal domain association initiates SNARE assembly; a middle domain suspends and controls SNARE assembly; and rapid sequential zippering of the C-terminal domain and the linker domain directly drive membrane fusion. In addition, the kinetics and pathway of the stagewise assembly are shared by other SNARE complexes. These measurements prove the SNARE zippering hypothesis and suggest new mechanisms for SNARE assembly regulated by other proteins. © 2017 The Protein Society.

Organized Emergence of Multiple-Generations of Teeth in Snakes Is Dysregulated by Activation of Wnt/Beta-Catenin Signalling

PubMed Central

Gaete, Marcia; Tucker, Abigail S.

2013-01-01

In contrast to mammals, most reptiles constantly regenerate their teeth. In the snake, the epithelial dental lamina ends in a successional lamina, which proliferates and elongates forming multiple tooth generations, all linked by a permanent dental lamina. To investigate the mechanisms used to control the initiation of new tooth germs in an ordered sequential pattern we utilized the polyphodont (multiple-generation) corn snake (Pantherophis guttatus). We observed that the dental lamina expressed the transcription factor Sox2, a multipotent stem cell marker, whereas the successional lamina cells expressed the transcription factor Lef1, a Wnt/β-catenin pathway target gene. Activation of the Wnt/β-catenin pathway in culture increased the number of developing tooth germs, in comparison to control untreated cultures. These additional tooth germs budded off from ectopic positions along the dental lamina, rather than in an ordered sequence from the successional lamina. Wnt/β-catenin activation enhanced cell proliferation, particularly in normally non-odontogenic regions of the dental lamina, which widely expressed Lef1, restricting the Sox2 domain. This suggests an expansion of the successional lamina at the expense of the dental lamina. Activation of the Wnt/β-catenin pathway in cultured snake dental organs, therefore, led to changes in proliferation and to the molecular pattern of the dental lamina, resulting in loss of the organised emergence of tooth germs. These results suggest that epithelial compartments are critical for the arrangement of organs that develop in sequence, and highlight the role of Wnt/β-catenin signalling in such processes. PMID:24019968

Using environmental tracers and transient hydraulic heads to estimate groundwater recharge and conductivity

NASA Astrophysics Data System (ADS)

Erdal, Daniel; Cirpka, Olaf A.

2017-04-01

Regional groundwater flow strongly depends on groundwater recharge and hydraulic conductivity. While conductivity is a spatially variable field, recharge can vary in both space and time. None of the two fields can be reliably observed on larger scales, and their estimation from other sparse data sets is an open topic. Further, common hydraulic-head observations may not suffice to constrain both fields simultaneously. In the current work we use the Ensemble Kalman filter to estimate spatially variable conductivity, spatiotemporally variable recharge and porosity for a synthetic phreatic aquifer. We use transient hydraulic-head and one spatially distributed set of environmental tracer observations to constrain the estimation. As environmental tracers generally reside for a long time in an aquifer, they require long simulation times and carries a long memory that makes them highly unsuitable for use in a sequential framework. Therefore, in this work we use the environmental tracer information to precondition the initial ensemble of recharge and conductivities, before starting the sequential filter. Thereby, we aim at improving the performance of the sequential filter by limiting the range of the recharge to values similar to the long-term annual recharge means and by creating an initial ensemble of conductivities that show similar pattern and values to the true field. The sequential filter is then used to further improve the parameters and to estimate the short term temporal behavior as well as the temporally evolving head field needed for short term predictions within the aquifer. For a virtual reality covering a subsection of the river Neckar it is shown that the use of environmental tracers can improve the performance of the filter. Results using the EnKF with and without this preconditioned initial ensemble are evaluated and discussed.

Article and method of forming an article

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

Lacy, Benjamin Paul; Kottilingam, Srikanth Chandrudu; Dutta, Sandip

Provided are an article and a method of forming an article. The method includes providing a metallic powder, heating the metallic powder to a temperature sufficient to joint at least a portion of the metallic powder to form an initial layer, sequentially forming additional layers in a build direction by providing a distributed layer of the metallic powder over the initial layer and heating the distributed layer of the metallic powder, repeating the steps of sequentially forming the additional layers in the build direction to form a portion of the article having a hollow space formed in the build direction,more » and forming an overhang feature extending into the hollow space. The article includes an article formed by the method described herein.« less

Sequential memory: Binding dynamics

NASA Astrophysics Data System (ADS)

Afraimovich, Valentin; Gong, Xue; Rabinovich, Mikhail

2015-10-01

Temporal order memories are critical for everyday animal and human functioning. Experiments and our own experience show that the binding or association of various features of an event together and the maintaining of multimodality events in sequential order are the key components of any sequential memories—episodic, semantic, working, etc. We study a robustness of binding sequential dynamics based on our previously introduced model in the form of generalized Lotka-Volterra equations. In the phase space of the model, there exists a multi-dimensional binding heteroclinic network consisting of saddle equilibrium points and heteroclinic trajectories joining them. We prove here the robustness of the binding sequential dynamics, i.e., the feasibility phenomenon for coupled heteroclinic networks: for each collection of successive heteroclinic trajectories inside the unified networks, there is an open set of initial points such that the trajectory going through each of them follows the prescribed collection staying in a small neighborhood of it. We show also that the symbolic complexity function of the system restricted to this neighborhood is a polynomial of degree L - 1, where L is the number of modalities.

Sequential memory: Binding dynamics.

PubMed

Afraimovich, Valentin; Gong, Xue; Rabinovich, Mikhail

2015-10-01

Temporal order memories are critical for everyday animal and human functioning. Experiments and our own experience show that the binding or association of various features of an event together and the maintaining of multimodality events in sequential order are the key components of any sequential memories-episodic, semantic, working, etc. We study a robustness of binding sequential dynamics based on our previously introduced model in the form of generalized Lotka-Volterra equations. In the phase space of the model, there exists a multi-dimensional binding heteroclinic network consisting of saddle equilibrium points and heteroclinic trajectories joining them. We prove here the robustness of the binding sequential dynamics, i.e., the feasibility phenomenon for coupled heteroclinic networks: for each collection of successive heteroclinic trajectories inside the unified networks, there is an open set of initial points such that the trajectory going through each of them follows the prescribed collection staying in a small neighborhood of it. We show also that the symbolic complexity function of the system restricted to this neighborhood is a polynomial of degree L - 1, where L is the number of modalities.

Two-IMU FDI performance of the sequential probability ratio test during shuttle entry

NASA Technical Reports Server (NTRS)

Rich, T. M.

1976-01-01

Performance data for the sequential probability ratio test (SPRT) during shuttle entry are presented. Current modeling constants and failure thresholds are included for the full mission 3B from entry through landing trajectory. Minimum 100 percent detection/isolation failure levels and a discussion of the effects of failure direction are presented. Finally, a limited comparison of failures introduced at trajectory initiation shows that the SPRT algorithm performs slightly worse than the data tracking test.

A Cross-Grade Study Validating the Evolutionary Pathway of Student Mental Models in Electric Circuits

ERIC Educational Resources Information Center

Lin, Jing-Wen

2017-01-01

Cross-grade studies are valuable for the development of sequential curriculum. However such studies are time and resource intensive and fail to provide a clear representation to integrate different levels of representational complexity. Lin (Lin, 2006; Lin & Chiu, 2006; Lin, Chiu, & Hsu, 2006) proposed a cladistics approach in conceptual…

Parasitism by Cuscuta pentagona sequentially induces JA and SA defence pathways in tomato

Treesearch

Justin B. Runyon; Mark C. Mescher; Gary W. Felton; Consuelo M. De Moraes

2010-01-01

While plant responses to herbivores and pathogens are well characterized, responses to attack by other plants remain largely unexplored. We measured phytohormones and C18 fatty acids in tomato attacked by the parasitic plant Cuscuta pentagona, and used transgenic and mutant plants to explore the roles of the defence-related phytohormones salicylic...

Molecular characterization of the fatty alcohol oxidation pathway for wax-ester mobilization in germinated jojoba seeds

USDA-ARS?s Scientific Manuscript database

Jojoba (Simmondsia chinensis) is the only plant species known to use liquid wax esters (WE) as a primary seed storage reserve. Upon germination, WE hydrolysis releases very long-chain fatty alcohols, which must be oxidised to fatty acids by the sequential action of a fatty alcohol oxidase (FAO) and ...

Protein quality control in the early secretory pathway

PubMed Central

Anelli, Tiziana; Sitia, Roberto

2008-01-01

Eukaryotic cells are able to discriminate between native and non-native polypeptides, selectively transporting the former to their final destinations. Secretory proteins are scrutinized at the endoplasmic reticulum (ER)–Golgi interface. Recent findings reveal novel features of the underlying molecular mechanisms, with several chaperone networks cooperating in assisting the maturation of complex proteins and being selectively induced to match changing synthetic demands. ‘Public' and ‘private' chaperones, some of which enriched in specializes subregions, operate for most or selected substrates, respectively. Moreover, sequential checkpoints are distributed along the early secretory pathway, allowing efficiency and fidelity in protein secretion. PMID:18216874

Aqueous Angiography–Mediated Guidance of Trabecular Bypass Improves Angiographic Outflow in Human Enucleated Eyes

PubMed Central

Huang, Alex S.; Saraswathy, Sindhu; Dastiridou, Anna; Begian, Alan; Mohindroo, Chirayu; Tan, James C. H.; Francis, Brian A.; Hinton, David R.; Weinreb, Robert N.

2016-01-01

Purpose To assess the ability of trabecular micro-bypass stents to improve aqueous humor outflow (AHO) in regions initially devoid of AHO as assessed by aqueous angiography. Methods Enucleated human eyes (14 total from 7 males and 3 females [ages 52–84]) were obtained from an eye bank within 48 hours of death. Eyes were oriented by inferior oblique insertion, and aqueous angiography was performed with indocyanine green (ICG; 0.4%) or fluorescein (2.5%) at 10 mm Hg. With an angiographer, infrared and fluorescent images were acquired. Concurrent anterior segment optical coherence tomography (OCT) was performed, and fixable fluorescent dextrans were introduced into the eye for histologic analysis of angiographically positive and negative areas. Experimentally, some eyes (n = 11) first received ICG aqueous angiography to determine angiographic patterns. These eyes then underwent trabecular micro-bypass sham or stent placement in regions initially devoid of angiographic signal. This was followed by fluorescein aqueous angiography to query the effects. Results Aqueous angiography in human eyes yielded high-quality images with segmental patterns. Distally, angiographically positive but not negative areas demonstrated intrascleral lumens on OCT images. Aqueous angiography with fluorescent dextrans led to their trapping in AHO pathways. Trabecular bypass but not sham in regions initially devoid of ICG aqueous angiography led to increased aqueous angiography as assessed by fluorescein (P = 0.043). Conclusions Using sequential aqueous angiography in an enucleated human eye model system, regions initially without angiographic flow or signal could be recruited for AHO using a trabecular bypass stent. PMID:27588614

Sequential anaerobic/aerobic biodegradation of chloroethenes--aspects of field application.

PubMed

Tiehm, Andreas; Schmidt, Kathrin R

2011-06-01

Because of a range of different industrial activities, sites contaminated with chloroethenes are a world-wide problem. Chloroethenes can be biodegraded by reductive dechlorination under anaerobic conditions as well as by oxidation under aerobic conditions. The tendency of chloroethenes to undergo reductive dechlorination decreases with a decreasing number of chlorine substituents, whereas with less chlorine substituents chloroethenes more easily undergo oxidative degradation. There is currently a growing interest in aerobic metabolic degradation of chloroethenes, which demonstrates advantages compared to cometabolic degradation pathways. Sequential anaerobic/aerobic biodegradation can overcome the disadvantages of reductive dechlorination and leads to complete mineralization of the chlorinated pollutants. This approach shows promise for site remediation in natural settings and in engineered systems. Copyright © 2011 Elsevier Ltd. All rights reserved.

Simultaneous and Sequential Integration by Cre/loxP Site-Specific Recombination in Saccharomyces cerevisiae.

PubMed

Choi, Ho-Jung; Kim, Yeon-Hee

2018-05-28

A Cre/ loxP -δ-integration system was developed to allow sequential and simultaneous integration of a multiple gene expression cassette in Saccharomyces cerevisiae . To allow repeated integrations, the reusable Candida glabrata MARKER ( CgMARKER ) carrying loxP sequences was used, and the integrated CgMARKER was efficiently removed by inducing Cre recombinase. The XYLP and XYLB genes encoding endoxylanase and β-xylosidase, respectively, were used as model genes for xylan metabolism in this system, and the copy number of these genes was increased to 15.8 and 16.9 copies/cell, respectively, by repeated integration. This integration system is a promising approach for the easy construction of yeast strains with enhanced metabolic pathways through multicopy gene expression.

Comparison of Image Quality and Radiation Dose of Coronary Computed Tomography Angiography Between Conventional Helical Scanning and a Strategy Incorporating Sequential Scanning

PubMed Central

Einstein, Andrew J.; Wolff, Steven D.; Manheimer, Eric D.; Thompson, James; Terry, Sylvia; Uretsky, Seth; Pilip, Adalbert; Peters, M. Robert

2009-01-01

Radiation dose from coronary computed tomography angiography may be reduced using a sequential scanning protocol rather than a conventional helical scanning protocol. Here we compare radiation dose and image quality from coronary computed tomography angiography in a single center between an initial period during which helical scanning with electrocardiographically-controlled tube current modulation was used for all patients (n=138) and after adoption of a strategy incorporating sequential scanning whenever appropriate (n=261). Using the sequential-if-appropriate strategy, sequential scanning was employed in 86.2% of patients. Compared to the helical-only strategy, this strategy was associated with a 65.1% dose reduction (mean dose-length product of 305.2 vs. 875.1 and mean effective dose of 14.9 mSv vs. 5.2 mSv, respectively), with no significant change in overall image quality, step artifacts, motion artifacts, or perceived image noise. For the 225 patients undergoing sequential scanning, the dose-length product was 201.9 ± 90.0 mGy·cm, while for patients undergoing helical scanning under either strategy, the dose-length product was 890.9 ± 293.3 mGy·cm (p<0.0001), corresponding to mean effective doses of 3.4 mSv and 15.1 mSv, respectively, a 77.5% reduction. Image quality was significantly greater for the sequential studies, reflecting the poorer image quality in patients undergoing helical scanning in the sequential-if-appropriate strategy. In conclusion, a sequential-if-appropriate diagnostic strategy reduces dose markedly compared to a helical-only strategy, with no significant difference in image quality. PMID:19892048

Breast conserving treatment for breast cancer: dosimetric comparison of sequential versus simultaneous integrated photon boost.

PubMed

Van Parijs, Hilde; Reynders, Truus; Heuninckx, Karina; Verellen, Dirk; Storme, Guy; De Ridder, Mark

2014-01-01

Breast conserving surgery followed by whole breast irradiation is widely accepted as standard of care for early breast cancer. Addition of a boost dose to the initial tumor area further reduces local recurrences. We investigated the dosimetric benefits of a simultaneously integrated boost (SIB) compared to a sequential boost to hypofractionate the boost volume, while maintaining normofractionation on the breast. For 10 patients 4 treatment plans were deployed, 1 with a sequential photon boost, and 3 with different SIB techniques: on a conventional linear accelerator, helical TomoTherapy, and static TomoDirect. Dosimetric comparison was performed. PTV-coverage was good in all techniques. Conformity was better with all SIB techniques compared to sequential boost (P = 0.0001). There was less dose spilling to the ipsilateral breast outside the PTVboost (P = 0.04). The dose to the organs at risk (OAR) was not influenced by SIB compared to sequential boost. Helical TomoTherapy showed a higher mean dose to the contralateral breast, but less than 5 Gy for each patient. SIB showed less dose spilling within the breast and equal dose to OAR compared to sequential boost. Both helical TomoTherapy and the conventional technique delivered acceptable dosimetry. SIB seems a safe alternative and can be implemented in clinical routine.

Breast Conserving Treatment for Breast Cancer: Dosimetric Comparison of Sequential versus Simultaneous Integrated Photon Boost

PubMed Central

Reynders, Truus; Heuninckx, Karina; Verellen, Dirk; Storme, Guy; De Ridder, Mark

2014-01-01

Background. Breast conserving surgery followed by whole breast irradiation is widely accepted as standard of care for early breast cancer. Addition of a boost dose to the initial tumor area further reduces local recurrences. We investigated the dosimetric benefits of a simultaneously integrated boost (SIB) compared to a sequential boost to hypofractionate the boost volume, while maintaining normofractionation on the breast. Methods. For 10 patients 4 treatment plans were deployed, 1 with a sequential photon boost, and 3 with different SIB techniques: on a conventional linear accelerator, helical TomoTherapy, and static TomoDirect. Dosimetric comparison was performed. Results. PTV-coverage was good in all techniques. Conformity was better with all SIB techniques compared to sequential boost (P = 0.0001). There was less dose spilling to the ipsilateral breast outside the PTVboost (P = 0.04). The dose to the organs at risk (OAR) was not influenced by SIB compared to sequential boost. Helical TomoTherapy showed a higher mean dose to the contralateral breast, but less than 5 Gy for each patient. Conclusions. SIB showed less dose spilling within the breast and equal dose to OAR compared to sequential boost. Both helical TomoTherapy and the conventional technique delivered acceptable dosimetry. SIB seems a safe alternative and can be implemented in clinical routine. PMID:25162031

Oligomerization reactions for precursors to secondary organic aerosol: Comparison between two formation mechanisms for the oligomeric hydroxyalkyl hydroperoxides

NASA Astrophysics Data System (ADS)

Zhao, Qiangli; Wang, Weina; Liu, Fengyi; Lü, Jian; Wang, Wenliang

2017-10-01

To better understand the formation mechanism of oligomeric hydroxyalkyl hydroperoxides HOROO(SCI)nH composed of stabilized Criegee intermediate (SCI) as a chain unit, the reactions of SCI with hydroxyalkyl hydroperoxides (HOROOH) and hydroxyalkylperoxy radical (HORO2) as well as HO2 radical were investigated. For the reactions of HORO2 + SCI, two preferred pathways involving a SCI insertion in HOROOH hydroperoxide bond can be found, and the formation of HOROO(SCI)H is the dominant pathway in the reaction of HOCH2(CH3)2COOH + (CH3)2COO. The structures of the HORO2, HOROOH as well as the SCIs play a crucial role in determining the reactivity of the oligomerization. Both the reactions of HORO2 + SCI + HO2 and HOROOH + SCI could be the source of the processors to the formation of secondary organic aerosol (SOA). But from the point of free energy barriers, the formation of HOROO(SCI)H prefers to follow the mechanism involving initiation by the reaction of a HORO2 and a SCI, sequential addition of SCIs, and termination by reaction with the HO2 radical. The rate coefficients show negative temperature dependence and vary in different systems depending on the reactants. The reaction process and constituents of the products can be regulated by temperature and reactants.

Exosites in the substrate specificity of blood coagulation reactions.

PubMed

Bock, P E; Panizzi, P; Verhamme, I M A

2007-07-01

The specificity of blood coagulation proteinases for substrate, inhibitor, and effector recognition is mediated by exosites on the surfaces of the catalytic domains, physically separated from the catalytic site. Some thrombin ligands bind specifically to either exosite I or II, while others engage both exosites. The involvement of different, overlapping constellations of exosite residues enables binding of structurally diverse ligands. The flexibility of the thrombin structure is central to the mechanism of complex formation and the specificity of exosite interactions. Encounter complex formation is driven by electrostatic ligand-exosite interactions, followed by conformational rearrangement to a stable complex. Exosites on some zymogens are in low affinity proexosite states and are expressed concomitant with catalytic site activation. The requirement for exosite expression controls the specificity of assembly of catalytic complexes on the coagulation pathway, such as the membrane-bound factor Xa*factor Va (prothrombinase) complex, and prevents premature assembly. Substrate recognition by prothrombinase involves a two-step mechanism with initial docking of prothrombin to exosites, followed by a conformational change to engage the FXa catalytic site. Prothrombin and its activation intermediates bind prothrombinase in two alternative conformations determined by the zymogen to proteinase transition that are hypothesized to involve prothrombin (pro)exosite I interactions with FVa, which underpin the sequential activation pathway. The role of exosites as the major source of substrate specificity has stimulated development of exosite-targeted anticoagulants for treatment of thrombosis.

An autophagic mechanism is involved in the 6-hydroxydopamine-induced neurotoxicity in vivo.

PubMed

He, Xin; Yuan, Wei; Li, Zijian; Feng, Juan

2017-10-05

6-hydroxydopamine (6-OHDA) is one of the most common agents for modeling dopaminergic neuron degeneration in Parkinson's disease (PD). So far, the role of autophagy in 6-OHDA-induced neurotoxicity remains controversial and most evidence is collected from in vitro studies. In this study, we determined the role of autophagy activation in 6-OHDA-induced neurotoxicity in a rat model of PD. Following 6-OHDA treatment, we observed a concomitant activation of autophagy and apoptosis. To further explore the interaction between autophagy and apoptosis induced by 6-OHDA, autophagy inhibitor 3-methylademine (3-MA) or cysteine protease inhibitor Z-FA-fmk was applied. We found that both 3-MA and Z-FA-fmk could not only exert immediate protection against 6-OHDA-induced neuronal apoptosis, but also prevent dopaminergic neuron loss in the long-term, which was related to reduced autophagosome formation. Furthermore, by monitoring the sequential changes of mTOR-related signaling pathways, we found that reactive oxygen species (ROS)-mediated AKT/AMPK-mTOR signaling pathway participated in but was not the initial cause of autophagy activation by 6-OHDA. Collectively, our data suggest that 6-OHDA-induced autophagy activation contributes to its neurotoxicity and targeting autophagy activation or cysteine proteases could be promising for developing neuroprotective agents for PD. Copyright © 2017 Elsevier B.V. All rights reserved.

Conceptual model for assessing criteria air pollutants in a multipollutant context: A modified adverse outcome pathway approach.

PubMed

Buckley, Barbara; Farraj, Aimen

2015-09-01

Air pollution consists of a complex mixture of particulate and gaseous components. Individual criteria and other hazardous air pollutants have been linked to adverse respiratory and cardiovascular health outcomes. However, assessing risk of air pollutant mixtures is difficult since components are present in different combinations and concentrations in ambient air. Recent mechanistic studies have limited utility because of the inability to link measured changes to adverse outcomes that are relevant to risk assessment. New approaches are needed to address this challenge. The purpose of this manuscript is to describe a conceptual model, based on the adverse outcome pathway approach, which connects initiating events at the cellular and molecular level to population-wide impacts. This may facilitate hazard assessment of air pollution mixtures. In the case reports presented here, airway hyperresponsiveness and endothelial dysfunction are measurable endpoints that serve to integrate the effects of individual criteria air pollutants found in inhaled mixtures. This approach incorporates information from experimental and observational studies into a sequential series of higher order effects. The proposed model has the potential to facilitate multipollutant risk assessment by providing a framework that can be used to converge the effects of air pollutants in light of common underlying mechanisms. This approach may provide a ready-to-use tool to facilitate evaluation of health effects resulting from exposure to air pollution mixtures. Published by Elsevier Ireland Ltd.

Acute radiation nephritis. Its evolution on sequential bone imaging

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

Palestro, C.; Fineman, D.; Goldsmith, S.J.

1988-11-01

Acute radiation nephritis typically affects the kidneys 3-12 months after radiation exposure and may occur with doses as low as 2500 rads. After an initial latent period, the affected portions of the kidneys become swollen and edematous, and develop multiple petechiae. Necrotizing vasculitis and interstitial hemorrhage occur, and the end stage is that of scarring. Two patients are presented in whom localized acute radiation nephritis developed, and whose kidneys demonstrated the characteristic sequential changes of this entity on serial bone imaging.

Sequencing and fan-out mechanism for causing a set of at least two sequential instructions to be performed in a dataflow processing computer

DOEpatents

Grafe, Victor G.; Hoch, James E.

1993-01-01

A sequencing and data fanout mechanism is provided for a dataflow processor is activated by an input token which causes a sequence of operations to occur by initiating a first instruction to act on data contained within the token and then executing a sequential thread of instructions identified by either a repeat count and an offset within the token, or by an offset within each preceding instruction.

Dopamine reward prediction-error signalling: a two-component response

PubMed Central

Schultz, Wolfram

2017-01-01

Environmental stimuli and objects, including rewards, are often processed sequentially in the brain. Recent work suggests that the phasic dopamine reward prediction-error response follows a similar sequential pattern. An initial brief, unselective and highly sensitive increase in activity unspecifically detects a wide range of environmental stimuli, then quickly evolves into the main response component, which reflects subjective reward value and utility. This temporal evolution allows the dopamine reward prediction-error signal to optimally combine speed and accuracy. PMID:26865020

Inter-annual cascade effect on marine food web: A benthic pathway lagging nutrient supply to pelagic fish stock

PubMed Central

Fernandes, Lohengrin Dias de Almeida; Fagundes Netto, Eduardo Barros; Coutinho, Ricardo

2017-01-01

Currently, spatial and temporal changes in nutrients availability, marine planktonic, and fish communities are best described on a shorter than inter-annual (seasonal) scale, primarily because the simultaneous year-to-year variations in physical, chemical, and biological parameters are very complex. The limited availability of time series datasets furnishing simultaneous evaluations of temperature, nutrients, plankton, and fish have limited our ability to describe and to predict variability related to short-term process, as species-specific phenology and environmental seasonality. In the present study, we combine a computational time series analysis on a 15-year (1995–2009) weekly-sampled time series (high-resolution long-term time series, 780 weeks) with an Autoregressive Distributed Lag Model to track non-seasonal changes in 10 potentially related parameters: sea surface temperature, nutrient concentrations (NO2, NO3, NH4 and PO4), phytoplankton biomass (as in situ chlorophyll a biomass), meroplankton (barnacle and mussel larvae), and fish abundance (Mugil liza and Caranx latus). Our data demonstrate for the first time that highly intense and frequent upwelling years initiate a huge energy flux that is not fully transmitted through classical size-structured food web by bottom-up stimulus but through additional ontogenetic steps. A delayed inter-annual sequential effect from phytoplankton up to top predators as carnivorous fishes is expected if most of energy is trapped into benthic filter feeding organisms and their larval forms. These sequential events can explain major changes in ecosystem food web that were not predicted in previous short-term models. PMID:28886162

Asymmetric Synthesis of Spiropyrazolones by Sequential Organo- and Silver Catalysis

PubMed Central

Hack, Daniel; Dürr, Alexander B; Deckers, Kristina; Chauhan, Pankaj; Seling, Nico; Rübenach, Lukas; Mertens, Lucas; Raabe, Gerhard; Schoenebeck, Franziska; Enders, Dieter

2016-01-01

A stereoselective one-pot synthesis of spiropyrazolones through an organocatalytic asymmetric Michael addition and a formal Conia-ene reaction has been developed. Depending on the nitroalkene, the 5-exo-dig-cyclization could be achieved by silver-catalyzed alkyne activation or by oxidation of the intermediate enolate. The mechanistic pathways have been investigated using computational chemistry and mechanistic experiments. PMID:26676875

Oxidation of Ethylene Glycol by a Salt-Requiring Bacterium

PubMed Central

Caskey, William H.; Taber, Willard A.

1981-01-01

Bacterium T-52, cultured on ethylene glycol, readily oxidized glycolate and glyoxylate and exhibited elevated activities of ethylene glycol dehydrogenase and glycolate oxidase. Labeled glyoxylate was identified in reaction mixtures containing [14C]-ethylene glycol, but no glycolate was detected. The most likely pathway of ethylene glycol catabolism by bacterium T-52 is sequential oxidation to glycolate and glyoxylate. PMID:16345810

Component qualification and initial build of the AGT 100 advanced automotive gas turbine

NASA Technical Reports Server (NTRS)

Johnson, R. A.

1983-01-01

In advance of initial dynamometer testing of the AGT 100 engine, all prime components and subsystems were bench/rig tested. Included were compressor, combustor, turbines, regenerator, ceramic components, and electronic control system. Results are briefly reviewed. Initial engine buildup was completed and rolled-out for test cell installation in July 1982. Shakedown testing included motoring and sequential firing of the combustor's three fuel nozzles.

Improving Hospital-wide Patient Scheduling Decisions by Clinical Pathway Mining.

PubMed

Gartner, Daniel; Arnolds, Ines V; Nickel, Stefan

2015-01-01

Recent research has highlighted the need for solving hospital-wide patient scheduling problems. Inpatient scheduling, patient activities have to be scheduled on scarce hospital resources such that temporal relations between activities (e.g. for recovery times) are ensured. Common objectives are, among others, the minimization of the length of stay (LOS). In this paper, we consider a hospital-wide patient scheduling problem with LOS minimization based on uncertain clinical pathways. We approach the problem in three stages: First, we learn most likely clinical pathways using a sequential pattern mining approach. Second, we provide a mathematical model for patient scheduling and finally, we combine the two approaches. In an experimental study carried out using real-world data, we show that our approach outperforms baseline approaches on two metrics.

Protein design and engineering of a de novo pathway for microbial production of 1,3-propanediol from glucose.

PubMed

Chen, Zhen; Geng, Feng; Zeng, An-Ping

2015-02-01

Protein engineering to expand the substrate spectrum of native enzymes opens new possibilities for bioproduction of valuable chemicals from non-natural pathways. No natural microorganism can directly use sugars to produce 1,3-propanediol (PDO). Here, we present a de novo route for the biosynthesis of PDO from sugar, which may overcome the mentioned limitations by expanding the homoserine synthesis pathway. The accomplishment of pathway from homoserine to PDO is achieved by protein engineering of glutamate dehydrogenase (GDH) and pyruvate decarboxylase to sequentially convert homoserine to 4-hydroxy-2-ketobutyrate and 3-hydroxypropionaldehyde. The latter is finally converted to PDO by using a native alcohol dehydrogenase. In this work, we report on experimental accomplishment of this non-natural pathway, especially by protein engineering of GDH for the key step of converting homoserine to 4-hydroxy-2-ketobutyrate. These results show the feasibility and significance of protein engineering for de novo pathway design and overproduction of desired industrial products. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Randomized Controlled Trial for Behavioral Smoking and Weight Control Treatment: Effect of Concurrent versus Sequential Intervention

PubMed Central

Spring, Bonnie; Doran, Neal; Pagoto, Sherry; Schneider, Kristin; Pingitore, Regina; Hedeker, Don

2014-01-01

Prospects for changing multiple health behaviors conjointly remain controversial. We compared effects on tobacco abstinence and weight gain of adding diet and exercise concurrently or after smoking treatment. Female regular smokers (n=315) randomized to 3 conditions received 16 weeks of behavioral smoking treatment, quit at week 5, and were followed for 9 months after the quit date. Weight management was added to the first 8 weeks for Early Diet (ED), the final 8 weeks for Late Diet (LD), and omitted for Control. Both Diet groups tended to show greater bio-verified abstinence than Control although differences were nonsignificant. Compared to Control, ED initially suppressed weight gain but lost that effect over time, whereas LD initially lacked but gradually acquired a weight suppression effect that stabilized [p = .004]. Behavioral weight control did not undermine smoking cessation and slowed the rate of weight gain when initiated after the smoking quit date, supporting a sequential approach to multiple behavior change. PMID:15482037

Better together: reduced compliance after sequential versus simultaneous bilateral hearing aids fitting.

PubMed

Lavie, Limor; Banai, Karen; Attias, Joseph; Karni, Avi

2014-03-01

The purpose of this study was to determine the effects of sequential versus simultaneous bilateral hearing aids fitting on patient compliance. Thirty-six older adults with hearing impairment participated in this study. Twelve were fitted with bilateral hearing aids simultaneously. The remaining participants were fitted sequentially: One hearing aid (to the left or to the right ear) was used initially; 1 month later, the other ear was also fitted with a hearing aid for bilateral use. Self-reports on usefulness and compliance were elicited after the first and second months of hearing aid use. In addition, the number of hours the hearing aids were used was extracted from the data loggings of each device. Simultaneous fitting resulted in high levels of compliance and consistent usage throughout the study period. Sequential fitting resulted in abrupt reduction in compliance and hours of use once the second hearing aid was added, both in the clinical scoring and in the data loggings. Simultaneous fitting of bilateral hearing aids results in better compliance compared with sequential fitting. The addition of a second hearing aid after a relatively short period of monaural use may lead to inconsistent use of both hearing aids.

Effect of applied voltage, initial concentration and natural organic matter on sequential reduction/oxidation of nitrobenzene by graphite electrodes

PubMed Central

Sun, Mei; Reible, Danny D.; Lowry, Gregory V.; Gregory, Kelvin B.

2012-01-01

Carbon electrodes are proposed in reactive sediment caps for in situ treatment of contaminants. The electrodes produce reducing conditions and H2 at the cathode and oxidizing conditions and O2 at the anode. Emplaced perpendicular to seepage flow, the electrodes provide the opportunity for sequential reduction and oxidation of contaminants. The objectives of this study are to demonstrate degradation of nitrobenzene (NB) as a probe compound for sequential electrochemical reduction and oxidation, and to determine the effect of applied voltage, initial concentration and natural organic matter on the degradation rate. In H-cell reactors with graphite electrodes and buffer solution, NB was reduced stoichiometrically to aniline (AN) at the cathode with nitrosobenzene (NSB) as the intermediate. AN was then removed at the anode, faster than the reduction step. No common AN oxidation intermediate was detected in the system. Both the first order reduction rate constants of NB (kNB) and NSB (kNSB) increased with applied voltage between 2V and 3.5 V (when the initial NB concentration was 100 µM, kNB=0.3 d−1 and kNSB=0.04 d−1at 2V; kNB=1.6 d−1 and kNSB=0.64 d−1at 3.5 V) but stopped increasing beyond the threshold of 3.5V. When initial NB concentration decreased from 100 to 5 µM, kNB and kNSB became 9 and 5 times faster, respectively, suggesting that competition for active sites on the electrode surface is an important factor in NB degradation. Presence of natural organic matter (in forms of either humic acid or Anacostia River sediment porewater) decreased kNB while slightly increased kNSB, but only to a limited extent (~factor of 3) for dissolved organic carbon content up to 100 mg/l. These findings suggest that electrode-based reactive sediment capping via sequential reduction/oxidation is a potentially robust and tunable technology for in situ contaminants degradation. PMID:22571797

Sequential Auctions with Partially Substitutable Goods

NASA Astrophysics Data System (ADS)

Vetsikas, Ioannis A.; Jennings, Nicholas R.

In this paper, we examine a setting in which a number of partially substitutable goods are sold in sequential single unit auctions. Each bidder needs to buy exactly one of these goods. In previous work, this setting has been simplified by assuming that bidders do not know their valuations for all items a priori, but rather are informed of their true valuation for each item right before the corresponding auction takes place. This assumption simplifies the strategies of bidders, as the expected revenue from future auctions is the same for all bidders due to the complete lack of private information. In our analysis we don't make this assumption. This complicates the computation of the equilibrium strategies significantly. We examine this setting both for first and second-price auction variants, initially when the closing prices are not announced, for which we prove that sequential first and second-price auctions are revenue equivalent. Then we assume that the prices are announced; because of the asymmetry in the announced prices between the two auction variants, revenue equivalence does not hold in this case. We finish the paper, by giving some initial results about the case when free disposal is allowed, and therefore a bidder can purchase more than one item.

A two-pronged structural analysis of retroviral maturation indicates that core formation proceeds by a disassembly-reassembly pathway rather than a displacive transition.

PubMed

Keller, Paul W; Huang, Rick K; England, Matthew R; Waki, Kayoko; Cheng, Naiqian; Heymann, J Bernard; Craven, Rebecca C; Freed, Eric O; Steven, Alasdair C

2013-12-01

Retrovirus maturation involves sequential cleavages of the Gag polyprotein, initially arrayed in a spherical shell, leading to formation of capsids with polyhedral or conical morphology. Evidence suggests that capsids assemble de novo inside maturing virions from dissociated capsid (CA) protein, but the possibility persists of a displacive pathway in which the CA shell remains assembled but is remodeled. Inhibition of the final cleavage between CA and spacer peptide SP1/SP blocks the production of mature capsids. We investigated whether retention of SP might render CA assembly incompetent by testing the ability of Rous sarcoma virus (RSV) CA-SP to assemble in vitro into icosahedral capsids. Capsids were indeed assembled and were indistinguishable from those formed by CA alone, indicating that SP was disordered. We also used cryo-electron tomography to characterize HIV-1 particles produced in the presence of maturation inhibitor PF-46396 or with the cleavage-blocking CA5 mutation. Inhibitor-treated virions have a shell that resembles the CA layer of the immature Gag shell but is less complete. Some CA protein is generated but usually not enough for a mature core to assemble. We propose that inhibitors like PF-46396 bind to the Gag lattice where they deny the protease access to the CA-SP1 cleavage site and prevent the release of CA. CA5 particles, which exhibit no cleavage at the CA-SP1 site, have spheroidal shells with relatively thin walls. It appears that this lattice progresses displacively toward a mature-like state but produces neither conical cores nor infectious virions. These observations support the disassembly-reassembly pathway for core formation.

Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease

PubMed Central

1992-01-01

Serum mannose-binding protein (MBP) is a C-type lectin that binds to terminal mannose and N-acetylglucosamine moieties present on surfaces of certain pathogens and activates the classical complement pathway. In the present study, we describe the mechanism underlying the activation triggered by MBP. The human serum MBP fraction was obtained by sequential affinity chromatography on mannan-Sepharose, anti-IgM- Sepharose and anti-MBP-Sepharose in the presence of calcium ions. This fraction contained a C1s-like serine protease as assessed by C4 consumption. The C1s-like serine protease, designated MBP-associated serine protease (MASP), was separated from MBP by rechromatography on anti-MBP-Sepharose in the presence of ethylenediaminetetraacetic acid. MASP exhibited both C4- and C2-consuming activities. The molecular mass of MASP was estimated to be 83 kD with two polypeptides of heavy (66 kD) and light (L) (31 kD) chains linked by disulfide bonds. The serine residue responsible for protease activity is located on the L chain. Reconstitution experiments using MASP and MBP revealed that combination of the two components restores C4- and C2-activating capacity on mannan. Based on analyses of molecular size, antigenicity, and 11 NH2- terminal amino acid sequences of the L chain, we conclude that MASP is a novel protein different from C1r or C1s. Our findings are not in accord with a proposed mechanism by which MBP utilizes the C1r2-C1s2 complex to initiate the classical complement pathway. PMID:1460414

Self-compassion and physical health: Exploring the roles of perceived stress and health-promoting behaviors

PubMed Central

Homan, Kristin J; Sirois, Fuschia M

2017-01-01

Growing evidence indicates that self-compassion is associated with better physical health, but the pathways that mediate this relationship are not well understood. This study tested a serial mediation model that linked self-compassion, perceived stress, health behaviors, and a comprehensive index of physical health. A sample of 176 individuals completed an online survey posted on Amazon’s Mechanical Turk. Self-compassion had an indirect effect on physical health via both mediators and through the sequential pathway, suggesting that taking a kind, accepting and mindful stance toward one’s flaws and failures may have benefits for reducing stress and promoting health behaviors. PMID:29379620

77 FR 76871 - Approval and Promulgation of Implementation Plans; State of Colorado; Regional Haze State...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-31

... nitrogen oxides. xiii. The initials NPS mean or refer to National Park Service. xiv. The initials PM 2.5..., nitrogen deposition, and mercury emissions and deposition. The State spent considerable time and conducted sequential and extended hearings to develop a plan which seeks to balance a number of variables beyond those...

The Effects of Autonomy-Supportive Coaching, Need Satisfaction, and Self-Perceptions on Initiative and Identity in Youth Swimmers

ERIC Educational Resources Information Center

Coatsworth, J. Douglas; Conroy, David E.

2009-01-01

This study tested a sequential process model linking youth sport coaching climates (perceived coach behaviors and perceived need satisfaction) to youth self-perceptions (perceived competence and global self-esteem) and youth development outcomes (initiative, identity reflection, identity exploration). A sample of 119 youth between the ages of 10…

Orphan therapies: making best use of postmarket data.

PubMed

Maro, Judith C; Brown, Jeffrey S; Dal Pan, Gerald J; Li, Lingling

2014-08-01

Postmarket surveillance of the comparative safety and efficacy of orphan therapeutics is challenging, particularly when multiple therapeutics are licensed for the same orphan indication. To make best use of product-specific registry data collected to fulfill regulatory requirements, we propose the creation of a distributed electronic health data network among registries. Such a network could support sequential statistical analyses designed to detect early warnings of excess risks. We use a simulated example to explore the circumstances under which a distributed network may prove advantageous. We perform sample size calculations for sequential and non-sequential statistical studies aimed at comparing the incidence of hepatotoxicity following initiation of two newly licensed therapies for homozygous familial hypercholesterolemia. We calculate the sample size savings ratio, or the proportion of sample size saved if one conducted a sequential study as compared to a non-sequential study. Then, using models to describe the adoption and utilization of these therapies, we simulate when these sample sizes are attainable in calendar years. We then calculate the analytic calendar time savings ratio, analogous to the sample size savings ratio. We repeat these analyses for numerous scenarios. Sequential analyses detect effect sizes earlier or at the same time as non-sequential analyses. The most substantial potential savings occur when the market share is more imbalanced (i.e., 90% for therapy A) and the effect size is closest to the null hypothesis. However, due to low exposure prevalence, these savings are difficult to realize within the 30-year time frame of this simulation for scenarios in which the outcome of interest occurs at or more frequently than one event/100 person-years. We illustrate a process to assess whether sequential statistical analyses of registry data performed via distributed networks may prove a worthwhile infrastructure investment for pharmacovigilance.

The Mg2+-containing Water Cluster of Mammalian Cytochrome c Oxidase Collects Four Pumping Proton Equivalents in Each Catalytic Cycle*

PubMed Central

Yano, Naomine; Muramoto, Kazumasa; Shimada, Atsuhiro; Takemura, Shuhei; Baba, Junpei; Fujisawa, Hidenori; Mochizuki, Masao; Shinzawa-Itoh, Kyoko; Yamashita, Eiki; Tsukihara, Tomitake; Yoshikawa, Shinya

2016-01-01

Bovine heart cytochrome c oxidase (CcO) pumps four proton equivalents per catalytic cycle through the H-pathway, a proton-conducting pathway, which includes a hydrogen bond network and a water channel operating in tandem. Protons are transferred by H3O+ through the water channel from the N-side into the hydrogen bond network, where they are pumped to the P-side by electrostatic repulsion between protons and net positive charges created at heme a as a result of electron donation to O2 bound to heme a3. To block backward proton movement, the water channel remains closed after O2 binding until the sequential four-proton pumping process is complete. Thus, the hydrogen bond network must collect four proton equivalents before O2 binding. However, a region with the capacity to accept four proton equivalents was not discernable in the x-ray structures of the hydrogen bond network. The present x-ray structures of oxidized/reduced bovine CcO are improved from 1.8/1.9 to 1.5/1.6 Å resolution, increasing the structural information by 1.7/1.6 times and revealing that a large water cluster, which includes a Mg2+ ion, is linked to the H-pathway. The cluster contains enough proton acceptor groups to retain four proton equivalents. The redox-coupled x-ray structural changes in Glu198, which bridges the Mg2+ and CuA (the initial electron acceptor from cytochrome c) sites, suggest that the CuA-Glu198-Mg2+ system drives redox-coupled transfer of protons pooled in the water cluster to the H-pathway. Thus, these x-ray structures indicate that the Mg2+-containing water cluster is the crucial structural element providing the effective proton pumping in bovine CcO. PMID:27605664

The Mg2+-containing Water Cluster of Mammalian Cytochrome c Oxidase Collects Four Pumping Proton Equivalents in Each Catalytic Cycle.

PubMed

Yano, Naomine; Muramoto, Kazumasa; Shimada, Atsuhiro; Takemura, Shuhei; Baba, Junpei; Fujisawa, Hidenori; Mochizuki, Masao; Shinzawa-Itoh, Kyoko; Yamashita, Eiki; Tsukihara, Tomitake; Yoshikawa, Shinya

2016-11-11

Bovine heart cytochrome c oxidase (CcO) pumps four proton equivalents per catalytic cycle through the H-pathway, a proton-conducting pathway, which includes a hydrogen bond network and a water channel operating in tandem. Protons are transferred by H 3 O + through the water channel from the N-side into the hydrogen bond network, where they are pumped to the P-side by electrostatic repulsion between protons and net positive charges created at heme a as a result of electron donation to O 2 bound to heme a 3 To block backward proton movement, the water channel remains closed after O 2 binding until the sequential four-proton pumping process is complete. Thus, the hydrogen bond network must collect four proton equivalents before O 2 binding. However, a region with the capacity to accept four proton equivalents was not discernable in the x-ray structures of the hydrogen bond network. The present x-ray structures of oxidized/reduced bovine CcO are improved from 1.8/1.9 to 1.5/1.6 Å resolution, increasing the structural information by 1.7/1.6 times and revealing that a large water cluster, which includes a Mg 2+ ion, is linked to the H-pathway. The cluster contains enough proton acceptor groups to retain four proton equivalents. The redox-coupled x-ray structural changes in Glu 198 , which bridges the Mg 2+ and Cu A (the initial electron acceptor from cytochrome c) sites, suggest that the Cu A -Glu 198 -Mg 2+ system drives redox-coupled transfer of protons pooled in the water cluster to the H-pathway. Thus, these x-ray structures indicate that the Mg 2+ -containing water cluster is the crucial structural element providing the effective proton pumping in bovine CcO. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Sequential simulation (SqS) of clinical pathways: a tool for public and patient engagement in point-of-care diagnostics.

PubMed

Huddy, Jeremy R; Weldon, Sharon-Marie; Ralhan, Shvaita; Painter, Tim; Hanna, George B; Kneebone, Roger; Bello, Fernando

2016-09-13

Public and patient engagement (PPE) is fundamental to healthcare research. To facilitate effective engagement in novel point-of-care tests (POCTs), the test and downstream consequences of the result need to be considered. Sequential simulation (SqS) is a tool to represent patient journeys and the effects of intervention at each and subsequent stages. This case study presents a process evaluation of SqS as a tool for PPE in the development of a volatile organic compound-based breath test POCT for the diagnosis of oesophagogastric (OG) cancer. Three 3-hour workshops in central London. 38 members of public attended a workshop, 26 (68%) had no prior experience of the OG cancer diagnostic pathway. Clinical pathway SqS was developed from a storyboard of a patient, played by an actor, noticing symptoms of oesophageal cancer and following a typical diagnostic pathway. The proposed breath testing strategy was then introduced and incorporated into a second SqS to demonstrate pathway impact. Facilitated group discussions followed each SqS. Evaluation was conducted through pre-event and postevent questionnaires, field notes and analysis of audiovisual recordings. 38 participants attended a workshop. All participants agreed they were able to contribute to discussions and like the idea of an OG cancer breath test. Five themes emerged related to the proposed new breath test including awareness of OG cancer, barriers to testing and diagnosis, design of new test device, new clinical pathway and placement of test device. 3 themes emerged related to the use of SqS: participatory engagement, simulation and empathetic engagement, and why participants attended. SqS facilitated a shared immersive experience for participants and researchers that led to the coconstruction of knowledge that will guide future research activities and be of value to stakeholders concerned with the invention and adoption of POCT. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

An unsupervised classification technique for multispectral remote sensing data.

NASA Technical Reports Server (NTRS)

Su, M. Y.; Cummings, R. E.

1973-01-01

Description of a two-part clustering technique consisting of (a) a sequential statistical clustering, which is essentially a sequential variance analysis, and (b) a generalized K-means clustering. In this composite clustering technique, the output of (a) is a set of initial clusters which are input to (b) for further improvement by an iterative scheme. This unsupervised composite technique was employed for automatic classification of two sets of remote multispectral earth resource observations. The classification accuracy by the unsupervised technique is found to be comparable to that by traditional supervised maximum-likelihood classification techniques.

Unsupervised classification of earth resources data.

NASA Technical Reports Server (NTRS)

Su, M. Y.; Jayroe, R. R., Jr.; Cummings, R. E.

1972-01-01

A new clustering technique is presented. It consists of two parts: (a) a sequential statistical clustering which is essentially a sequential variance analysis and (b) a generalized K-means clustering. In this composite clustering technique, the output of (a) is a set of initial clusters which are input to (b) for further improvement by an iterative scheme. This unsupervised composite technique was employed for automatic classification of two sets of remote multispectral earth resource observations. The classification accuracy by the unsupervised technique is found to be comparable to that by existing supervised maximum liklihood classification technique.

Sequential Elution Interactome Analysis of the Mind Bomb 1 Ubiquitin Ligase Reveals a Novel Role in Dendritic Spine Outgrowth*

PubMed Central

Mertz, Joseph; Tan, Haiyan; Pagala, Vishwajeeth; Bai, Bing; Chen, Ping-Chung; Li, Yuxin; Cho, Ji-Hoon; Shaw, Timothy; Wang, Xusheng; Peng, Junmin

2015-01-01

The mind bomb 1 (Mib1) ubiquitin ligase is essential for controlling metazoan development by Notch signaling and possibly the Wnt pathway. It is also expressed in postmitotic neurons and regulates neuronal morphogenesis and synaptic activity by mechanisms that are largely unknown. We sought to comprehensively characterize the Mib1 interactome and study its potential function in neuron development utilizing a novel sequential elution strategy for affinity purification, in which Mib1 binding proteins were eluted under different stringency and then quantified by the isobaric labeling method. The strategy identified the Mib1 interactome with both deep coverage and the ability to distinguish high-affinity partners from low-affinity partners. A total of 817 proteins were identified during the Mib1 affinity purification, including 56 high-affinity partners and 335 low-affinity partners, whereas the remaining 426 proteins are likely copurified contaminants or extremely weak binding proteins. The analysis detected all previously known Mib1-interacting proteins and revealed a large number of novel components involved in Notch and Wnt pathways, endocytosis and vesicle transport, the ubiquitin-proteasome system, cellular morphogenesis, and synaptic activities. Immunofluorescence studies further showed colocalization of Mib1 with five selected proteins: the Usp9x (FAM) deubiquitinating enzyme, alpha-, beta-, and delta-catenins, and CDKL5. Mutations of CDKL5 are associated with early infantile epileptic encephalopathy-2 (EIEE2), a severe form of mental retardation. We found that the expression of Mib1 down-regulated the protein level of CDKL5 by ubiquitination, and antagonized CDKL5 function during the formation of dendritic spines. Thus, the sequential elution strategy enables biochemical characterization of protein interactomes; and Mib1 analysis provides a comprehensive interactome for investigating its role in signaling networks and neuronal development. PMID:25931508

Biobegradation and metabolic mechanism of cyprodinil by strain Acinetobacter sp. from a contaminated-agricultural soil in China.

PubMed

Chen, Xiaoxin; He, Sheng; Liu, Xiaolu; Hu, Jiye

2018-09-15

Using sequential soil and liquid culture enrichments with cyprodinil as the sole carbon source, a Gram-negative cyprodinil-degrader from cyprodinil-polluted agricultural soil was isolated. The sequencing analysis of 16 S rRNA indicated that the strain showed 99% homology to Acinetobacter sp. The strain could effectively degrade cyprodinil at the neutral condition. At the initial concentrations of 10, 20, 50, 100, 150 and 200 mg L -1 in minimal medium, cyprodinil was degraded by 10, 20, 49.3, 64.2, 57 and 24 mg L -1 within 14 days, respectively. Two metabolites (4-cyclopropyl-6-methyl-2-pyrimidpyridine amine and monohydroxylated para-substitution) were identified using high performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS/MS). A biodegradation pathway involving imines hydrolysis and monohydroxyl substitution on benzene ring was proposed on basis of the identified metabolites. Acinetobacter sp. would have a potential application in bioremediation of cyprodinil-contaminated soil, and the strain might have important implications in detoxification and bioremediation of pyrimidine analogues. Copyright © 2018 Elsevier Inc. All rights reserved.

An electrostatic selection mechanism controls sequential kinase signaling downstream of the T cell receptor

PubMed Central

Shah, Neel H; Wang, Qi; Yan, Qingrong; Karandur, Deepti; Kadlecek, Theresa A; Fallahee, Ian R; Russ, William P; Ranganathan, Rama; Weiss, Arthur; Kuriyan, John

2016-01-01

The sequence of events that initiates T cell signaling is dictated by the specificities and order of activation of the tyrosine kinases that signal downstream of the T cell receptor. Using a platform that combines exhaustive point-mutagenesis of peptide substrates, bacterial surface-display, cell sorting, and deep sequencing, we have defined the specificities of the first two kinases in this pathway, Lck and ZAP-70, for the T cell receptor ζ chain and the scaffold proteins LAT and SLP-76. We find that ZAP-70 selects its substrates by utilizing an electrostatic mechanism that excludes substrates with positively-charged residues and favors LAT and SLP-76 phosphosites that are surrounded by negatively-charged residues. This mechanism prevents ZAP-70 from phosphorylating its own activation loop, thereby enforcing its strict dependence on Lck for activation. The sequence features in ZAP-70, LAT, and SLP-76 that underlie electrostatic selectivity likely contribute to the specific response of T cells to foreign antigens. DOI: http://dx.doi.org/10.7554/eLife.20105.001 PMID:27700984

4-Chlorophenol biodegradation facilitator composed of recombinant multi-biocatalysts immobilized onto montmorillonite.

PubMed

Kwean, Oh Sung; Cho, Su Yeon; Yang, Jun Won; Cho, Wooyoun; Park, Sungyoon; Lim, Yejee; Shin, Min Chul; Kim, Han-Suk; Park, Joonhong; Kim, Han S

2018-07-01

A biodegradation facilitator which catalyzes the initial steps of 4-chlorophenol (4-CP) oxidation was prepared by immobilizing multiple enzymes (monooxygenase, CphC-I and dioxygenase, CphA-I) onto a natural inorganic support. The enzymes were obtained via overexpression and purification after cloning the corresponding genes (cphC-I and cphA-I) from Arthrobacter chlorophenolicus A6. Then, the recombinant CphC-I was immobilized onto fulvic acid-activated montmorillonite. The immobilization yield was 60%, and the high enzyme activity (82.6%) was retained after immobilization. Kinetic analysis indicated that the Michaelis-Menten model parameters for the immobilized CphC-I were similar to those for the free enzyme. The enzyme stability was markedly enhanced after immobilization. The immobilized enzyme exhibited a high level of activity even after repetitive use (84.7%) and powdering (65.8%). 4-CP was sequentially oxidized by a multiple enzyme complex, comprising the immobilized CphC-I and CphA-I, via the hydroquinone pathway: oxidative transformation of 4-CP to hydroxyquinol followed by ring fission of hydroxyquinol. Copyright © 2018 Elsevier Ltd. All rights reserved.

Recent Progress in the Diagnosis and Treatment of Ovarian Cancer

PubMed Central

Jelovac, Danijela; Armstrong, Deborah K.

2013-01-01

Epithelial ovarian cancer is the most lethal of the gynecologic malignancies, largely due to the advanced stage at diagnosis in most patients. Screening strategies using ultrasound and the cancer antigen (CA) 125 tumor marker are currently under study and may lower stage at diagnosis but have not yet been shown to improve survival. Women who have inherited a deleterious mutation in the BRCA1 or BRCA2 gene and those with the Lynch syndrome (hereditary nonpolyposis colorectal cancer) have the highest risk of developing ovarian cancer but account for only approximately 10% of those with the disease. Other less common and less well-defined genetic syndromes may increase the risk of ovarian cancer, but their contribution to genetic risk is small. A clear etiology for sporadic ovarian cancer has not been identified, but risk is affected by reproductive and hormonal factors. Surgery has a unique role in ovarian cancer, as it is used not only for diagnosis and staging but also therapeutically, even in patients with widely disseminated, advanced disease. Ovarian cancer is highly sensitive to chemotherapy drugs, particularly the platinum agents, and most patients will attain a remission with initial treatment. Recent advances in the delivery of chemotherapy using the intraperitoneal route have further improved survival after initial therapy. Although the majority of ovarian cancer patients will respond to initial chemotherapy, most will ultimately develop disease recurrence. Chemotherapy for recurrent disease includes platinum-based, multiagent regimens for women whose disease recurs more than 6 to 12 months after the completion of initial therapy and sequential single agents for those whose disease recurs earlier. New targeted biologic agents, particularly those involved with the vascular endothelial growth factor pathway and those targeting the poly (ADP-ribose) polymerase (PARP) enzyme, hold great promise for improving the outcome of ovarian cancer. PMID:21521830

Radical Rearrangement Chemistry in Ultraviolet Photodissociation of Iodotyrosine Systems: Insights from Metastable Dissociation, Infrared Ion Spectroscopy, and Reaction Pathway Calculations.

PubMed

Ranka, Karnamohit; Zhao, Ning; Yu, Long; Stanton, John F; Polfer, Nicolas C

2018-05-29

We report on the ultraviolet photodissociation (UVPD) chemistry of protonated tyrosine, iodotyrosine, and diiodotyrosine. Distonic loss of the iodine creates a high-energy radical at the aromatic ring that engages in hydrogen/proton rearrangement chemistry. Based on UVPD kinetics measurements, the appearance of this radical is coincident with the UV irradiation pulse (8 ns). Conversely, sequential UVPD product ions exhibit metastable decay on ca. 100 ns timescales. Infrared ion spectroscopy is capable of confirming putative structures of the rearrangement products as proton transfers from the imine and β-carbon hydrogens. Potential energy surfaces for the various reaction pathways indicate that the rearrangement chemistry is highly complex, compatible with a cascade of rearrangements, and that there is no preferred rearrangement pathway even in small molecular systems like these. Graphical Abstract.

Fundamental Pathways for the Adsorption and Transport of Hydrogen on TiO2 Surfaces: Origin for Effective Sensing at about Room Temperature.

PubMed

Wang, Zhuo; Xia, Xiaohong; Guo, Meilan; Shao, Guosheng

2016-12-28

Effective detection of hydrogen at lowered temperature is highly desirable in promoting safety in using this abundant gas as a clean energy source. Through first-principle calculations in the framework of density functional theory, we find that the high-energy (002) surface for rutile TiO 2 is significantly more effective in adsorbing hydrogen atoms through dissociating hydrogen molecules. The pathways for the dissociation of hydrogen molecules and sequential migration of hydrogen atoms are identified through searching along various transitional states. Pathways of low potential barriers indicate promise for hydrogen sensing, even close to room temperature. This has been proven through sensors made of thin films of well-aligned rutile nanorods, wherein the high-energy (002) surface dictates the top surface of the active layer of the sensors.

Curcuminoid Binding to Embryonal Carcinoma Cells: Reductive Metabolism, Induction of Apoptosis, Senescence, and Inhibition of Cell Proliferation

PubMed Central

Quitschke, Wolfgang W.

2012-01-01

Curcumin preparations typically contain a mixture of polyphenols, collectively referred to as curcuminoids. In addition to the primary component curcumin, they also contain smaller amounts of the co-extracted derivatives demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids can be differentially solubilized in serum, which allows for the systematic analysis of concentration-dependent cellular binding, biological effects, and metabolism. Technical grade curcumin was solubilized in fetal calf serum by two alternative methods yielding saturated preparations containing either predominantly curcumin (60%) or bisdemethoxycurcumin (55%). Continual exposure of NT2/D1 cells for 4–6 days to either preparation in cell culture media reduced cell division (1–5 µM), induced senescence (6–7 µM) or comprehensive cell death (8–10 µM) in a concentration-dependent manner. Some of these effects could also be elicited in cells transiently exposed to higher concentrations of curcuminoids (47 µM) for 0.5–4 h. Curcuminoids induced apoptosis by generalized activation of caspases but without nucleosomal fragmentation. The equilibrium binding of serum-solubilized curcuminoids to NT2/D1 cells incubated with increasing amounts of curcuminoid-saturated serum occurred with apparent overall dissociation constants in the 6–10 µM range. However, the presence of excess free serum decreased cellular binding in a hyperbolic manner. Cellular binding was overwhelmingly associated with membrane fractions and bound curcuminoids were metabolized in NT2/D1 cells via a previously unidentified reduction pathway. Both the binding affinities for curcuminoids and their reductive metabolic pathways varied in other cell lines. These results suggest that curcuminoids interact with cellular binding sites, thereby activating signal transduction pathways that initiate a variety of biological responses. The dose-dependent effects of these responses further imply that distinct cellular pathways are sequentially activated and that this activation is dependent on the affinity of curcuminoids for the respective binding sites. Defined serum-solubilized curcuminoids used in cell culture media are thus suitable for further investigating the differential activation of signal transduction pathways. PMID:22768090

An evaluation of the phosphorus storage capacity of an anaerobic/aerobic sequential batch biofilm reactor.

PubMed

Chiou, Ren-Jie; Yang, Yi-Rong

2008-07-01

The aim of this work was to assess the phosphorus storage capability of the polyphosphate (poly-P) accumulating organisms (PAO) in the biofilm using a sequential batch biofilm reactor (SBBR). In the anaerobic phase, the specific COD uptake rates increases from 0.05 to 0.22 (mg-COD/mg-biomass/h) as the initial COD increases and the main COD uptake activity occurs in the initial 30 min. The polyhydroxyalkanoates (PHAs) accumulation from 18 to 38 (mg-PHA/g-biomass) and phosphorus release from 20 to 60 (mg-P/L) share a similar trend. The adsorbed COD cannot be immediately transformed to PHAs. Since the PHAs' demand per released phosphorus is independent of the initial COD, the enhancement of the PHA accumulation would be of benefit to phosphorus release. The only requirement is to have an initial amount of substrate that will result in sufficient PHA accumulation (approximately 20 mg-PHA/g-biomass) for phosphorus release. During the aerobic phase, the aeration should not only provide sufficient dissolved oxygen, but should also enhance the mass transfer and the diffusion. In other words, the limitation to the phosphorus storage capability always occurs during the anaerobic phase, not the aerobic phase.

Entry of Botulinum Neurotoxin Subtypes A1 and A2 into Neurons

PubMed Central

Kroken, Abby R.; Blum, Faith C.; Zuverink, Madison

2016-01-01

ABSTRACT Botulinum neurotoxins (BoNTs) are the most toxic proteins for humans but also are common therapies for neurological diseases. BoNTs are dichain toxins, comprising an N-terminal catalytic domain (LC) disulfide bond linked to a C-terminal heavy chain (HC) which includes a translocation domain (HN) and a receptor binding domain (HC). Recently, the BoNT serotype A (BoNT/A) subtypes A1 and A2 were reported to possess similar potencies but different rates of cellular intoxication and pathology in a mouse model of botulism. The current study measured HCA1 and HCA2 entry into rat primary neurons and cultured Neuro2A cells. We found that there were two sequential steps during the association of BoNT/A with neurons. The initial step was ganglioside dependent, while the subsequent step involved association with synaptic vesicles. HCA1 and HCA2 entered the same population of synaptic vesicles and entered cells at similar rates. The primary difference was that HCA2 had a higher degree of receptor occupancy for cells and neurons than HcA1. Thus, HCA2 and HCA1 share receptors and entry pathway but differ in their affinity for receptor. The initial interaction of HCA1 and HCA2 with neurons may contribute to the unique pathologies of BoNT/A1 and BoNT/A2 in mouse models. PMID:27795365

Biaxially mechanical tuning of 2-D reversible and irreversible surface topologies through simultaneous and sequential wrinkling.

PubMed

Yin, Jie; Yagüe, Jose Luis; Boyce, Mary C; Gleason, Karen K

2014-02-26

Controlled buckling is a facile means of structuring surfaces. The resulting ordered wrinkling topologies provide surface properties and features desired for multifunctional applications. Here, we study the biaxially dynamic tuning of two-dimensional wrinkled micropatterns under cyclic mechanical stretching/releasing/restretching simultaneously or sequentially. A biaxially prestretched PDMS substrate is coated with a stiff polymer deposited by initiated chemical vapor deposition (iCVD). Applying a mechanical release/restretch cycle in two directions loaded simultaneously or sequentially to the wrinkled system results in a variety of dynamic and tunable wrinkled geometries, the evolution of which is investigated using in situ optical profilometry, numerical simulations, and theoretical modeling. Results show that restretching ordered herringbone micropatterns, created through sequential release of biaxial prestrain, leads to reversible and repeatable surface topography. The initial flat surface and the same wrinkled herringbone pattern are obtained alternatively after cyclic release/restretch processes, owing to the highly ordered structure leaving no avenue for trapping irregular topological regions during cycling as further evidenced by the uniformity of strains distributions and negligible residual strain. Conversely, restretching disordered labyrinth micropatterns created through simultaneous release shows an irreversible surface topology whether after sequential or simultaneous restretching due to creation of irregular surface topologies with regions of highly concentrated strain upon formation of the labyrinth which then lead to residual strains and trapped topologies upon cycling; furthermore, these trapped topologies depend upon the subsequent strain histories as well as the cycle. The disordered labyrinth pattern varies after each cyclic release/restretch process, presenting residual shallow patterns instead of achieving a flat state. The ability to dynamically tune the highly ordered herringbone patterning through mechanical stretching or other actuation makes these wrinkles excellent candidates for tunable multifunctional surfaces properties such as reflectivity, friction, anisotropic liquid flow or boundary layer control.

A sequential analysis of classroom discourse in Italian primary schools: the many faces of the IRF pattern.

PubMed

Molinari, Luisa; Mameli, Consuelo; Gnisci, Augusto

2013-09-01

A sequential analysis of classroom discourse is needed to investigate the conditions under which the triadic initiation-response-feedback (IRF) pattern may host different teaching orientations. The purpose of the study is twofold: first, to describe the characteristics of classroom discourse and, second, to identify and explore the different interactive sequences that can be captured with a sequential statistical analysis. Twelve whole-class activities were video recorded in three Italian primary schools. We observed classroom interaction as it occurs naturally on an everyday basis. In total, we collected 587 min of video recordings. Subsequently, 828 triadic IRF patterns were extracted from this material and analysed with the programme Generalized Sequential Query (GSEQ). The results indicate that classroom discourse may unfold in different ways. In particular, we identified and described four types of sequences. Dialogic sequences were triggered by authentic questions, and continued through further relaunches. Monologic sequences were directed to fulfil the teachers' pre-determined didactic purposes. Co-constructive sequences fostered deduction, reasoning, and thinking. Scaffolding sequences helped and sustained children with difficulties. The application of sequential analyses allowed us to show that interactive sequences may account for a variety of meanings, thus making a significant contribution to the literature and research practice in classroom discourse. © 2012 The British Psychological Society.

Enhanced debromination of decabrominated diphenyl ether in aqueous solution by attapulgite supported Fe/Ni bimetallic nanoparticles: kinetics and pathways

NASA Astrophysics Data System (ADS)

Liu, Zongtang; Gu, Chenggang; Bian, Yongrong; Jiang, Xin; Sun, Yufeng; Fei, Zhenghao; Dai, Jingtao

2017-08-01

In this study, Fe/Ni bimetallic nanoparticles were supported on the attapulgite (A-Fe/Ni) to enhance the degradation reactivity of decabrominated diphenyl ether (BDE209) in aqueous solution. The Fe/Ni nanoparticles were well distributed on the attapulgite surface with an average diameter of 20-40 nm. The removal percentage of BDE209 by A-Fe/Ni was 1.59 times higher than Fe/Ni nanoparticles alone because attapulgite could act as supporting material to disperse Fe/Ni nanoparticles and prevent Fe/Ni nanoparticles from aggregation. The degradation kinetics for BDE209 debromination by A-Fe/Ni could be well described by a pseudo-first-order model, and the debromination rate constant of BDE209 increased with increasing the dosage of A-Fe/Ni, water/THF ratio, and decreasing the initial BDE209 concentration and solution pH. The degradation products were identified using a third-order polynomial regression equation between the experimental and reference gas chromatography relative retention times. Stepwise debromination from n-bromo-DE to (n  -  1)-bromo-DE was a possible pathway with bromines being substituted sequentially by hydrogen. The preferred elimination of bromines of BDE209 by A-Fe/Ni followed the debromination preference of para-Br  >  meta-Br  >  ortho-Br. The results provide evidences for understanding the debromination mechanism of polybrominated diphenyl ether by clay-supported Fe/Ni nanoparticles.

Cortico-Cortical, Cortico-Striatal, and Cortico-Thalamic White Matter Fiber Tracts Generated in the Macaque Brain via Dynamic Programming

PubMed Central

Lal, Rakesh M.; An, Michael; Poynton, Clare B.; Li, Muwei; Jiang, Hangyi; Oishi, Kenichi; Selemon, Lynn D.; Mori, Susumu; Miller, Michael I.

2013-01-01

Abstract Probabilistic methods have the potential to generate multiple and complex white matter fiber tracts in diffusion tensor imaging (DTI). Here, a method based on dynamic programming (DP) is introduced to reconstruct fibers pathways whose complex anatomical structures cannot be resolved beyond the resolution of standard DTI data. DP is based on optimizing a sequentially additive cost function derived from a Gaussian diffusion model whose covariance is defined by the diffusion tensor. DP is used to determine the optimal path between initial and terminal nodes by efficiently searching over all paths, connecting the nodes, and choosing the path in which the total probability is maximized. An ex vivo high-resolution scan of a macaque hemi-brain is used to demonstrate the advantages and limitations of DP. DP can generate fiber bundles between distant cortical areas (superior longitudinal fasciculi, arcuate fasciculus, uncinate fasciculus, and fronto-occipital fasciculus), neighboring cortical areas (dorsal and ventral banks of the principal sulcus), as well as cortical projections to the hippocampal formation (cingulum bundle), neostriatum (motor cortical projections to the putamen), thalamus (subcortical bundle), and hippocampal formation projections to the mammillary bodies via the fornix. Validation is established either by comparison with in vivo intracellular transport of horseradish peroxidase in another macaque monkey or by comparison with atlases. DP is able to generate known pathways, including crossing and kissing tracts. Thus, DP has the potential to enhance neuroimaging studies of cortical connectivity. PMID:23879573

Consecutive interactions with HSP90 and eEF1A underlie a functional maturation and storage pathway of AID in the cytoplasm

PubMed Central

Methot, Stephen P.; Litzler, Ludivine C.; Trajtenberg, Felipe; Zahn, Astrid; Robert, Francis; Pelletier, Jerry; Buschiazzo, Alejandro; Magor, Brad G.

2015-01-01

Activation-induced deaminase (AID) initiates mutagenic pathways to diversify the antibody genes during immune responses. The access of AID to the nucleus is limited by CRM1-mediated nuclear export and by an uncharacterized mechanism of cytoplasmic retention. Here, we define a conformational motif in AID that dictates its cytoplasmic retention and demonstrate that the translation elongation factor eukaryotic elongation factor 1 α (eEF1A) is necessary for AID cytoplasmic sequestering. The mechanism is independent of protein synthesis but dependent on a tRNA-free form of eEF1A. Inhibiting eEF1A prevents the interaction with AID, which accumulates in the nucleus and increases class switch recombination as well as chromosomal translocation byproducts. Most AID is associated to unspecified cytoplasmic complexes. We find that the interactions of AID with eEF1A and heat-shock protein 90 kD (HSP90) are inversely correlated. Despite both interactions stabilizing AID, the nature of the AID fractions associated with HSP90 or eEF1A are different, defining two complexes that sequentially produce and store functional AID in the cytoplasm. In addition, nuclear export and cytoplasmic retention cooperate to exclude AID from the nucleus but might not be functionally equivalent. Our results elucidate the molecular basis of AID cytoplasmic retention, define its functional relevance and distinguish it from other mechanisms regulating AID. PMID:25824822

Moving Synergistically Acting Drug Combinations to the Clinic by Comparing Sequential versus Simultaneous Drug Administrations.

PubMed

Dinavahi, Saketh S; Noory, Mohammad A; Gowda, Raghavendra; Drabick, Joseph J; Berg, Arthur; Neves, Rogerio I; Robertson, Gavin P

2018-03-01

Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. Protein kinase B (AKT) is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 (mitotic inhibitor kinase) seems to have potential to make AKT-based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine these agents sequentially, enabling the use of existing phase I clinical trial toxicity data. Therefore, a rapid preclinical approach is needed to evaluate whether simultaneous or sequential drug treatment has maximal therapeutic efficacy, which is based on a mechanistic rationale. To develop this approach, melanoma cell lines were treated with AKT inhibitor AZD5363 [4-amino- N -[(1 S )-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)piperidine-4-carboxamide] and WEE1 inhibitor AZD1775 [2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1 H -pyrazolo[3,4- d ]pyrimidin-3(2 H )-one] using simultaneous and sequential dosing schedules. Simultaneous treatment synergistically reduced melanoma cell survival and tumor growth. In contrast, sequential treatment was antagonistic and had a minimal tumor inhibitory effect compared with individual agents. Mechanistically, simultaneous targeting of AKT and WEE1 enhanced deregulation of the cell cycle and DNA damage repair pathways by modulating transcription factors p53 and forkhead box M1, which was not observed with sequential treatment. Thus, this study identifies a rapid approach to assess the drug combinations with a mechanistic basis for selection, which suggests that combining AKT and WEE1 inhibitors is needed for maximal efficacy. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Forecasting daily streamflow using online sequential extreme learning machines

NASA Astrophysics Data System (ADS)

Lima, Aranildo R.; Cannon, Alex J.; Hsieh, William W.

2016-06-01

While nonlinear machine methods have been widely used in environmental forecasting, in situations where new data arrive continually, the need to make frequent model updates can become cumbersome and computationally costly. To alleviate this problem, an online sequential learning algorithm for single hidden layer feedforward neural networks - the online sequential extreme learning machine (OSELM) - is automatically updated inexpensively as new data arrive (and the new data can then be discarded). OSELM was applied to forecast daily streamflow at two small watersheds in British Columbia, Canada, at lead times of 1-3 days. Predictors used were weather forecast data generated by the NOAA Global Ensemble Forecasting System (GEFS), and local hydro-meteorological observations. OSELM forecasts were tested with daily, monthly or yearly model updates. More frequent updating gave smaller forecast errors, including errors for data above the 90th percentile. Larger datasets used in the initial training of OSELM helped to find better parameters (number of hidden nodes) for the model, yielding better predictions. With the online sequential multiple linear regression (OSMLR) as benchmark, we concluded that OSELM is an attractive approach as it easily outperformed OSMLR in forecast accuracy.

Sequential Electrolytic Degradation of Energetic Compounds in Groundwater

DTIC Science & Technology

2004-11-12

Investigators: Dave Gilbert, Ph.D. and Tom Sale, Ph.D. Date: November 12, 2004 Revision: 1.0 Distribution Statement A: Approved for...Degradation of Energetic Compounds in Groundwater 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Dave Gilbert, Ph.D. and...catholyte include MNX and nitramide indicating that reduction pathways suggested by others are likely ( Bonin , et al., 2004). As in the TNT

Corruption of homeostatic mechanisms in the guanylyl cyclase C signaling pathway underlying colorectal tumorigenesis

PubMed Central

Waldman, Scott A

2010-01-01

Colon cancer, the second leading cause of cancer-related mortality worldwide, originates from the malignant transformation of intestinal epithelial cells. The intestinal epithelium undergoes a highly organized process of rapid regeneration along the crypt-villus axis, characterized by proliferation, migration, differentiation and apoptosis, whose coordination is essential to maintaining the mucosal barrier. Disruption of these homeostatic processes predisposes cells to mutations in tumor suppressors or oncogenes, whose dysfunction provides transformed cells an evolutionary growth advantage. While sequences of genetic mutations at different stages along the neoplastic continuum have been established, little is known of the events initiating tumorigenesis prior to adenomatous polyposis coli (APC) mutations. Here, we examine a role for the corruption of homeostasis induced by silencing novel tumor suppressors, including the intestine-specific transcription factor CDX2 and its gene target guanylyl cyclase C (GCC), as early events predisposing cells to mutations in APC and other sequential genes that initiate colorectal cancer. CDX2 and GCC maintain homeostatic regeneration in the intestine by restricting cell proliferation, promoting cell maturation and adhesion, regulating cell migration and defending the intestinal barrier and genomic integrity. Elimination of CDX2 or GCC promotes intestinal tumor initiation and growth in aged mice, mice carrying APC mutations or mice exposed to carcinogens. The roles of CDX2 and GCC in suppressing intestinal tumorigenesis, universal disruption in their signaling through silencing of hormones driving GCC, and the uniform overexpression of GCC by tumors underscore the potential value of oral replacement with GCC ligands as targeted prevention and therapy for colorectal cancer. PMID:20592492

A common mechanism underlies changes of mind about decisions and confidence.

PubMed

van den Berg, Ronald; Anandalingam, Kavitha; Zylberberg, Ariel; Kiani, Roozbeh; Shadlen, Michael N; Wolpert, Daniel M

2016-02-01

Decisions are accompanied by a degree of confidence that a selected option is correct. A sequential sampling framework explains the speed and accuracy of decisions and extends naturally to the confidence that the decision rendered is likely to be correct. However, discrepancies between confidence and accuracy suggest that confidence might be supported by mechanisms dissociated from the decision process. Here we show that this discrepancy can arise naturally because of simple processing delays. When participants were asked to report choice and confidence simultaneously, their confidence, reaction time and a perceptual decision about motion were explained by bounded evidence accumulation. However, we also observed revisions of the initial choice and/or confidence. These changes of mind were explained by a continuation of the mechanism that led to the initial choice. Our findings extend the sequential sampling framework to vacillation about confidence and invites caution in interpreting dissociations between confidence and accuracy.

Article and method for making an article

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

Lacy, Benjamin Paul; Schick, David Edward; Kottilingam, Srikanth Chandrudu

An article and a method for making shaped cooling holes in an article are provided. The method includes the steps of depositing a metal alloy powder to form an initial layer including at least one aperture, melting the metal alloy powder with a focused energy source to transform the powder layer to a sheet of metal alloy, sequentially depositing an additional layer of the metal alloy powder to form a layer including at least one aperture corresponding to the at least one aperture in the initial layer, melting the additional layer of the metal alloy powder with the focused energymore » source to increase the sheet thickness, and repeating the steps of sequentially depositing and melting the additional layers of metal alloy powder until a structure including at least one aperture having a predetermined profile is obtained. The structure is attached to a substrate to make the article.« less

Models of initial training and pathways to registration: a selective review of policy in professional regulation.

PubMed

Fealy, Gerard M; Carney, Marie; Drennan, Jonathan; Treacy, Margaret; Burke, Jacqueline; O'Connell, Dympna; Howley, Breeda; Clancy, Alison; McHugh, Aine; Patton, Declan; Sheerin, Fintan

2009-09-01

To provide a synthesis of literature on international policy concerning professional regulation in nursing and midwifery, with reference to routes of entry into training and pathways to licensure. Internationally, there is evidence of multiple points of entry into initial training, multiple divisions of the professional register and multiple pathways to licensure. Policy documents and commentary articles concerned with models of initial training and pathways to licensure were reviewed. Item selection, quality appraisal and data extraction were undertaken and documentary analysis was performed on all retrieved texts. Case studies of five Western countries indicate no single uniform system of routes of entry into initial training and no overall consensus regarding the optimal model of initial training. Multiple regulatory systems, with multiple routes of entry into initial training and multiple pathways to licensure pose challenges, in terms of achieving commonly-agreed understandings of practice competence. The variety of models of initial training present nursing managers with challenges in the recruitment and deployment of personnel trained in many different jurisdictions. Nursing managers need to consider the potential for considerable variation in competency repertoires among nurses trained in generic and specialist initial training models.

Forbidden tangential orbit transfers between intersecting Keplerian orbits

NASA Technical Reports Server (NTRS)

Burns, Rowland E.

1990-01-01

The classical problem of tangential impulse transfer between coplanar Keplerian orbits is addressed. A completely analytic solution which does not rely on sequential calculation is obtained and this solution is used to demonstrate that certain initially chosen angles can produce singularities in the parameters of the transfer orbit. A necessary and sufficient condition for such singularities is that the initial and final orbits intersect.

Phosphorylation by PINK1 Releases the UBL Domain and Initializes the Conformational Opening of the E3 Ubiquitin Ligase Parkin

PubMed Central

Moussaud-Lamodière, Elisabeth L.; Dourado, Daniel F. A. R.; Flores, Samuel C.; Springer, Wolfdieter

2014-01-01

Loss-of-function mutations in PINK1 or PARKIN are the most common causes of autosomal recessive Parkinson's disease. Both gene products, the Ser/Thr kinase PINK1 and the E3 Ubiquitin ligase Parkin, functionally cooperate in a mitochondrial quality control pathway. Upon stress, PINK1 activates Parkin and enables its translocation to and ubiquitination of damaged mitochondria to facilitate their clearance from the cell. Though PINK1-dependent phosphorylation of Ser65 is an important initial step, the molecular mechanisms underlying the activation of Parkin's enzymatic functions remain unclear. Using molecular modeling, we generated a complete structural model of human Parkin at all atom resolution. At steady state, the Ub ligase is maintained inactive in a closed, auto-inhibited conformation that results from intra-molecular interactions. Evidently, Parkin has to undergo major structural rearrangements in order to unleash its catalytic activity. As a spark, we have modeled PINK1-dependent Ser65 phosphorylation in silico and provide the first molecular dynamics simulation of Parkin conformations along a sequential unfolding pathway that could release its intertwined domains and enable its catalytic activity. We combined free (unbiased) molecular dynamics simulation, Monte Carlo algorithms, and minimal-biasing methods with cell-based high content imaging and biochemical assays. Phosphorylation of Ser65 results in widening of a newly defined cleft and dissociation of the regulatory N-terminal UBL domain. This motion propagates through further opening conformations that allow binding of an Ub-loaded E2 co-enzyme. Subsequent spatial reorientation of the catalytic centers of both enzymes might facilitate the transfer of the Ub moiety to charge Parkin. Our structure-function study provides the basis to elucidate regulatory mechanisms and activity of the neuroprotective Parkin. This may open up new avenues for the development of small molecule Parkin activators through targeted drug design. PMID:25375667

Hospital's activity-based financing system and manager-physician [corrected] interaction.

PubMed

Crainich, David; Leleu, Hervé; Mauleon, Ana

2011-10-01

This paper examines the consequences of the introduction of an activity-based reimbursement system on the behavior of physicians and hospital's managers. We consider a private for-profit sector where both hospitals and physicians are initially paid on a fee-for-service basis. We show that the benefit of the introduction of an activity-based system depends on the type of interaction between managers and physicians (simultaneous or sequential decision-making games). It is shown that, under the activity-based system, a sequential interaction with physician leader could be beneficial for both agents in the private sector. We further model an endogenous timing game à la Hamilton and Slutsky (Games Econ Behav 2: 29-46, 1990) in which the type of interaction is determined endogenously. We show that, under the activity-based system, the sequential interaction with physician leader is the unique subgame perfect equilibrium.

Air and radon pathways screenings methodologies for the next revision of the E-area PA

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

Dyer, J. A.

The strategic plan for the next E-Area Low-Level Waste Facility Performance Assessment includes recommended changes to the screening criteria used to reduce the number of radioisotopes that are to be considered in the air and radon pathways incorporated into the GoldSim® atmospheric release model (ARM). For the air pathway, a revised screening methodology was developed based on refinement of previous E-Area PA screening approaches and consideration of the strategic plan recommendations. The revised methodology has three sequential screening steps for each radioisotope: (1) volatility test using the Periodic Table of the Elements, (2) stability test based on half-life, and (3)more » stability test based on volatility as measured by the Henry’s Law constant for the assumed dominant gaseous species or vapor pressure in the case of tritiated water. Of the 1252 radioisotopes listed in the International Commission on Radiological Protection Publication 107, only the 10 that satisfied all three steps of the revised screening methodology will be included in the ARM. They are: Ar-37, Ar-39, Ar-42, C-14, H-3, Hg-194, Hg-203, Kr-81, Kr-85, and Xe-127. For the radon pathway, a revised screening methodology was developed that also has three sequential steps: (1) identify all decay chains that terminate at Rn-222, (2) screen out parents that decay through U-238 because of its 4.5-billion-year primordial half-life, and (3) eliminate remaining parents whose half-life is shorter than one day. Of the 86 possible decay chains leading to Rn-222, six decay chains consist of 15 unique radioisotopes that will be incorporated into the ARM. The 15 radioisotopes are: U-238, Th-234, Pa-234m, Pu-238, U-234, Th-230, Ra-226, Cf-246, Cm-242, Am-242m, Am-242, Np-238, Np-234, Pa-230, and Rn-222.« less

Discovery of β-1,4-D-mannosyl-N-acetyl-D-glucosamine phosphorylase involved in the metabolism of N-glycans.

PubMed

Nihira, Takanori; Suzuki, Erika; Kitaoka, Motomitsu; Nishimoto, Mamoru; Ohtsubo, Ken'ichi; Nakai, Hiroyuki

2013-09-20

A gene cluster involved in N-glycan metabolism was identified in the genome of Bacteroides thetaiotaomicron VPI-5482. This gene cluster encodes a major facilitator superfamily transporter, a starch utilization system-like transporter consisting of a TonB-dependent oligosaccharide transporter and an outer membrane lipoprotein, four glycoside hydrolases (α-mannosidase, β-N-acetylhexosaminidase, exo-α-sialidase, and endo-β-N-acetylglucosaminidase), and a phosphorylase (BT1033) with unknown function. It was demonstrated that BT1033 catalyzed the reversible phosphorolysis of β-1,4-D-mannosyl-N-acetyl-D-glucosamine in a typical sequential Bi Bi mechanism. These results indicate that BT1033 plays a crucial role as a key enzyme in the N-glycan catabolism where β-1,4-D-mannosyl-N-acetyl-D-glucosamine is liberated from N-glycans by sequential glycoside hydrolase-catalyzed reactions, transported into the cell, and intracellularly converted into α-D-mannose 1-phosphate and N-acetyl-D-glucosamine. In addition, intestinal anaerobic bacteria such as Bacteroides fragilis, Bacteroides helcogenes, Bacteroides salanitronis, Bacteroides vulgatus, Prevotella denticola, Prevotella dentalis, Prevotella melaninogenica, Parabacteroides distasonis, and Alistipes finegoldii were also suggested to possess the similar metabolic pathway for N-glycans. A notable feature of the new metabolic pathway for N-glycans is the more efficient use of ATP-stored energy, in comparison with the conventional pathway where β-mannosidase and ATP-dependent hexokinase participate, because it is possible to directly phosphorylate the D-mannose residue of β-1,4-D-mannosyl-N-acetyl-D-glucosamine to enter glycolysis. This is the first report of a metabolic pathway for N-glycans that includes a phosphorylase. We propose 4-O-β-D-mannopyranosyl-N-acetyl-D-glucosamine:phosphate α-D-mannosyltransferase as the systematic name and β-1,4-D-mannosyl-N-acetyl-D-glucosamine phosphorylase as the short name for BT1033.

Pathway cross-talk network analysis identifies critical pathways in neonatal sepsis.

PubMed

Meng, Yu-Xiu; Liu, Quan-Hong; Chen, Deng-Hong; Meng, Ying

2017-06-01

Despite advances in neonatal care, sepsis remains a major cause of morbidity and mortality in neonates worldwide. Pathway cross-talk analysis might contribute to the inference of the driving forces in bacterial sepsis and facilitate a better understanding of underlying pathogenesis of neonatal sepsis. This study aimed to explore the critical pathways associated with the progression of neonatal sepsis by the pathway cross-talk analysis. By integrating neonatal transcriptome data with known pathway data and protein-protein interaction data, we systematically uncovered the disease pathway cross-talks and constructed a disease pathway cross-talk network for neonatal sepsis. Then, attract method was employed to explore the dysregulated pathways associated with neonatal sepsis. To determine the critical pathways in neonatal sepsis, rank product (RP) algorithm, centrality analysis and impact factor (IF) were introduced sequentially, which synthetically considered the differential expression of genes and pathways, pathways cross-talks and pathway parameters in the network. The dysregulated pathways with the highest IF values as well as RP<0.01 were defined as critical pathways in neonatal sepsis. By integrating three kinds of data, only 6919 common genes were included to perform the pathway cross-talk analysis. By statistic analysis, a total of 1249 significant pathway cross-talks were selected to construct the pathway cross-talk network. Moreover, 47 dys-regulated pathways were identified via attract method, 20 pathways were identified under RP<0.01, and the top 10 pathways with the highest IF were also screened from the pathway cross-talk network. Among them, we selected 8 common pathways, i.e. critical pathways. In this study, we systematically tracked 8 critical pathways involved in neonatal sepsis by integrating attract method and pathway cross-talk network. These pathways might be responsible for the host response in infection, and of great value for advancing diagnosis and therapy of neonatal sepsis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Experimental Approaches to Systematic Discovery and Development of Reproductive Adverse Outcome Pathways in Fish

EPA Science Inventory

Adverse outcome pathways (AOPs) are conceptual frameworks that portray causal and predictive linkages between key events at multiple scales of biological organization that connect molecular initiating events and early cellular perturbations (e.g., initiation of toxicity pathways)...

Effect of protonation on the mechanism of phosphate monoester hydrolysis and comparison with the hydrolysis of nucleoside triphosphate in biomolecular motors.

PubMed

Hassan, Hammad Ali; Rani, Sadaf; Fatima, Tabeer; Kiani, Farooq Ahmad; Fischer, Stefan

2017-11-01

Hydrolysis of phosphate groups is a crucial reaction in living cells. It involves the breaking of two strong bonds, i.e. the O a H bond of the attacking water molecule, and the PO l bond of the substrate (O a and O l stand for attacking and leaving oxygen atoms). Mechanism of the hydrolysis reaction can proceed either by a concurrent or a sequential mechanism. In the concurrent mechanism, the breaking of O a H and PO l bonds occurs simultaneously, whereas in the sequential mechanism, the O a H and PO l bonds break at different stages of the reaction. To understand how protonation affects the mechanism of hydrolysis of phosphate monoester, we have studied the mechanism of hydrolysis of protonated and deprotonated phosphate monoester at M06-2X/6-311+G**//M06-2X/6-31+G*+ZPE level of theory (where ZPE stands for zero point energy). Our calculations show that in both protonated and deprotonated cases, the breaking of the water O a H bond occurs before the breaking of the PO l bond. Because the two events are not separated by a stable intermediate, the mechanism can be categorized as semi-concurrent. The overall energy barrier is 41kcalmol -1 in the unprotonated case. Most (5/6th) of this is due to the initial breaking of the water O a H bond. This component is lowered from 34 to 25kcalmol -1 by adding one proton to the phosphate. The rest of the overall energy barrier comes from the subsequent breaking of the PO l bond and is not sensitive to protonation. This is consistent with previous findings about the effect of triphosphate protonation on the hydrolysis, where the equivalent protonation (on the γ-phosphate) was seen to lower the barrier of breaking the water O a H bond and to have little effect on the PO l bond breaking. Hydrolysis pathways of phosphate monoester with initial breaking of the PO l bond could not be found here. This is because the leaving group in phosphate monoester cannot be protonated, unlike in triphosphate hydrolysis, where protonation of the β- and γ-phosphates had been shown to promote a mechanism where the PO l bond breaks before the O a H bond does. We also point out that the charge shift due to PO l bond breaking during sequential ATP hydrolysis in bio-molecular motors onsets the week unbinding of hydrolysis product that finally leads to the product release during power stroke. Copyright © 2017 Elsevier B.V. All rights reserved.

Asymmetric Synthesis of Spiropyrazolones by Sequential Organo- and Silver Catalysis.

PubMed

Hack, Daniel; Dürr, Alexander B; Deckers, Kristina; Chauhan, Pankaj; Seling, Nico; Rübenach, Lukas; Mertens, Lucas; Raabe, Gerhard; Schoenebeck, Franziska; Enders, Dieter

2016-01-26

A stereoselective one-pot synthesis of spiropyrazolones through an organocatalytic asymmetric Michael addition and a formal Conia-ene reaction has been developed. Depending on the nitroalkene, the 5-exo-dig-cyclization could be achieved by silver-catalyzed alkyne activation or by oxidation of the intermediate enolate. The mechanistic pathways have been investigated using computational chemistry and mechanistic experiments. © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Making assessments while taking repeated risks: a pattern of multiple response pathways.

PubMed

Pleskac, Timothy J; Wershbale, Avishai

2014-02-01

Beyond simply a decision process, repeated risky decisions also require a number of cognitive processes including learning, search and exploration, and attention. In this article, we examine how multiple response pathways develop over repeated risky decisions. Using the Balloon Analogue Risk Task (BART) as a case study, we show that 2 different response pathways emerge over the course of the task. The assessment pathway is a slower, more controlled pathway where participants deliberate over taking a risk. The 2nd pathway is a faster, more automatic process where no deliberation occurs. Results imply the slower assessment pathway is taken as choice conflict increases and that the faster automatic response is a learned response. Based on these results, we modify an existing formal cognitive model of decision making during the BART to account for these dual response pathways. The slower more deliberative response process is modeled with a sequential sampling process where evidence is accumulated to a threshold, while the other response is given automatically. We show that adolescents with conduct disorder and substance use disorder symptoms not only evaluate risks differently during the BART but also differ in the rate at which they develop the more automatic response. More broadly, our results suggest cognitive models of judgment decision making need to transition from treating observed decisions as the result of a single response pathway to the result of multiple response pathways that change and develop over time.

Programs of Study as a State Policy Mandate: A Longitudinal Study of the South Carolina Personal Pathways to Success Initiative. Executive Summary

ERIC Educational Resources Information Center

Hammond, Cathy; Drew, Sam F.; Withington, Cairen; Griffith, Cathy; Swiger, Caroline M.; Mobley, Catherine; Sharp, Julia L.; Stringfield, Samuel C.; Stipanovic, Natalie; Daugherty, Lindsay

2013-01-01

This executive summary outlines key findings from the final technical report of a five-year study of South Carolina's Personal Pathways to Success Initiative, which was authorized by the state's Education and Economic Development Act (EEDA) in 2005. The Personal Pathways initiative is a K-16, career-focused school reform model intended to improve…

Computational Modeling of the Dielectric Barrier Discharge (DBD) Device for Aeronautical Applications

DTIC Science & Technology

2006-06-01

electron energy equation are solved semi-implicitly in a sequential manner. Each of the governing equations is solved by casting them onto a tridiagonal ...actuator for different device configurations and operating parameters. This will provide the Air Force with a low cost, quick turn around...Atmosphere (ATM) (20:8). Initially, the applied potential difference on the electrodes must be great enough to initiate gas breakdown. While

Sequential geophysical and flow inversion to characterize fracture networks in subsurface systems

DOE PAGES

Mudunuru, Maruti Kumar; Karra, Satish; Makedonska, Nataliia; ...

2017-09-05

Subsurface applications, including geothermal, geological carbon sequestration, and oil and gas, typically involve maximizing either the extraction of energy or the storage of fluids. Fractures form the main pathways for flow in these systems, and locating these fractures is critical for predicting flow. However, fracture characterization is a highly uncertain process, and data from multiple sources, such as flow and geophysical are needed to reduce this uncertainty. We present a nonintrusive, sequential inversion framework for integrating data from geophysical and flow sources to constrain fracture networks in the subsurface. In this framework, we first estimate bounds on the statistics formore » the fracture orientations using microseismic data. These bounds are estimated through a combination of a focal mechanism (physics-based approach) and clustering analysis (statistical approach) of seismic data. Then, the fracture lengths are constrained using flow data. In conclusion, the efficacy of this inversion is demonstrated through a representative example.« less

Sequential geophysical and flow inversion to characterize fracture networks in subsurface systems

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

Mudunuru, Maruti Kumar; Karra, Satish; Makedonska, Nataliia

Subsurface applications, including geothermal, geological carbon sequestration, and oil and gas, typically involve maximizing either the extraction of energy or the storage of fluids. Fractures form the main pathways for flow in these systems, and locating these fractures is critical for predicting flow. However, fracture characterization is a highly uncertain process, and data from multiple sources, such as flow and geophysical are needed to reduce this uncertainty. We present a nonintrusive, sequential inversion framework for integrating data from geophysical and flow sources to constrain fracture networks in the subsurface. In this framework, we first estimate bounds on the statistics formore » the fracture orientations using microseismic data. These bounds are estimated through a combination of a focal mechanism (physics-based approach) and clustering analysis (statistical approach) of seismic data. Then, the fracture lengths are constrained using flow data. In conclusion, the efficacy of this inversion is demonstrated through a representative example.« less

Comparison of Sequential Drug Release in Vitro and in Vivo

PubMed Central

Sundararaj, Sharath C.; Al-Sabbagh, Mohanad; Rabek, Cheryl L.; Dziubla, Thomas D.; Thomas, Mark V.; Puleo, David A.

2015-01-01

Development of drug delivery devices typically involves characterizing in vitro release performance with the inherent assumption that this will closely approximate in vivo performance. Yet, as delivery devices become more complex, for instance with a sequential drug release pattern, it is important to confirm that in vivo properties correlate with the expected “programming” achieved in vitro. In this work, a systematic comparison between in vitro and in vivo biomaterial erosion and sequential release was performed for a multilayered association polymer system comprising cellulose acetate phthalate and Pluronic F-127. After assessing the materials during incubation in phosphate-buffered saline, devices were implanted supracalvarially in rats. Devices with two different doses and with different erosion rates were harvested at increasing times post-implantation, and the in vivo thickness loss, mass loss, and the drug release profiles were compared with their in vitro counterparts. The sequential release of four different drugs observed in vitro was successfully translated to in vivo conditions. Results suggest, however, that the total erosion time of the devices was longer and release rates of the four drugs were different, with drugs initially released more quickly and then more slowly in vivo. Whereas many comparative studies of in vitro and in vivo drug release from biodegradable polymers involved a single drug, the present research demonstrated that sequential release of four drugs can be maintained following implantation. PMID:26111338

Modeling eye gaze patterns in clinician-patient interaction with lag sequential analysis.

PubMed

Montague, Enid; Xu, Jie; Chen, Ping-Yu; Asan, Onur; Barrett, Bruce P; Chewning, Betty

2011-10-01

The aim of this study was to examine whether lag sequential analysis could be used to describe eye gaze orientation between clinicians and patients in the medical encounter. This topic is particularly important as new technologies are implemented into multiuser health care settings in which trust is critical and nonverbal cues are integral to achieving trust. This analysis method could lead to design guidelines for technologies and more effective assessments of interventions. Nonverbal communication patterns are important aspects of clinician-patient interactions and may affect patient outcomes. The eye gaze behaviors of clinicians and patients in 110 videotaped medical encounters were analyzed using the lag sequential method to identify significant behavior sequences. Lag sequential analysis included both event-based lag and time-based lag. Results from event-based lag analysis showed that the patient's gaze followed that of the clinician, whereas the clinician's gaze did not follow the patient's. Time-based sequential analysis showed that responses from the patient usually occurred within 2 s after the initial behavior of the clinician. Our data suggest that the clinician's gaze significantly affects the medical encounter but that the converse is not true. Findings from this research have implications for the design of clinical work systems and modeling interactions. Similar research methods could be used to identify different behavior patterns in clinical settings (physical layout, technology, etc.) to facilitate and evaluate clinical work system designs.

Modeling Eye Gaze Patterns in Clinician-Patient Interaction with Lag Sequential Analysis

PubMed Central

Montague, E; Xu, J; Asan, O; Chen, P; Chewning, B; Barrett, B

2011-01-01

Objective The aim of this study was to examine whether lag-sequential analysis could be used to describe eye gaze orientation between clinicians and patients in the medical encounter. This topic is particularly important as new technologies are implemented into multi-user health care settings where trust is critical and nonverbal cues are integral to achieving trust. This analysis method could lead to design guidelines for technologies and more effective assessments of interventions. Background Nonverbal communication patterns are important aspects of clinician-patient interactions and may impact patient outcomes. Method Eye gaze behaviors of clinicians and patients in 110-videotaped medical encounters were analyzed using the lag-sequential method to identify significant behavior sequences. Lag-sequential analysis included both event-based lag and time-based lag. Results Results from event-based lag analysis showed that the patients’ gaze followed that of clinicians, while clinicians did not follow patients. Time-based sequential analysis showed that responses from the patient usually occurred within two seconds after the initial behavior of the clinician. Conclusion Our data suggest that the clinician’s gaze significantly affects the medical encounter but not the converse. Application Findings from this research have implications for the design of clinical work systems and modeling interactions. Similar research methods could be used to identify different behavior patterns in clinical settings (physical layout, technology, etc.) to facilitate and evaluate clinical work system designs. PMID:22046723

Image Quality of 3rd Generation Spiral Cranial Dual-Source CT in Combination with an Advanced Model Iterative Reconstruction Technique: A Prospective Intra-Individual Comparison Study to Standard Sequential Cranial CT Using Identical Radiation Dose

PubMed Central

Wenz, Holger; Maros, Máté E.; Meyer, Mathias; Förster, Alex; Haubenreisser, Holger; Kurth, Stefan; Schoenberg, Stefan O.; Flohr, Thomas; Leidecker, Christianne; Groden, Christoph; Scharf, Johann; Henzler, Thomas

2015-01-01

Objectives To prospectively intra-individually compare image quality of a 3rd generation Dual-Source-CT (DSCT) spiral cranial CT (cCT) to a sequential 4-slice Multi-Slice-CT (MSCT) while maintaining identical intra-individual radiation dose levels. Methods 35 patients, who had a non-contrast enhanced sequential cCT examination on a 4-slice MDCT within the past 12 months, underwent a spiral cCT scan on a 3rd generation DSCT. CTDIvol identical to initial 4-slice MDCT was applied. Data was reconstructed using filtered backward projection (FBP) and 3rd-generation iterative reconstruction (IR) algorithm at 5 different IR strength levels. Two neuroradiologists independently evaluated subjective image quality using a 4-point Likert-scale and objective image quality was assessed in white matter and nucleus caudatus with signal-to-noise ratios (SNR) being subsequently calculated. Results Subjective image quality of all spiral cCT datasets was rated significantly higher compared to the 4-slice MDCT sequential acquisitions (p<0.05). Mean SNR was significantly higher in all spiral compared to sequential cCT datasets with mean SNR improvement of 61.65% (p*Bonferroni0.05<0.0024). Subjective image quality improved with increasing IR levels. Conclusion Combination of 3rd-generation DSCT spiral cCT with an advanced model IR technique significantly improves subjective and objective image quality compared to a standard sequential cCT acquisition acquired at identical dose levels. PMID:26288186

Image Quality of 3rd Generation Spiral Cranial Dual-Source CT in Combination with an Advanced Model Iterative Reconstruction Technique: A Prospective Intra-Individual Comparison Study to Standard Sequential Cranial CT Using Identical Radiation Dose.

PubMed

Wenz, Holger; Maros, Máté E; Meyer, Mathias; Förster, Alex; Haubenreisser, Holger; Kurth, Stefan; Schoenberg, Stefan O; Flohr, Thomas; Leidecker, Christianne; Groden, Christoph; Scharf, Johann; Henzler, Thomas

2015-01-01

To prospectively intra-individually compare image quality of a 3rd generation Dual-Source-CT (DSCT) spiral cranial CT (cCT) to a sequential 4-slice Multi-Slice-CT (MSCT) while maintaining identical intra-individual radiation dose levels. 35 patients, who had a non-contrast enhanced sequential cCT examination on a 4-slice MDCT within the past 12 months, underwent a spiral cCT scan on a 3rd generation DSCT. CTDIvol identical to initial 4-slice MDCT was applied. Data was reconstructed using filtered backward projection (FBP) and 3rd-generation iterative reconstruction (IR) algorithm at 5 different IR strength levels. Two neuroradiologists independently evaluated subjective image quality using a 4-point Likert-scale and objective image quality was assessed in white matter and nucleus caudatus with signal-to-noise ratios (SNR) being subsequently calculated. Subjective image quality of all spiral cCT datasets was rated significantly higher compared to the 4-slice MDCT sequential acquisitions (p<0.05). Mean SNR was significantly higher in all spiral compared to sequential cCT datasets with mean SNR improvement of 61.65% (p*Bonferroni0.05<0.0024). Subjective image quality improved with increasing IR levels. Combination of 3rd-generation DSCT spiral cCT with an advanced model IR technique significantly improves subjective and objective image quality compared to a standard sequential cCT acquisition acquired at identical dose levels.

Research on parallel algorithm for sequential pattern mining

NASA Astrophysics Data System (ADS)

Zhou, Lijuan; Qin, Bai; Wang, Yu; Hao, Zhongxiao

2008-03-01

Sequential pattern mining is the mining of frequent sequences related to time or other orders from the sequence database. Its initial motivation is to discover the laws of customer purchasing in a time section by finding the frequent sequences. In recent years, sequential pattern mining has become an important direction of data mining, and its application field has not been confined to the business database and has extended to new data sources such as Web and advanced science fields such as DNA analysis. The data of sequential pattern mining has characteristics as follows: mass data amount and distributed storage. Most existing sequential pattern mining algorithms haven't considered the above-mentioned characteristics synthetically. According to the traits mentioned above and combining the parallel theory, this paper puts forward a new distributed parallel algorithm SPP(Sequential Pattern Parallel). The algorithm abides by the principal of pattern reduction and utilizes the divide-and-conquer strategy for parallelization. The first parallel task is to construct frequent item sets applying frequent concept and search space partition theory and the second task is to structure frequent sequences using the depth-first search method at each processor. The algorithm only needs to access the database twice and doesn't generate the candidated sequences, which abates the access time and improves the mining efficiency. Based on the random data generation procedure and different information structure designed, this paper simulated the SPP algorithm in a concrete parallel environment and implemented the AprioriAll algorithm. The experiments demonstrate that compared with AprioriAll, the SPP algorithm had excellent speedup factor and efficiency.

The Evolution of Grain Size Distribution in Explosive Rock Fragmentation - Sequential Fragmentation Theory Revisited

NASA Astrophysics Data System (ADS)

Scheu, B.; Fowler, A. C.

2015-12-01

Fragmentation is a ubiquitous phenomenon in many natural and engineering systems. It is the process by which an initially competent medium, solid or liquid, is broken up into a population of constituents. Examples occur in collisions and impacts of asteroids/meteorites, explosion driven fragmentation of munitions on a battlefield, as well as of magma in a volcanic conduit causing explosive volcanic eruptions and break-up of liquid drops. Besides the mechanism of fragmentation the resulting frequency-size distribution of the generated constituents is of central interest. Initially their distributions were fitted empirically using lognormal, Rosin-Rammler and Weibull distributions (e.g. Brown & Wohletz 1995). The sequential fragmentation theory (Brown 1989, Wohletz at al. 1989, Wohletz & Brown 1995) and the application of fractal theory to fragmentation products (Turcotte 1986, Perfect 1997, Perugini & Kueppers 2012) attempt to overcome this shortcoming by providing a more physical basis for the applied distribution. Both rely on an at least partially scale-invariant and thus self-similar random fragmentation process. Here we provide a stochastic model for the evolution of grain size distribution during the explosion process. Our model is based on laboratory experiments in which volcanic rock samples explode naturally when rapidly depressurized from initial pressures of several MPa to ambient conditions. The physics governing this fragmentation process has been successfully modelled and the observed fragmentation pattern could be numerically reproduced (Fowler et al. 2010). The fragmentation of these natural rocks leads to grain size distributions which vary depending on the experimental starting conditions. Our model provides a theoretical description of these different grain size distributions. Our model combines a sequential model of the type outlined by Turcotte (1986), but generalized to cater for the explosive process appropriate here, in particular by including in the description of the fracturing events in which the rock fragments, with a recipe for the production of fines, as observed in the experiments. To our knowledge, this implementation of a deterministic fracturing process into a stochastic (sequential) model is unique, further it provides the model with some forecasting power.

Overproduction of Geranylgeraniol by Metabolically Engineered Saccharomyces cerevisiae▿

PubMed Central

Tokuhiro, Kenro; Muramatsu, Masayoshi; Ohto, Chikara; Kawaguchi, Toshiya; Obata, Shusei; Muramoto, Nobuhiko; Hirai, Masana; Takahashi, Haruo; Kondo, Akihiko; Sakuradani, Eiji; Shimizu, Sakayu

2009-01-01

(E, E, E)-Geranylgeraniol (GGOH) is a valuable starting material for perfumes and pharmaceutical products. In the yeast Saccharomyces cerevisiae, GGOH is synthesized from the end products of the mevalonate pathway through the sequential reactions of farnesyl diphosphate synthetase (encoded by the ERG20 gene), geranylgeranyl diphosphate synthase (the BTS1 gene), and some endogenous phosphatases. We demonstrated that overexpression of the diacylglycerol diphosphate phosphatase (DPP1) gene could promote GGOH production. We also found that overexpression of a BTS1-DPP1 fusion gene was more efficient for producing GGOH than coexpression of these genes separately. Overexpression of the hydroxymethylglutaryl-coenzyme A reductase (HMG1) gene, which encodes the major rate-limiting enzyme of the mevalonate pathway, resulted in overproduction of squalene (191.9 mg liter−1) rather than GGOH (0.2 mg liter−1) in test tube cultures. Coexpression of the BTS1-DPP1 fusion gene along with the HMG1 gene partially redirected the metabolic flux from squalene to GGOH. Additional expression of a BTS1-ERG20 fusion gene resulted in an almost complete shift of the flux to GGOH production (228.8 mg liter−1 GGOH and 6.5 mg liter−1 squalene). Finally, we constructed a diploid prototrophic strain coexpressing the HMG1, BTS1-DPP1, and BTS1-ERG20 genes from multicopy integration vectors. This strain attained 3.31 g liter−1 GGOH production in a 10-liter jar fermentor with gradual feeding of a mixed glucose and ethanol solution. The use of bifunctional fusion genes such as the BTS1-DPP1 and ERG20-BTS1 genes that code sequential enzymes in the metabolic pathway was an effective method for metabolic engineering. PMID:19592534

A sequential method for spline approximation with variable knots. [recursive piecewise polynomial signal processing

NASA Technical Reports Server (NTRS)

Mier Muth, A. M.; Willsky, A. S.

1978-01-01

In this paper we describe a method for approximating a waveform by a spline. The method is quite efficient, as the data are processed sequentially. The basis of the approach is to view the approximation problem as a question of estimation of a polynomial in noise, with the possibility of abrupt changes in the highest derivative. This allows us to bring several powerful statistical signal processing tools into play. We also present some initial results on the application of our technique to the processing of electrocardiograms, where the knot locations themselves may be some of the most important pieces of diagnostic information.

Sequential infiltration synthesis for advanced lithography

DOEpatents

Darling, Seth B.; Elam, Jeffrey W.; Tseng, Yu-Chih; Peng, Qing

2015-03-17

A plasma etch resist material modified by an inorganic protective component via sequential infiltration synthesis (SIS) and methods of preparing the modified resist material. The modified resist material is characterized by an improved resistance to a plasma etching or related process relative to the unmodified resist material, thereby allowing formation of patterned features into a substrate material, which may be high-aspect ratio features. The SIS process forms the protective component within the bulk resist material through a plurality of alternating exposures to gas phase precursors which infiltrate the resist material. The plasma etch resist material may be initially patterned using photolithography, electron-beam lithography or a block copolymer self-assembly process.

Folding pathway of a multidomain protein depends on its topology of domain connectivity

PubMed Central

Inanami, Takashi; Terada, Tomoki P.; Sasai, Masaki

2014-01-01

How do the folding mechanisms of multidomain proteins depend on protein topology? We addressed this question by developing an Ising-like structure-based model and applying it for the analysis of free-energy landscapes and folding kinetics of an example protein, Escherichia coli dihydrofolate reductase (DHFR). DHFR has two domains, one comprising discontinuous N- and C-terminal parts and the other comprising a continuous middle part of the chain. The simulated folding pathway of DHFR is a sequential process during which the continuous domain folds first, followed by the discontinuous domain, thereby avoiding the rapid decrease in conformation entropy caused by the association of the N- and C-terminal parts during the early phase of folding. Our simulated results consistently explain the observed experimental data on folding kinetics and predict an off-pathway structural fluctuation at equilibrium. For a circular permutant for which the topological complexity of wild-type DHFR is resolved, the balance between energy and entropy is modulated, resulting in the coexistence of the two folding pathways. This coexistence of pathways should account for the experimentally observed complex folding behavior of the circular permutant. PMID:25267632

The Hedgehog Signal Transduction Network

PubMed Central

Robbins, David J.; Fei, Dennis Liang; Riobo, Natalia A.

2013-01-01

Hedgehog (Hh) proteins regulate the development of a wide range of metazoan embryonic and adult structures, and disruption of Hh signaling pathways results in various human diseases. Here, we provide a comprehensive review of the signaling pathways regulated by Hh, consolidating data from a diverse array of organisms in a variety of scientific disciplines. Similar to the elucidation of many other signaling pathways, our knowledge of Hh signaling developed in a sequential manner centered on its earliest discoveries. Thus, our knowledge of Hh signaling has for the most part focused on elucidating the mechanism by which Hh regulates the Gli family of transcription factors, the so-called “canonical” Hh signaling pathway. However, in the past few years, numerous studies have shown that Hh proteins can also signal through Gli-independent mechanisms collectively referred to as “noncanonical” signaling pathways. Noncanonical Hh signaling is itself subdivided into two distinct signaling modules: (i) those not requiring Smoothened (Smo) and (ii) those downstream of Smo that do not require Gli transcription factors. Thus, Hh signaling is now proposed to occur through a variety of distinct context-dependent signaling modules that have the ability to crosstalk with one another to form an interacting, dynamic Hh signaling network. PMID:23074268

Reiterative Recombination for the in vivo assembly of libraries of multigene pathways.

PubMed

Wingler, Laura M; Cornish, Virginia W

2011-09-13

The increasing sophistication of synthetic biology is creating a demand for robust, broadly accessible methodology for constructing multigene pathways inside of the cell. Due to the difficulty of rationally designing pathways that function as desired in vivo, there is a further need to assemble libraries of pathways in parallel, in order to facilitate the combinatorial optimization of performance. While some in vitro DNA assembly methods can theoretically make libraries of pathways, these techniques are resource intensive and inherently require additional techniques to move the DNA back into cells. All previously reported in vivo assembly techniques have been low yielding, generating only tens to hundreds of constructs at a time. Here, we develop "Reiterative Recombination," a robust method for building multigene pathways directly in the yeast chromosome. Due to its use of endonuclease-induced homologous recombination in conjunction with recyclable markers, Reiterative Recombination provides a highly efficient, technically simple strategy for sequentially assembling an indefinite number of DNA constructs at a defined locus. In this work, we describe the design and construction of the first Reiterative Recombination system in Saccharomyces cerevisiae, and we show that it can be used to assemble multigene constructs. We further demonstrate that Reiterative Recombination can construct large mock libraries of at least 10(4) biosynthetic pathways. We anticipate that our system's simplicity and high efficiency will make it a broadly accessible technology for pathway construction and render it a valuable tool for optimizing pathways in vivo.

Reiterative Recombination for the in vivo assembly of libraries of multigene pathways

PubMed Central

Wingler, Laura M.; Cornish, Virginia W.

2011-01-01

The increasing sophistication of synthetic biology is creating a demand for robust, broadly accessible methodology for constructing multigene pathways inside of the cell. Due to the difficulty of rationally designing pathways that function as desired in vivo, there is a further need to assemble libraries of pathways in parallel, in order to facilitate the combinatorial optimization of performance. While some in vitro DNA assembly methods can theoretically make libraries of pathways, these techniques are resource intensive and inherently require additional techniques to move the DNA back into cells. All previously reported in vivo assembly techniques have been low yielding, generating only tens to hundreds of constructs at a time. Here, we develop “Reiterative Recombination,” a robust method for building multigene pathways directly in the yeast chromosome. Due to its use of endonuclease-induced homologous recombination in conjunction with recyclable markers, Reiterative Recombination provides a highly efficient, technically simple strategy for sequentially assembling an indefinite number of DNA constructs at a defined locus. In this work, we describe the design and construction of the first Reiterative Recombination system in Saccharomyces cerevisiae, and we show that it can be used to assemble multigene constructs. We further demonstrate that Reiterative Recombination can construct large mock libraries of at least 104 biosynthetic pathways. We anticipate that our system’s simplicity and high efficiency will make it a broadly accessible technology for pathway construction and render it a valuable tool for optimizing pathways in vivo. PMID:21876185

Genomics and expression profiles of the Hedgehog and Notch signaling pathways in sea urchin development.

PubMed

Walton, Katherine D; Croce, Jenifer C; Glenn, Thomas D; Wu, Shu-Yu; McClay, David R

2006-12-01

The Hedgehog (Hh) and Notch signal transduction pathways control a variety of developmental processes including cell fate choice, differentiation, proliferation, patterning and boundary formation. Because many components of these pathways are conserved, it was predicted and confirmed that pathway components are largely intact in the sea urchin genome. Spatial and temporal location of these pathways in the embryo, and their function in development offer added insight into their mechanistic contributions. Accordingly, all major components of both pathways were identified and annotated in the sea urchin Strongylocentrotus purpuratus genome and the embryonic expression of key components was explored. Relationships of the pathway components, and modifiers predicted from the annotation of S. purpuratus, were compared against cnidarians, arthropods, urochordates, and vertebrates. These analyses support the prediction that the pathways are highly conserved through metazoan evolution. Further, the location of these two pathways appears to be conserved among deuterostomes, and in the case of Notch at least, display similar capacities in endomesoderm gene regulatory networks. RNA expression profiles by quantitative PCR and RNA in situ hybridization reveal that Hedgehog is produced by the endoderm beginning just prior to invagination, and signals to the secondary mesenchyme-derived tissues at least until the pluteus larva stage. RNA in situ hybridization of Notch pathway members confirms that Notch functions sequentially in the vegetal-most secondary mesenchyme cells and later in the endoderm. Functional analyses in future studies will embed these pathways into the growing knowledge of gene regulatory networks that govern early specification and morphogenesis.

Sequential delivery of BMP-2 and IGF-1 using a chitosan gel with gelatin microspheres enhances early osteoblastic differentiation

PubMed Central

Kim, Sungwoo; Kang, Yunqing; Krueger, Chad A.; Sen, Milan; Holcomb, John B.; Chen, Di; Wenke, Joseph C.; Yang, Yunzhi

2012-01-01

The purpose of this study was to develop and characterize a chitosan gel/gelatin microspheres (MSs) dual delivery system for sequential release of bone morphogenetic protein-2 (BMP-2) and insulin-like growth factor-1 (IGF-1) to enhance osteoblast differentiation in vitro. We made and characterized the delivery system based on its degree of cross-linking, degradation, and release kinetics. We also evaluated the cytotoxicity of the delivery system and the effect of growth factors on cell response using pre-osteoblast W-20-17 mouse bone marrow stromal cells. IGF-1 was first loaded into MSs, and then the IGF-1 containing MSs were encapsulated into the chitosan gel which contained BMP-2. Cross-linking of gelatin with glyoxal via Schiff bases significantly increased thermal stability and decreased the solubility of the MSs, leading to a significant decrease in the initial release of IGF-1. Encapsulation of the MSs into the chitosan gel generated polyelectrolyte complexes by intermolecular interactions, which further affected the release kinetics of IGF-1. This combinational delivery system provided an initial release of BMP-2 followed by a slow and sustained release of IGF-1. Significantly greater alkaline phosphatase activity was found in W-20-17 cells treated with the sequential delivery system than other treatments (p<0.05) after a week of culture. PMID:22293583

The Neural Representation of Prospective Choice during Spatial Planning and Decisions

PubMed Central

Kaplan, Raphael; Koster, Raphael; Penny, William D.; Burgess, Neil; Friston, Karl J.

2017-01-01

We are remarkably adept at inferring the consequences of our actions, yet the neuronal mechanisms that allow us to plan a sequence of novel choices remain unclear. We used functional magnetic resonance imaging (fMRI) to investigate how the human brain plans the shortest path to a goal in novel mazes with one (shallow maze) or two (deep maze) choice points. We observed two distinct anterior prefrontal responses to demanding choices at the second choice point: one in rostrodorsal medial prefrontal cortex (rd-mPFC)/superior frontal gyrus (SFG) that was also sensitive to (deactivated by) demanding initial choices and another in lateral frontopolar cortex (lFPC), which was only engaged by demanding choices at the second choice point. Furthermore, we identified hippocampal responses during planning that correlated with subsequent choice accuracy and response time, particularly in mazes affording sequential choices. Psychophysiological interaction (PPI) analyses showed that coupling between the hippocampus and rd-mPFC increases during sequential (deep versus shallow) planning and is higher before correct versus incorrect choices. In short, using a naturalistic spatial planning paradigm, we reveal how the human brain represents sequential choices during planning without extensive training. Our data highlight a network centred on the cortical midline and hippocampus that allows us to make prospective choices while maintaining initial choices during planning in novel environments. PMID:28081125

Sequential Classifier Training for Rice Mapping with Multitemporal Remote Sensing Imagery

NASA Astrophysics Data System (ADS)

Guo, Y.; Jia, X.; Paull, D.

2017-10-01

Most traditional methods for rice mapping with remote sensing data are effective when they are applied to the initial growing stage of rice, as the practice of flooding during this period makes the spectral characteristics of rice fields more distinguishable. In this study, we propose a sequential classifier training approach for rice mapping that can be used over the whole growing period of rice for monitoring various growth stages. Rice fields are firstly identified during the initial flooding period. The identified rice fields are used as training data to train a classifier that separates rice and non-rice pixels. The classifier is then used as a priori knowledge to assist the training of classifiers for later rice growing stages. This approach can be applied progressively to sequential image data, with only a small amount of training samples being required from each image. In order to demonstrate the effectiveness of the proposed approach, experiments were conducted at one of the major rice-growing areas in Australia. The proposed approach was applied to a set of multitemporal remote sensing images acquired by the Sentinel-2A satellite. Experimental results show that, compared with traditional spectral-indexbased algorithms, the proposed method is able to achieve more stable and consistent rice mapping accuracies and it reaches higher than 80% during the whole rice growing period.

Validation of a motion-robust 2D sequential technique for quantification of hepatic proton density fat fraction during free breathing.

PubMed

Pooler, B Dustin; Hernando, Diego; Ruby, Jeannine A; Ishii, Hiroshi; Shimakawa, Ann; Reeder, Scott B

2018-04-17

Current chemical-shift-encoded (CSE) MRI techniques for measuring hepatic proton density fat fraction (PDFF) are sensitive to motion artifacts. Initial validation of a motion-robust 2D-sequential CSE-MRI technique for quantification of hepatic PDFF. Phantom study and prospective in vivo cohort. Fifty adult patients (27 women, 23 men, mean age 57.2 years). 3D, 2D-interleaved, and 2D-sequential CSE-MRI acquisitions at 1.5T. Three CSE-MRI techniques (3D, 2D-interleaved, 2D-sequential) were performed in a PDFF phantom and in vivo. Reference standards were 3D CSE-MRI PDFF measurements for the phantom study and single-voxel MR spectroscopy hepatic PDFF measurements (MRS-PDFF) in vivo. In vivo hepatic MRI-PDFF measurements were performed during a single breath-hold (BH) and free breathing (FB), and were repeated by a second reader for the FB 2D-sequential sequence to assess interreader variability. Correlation plots to validate the 2D-sequential CSE-MRI against the phantom and in vivo reference standards. Bland-Altman analysis of FB versus BH CSE-MRI acquisitions to evaluate robustness to motion. Bland-Altman analysis to assess interreader variability. Phantom 2D-sequential CSE-MRI PDFF measurements demonstrated excellent agreement and correlation (R 2 > 0.99) with 3D CSE-MRI. In vivo, the mean (±SD) hepatic PDFF was 8.8 ± 8.7% (range 0.6-28.5%). Compared with BH acquisitions, FB hepatic PDFF measurements demonstrated bias of +0.15% for 2D-sequential compared with + 0.53% for 3D and +0.94% for 2D-interleaved. 95% limits of agreement (LOA) were narrower for 2D-sequential (±0.99%), compared with 3D (±3.72%) and 2D-interleaved (±3.10%). All CSE-MRI techniques had excellent correlation with MRS (R 2 > 0.97). The FB 2D-sequential acquisition demonstrated little interreader variability, with mean bias of +0.07% and 95% LOA of ± 1.53%. This motion-robust 2D-sequential CSE-MRI can accurately measure hepatic PDFF during free breathing in a patient population with a range of PDFF values of 0.6-28.5%, permitting accurate quantification of liver fat content without the need for suspended respiration. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. © 2018 International Society for Magnetic Resonance in Medicine.

The Effect of Social Support on Glycemic Control in Patients with Type 2 Diabetes Mellitus: The Mediating Roles of Self-Efficacy and Adherence

PubMed Central

Shao, Yechang; Liang, Lu; Shi, Linjing; Yu, Shouyi

2017-01-01

Ample evidence suggests that social support, self-efficacy, and adherence significantly, independently, and together affect glycemic control in patients with type 2 diabetes mellitus (T2DM), but the pathway from social support to glycemic control remains unclear. This study hypothesized that the effect of social support on glycemic control was mediated sequentially by self-efficacy and adherence. Patients with T2DM were recruited from two hospitals in Guangzhou, China, from January 1 to July 31, 2014, and their sociodemographic clinical data and their assessments on social support, self-efficacy, and adherence were obtained from medical records and self-completed questionnaires. Of the 532 patients who participated, 35% achieved glycemic control (i.e., HbA1c < 7%). Social support, self-efficacy, and adherence had significant correlations with each other and with glycemic control (P < 0.05). Regression analyses and structural equation modeling showed that better social support was associated to better patient self-efficacy, which, in turn, was associated with better medical adherence, which was associated with improved glycemic control, and the relationship between social support and glycemic control was sequentially and completely mediated by self-efficacy and adherence. The five goodness-of-fit indices confirmed that our data fitted the hypothesized pathway model strongly. PMID:28626769

Giant Virus Megavirus chilensis Encodes the Biosynthetic Pathway for Uncommon Acetamido Sugars*

PubMed Central

Piacente, Francesco; De Castro, Cristina; Jeudy, Sandra; Molinaro, Antonio; Salis, Annalisa; Damonte, Gianluca; Bernardi, Cinzia; Abergel, Chantal; Tonetti, Michela G.

2014-01-01

Giant viruses mimicking microbes, by the sizes of their particles and the heavily glycosylated fibrils surrounding their capsids, infect Acanthamoeba sp., which are ubiquitous unicellular eukaryotes. The glycans on fibrils are produced by virally encoded enzymes, organized in gene clusters. Like Mimivirus, Megavirus glycans are mainly composed of virally synthesized N-acetylglucosamine (GlcNAc). They also contain N-acetylrhamnosamine (RhaNAc), a rare sugar; the enzymes involved in its synthesis are encoded by a gene cluster specific to Megavirus close relatives. We combined activity assays on two enzymes of the pathway with mass spectrometry and NMR studies to characterize their specificities. Mg534 is a 4,6-dehydratase 5-epimerase; its three-dimensional structure suggests that it belongs to a third subfamily of inverting dehydratases. Mg535, next in the pathway, is a bifunctional 3-epimerase 4-reductase. The sequential activity of the two enzymes leads to the formation of UDP-l-RhaNAc. This study is another example of giant viruses performing their glycan synthesis using enzymes different from their cellular counterparts, raising again the question of the origin of these pathways. PMID:25035429

Protein Folding—How and Why: By Hydrogen Exchange, Fragment Separation, and Mass Spectrometry

PubMed Central

Englander, S. Walter; Mayne, Leland; Kan, Zhong-Yuan; Hu, Wenbing

2017-01-01

Advanced hydrogen exchange (HX) methodology can now determine the structure of protein folding intermediates and their progression in folding pathways. Key developments over time include the HX pulse labeling method with nuclear magnetic resonance analysis, development of the fragment separation method, the addition to it of mass spectrometric (MS) analysis, and recent improvements in the HX MS technique and data analysis. Also, the discovery of protein foldons and their role supplies an essential interpretive link. Recent work using HX pulse labeling with HX MS analysis finds that a number of proteins fold by stepping through a reproducible sequence of native-like intermediates in an ordered pathway. The stepwise nature of the pathway is dictated by the cooperative foldon unit construction of the protein. The pathway order is determined by a sequential stabilization principle; prior native-like structure guides the formation of adjacent native-like structure. This view does not match the funneled energy landscape paradigm of a very large number of folding tracks, which was framed before foldons were known. PMID:27145881

The Professional Development Needs of School-Based Leadership in Preparation for a District-Wide One-to-One Initiative in a Large Urban School District

ERIC Educational Resources Information Center

Simmons, Brandon Dean

2015-01-01

The purpose of this study was to determine the professional development needs of school-based leadership in preparation for a district-wide one-to-one initiative in a large urban school district. This study used an explanatory sequential mixed methods design to answer the three research questions that drove the study. Research for this study was…

Sequential nitric oxide measurements during the emergency department treatment of acute vasoocclusive sickle cell crisis.

PubMed

Lopez, B L; Davis-Moon, L; Ballas, S K; Ma, X L

2000-05-01

This prospective study was designed to examine the relationship between serial serum nitric oxide (NO) levels and pain during the emergency department (ED) treatment of acute vasoocclusive sickle cell crisis (SCC). 102 patient visits, age > or =18 years of age, presenting to the ED with uncomplicated, typical SCC pain had serum NO levels obtained at 2-hr intervals during treatment of pain and were measured using an NO-specific chemiluminesence technique. Pain was measured prior to each NO measurement using a 10 cm visual analog scale (VAS), and subjects were divided into a persistent pain group and an improved pain group. Patients with persistent pain had significantly low initial NO levels (11.51 microM +/- 2.8, P < 0.05) while those with pain improvement had higher initial NO levels (18.1 microM +/- 3.08, P < 0.05). There was no significant correlation between changes in NO and changes in pain scores. These results suggest that the initial NO level may serve as a marker for the severity of tissue ischemia. Sequential NO levels do not appear useful in predicting the course of SCC.

Triterpene Functional Genomics in Licorice for Identification of CYP72A154 Involved in the Biosynthesis of Glycyrrhizin[C][W][OA

PubMed Central

Seki, Hikaru; Sawai, Satoru; Ohyama, Kiyoshi; Mizutani, Masaharu; Ohnishi, Toshiyuki; Sudo, Hiroshi; Fukushima, Ery Odette; Akashi, Tomoyoshi; Aoki, Toshio; Saito, Kazuki; Muranaka, Toshiya

2011-01-01

Glycyrrhizin, a triterpenoid saponin derived from the underground parts of Glycyrrhiza plants (licorice), has several pharmacological activities and is also used worldwide as a natural sweetener. The biosynthesis of glycyrrhizin involves the initial cyclization of 2,3-oxidosqualene to the triterpene skeleton β-amyrin, followed by a series of oxidative reactions at positions C-11 and C-30, and glycosyl transfers to the C-3 hydroxyl group. We previously reported the identification of a cytochrome P450 monooxygenase (P450) gene encoding β-amyrin 11-oxidase (CYP88D6) as the initial P450 gene in glycyrrhizin biosynthesis. In this study, a second relevant P450 (CYP72A154) was identified and shown to be responsible for C-30 oxidation in the glycyrrhizin pathway. CYP72A154 expressed in an engineered yeast strain that endogenously produces 11-oxo-β-amyrin (a possible biosynthetic intermediate between β-amyrin and glycyrrhizin) catalyzed three sequential oxidation steps at C-30 of 11-oxo-β-amyrin supplied in situ to produce glycyrrhetinic acid, a glycyrrhizin aglycone. Furthermore, CYP72A63 of Medicago truncatula, which has high sequence similarity to CYP72A154, was able to catalyze C-30 oxidation of β-amyrin. These results reveal a function of CYP72A subfamily proteins as triterpene-oxidizing enzymes and provide a genetic tool for engineering the production of glycyrrhizin. PMID:22128119

Genomic Landscape of Colorectal Mucosa and Adenomas in Familial Adenomatous Polyposis

PubMed Central

Borras, Ester; San Lucas, F. Anthony; Chang, Kyle; Zhou, Ruoji; Masand, Gita; Fowler, Jerry; Mork, Maureen E.; You, Y. Nancy; Taggart, Melissa W.; McAllister, Florencia; Jones, David A.; Davies, Gareth E.; Edelmann, Winfried; Ehli, Erik A.; Lynch, Patrick M.; Hawk, Ernest T.; Capella, Gabriel; Scheet, Paul; Vilar, Eduardo

2016-01-01

Purpose The molecular basis of the adenoma to carcinoma transition has been deduced using comparative analysis of genetic alterations observed through the sequential steps of intestinal carcinogenesis. However, comprehensive genomic analyses of adenomas and at-risk mucosa are still lacking. Therefore, our aim was to characterize the genomic landscape of colonic at-risk mucosa and adenomas. Experimental Design We analyzed the mutation profile and copy number changes of 25 adenomas and adjacent mucosa from 12 familial adenomatous polyposis patients using whole-exome sequencing and validated allelic imbalances in 37 adenomas using SNP arrays. We assessed for evidence of clonality and performed estimations on the proportions of driver and passenger mutations using a systems biology approach. Results Adenomas had lower mutational rates than did colorectal cancers and showed recurrent alterations in known cancer-driver genes (APC, KRAS, FBXW7, TCF7L2) and allelic imbalances in chromosomes 5, 7 and 13. Moreover, 80% of adenomas had somatic alterations in WNT pathway genes. Adenomas displayed evidence of multiclonality similar to stage I carcinomas. Strong correlations between mutational rate and patient age were observed in at-risk mucosa and adenomas. Our data indicate that at least 23% of somatic mutations are present in at-risk mucosa prior to adenoma initiation. Conclusions The genomic profiles of at-risk mucosa and adenomas illustrate the evolution from normal tissue to carcinoma via greater resolution of molecular changes at the inflection point of premalignant lesions. Furthermore, substantial genomic variation exists in at-risk mucosa before adenoma formation, and deregulation of the WNT pathway is required to foster carcinogenesis. PMID:27221540

Refining and validating a conceptual model of Clinical Nurse Leader integrated care delivery.

PubMed

Bender, Miriam; Williams, Marjory; Su, Wei; Hites, Lisle

2017-02-01

To empirically validate a conceptual model of Clinical Nurse Leader integrated care delivery. There is limited evidence of frontline care delivery models that consistently achieve quality patient outcomes. Clinical Nurse Leader integrated care delivery is a promising nursing model with a growing record of success. However, theoretical clarity is necessary to generate causal evidence of effectiveness. Sequential mixed methods. A preliminary Clinical Nurse Leader practice model was refined and survey items developed to correspond with model domains, using focus groups and a Delphi process with a multi-professional expert panel. The survey was administered in 2015 to clinicians and administrators involved in Clinical Nurse Leader initiatives. Confirmatory factor analysis and structural equation modelling were used to validate the measurement and model structure. Final sample n = 518. The model incorporates 13 components organized into five conceptual domains: 'Readiness for Clinical Nurse Leader integrated care delivery'; 'Structuring Clinical Nurse Leader integrated care delivery'; 'Clinical Nurse Leader Practice: Continuous Clinical Leadership'; 'Outcomes of Clinical Nurse Leader integrated care delivery'; and 'Value'. Sample data had good fit with specified model and two-level measurement structure. All hypothesized pathways were significant, with strong coefficients suggesting good fit between theorized and observed path relationships. The validated model articulates an explanatory pathway of Clinical Nurse Leader integrated care delivery, including Clinical Nurse Leader practices that result in improved care dynamics and patient outcomes. The validated model provides a basis for testing in practice to generate evidence that can be deployed across the healthcare spectrum. © 2016 John Wiley & Sons Ltd.

Rational and design of a stepped-wedge cluster randomized trial evaluating quality improvement initiative for reducing cardiovascular events among patients with acute coronary syndromes in resource-constrained hospitals in China.

PubMed

Li, Shenshen; Wu, Yangfeng; Du, Xin; Li, Xian; Patel, Anushka; Peterson, Eric D; Turnbull, Fiona; Lo, Serigne; Billot, Laurent; Laba, Tracey; Gao, Runlin

2015-03-01

Acute coronary syndromes (ACSs) are a major cause of morbidity and mortality, yet effective ACS treatments are frequently underused in clinical practice. Randomized trials including the CPACS-2 study suggest that quality improvement initiatives can increase the use of effective treatments, but whether such programs can impact hard clinical outcomes has never been demonstrated in a well-powered randomized controlled trial. The CPACS-3 study is a stepped-wedge cluster-randomized trial conducted in 104 remote level 2 hospitals without PCI facilities in China. All hospitalized ACS patients will be recruited consecutively over a 30-month period to an anticipated total study population of more than 25,000 patients. After a 6-month baseline period, hospitals will be randomized to 1 of 4 groups, and a 6-component quality improvement intervention will be implemented sequentially in each group every 6months. These components include the following: establishment of a quality improvement team, implementation of a clinical pathway, training of physicians and nurses, hospital performance audit and feedback, online technical support, and patient education. All patients will be followed up for 6months postdischarge. The primary outcome will be the incidence of in-hospital major adverse cardiovascular events comprising all-cause mortality, myocardial infarction or reinfarction, and nonfatal stroke. The CPACS-3 study will be the first large randomized trial with sufficient power to assess the effects of a multifaceted quality of care improvement initiative on hard clinical outcomes, in patients with ACS. Copyright © 2014 Elsevier Inc. All rights reserved.

Stepwise Organization of the β-Structure Identifies Key Regions Essential for the Propagation and Cytotoxicity of Insulin Amyloid Fibrils*

PubMed Central

Chatani, Eri; Imamura, Hiroshi; Yamamoto, Naoki; Kato, Minoru

2014-01-01

Amyloid fibrils are supramolecular assemblies, the deposition of which is associated with many serious diseases including Alzheimer, prion, and Huntington diseases. Several smaller aggregates such as oligomers and protofibrils have been proposed to play a role in early stages of the fibrillation process; however, little is known about how these species contribute to the formation of mature amyloid fibrils with a rigid cross-β structure. Here, we identified a new pathway for the formation of insulin amyloid fibrils at a high concentration of salt in which mature fibrils were formed in a stepwise manner via a prefibrillar intermediate: minute prefibrillar species initially accumulated, followed by the subsequent formation of thicker amyloid fibrils. Fourier transform infrared spectra suggested the sequential formation of two types of β-sheets with different strength hydrogen bonds, one of which was developed concomitantly with the mutual assembly of the prefibrillar intermediate to form mature fibrils. Interestingly, fibril propagation and cellular toxicity appeared only after the later step of structural organization, and a comparison of β-sheet regions between the prefibrillar intermediate and mature fibrils using proteolysis led to the proposal of specific regions essential for manifestation of these properties. PMID:24569992

Career Technical Education Pathways Initiative

ERIC Educational Resources Information Center

California Community Colleges, Chancellor's Office, 2013

2013-01-01

California's education system--the largest in the United States--is an essential resource for ensuring strong economic growth in the state. The Career Technical Education Pathways Initiative (referred to as the Initiative in this report), which became law in 2005, brings together community colleges, K-12 school districts, employers, organized…

A common mechanism underlies changes of mind about decisions and confidence

PubMed Central

van den Berg, Ronald; Anandalingam, Kavitha; Zylberberg, Ariel; Kiani, Roozbeh; Shadlen, Michael N; Wolpert, Daniel M

2016-01-01

Decisions are accompanied by a degree of confidence that a selected option is correct. A sequential sampling framework explains the speed and accuracy of decisions and extends naturally to the confidence that the decision rendered is likely to be correct. However, discrepancies between confidence and accuracy suggest that confidence might be supported by mechanisms dissociated from the decision process. Here we show that this discrepancy can arise naturally because of simple processing delays. When participants were asked to report choice and confidence simultaneously, their confidence, reaction time and a perceptual decision about motion were explained by bounded evidence accumulation. However, we also observed revisions of the initial choice and/or confidence. These changes of mind were explained by a continuation of the mechanism that led to the initial choice. Our findings extend the sequential sampling framework to vacillation about confidence and invites caution in interpreting dissociations between confidence and accuracy. DOI: http://dx.doi.org/10.7554/eLife.12192.001 PMID:26829590

A multi-signal fluorescent probe for simultaneously distinguishing and sequentially sensing cysteine/homocysteine, glutathione, and hydrogen sulfide in living cells† †Electronic supplementary information (ESI) available: Experimental details for chemical synthesis of all compounds, chemical structure characterization, supplementary spectra of probe, and fluorescence imaging methods and data. See DOI: 10.1039/c7sc00423k Click here for additional data file.

PubMed Central

He, Longwei; Yang, Xueling; Xu, Kaixin; Kong, Xiuqi

2017-01-01

Biothiols, which have a close network of generation and metabolic pathways among them, are essential reactive sulfur species (RSS) in the cells and play vital roles in human physiology. However, biothiols possess highly similar chemical structures and properties, resulting in it being an enormous challenge to simultaneously discriminate them from each other. Herein, we develop a unique fluorescent probe (HMN) for not only simultaneously distinguishing Cys/Hcy, GSH, and H2S from each other, but also sequentially sensing Cys/Hcy/GSH and H2S using a multi-channel fluorescence mode for the first time. When responding to the respective biothiols, the robust probe exhibits multiple sets of fluorescence signals at three distinct emission bands (blue-green-red). The new probe can also sense H2S at different concentration levels with changes of fluorescence at the blue and red emission bands. In addition, the novel probe HMN is able to discriminate and sequentially sense biothiols in biological environments via three-color fluorescence imaging. We expect that the development of the robust probe HMN will provide a powerful strategy to design fluorescent probes for the discrimination and sequential detection of biothiols, and offer a promising tool for exploring the interrelated roles of biothiols in various physiological and pathological conditions. PMID:28989659

HNCA-TOCSY-CANH experiments with alternate 13C-12C labeling: a set of 3D experiment with unique supra-sequential information for mainchain resonance assignment

PubMed Central

Takeuchi, Koh; Gal, Maayan; Takahashi, Hideo; Shimada, Ichio

2011-01-01

Described here is a set of three-dimensional (3D) NMR experiments that rely on CACA-TOCSY magnetization transfer via the weak 3JCαCα coupling. These pulse sequences, which resemble recently described 13C detected CACA-TOCSY (Takeuchi et al. 2010) experiments, are recorded in 1H2O, and use 1H excitation and detection. These experiments require alternate 13C-12C labeling together with perdeuteration, which allows utilizing the small 3JCαCα scalar coupling that is otherwise masked by the stronger 1JCC couplings in uniformly 13C labeled samples. These new experiments provide a unique assignment ladder-mark that yields bidirectional supra-sequential information and can readily straddle proline residues. Unlike the conventional HNCA experiment, which contains only sequential information to the 13Cα of the preceding residue, the 3D hnCA-TOCSY-caNH experiment can yield sequential correlations to alpha carbons in positions i−1, i + 1 and i−2. Furthermore, the 3D hNca-TOCSY-caNH and Hnca-TOC-SY-caNH experiments, which share the same magnetization pathway but use a different chemical shift encoding, directly couple the 15N-1H spin pair of residue i to adjacent amide protons and nitrogens at positions i−2, i−1, i + 1 and i + 2, respectively. These new experimental features make protein backbone assignments more robust by reducing the degeneracy problem associated with the conventional 3D NMR experiments. PMID:21110064

Precise Sequential DNA Ligation on A Solid Substrate: Solid-Based Rapid Sequential Ligation of Multiple DNA Molecules

PubMed Central

Takita, Eiji; Kohda, Katsunori; Tomatsu, Hajime; Hanano, Shigeru; Moriya, Kanami; Hosouchi, Tsutomu; Sakurai, Nozomu; Suzuki, Hideyuki; Shinmyo, Atsuhiko; Shibata, Daisuke

2013-01-01

Ligation, the joining of DNA fragments, is a fundamental procedure in molecular cloning and is indispensable to the production of genetically modified organisms that can be used for basic research, the applied biosciences, or both. Given that many genes cooperate in various pathways, incorporating multiple gene cassettes in tandem in a transgenic DNA construct for the purpose of genetic modification is often necessary when generating organisms that produce multiple foreign gene products. Here, we describe a novel method, designated PRESSO (precise sequential DNA ligation on a solid substrate), for the tandem ligation of multiple DNA fragments. We amplified donor DNA fragments with non-palindromic ends, and ligated the fragment to acceptor DNA fragments on solid beads. After the final donor DNA fragments, which included vector sequences, were joined to the construct that contained the array of fragments, the ligation product (the construct) was thereby released from the beads via digestion with a rare-cut meganuclease; the freed linear construct was circularized via an intra-molecular ligation. PRESSO allowed us to rapidly and efficiently join multiple genes in an optimized order and orientation. This method can overcome many technical challenges in functional genomics during the post-sequencing generation. PMID:23897972

One-pot multienzyme (OPME) systems for chemoenzymatic synthesis of carbohydrates

PubMed Central

Yu, Hai; Chen, Xi

2016-01-01

Glycosyltransferase-catalyzed enzymatic and chemoenzymatic syntheses are powerful approaches for the production of oligosaccharides, polysaccharides, glycoconjugates, and their derivatives. Enzymes involved in the biosynthesis of sugar nucleotide donors can be combined with the glycosyltransferases in one pot for efficient production of target glycans from simple monosaccharides and accpetors. The identification of enzymes involved in the salvage pathway of sugar nucleotide generation has greatly facilitate the development of simplified and efficient one-pot multienzyme (OPME) systems for synthesizing major glycan epitopes in mammalian glycomes. The applications of OPME methods are steadily gaining popularity mainly due to the increasing availability of wild-type and engineered enzymes. Substrate promiscuity of these enzymes and their mutants allows OPME synthesis of carbohydrates with naturally occurring post-glycosylational modificiation (PGMs) and their non-natural derivatives using modified monosaccharides as precursors. The OPME systems can be applied in sequential for synthesizing complex carbohydrates. The sequence of the sequential OPME processes, the glycosyltransferase used, and the substrate specificities of glycosyltransferasese define the structures of the products. The OPME and sequential OPME strategies can be extended to diverse glycans in other glycomes when suitable enzymes with substrate promiscuity become available. The Perspective summariezes the work of the authors and collaborators on the development of glycosyltransferase-based OPME systems for carbohydrate synthesis. Future directions are also discussed. PMID:26881499

A randomized pilot comparative study of topical methyl aminolevulinate photodynamic therapy versus imiquimod 5% versus sequential application of both therapies in immunocompetent patients with actinic keratosis: clinical and histologic outcomes.

PubMed

Serra-Guillén, Carlos; Nagore, Eduardo; Hueso, Luis; Traves, Victor; Messeguer, Francesc; Sanmartín, Onofre; Llombart, Beatriz; Requena, Celia; Botella-Estrada, Rafael; Guillén, Carlos

2012-04-01

Photodynamic therapy (PDT) and imiquimod are the treatments of choice for actinic keratosis (AK). As they have different mechanisms of action, it seems reasonable to assume that applying both treatments sequentially would be efficacious. We sought to determine which of these therapeutic modalities provides a better clinical and histologic response in patients with AK and whether sequential use of both was more efficacious than each separately. Patients were randomly assigned to one treatment group: group 1, PDT only; group 2, imiquimod only; or group 3, sequential use of PDT and imiquimod. The primary outcome measure was complete clinical response. Partial clinical response was defined as a reduction of more than 75% in the initial number of lesions. A complete clinicopathologic response was defined as lack of evidence of AK in the biopsy specimen. In all, 105 patients completed the study (group 1, 40 patients; group 2, 33 patients; group 3, 32 patients). Sequential application of PDT and imiquimod was more efficacious in all the outcome measures. More patients were satisfied with PDT than with the other two modalities (P = .003). No significant differences were observed among the 3 modalities and tolerance to treatment. Only one cycle of imiquimod was administered. The follow-up period was brief. Sequential application of PDT and imiquimod provides a significantly better clinical and histologic response in the treatment of AK than PDT or imiquimod monotherapy. It also produces less intense local reactions and better tolerance and satisfaction than imiquimod monotherapy. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

The quality of metabolic pathway resources depends on initial enzymatic function assignments: a case for maize

DOE PAGES

Walsh, Jesse R.; Schaeffer, Mary L.; Zhang, Peifen; ...

2016-11-29

As metabolic pathway resources become more commonly available, researchers have unprecedented access to information about their organism of interest. Despite efforts to ensure consistency between various resources, information content and quality can vary widely. Two maize metabolic pathway resources for the B73 inbred line, CornCyc 4.0 and MaizeCyc 2.2, are based on the same gene model set and were developed using Pathway Tools software. These resources differ in their initial enzymatic function assignments and in the extent of manual curation. Here, we present an in-depth comparison between CornCyc and MaizeCyc to demonstrate the effect of initial computational enzymatic function assignmentsmore » on the quality and content of metabolic pathway resources.« less

The quality of metabolic pathway resources depends on initial enzymatic function assignments: a case for maize

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

Walsh, Jesse R.; Schaeffer, Mary L.; Zhang, Peifen

As metabolic pathway resources become more commonly available, researchers have unprecedented access to information about their organism of interest. Despite efforts to ensure consistency between various resources, information content and quality can vary widely. Two maize metabolic pathway resources for the B73 inbred line, CornCyc 4.0 and MaizeCyc 2.2, are based on the same gene model set and were developed using Pathway Tools software. These resources differ in their initial enzymatic function assignments and in the extent of manual curation. Here, we present an in-depth comparison between CornCyc and MaizeCyc to demonstrate the effect of initial computational enzymatic function assignmentsmore » on the quality and content of metabolic pathway resources.« less

Functional Pathway Analysis Using SCNP of FLT3 Receptor Pathway Deregulation in AML Provides Prognostic Information Independent from Mutational Status

PubMed Central

Cesano, Alessandra; Putta, Santosh; Rosen, David B.; Cohen, Aileen C.; Gayko, Urte; Mathi, Kavita; Woronicz, John; Hawtin, Rachael E.; Cripe, Larry; Sun, Zhuoxin; Tallman, Martin S.; Paietta, Elisabeth

2013-01-01

FMS-like tyrosine kinase 3 receptor (FLT3) internal tandem duplication (ITD) mutations result in constitutive activation of this receptor and have been shown to increase the risk of relapse in patients with acute myeloid leukemia (AML); however, substantial heterogeneity in clinical outcomes still exists within both the ITD mutated and unmutated AML subgroups, suggesting alternative mechanisms of disease relapse not accounted by FLT3 mutational status. Single cell network profiling (SCNP) is a multiparametric flow cytometry based assay that simultaneously measures, in a quantitative fashion and at the single cell level, both extracellular surface marker levels and changes in intracellular signaling proteins in response to extracellular modulators. We previously reported an initial characterization of FLT3 ITD-mediated signaling using SCNP. Herein SCNP was applied sequentially to two separate cohorts of samples collected from elderly AML patients at diagnosis. In the first (training) study, AML samples carrying unmutated, wild-type FLT3 (FLT3 WT) displayed a wide range of induced signaling, with a fraction having signaling profiles comparable to FLT3 ITD AML samples. Conversely, the FLT3 ITD AML samples displayed more homogeneous induced signaling, with the exception of patients with low (<40%) mutational load, which had profiles comparable to FLT3 WT AML samples. This observation was then confirmed in an independent (verification) cohort. Data from the second cohort were also used to assess the association between SCNP data and disease-free survival (DFS) in the context of FLT3 and nucleophosmin (NPM1) mutational status among patients who achieved complete remission (CR) to induction chemotherapy. The combination of SCNP read outs together with FLT3 and NPM1 molecular status improved the DFS prediction accuracy of the latter. Taken together, these results emphasize the value of comprehensive functional assessment of biologically relevant signaling pathways in AML as a basis for the development of highly predictive tests for guidance of post-remission therapy. PMID:23431389

Biodegradation and detoxification of textile azo dyes by bacterial consortium under sequential microaerophilic/aerobic processes

PubMed Central

Lade, Harshad; Kadam, Avinash; Paul, Diby; Govindwar, Sanjay

2015-01-01

Release of textile azo dyes to the environment is an issue of health concern while the use of microorganisms has proved to be the best option for remediation. Thus, in the present study, a bacterial consortium consisting of Providencia rettgeri strain HSL1 and Pseudomonas sp. SUK1 has been investigated for degradation and detoxification of structurally different azo dyes. The consortium showed 98-99 % decolorization of all the selected azo dyes viz. Reactive Black 5 (RB 5), Reactive Orange 16 (RO 16), Disperse Red 78 (DR 78) and Direct Red 81 (DR 81) within 12 to 30 h at 100 mg L-1 concentration at 30 ± 0.2 °C under microaerophilic, sequential aerobic/microaerophilic and microaerophilic/aerobic processes. However, decolorization under microaerophilic conditions viz. RB 5 (0.26 mM), RO 16 (0.18 mM), DR 78 (0.20 mM) and DR 81 (0.23 mM) and sequential aerobic/microaerophilic processes viz. RB 5 (0.08 mM), RO 16 (0.06 mM), DR 78 (0.07 mM) and DR 81 (0.09 mM) resulted into the formation of aromatic amines. In distinction, sequential microaerophilic/ aerobic process doesn’t show the formation of amines. Additionally, 62-72 % reduction in total organic carbon content was observed in all the dyes decolorized broths under sequential microaerophilic/aerobic processes suggesting the efficacy of method in mineralization of dyes. Notable induction within the levels of azoreductase and NADH-DCIP reductase (97 and 229 % for RB 5, 55 and 160 % for RO 16, 63 and 196 % for DR 78, 108 and 258 % for DR 81) observed under sequential microaerophilic/aerobic processes suggested their critical involvements in the initial breakdown of azo bonds, whereas, a slight increase in the levels of laccase and veratryl alcohol oxidase confirmed subsequent oxidation of formed amines. Also, the acute toxicity assay with Daphnia magna revealed the nontoxic nature of the dye-degraded metabolites under sequential microaerophilic/aerobic processes. As biodegradation under sequential microaerophilic/aerobic process completely detoxified all the selected textile azo dyes, further efforts should be made to implement such methods for large scale dye wastewater treatment technologies. PMID:26417357

Design and validation of a critical pathway for hospital management of patients with severe traumatic brain injury.

PubMed

Espinosa-Aguilar, Amilcar; Reyes-Morales, Hortensia; Huerta-Posada, Carlos E; de León, Itzcoatl Limón-Pérez; López-López, Fernando; Mejía-Hernández, Margarita; Mondragón-Martínez, María A; Calderón-Téllez, Ligia M; Amezcua-Cuevas, Rosa L; Rebollar-González, Jorge A

2008-05-01

Critical pathways for the management of patients with severe traumatic brain injury (STBI) may contribute to reducing the incidence of hospital complications, length of hospitalization stay, and cost of care. Such pathways have previously been developed for departments with significant resource availability. In Mexico, STBI is the most important cause of complications and length of stay in neurotrauma services at public hospitals. Although current treatment is designed basically in accordance with the Brain Trauma Foundation guidelines, shortfalls in the availability of local resources make it difficult to comply with these standards, and no critical pathway is available that accords with the resources of public hospitals. The purpose of the present study was to design and to validate a critical pathway for managing STBI patients that would be suitable for implementation in neurotrauma departments of middle-income level countries. The study comprised two phases: design (through literature review and design plan) and validation (content, construct, and appearance) of the critical pathway. The validated critical pathway for managing STBI patients entails four sequential subprocesses summarizing the hospital's care procedures, and includes three components: (1) nodes and criteria (in some cases, indicators are also included); (2) health team members in charge of the patient; (3) maximum estimated time for compliance with recommendations. This validated critical pathway is based on the current scientific evidence and accords with the availability of resources of middle-income countries.

A three-tiered approach for linking pharmacokinetic considerations to the adverse outcome pathway framework for chemical-specific risk assessment

EPA Science Inventory

The power of the adverse outcome pathway (AOP) framework arises from its utilization of pathway-based data to describe the initial interaction of a chemical with a molecular target (molecular initiating event; (MIE), followed by a progression through a series of key events that l...

47 CFR 52.20 - Thousands-block number pooling.

Code of Federal Regulations, 2010 CFR

2010-10-01

... separated into ten sequential blocks of 1,000 numbers each (thousands-blocks), and allocated separately... required to participate in thousands-block number pooling shall donate thousands-blocks with ten percent or... ten percent or less contaminated, as an initial block or footprint block. (d) Thousands-Block Pooling...

Demotivation--Its Cause and Cure

ERIC Educational Resources Information Center

Meyer, Mary Coeli

1978-01-01

The author discusses several organizational and individual factors that lead to loss of motivation and explains how the psychological contract between employer and employee which is made during the initial interview is a critical factor. The demotivation process is more specifically examined as a sequential process including confusion, anger,…

Calcium-independent haemolysis via the lectin pathway of complement activation in the guinea-pig and other *

PubMed Central

Zhang, Y; Suankratay, C; Zhang, X-H; Jones, D R; Lint, T F; Gewurz, H

1999-01-01

We previously reported that complement-dependent haemolysis of sheep erythrocytes (E) coated with mannan (M) and sensitized with human mannan-binding lectin (MBL) via the lectin pathway in man occurs in Mg-EGTA and requires alternative pathway amplification. Calcium was required for MBL binding to E-M, but once the E-M-MBL intermediate was formed, MBL was retained and haemolysis occurred in the absence of calcium. Comparable or greater lectin pathway haemolysis in the absence of calcium was observed upon incubation of E-M-MBL in guinea-pig, rat, dog and pig sera, and was further investigated in the guinea-pig, in which titres were much higher (∼14-fold) than in man, and in contrast to humans, greater than classical pathway haemolytic activity. As in human serum, no lysis was observed in C4- or C2-deficient guinea-pig serum until purified C4 or C2, respectively, were restored. However, lectin pathway haemolytic activity in the guinea-pig did not require the alternative pathway. Removal (>98%) of factor D activity by three sequential passages through Sephadex G-75, resulting in serum which retained a normal classical pathway but no alternative pathway haemolytic activity, did not reduce the ability of guinea-pig serum to mediate haemolysis via the lectin pathway. Further, the C3-convertase formed via the lectin pathway (E-M-MBL-C4,2) lysed in C2-deficient guinea-pig but not human serum chelated with EDTA, a condition which precludes alternative pathway amplification. Thus, lectin pathway haemolysis occurs efficiently in guinea-pig serum, in the absence of calcium and without requirement for alternative pathway amplification. The guinea-pig provides a model for studying the assembly and haemolytic function of a lectin pathway which contrasts with the lectin pathway of man, and allows for comparisons that may help clarify the role of this pathway in complement biology. PMID:10457224

Patterns of drug use from adolescence to young adulthood: III. Predictors of progression.

PubMed Central

Yamaguchi, K; Kandel, D B

1984-01-01

Possible linkages of influence among classes of drugs in the observed sequential progression from adolescence to young adulthood are investigated through event history analyses. Three stages are examined: initiation to marijuana, to the use of other illicit drugs, and to prescribed psychoactive drugs. The data are based on a follow-up cohort of former adolescents representative of high school students in grade 10 and 11 in New York State who were reinterviewed nine years later at ages 24-25. The sequential order between alcohol and/or cigarettes and marijuana reflects not only the effect of the use of legal drugs on marijuana initiation, but also age effects on onset of these drugs, controlling for individual characteristics measured in adolescence; marijuana use by one's friends in adolescence is an additional important predictor of marijuana initiation. Prior use of marijuana is necessary for progression to other illicit drugs. Multiple factors are involved in the progression to prescribed drugs, with adolescent depressive symptomatology and use of other illicit drugs important for both sexes, and maternal use of psychoactive drugs, dropping out of school, and prior use of marijuana of additional importance for women. Although licit drugs influence initiation into marijuana independently of age effects, it is especially for the progression from marijuana to other illicit drugs that the earlier drug is associated with the progression to a higher stage drug. PMID:6742253

In vivo gene manipulation reveals the impact of stress-responsive MAPK pathways on tumor progression

PubMed Central

Kamiyama, Miki; Naguro, Isao; Ichijo, Hidenori

2015-01-01

It has been widely accepted that tumor cells and normal stromal cells in the host environment coordinately modulate tumor progression. Mitogen-activated protein kinase pathways are the representative stress-responsive cascades that exert proper cellular responses to divergent environmental stimuli. Genetically engineered mouse models and chemically induced tumorigenesis models have revealed that components of the MAPK pathway not only regulate the behavior of tumor cells themselves but also that of surrounding normal stromal cells in the host environment during cancer pathogenesis. The individual functions of MAPK pathway components in tumor initiation and progression vary depending on the stimuli and the stromal cell types involved in tumor progression, in addition to the molecular isoforms of the components and the origins of the tumor. Recent studies have indicated that MAPK pathway components synergize with environmental factors (e.g. tobacco smoke and diet) to affect tumor initiation and progression. Moreover, some components play distinct roles in the course of tumor progression, such as before and after the establishment of tumors. Hence, a comprehensive understanding of the multifaceted functions of MAPK pathway components in tumor initiation and progression is essential for the improvement of cancer therapy. In this review, we focus on the reports that utilized knockout, conditional knockout, and transgenic mice of MAPK pathway components to investigate the effects of MAPK pathway components on tumor initiation and progression in the host environment. PMID:25880821

Automated synthesis of a library of triazolated 1,2,5-thiadiazepane 1,1-dioxides via a double aza-Michael strategy.

PubMed

Zang, Qin; Javed, Salim; Hill, David; Ullah, Farman; Bi, Danse; Porubsky, Patrick; Neuenswander, Benjamin; Lushington, Gerald H; Santini, Conrad; Organ, Michael G; Hanson, Paul R

2012-08-13

The construction of a 96-member library of triazolated 1,2,5-thiadiazepane 1,1-dioxides was performed on a Chemspeed Accelerator (SLT-100) automated parallel synthesis platform, culminating in the successful preparation of 94 out of 96 possible products. The key step, a one-pot, sequential elimination, double-aza-Michael reaction, and [3 + 2] Huisgen cycloaddition pathway has been automated and utilized in the production of two sets of triazolated sultam products.

Automated Synthesis of a Library of Triazolated 1,2,5-Thiadiazepane 1,1-Dioxides via a Double aza-Michael Strategy

PubMed Central

Zang, Qin; Javed, Salim; Hill, David; Ullah, Farman; Bi, Danse; Porubsky, Patrick; Neuenswander, Benjamin; Lushington, Gerald H.; Santini, Conrad; Organ, Michael G.; Hanson, Paul R.

2013-01-01

The construction of a 96-member library of triazolated 1,2,5-thiadiazepane 1,1-dioxides was performed on a Chemspeed Accelerator (SLT-100) automated parallel synthesis platform, culminating in the successful preparation of 94 out of 96 possible products. The key step, a one-pot, sequential elimination, double-aza-Michael reaction, and [3+2] Huisgen cycloaddition pathway has been automated and utilized in the production of two sets of triazolated sultam products. PMID:22853708

Bifurcations on Potential Energy Surfaces of Organic Reactions

PubMed Central

Ess, Daniel H.; Wheeler, Steven E.; Iafe, Robert G.; Xu, Lai; Çelebi-Ölçüm, Nihan; Houk, K. N.

2009-01-01

A single transition state may lead to multiple intermediates or products if there is a post-transition state reaction path bifurcation. These bifurcations arise when there are sequential transition states with no intervening energy minimum. For such systems, the shape of the potential energy surface and dynamic effects control selectivity rather than transition state energetics. This minireview covers recent investigations of organic reactions exhibiting reaction pathway bifurcations. Such phenomena are surprisingly general and affect experimental observables such as kinetic isotope effects and product distributions. PMID:18767086

(Na+ + K+)-ATPase Is a Target for Phosphoinositide 3-Kinase/Protein Kinase B and Protein Kinase C Pathways Triggered by Albumin*

PubMed Central

Peruchetti, Diogo B.; Pinheiro, Ana Acacia S.; Landgraf, Sharon S.; Wengert, Mira; Takiya, Christina M.; Guggino, William B.; Caruso-Neves, Celso

2011-01-01

In recent decades, evidence has confirmed the crucial role of albumin in the progression of renal disease. However, the possible role of signaling pathways triggered by physiologic concentrations of albumin in the modulation of proximal tubule (PT) sodium reabsorption has not been considered. In the present work, we have shown that a physiologic concentration of albumin increases the expression of the α1 subunit of (Na+ + K+)-ATPase in LLC-PK1 cells leading to an increase in enzyme activity. This process involves the sequential activation of PI3K/protein kinase B and protein kinase C pathways promoting inhibition of protein kinase A. This integrative network is inhibited when albumin concentration is increased, similar to renal disease, leading to a decrease in the α1 subunit of (Na+ + K+)-ATPase expression. Together, the results indicate that variation in albumin concentration in PT cells has an important effect on PT sodium reabsorption and, consequently, on renal sodium excretion. PMID:22057272

In vitro protease cleavage and computer simulations reveal the HIV-1 capsid maturation pathway

NASA Astrophysics Data System (ADS)

Ning, Jiying; Erdemci-Tandogan, Gonca; Yufenyuy, Ernest L.; Wagner, Jef; Himes, Benjamin A.; Zhao, Gongpu; Aiken, Christopher; Zandi, Roya; Zhang, Peijun

2016-12-01

HIV-1 virions assemble as immature particles containing Gag polyproteins that are processed by the viral protease into individual components, resulting in the formation of mature infectious particles. There are two competing models for the process of forming the mature HIV-1 core: the disassembly and de novo reassembly model and the non-diffusional displacive model. To study the maturation pathway, we simulate HIV-1 maturation in vitro by digesting immature particles and assembled virus-like particles with recombinant HIV-1 protease and monitor the process with biochemical assays and cryoEM structural analysis in parallel. Processing of Gag in vitro is accurate and efficient and results in both soluble capsid protein and conical or tubular capsid assemblies, seemingly converted from immature Gag particles. Computer simulations further reveal probable assembly pathways of HIV-1 capsid formation. Combining the experimental data and computer simulations, our results suggest a sequential combination of both displacive and disassembly/reassembly processes for HIV-1 maturation.

The structure and evolution of galacto-detonation waves - Some analytic results in sequential star formation models of spiral galaxies

NASA Technical Reports Server (NTRS)

Cowie, L. L.; Rybicki, G. B.

1982-01-01

Waves of star formation in a uniform, differentially rotating disk galaxy are treated analytically as a propagating detonation wave front. It is shown, that if single solitary waves could be excited, they would evolve asymptotically to one of two stable spiral forms, each of which rotates with a fixed pattern speed. Simple numerical solutions confirm these results. However, the pattern of waves that develop naturally from an initially localized disturbance is more complex and dies out within a few rotation periods. These results suggest a conclusive observational test for deciding whether sequential star formation is an important determinant of spiral structure in some class of galaxies.

Method of Real-Time Principal-Component Analysis

NASA Technical Reports Server (NTRS)

Duong, Tuan; Duong, Vu

2005-01-01

Dominant-element-based gradient descent and dynamic initial learning rate (DOGEDYN) is a method of sequential principal-component analysis (PCA) that is well suited for such applications as data compression and extraction of features from sets of data. In comparison with a prior method of gradient-descent-based sequential PCA, this method offers a greater rate of learning convergence. Like the prior method, DOGEDYN can be implemented in software. However, the main advantage of DOGEDYN over the prior method lies in the facts that it requires less computation and can be implemented in simpler hardware. It should be possible to implement DOGEDYN in compact, low-power, very-large-scale integrated (VLSI) circuitry that could process data in real time.

Sequential infiltration synthesis for advanced lithography

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

Darling, Seth B.; Elam, Jeffrey W.; Tseng, Yu-Chih

A plasma etch resist material modified by an inorganic protective component via sequential infiltration synthesis (SIS) and methods of preparing the modified resist material. The modified resist material is characterized by an improved resistance to a plasma etching or related process relative to the unmodified resist material, thereby allowing formation of patterned features into a substrate material, which may be high-aspect ratio features. The SIS process forms the protective component within the bulk resist material through a plurality of alternating exposures to gas phase precursors which infiltrate the resist material. The plasma etch resist material may be initially patterned usingmore » photolithography, electron-beam lithography or a block copolymer self-assembly process.« less

Sequential measurement of conjugate variables as an alternative quantum state tomography.

PubMed

Di Lorenzo, Antonio

2013-01-04

It is shown how it is possible to reconstruct the initial state of a one-dimensional system by sequentially measuring two conjugate variables. The procedure relies on the quasicharacteristic function, the Fourier transform of the Wigner quasiprobability. The proper characteristic function obtained by Fourier transforming the experimentally accessible joint probability of observing "position" then "momentum" (or vice versa) can be expressed as a product of the quasicharacteristic function of the two detectors and that unknown of the quantum system. This allows state reconstruction through the sequence (1) data collection, (2) Fourier transform, (3) algebraic operation, and (4) inverse Fourier transform. The strength of the measurement should be intermediate for the procedure to work.

Career Technical Education Pathways Initiative Annual Report

ERIC Educational Resources Information Center

California Community Colleges, Chancellor's Office, 2014

2014-01-01

California's education system--the largest in the United States--is an essential resource for ensuring strong economic growth in the state. The Career Technical Education Pathways Initiative (the Initiative) became law in 2005 with Senate Bills 70 and 1133 and provided more than $380 million over eight years to improve career technical education…

Sequential and prosodic design of English and Greek non-valenced news receipts.

PubMed

Kaimaki, Marianna

2012-03-01

Results arising from a prosodic and interactional study of the organization of everyday talk in English suggest that news receipts can be grouped into two categories: valenced (e.g., oh good) and non-valenced (e.g., oh really). In-depth investigation of both valenced and non-valenced news receipts shows that differences in their prosodic design do not seem to affect the sequential structure of the news informing sequence. News receipts with falling and rising pitch may have the same uptake and are treated in the same way by co-participants. A preliminary study of a Greek telephone corpus yielded the following receipts of news announcements: a malista, a(h) orea, a ne, a, oh. These are news markers composed of a standalone particle or a particle followed by an adverb or a response token (ne). Analysis of the sequential and prosodic design of Greek news announcement sequences is made to determine any interactional patterns and/or prosodic constraints. By examining the way in which co-participants display their interpretation of these turns I show that the phonological systems of contrast are different depending on the sequential environment, in much the same way that consonantal systems of contrast are not the same syllable initially and finally.

Sequential Levels of Reading Skills, Prekindergarten--Grade 12.

ERIC Educational Resources Information Center

New York City Board of Education, Brooklyn, NY.

This guide is designed to help teachers, staff members responsible for teacher training, and reading supervisors provide better reading instruction. The skills that lead to mature reading are arranged on eight levels of developmental sequence. Level A is concerned with developing prereading skills. Levels B to D treat initiating and developing…

Sequential Ideal-Observer Analysis of Visual Discriminations.

ERIC Educational Resources Information Center

Geisler, Wilson S.

1989-01-01

A new analysis, based on the concept of the ideal observer in signal detection theory, is described. It allows: tracing of the flow of discrimination information through the initial physiological stages of visual processing for arbitrary spatio-chromatic stimuli, and measurement of the information content of said visual stimuli. (TJH)

Teacher and Peer Support for Young Adolescents' Motivation, Engagement, and School Belonging

ERIC Educational Resources Information Center

Kiefer, Sarah M.; Alley, Kathleen M.; Ellerbrock, Cheryl R.

2015-01-01

The purpose of this sequential explanatory mixed methods study was to investigate teacher and peer support for young adolescents' academic motivation, classroom engagement, and school belonging within one large, urban, ethnically diverse middle school. In the initial quantitative phase, associations among aspects of teacher support (autonomy,…

Sequential use of simulation and optimization in analysis and planning

Treesearch

Hans R. Zuuring; Jimmie D. Chew; J. Greg Jones

2000-01-01

Management activities are analyzed at landscape scales employing both simulation and optimization. SIMPPLLE, a stochastic simulation modeling system, is initially applied to assess the risks associated with a specific natural process occurring on the current landscape without management treatments, but with fire suppression. These simulation results are input into...

Shoot Morphogenesis Associated With Flowering in Populus deltoides (Salicaceae)

Treesearch

Cetin Yuceer; Samuel B. Land; Mark E. Kubiske; Richard L. Harkess

2003-01-01

Temporal and spatial formation and differentiation of axillary buds in developing shoots of mature eastern cottonwood (Populus deltoides) were investigated. Shoots sequentially initiate early vegetative, floral, and late vegetative buds. Associated with these buds is the formation of three distinct leaf types. In May of the first growing season, the...

Provoking Reflective Thinking in Post Observation Conversations

ERIC Educational Resources Information Center

Kim, Younhee; Silver, Rita Elaine

2016-01-01

We present a micro-analysis of post observation conversations between classroom teachers and mentors. Using the approach of conversation analysis, we show how the sequential organization of an episode (i.e., who initiates the interaction, question format used by mentors) could potentially serve to provoke or hinder teacher reflection. Our analysis…

78 FR 72571 - Extension of Expiration Date for Mental Disorders Body System Listings

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-03

... of Expiration Date for Mental Disorders Body System Listings AGENCY: Social Security Administration. ACTION: Final rule. SUMMARY: We are extending the expiration date of the Mental Disorders body system in... need to evaluate mental disorders at step three of the sequential evaluation processes for initial...

Elucidation of Altered Pathways in Tumor-Initiating Cells of Triple-Negative Breast Cancer: A Useful Cell Model System for Drug Screening.

PubMed

Christensen, Anne G; Ehmsen, Sidse; Terp, Mikkel G; Batra, Richa; Alcaraz, Nicolas; Baumbach, Jan; Noer, Julie B; Moreira, José; Leth-Larsen, Rikke; Larsen, Martin R; Ditzel, Henrik J

2017-08-01

A limited number of cancer cells within a tumor are thought to have self-renewing and tumor-initiating capabilities that produce the remaining cancer cells in a heterogeneous tumor mass. Elucidation of central pathways preferentially used by tumor-initiating cells/cancer stem cells (CSCs) may allow their exploitation as potential cancer therapy targets. We used single cell cloning to isolate and characterize four isogenic cell clones from a triple-negative breast cancer cell line; two exhibited mesenchymal-like and two epithelial-like characteristics. Within these pairs, one, but not the other, resulted in tumors in immunodeficient NOD/Shi-scid/IL-2 Rγ null mice and efficiently formed mammospheres. Quantitative proteomics and phosphoproteomics were used to map signaling pathways associated with the tumor-initiating ability. Signaling associated with apoptosis was suppressed in tumor-initiating versus nontumorigenic counterparts with pro-apoptotic proteins, such as Bcl2-associated agonist of cell death (BAD), FAS-associated death domain protein (FADD), and myeloid differentiation primary response protein (MYD88), downregulated in tumor-initiating epithelial-like cells. Functional studies confirmed significantly lower apoptosis in tumor-initiating versus nontumorigenic cells. Moreover, central pathways, including β-catenin and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-related signaling, exhibited increased activation in the tumor-initiating cells. To evaluate the CSC model as a tool for drug screening, we assessed the effect of separately blocking NF-κB and Wnt/β-catenin signaling and found markedly reduced mammosphere formation, particularly for tumor-initiating cells. Similar reduction was also observed using patient-derived primary cancer cells. Furthermore, blocking NF-κB signaling in mice transplanted with tumor-initiating cells significantly reduced tumor outgrowth. Our study demonstrates that suppressed apoptosis, activation of pathways associated with cell viability, and CSCs are the major differences between tumor-initiating and nontumorigenic cells independent of their epithelial-like/mesenchymal-like phenotype. These altered pathways may provide targets for future drug development to eliminate CSCs, and the cell model may be a useful tool in such drug screenings. Stem Cells 2017;35:1898-1912. © 2017 AlphaMed Press.

Design and protocol of a randomized multiple behavior change trial: Make Better Choices 2 (MBC2).

PubMed

Pellegrini, Christine A; Steglitz, Jeremy; Johnston, Winter; Warnick, Jennifer; Adams, Tiara; McFadden, H G; Siddique, Juned; Hedeker, Donald; Spring, Bonnie

2015-03-01

Suboptimal diet and inactive lifestyle are among the most prevalent preventable causes of premature death. Interventions that target multiple behaviors are potentially efficient; however the optimal way to initiate and maintain multiple health behavior changes is unknown. The Make Better Choices 2 (MBC2) trial aims to examine whether sustained healthful diet and activity change are best achieved by targeting diet and activity behaviors simultaneously or sequentially. Study design approximately 250 inactive adults with poor quality diet will be randomized to 3 conditions examining the best way to prescribe healthy diet and activity change. The 3 intervention conditions prescribe: 1) an increase in fruit and vegetable consumption (F/V+), decrease in sedentary leisure screen time (Sed-), and increase in physical activity (PA+) simultaneously (Simultaneous); 2) F/V+ and Sed- first, and then sequentially add PA+ (Sequential); or 3) Stress Management Control that addresses stress, relaxation, and sleep. All participants will receive a smartphone application to self-monitor behaviors and regular coaching calls to help facilitate behavior change during the 9 month intervention. Healthy lifestyle change in fruit/vegetable and saturated fat intakes, sedentary leisure screen time, and physical activity will be assessed at 3, 6, and 9 months. MBC2 is a randomized m-Health intervention examining methods to maximize initiation and maintenance of multiple healthful behavior changes. Results from this trial will provide insight about an optimal technology supported approach to promote improvement in diet and physical activity. Copyright © 2015 Elsevier Inc. All rights reserved.

Testicular Lumicrine Factors Regulate ERK, STAT, and NFKB Pathways in the Initial Segment of the Rat Epididymis to Prevent Apoptosis1

PubMed Central

Xu, Bingfang; Abdel-Fattah, Rana; Yang, Ling; Crenshaw, Sallie A.; Black, Michael B.; Hinton, Barry T.

2011-01-01

The initial segment of the epididymis is vital for male fertility; therefore, it is important to understand the mechanisms that regulate this important region. Deprival of testicular luminal fluid factors/lumicrine factors from the epididymis results in a wave of apoptosis in the initial segment. In this study, a combination of protein array and microarray analyses was used to examine the early changes in downstream signal transduction pathways following loss of lumicrine factors. We discovered the following cascade of events leading to the loss of protection and eventual apoptosis: in the first 6 h after loss of lumicrine factors, down-regulation of the ERK pathway components was observed at the mRNA expression and protein activity levels. Microarray analysis revealed that mRNA levels of several key components of the ERK pathway, Dusp6, Dusp5, and Etv5, decreased sharply, while the analysis from the protein array revealed a decline in the activities of MAP2K1/2 and MAPK1. Immunostaining of phospho-MAPK3/1 indicated that down-regulation of the ERK pathway was specific to the epithelial cells of the initial segment. Subsequently, after 12 h of loss of lumicrine factors, levels of mRNA expression of STAT and NFKB pathway components increased, mRNA levels of several genes encoding cell cycle inhibitors increased, and levels of protein expression of several proapoptotic phosphatases increased. Finally, after 18 h of loss of protection from lumicrine factors, apoptosis was observed. In conclusion, testicular lumicrine factors protect the cells of the initial segment by activating the ERK pathway, repressing STAT and NFKB pathways, and thereby preventing apoptosis. PMID:21311037

Evidence for the Existence in Arabidopsis thaliana of the Proteasome Proteolytic Pathway

PubMed Central

Polge, Cécile; Jaquinod, Michel; Holzer, Frances; Bourguignon, Jacques; Walling, Linda; Brouquisse, Renaud

2009-01-01

Heavy metals are known to generate reactive oxygen species that lead to the oxidation and fragmentation of proteins, which become toxic when accumulated in the cell. In this study, we investigated the role of the proteasome during cadmium stress in the leaves of Arabidopsis thaliana plants. Using biochemical and proteomics approaches, we present the first evidence of an active proteasome pathway in plants. We identified and characterized the peptidases acting sequentially downstream from the proteasome in animal cells as follows: tripeptidyl-peptidase II, thimet oligopeptidase, and leucine aminopeptidase. We investigated the proteasome proteolytic pathway response in the leaves of 6-week-old A. thaliana plants grown hydroponically for 24, 48, and 144 h in the presence or absence of 50 μm cadmium. The gene expression and proteolytic activity of the proteasome and the different proteases of the pathway were found to be up-regulated in response to cadmium. In an in vitro assay, oxidized bovine serum albumin and lysozyme were more readily degraded in the presence of 20 S proteasome and tripeptidyl-peptidase II than their nonoxidized form, suggesting that oxidized proteins are preferentially degraded by the Arabidopsis 20 S proteasome pathway. These results show that, in response to cadmium, the 20 S proteasome proteolytic pathway is up-regulated at both RNA and activity levels in Arabidopsis leaves and may play a role in degrading oxidized proteins generated by the stress. PMID:19822524

Alx4 relays sequential FGF signaling to induce lacrimal gland morphogenesis

PubMed Central

Garg, Ankur; Gotoh, Noriko; Feng, Gen-Sheng; Zhong, Jian; Wang, Fen; Kariminejad, Ariana; Brooks, Steven

2017-01-01

The sequential use of signaling pathways is essential for the guidance of pluripotent progenitors into diverse cell fates. Here, we show that Shp2 exclusively mediates FGF but not PDGF signaling in the neural crest to control lacrimal gland development. In addition to preventing p53-independent apoptosis and promoting the migration of Sox10-expressing neural crests, Shp2 is also required for expression of the homeodomain transcription factor Alx4, which directly controls Fgf10 expression in the periocular mesenchyme that is necessary for lacrimal gland induction. We show that Alx4 binds an Fgf10 intronic element conserved in terrestrial but not aquatic animals, underlying the evolutionary emergence of the lacrimal gland system in response to an airy environment. Inactivation of ALX4/Alx4 causes lacrimal gland aplasia in both human and mouse. These results reveal a key role of Alx4 in mediating FGF-Shp2-FGF signaling in the neural crest for lacrimal gland development. PMID:29028795

Quantification of small GTPase glucosylation by clostridial glucosylating toxins using multiplexed MRM analysis.

PubMed

Junemann, Johannes; Lämmerhirt, Chantal M; Polten, Felix; Just, Ingo; Gerhard, Ralf; Genth, Harald; Pich, Andreas

2017-05-01

Large clostridial toxins mono-O-glucosylate small GTPases of the Rho and Ras subfamily. As a result of glucosylation, the GTPases are inhibited and thereby corresponding downstream signaling pathways are disturbed. Current methods for quantifying the extent of glucosylation include sequential [ 14 C]glucosylation, sequential [ 32 P]ADP-ribosylation, and Western Blot detection of nonglucosylated GTPases, with neither method allowing the quantification of the extent of glucosylation of an individual GTPase. Here, we describe a novel MS-based multiplexed MRM assay to specifically quantify the glucosylation degree of small GTPases. This targeted proteomics approach achieves a high selectivity and reproducibility, which allows determination of the in vivo substrate pattern of glucosylating toxins. As proof of principle, GTPase glucosylation was analyzed in CaCo-2 cells treated with TcdA, and glucosylation kinetics were determined for RhoA/B, RhoC, RhoG, Ral, Rap1, Rap2, (H/K/N)Ras, and R-Ras2. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Income and children's behavioral functioning: a sequential mediation analysis.

PubMed

Shelleby, Elizabeth C; Votruba-Drzal, Elizabeth; Shaw, Daniel S; Dishion, Thomas J; Wilson, Melvin N; Gardner, Frances

2014-12-01

Children from low-income households tend to exhibit higher levels of conduct problems and emotional problems, yet the pathways linking economic disadvantage to children's behavioral functioning are not well understood. This study uses data from the Early Steps Multisite (ESM) project (N = 731) to investigate associations between family income in early childhood and children's conduct problems and emotional problems in middle childhood. The study explores whether the associations from income to child conduct problems and emotional problems operate through maternal depressive symptoms and 3 family risk factors in early childhood-harsh parenting, parenting hassles, and chaos in the home environment. Results of a sequential mediation model revealed significant indirect effects of family income on children's conduct problems operating through maternal depressive symptoms and parenting hassles and indirect effects of family income on children's emotional problems operating through maternal depressive symptoms, chaos in the home environment, and parenting hassles. Implications of these findings for understanding processes through which income influences child functioning are discussed.

Alx4 relays sequential FGF signaling to induce lacrimal gland morphogenesis.

PubMed

Garg, Ankur; Bansal, Mukesh; Gotoh, Noriko; Feng, Gen-Sheng; Zhong, Jian; Wang, Fen; Kariminejad, Ariana; Brooks, Steven; Zhang, Xin

2017-10-01

The sequential use of signaling pathways is essential for the guidance of pluripotent progenitors into diverse cell fates. Here, we show that Shp2 exclusively mediates FGF but not PDGF signaling in the neural crest to control lacrimal gland development. In addition to preventing p53-independent apoptosis and promoting the migration of Sox10-expressing neural crests, Shp2 is also required for expression of the homeodomain transcription factor Alx4, which directly controls Fgf10 expression in the periocular mesenchyme that is necessary for lacrimal gland induction. We show that Alx4 binds an Fgf10 intronic element conserved in terrestrial but not aquatic animals, underlying the evolutionary emergence of the lacrimal gland system in response to an airy environment. Inactivation of ALX4/Alx4 causes lacrimal gland aplasia in both human and mouse. These results reveal a key role of Alx4 in mediating FGF-Shp2-FGF signaling in the neural crest for lacrimal gland development.

Kupffer cell ablation attenuates cyclooxygenase-2 expression after trauma and sepsis.

PubMed

Keller, Steve A; Paxian, Marcus; Lee, Sun M; Clemens, Mark G; Huynh, Toan

2005-03-01

Prostaglandins, synthesized by cyclooxygenase (COX), play an important role in the pathophysiology of inflammation. Severe injuries result in immunosuppression, mediated, in part, by maladaptive changes in macrophages. Herein, we assessed Kupffer cell-mediated cyclooxygenase-2 (COX-2) expression on liver function and damage after trauma and sepsis. To ablate Kupffer cells, Sprague Dawley rats were treated with gadolinium chloride (GdCl3) 48 and 24 h before experimentation. Animals then underwent femur fracture (FFx) followed 48 h later by cecal ligation and puncture (CLP). Controls received sham operations. After 24 h, liver samples were obtained, and mRNA and protein expression were determined by PCR, Western blot, and immunohistochemistry. Indocyanine-Green (ICG) clearance and plasma alanine aminotransferase (ALT) levels were determined to assess liver function and damage, respectively. One-way analysis of variance (ANOVA) with Student-Newman-Keuls test was used to assess statistical significance. After CLP alone, FFx+CLP, and GdCl3+FFx+CLP, clearance of ICG decreased. Plasma ALT levels increased in parallel with severity of injury. Kupffer cell depletion attenuated the increased ALT levels after FFx+CLP. Femur fracture alone did not alter COX-2 protein compared with sham. By contrast, COX-2 protein increased after CLP and was potentiated by sequential stress. Again, Kupffer cell depletion abrogated the increase in COX-2 after sequential stress. Immunohistochemical data confirmed COX-2 positive cells to be Kupffer cells. In this study, sequential stress increased hepatic COX-2 protein. Depletion of Kupffer cells reduced COX-2 and attenuated hepatocellular injuries. Our data suggest that Kupffer cell-dependent pathways may contribute to the inflammatory response leading to increased mortality after sequential stress.

The Temporal Sequence of Social Anxiety and Depressive Symptoms following Interpersonal Stressors during Adolescence

PubMed Central

Hamilton, Jessica L.; Potter, Carrie M.; Olino, Thomas M.; Abramson, Lyn Y.; Heimberg, Richard G.; Alloy, Lauren B.

2015-01-01

Social anxiety and depressive symptoms dramatically increase and frequently co-occur during adolescence. Although research indicates that general interpersonal stressors, peer victimization, and familial emotional maltreatment predict symptoms of social anxiety and depression, it remains unclear how these stressors contribute to the sequential development of these internalizing symptoms. Thus, the present study examined the sequential development of social anxiety and depressive symptoms following the occurrence of interpersonal stressors, peer victimization, and familial emotional maltreatment. Participants included 410 early adolescents (53% female; 51% African American; Mean age =12.84 years) who completed measures of social anxiety and depressive symptoms at three time points (Times 1–3), as well as measures of general interpersonal stressors, peer victimization, and emotional maltreatment at Time 2. Path analyses revealed that interpersonal stressors, peer victimization, and emotional maltreatment predicted both depressive and social anxiety symptoms concurrently. However, depressive symptoms significantly mediated the pathway from interpersonal stressors, peer victimization, and familial emotional maltreatment to subsequent levels of social anxiety symptoms. In contrast, social anxiety did not mediate the relationship between these stressors and subsequent depressive symptoms. There was no evidence of sex or racial differences in these mediational pathways. Findings suggest that interpersonal stressors, including the particularly detrimental stressors of peer victimization and familial emotional maltreatment, may predict both depressive and social anxiety symptoms; however, adolescents who have more immediate depressogenic reactions may be at greater risk for later development of symptoms of social anxiety. PMID:26142495

The Temporal Sequence of Social Anxiety and Depressive Symptoms Following Interpersonal Stressors During Adolescence.

PubMed

Hamilton, Jessica L; Potter, Carrie M; Olino, Thomas M; Abramson, Lyn Y; Heimberg, Richard G; Alloy, Lauren B

2016-04-01

Social anxiety and depressive symptoms dramatically increase and frequently co-occur during adolescence. Although research indicates that general interpersonal stressors, peer victimization, and familial emotional maltreatment predict symptoms of social anxiety and depression, it remains unclear how these stressors contribute to the sequential development of these internalizing symptoms. Thus, the present study examined the sequential development of social anxiety and depressive symptoms following the occurrence of interpersonal stressors, peer victimization, and familial emotional maltreatment. Participants included 410 early adolescents (53% female; 51% African American; Mean age =12.84 years) who completed measures of social anxiety and depressive symptoms at three time points (Times 1-3), as well as measures of general interpersonal stressors, peer victimization, and emotional maltreatment at Time 2. Path analyses revealed that interpersonal stressors, peer victimization, and emotional maltreatment predicted both depressive and social anxiety symptoms concurrently. However, depressive symptoms significantly mediated the pathway from interpersonal stressors, peer victimization, and familial emotional maltreatment to subsequent levels of social anxiety symptoms. In contrast, social anxiety did not mediate the relationship between these stressors and subsequent depressive symptoms. There was no evidence of sex or racial differences in these mediational pathways. Findings suggest that interpersonal stressors, including the particularly detrimental stressors of peer victimization and familial emotional maltreatment, may predict both depressive and social anxiety symptoms; however, adolescents who have more immediate depressogenic reactions may be at greater risk for later development of symptoms of social anxiety.

Timed sequential chemotherapy of cytoxan-refractory multiple myeloma with cytoxan and adriamycin based on induced tumor proliferation.

PubMed

Karp, J E; Humphrey, R L; Burke, P J

1981-03-01

Malignant plasma cell proliferation and induced humoral stimulatory activity (HSA) occur in vivo at a predictable time following drug administration. Sequential sera from 11 patients with poor-risk multiple myeloma (MM) undergoing treatment with Cytoxan (CY) 2400 mq/sq m were assayed for their in vitro effects on malignant bone marrow plasma cell tritiated thymidine (3HTdR) incorporation. Peak HSA was detected day 9 following CY. Sequential changes in marrow malignant plasma cell 3HTdR-labeling indices (LI) paralleled changes in serum activity, with peak LI occurring at the time of peak HS. An in vitro model of chemotherapy demonstrated that malignant plasma cell proliferation was enhanced by HSA, as determined by 3HTdR incorporation assay, 3HTdR LI, and tumor cells counts, and that stimulated plasma cells were more sensitive to cytotoxic effects of adriamycin (ADR) than were cells cultured in autologous pretreatment serum. Based on these studies, we designed a clinical trial to treat 12 CY-refractory poor-risk patients with MM in which ADR (60 mg/sq m) was administered at the time of peak HSA and residual tumor cell LI (day 9) following initial CY, 2400 mg/m (CY1ADR9). Eight of 12 (67%) responded to timed sequential chemotherapy with a greater than 50% decrement in monoclonal protein marker and a median survival projected to be greater than 8 mo duration (range 4-21+ mo). These clinical results using timed sequential CY1ADR9 compare favorably with results obtained using ADR in nonsequential chemotherapeutic regimens.

Cost-effectiveness of allopurinol and febuxostat for the management of gout.

PubMed

Jutkowitz, Eric; Choi, Hyon K; Pizzi, Laura T; Kuntz, Karen M

2014-11-04

Gout is the most common inflammatory arthritis in the United States. To evaluate the cost-effectiveness of urate-lowering treatment strategies for the management of gout. Markov model. Published literature and expert opinion. Patients for whom allopurinol or febuxostat is a suitable initial urate-lowering treatment. Lifetime. Health care payer. 5 urate-lowering treatment strategies were evaluated: no treatment; allopurinol- or febuxostat-only therapy; allopurinol-febuxostat sequential therapy; and febuxostat-allopurinol sequential therapy. Two dosing scenarios were investigated: fixed dose (80 mg of febuxostat daily, 0.80 success rate; 300 mg of allopurinol daily, 0.39 success rate) and dose escalation (≤120 mg of febuxostat daily, 0.82 success rate; ≤800 mg of allopurinol daily, 0.78 success rate). Discounted costs, discounted quality-adjusted life-years, and incremental cost-effectiveness ratios. In both dosing scenarios, allopurinol-only therapy was cost-saving. Dose-escalation allopurinol-febuxostat sequential therapy was more costly but more effective than dose-escalation allopurinol therapy, with an incremental cost-effectiveness ratio of $39 400 per quality-adjusted life-year. The relative rankings of treatments did not change. Our results were relatively sensitive to several potential variations of model assumptions; however, the cost-effectiveness ratios of dose escalation with allopurinol-febuxostat sequential therapy remained lower than the willingness-to-pay threshold of $109 000 per quality-adjusted life-year. Long-term outcome data for patients with gout, including medication adherence, are limited. Allopurinol single therapy is cost-saving compared with no treatment. Dose-escalation allopurinol-febuxostat sequential therapy is cost-effective compared with accepted willingness-to-pay thresholds. Agency for Healthcare Research and Quality.

Vapor Grown Perovskite Solar Cells

NASA Astrophysics Data System (ADS)

Abdussamad Abbas, Hisham

Perovskite solar cells has been the fastest growing solar cell material till date with verified efficiencies of over 22%. Most groups in the world focuses their research on solution based devices that has residual solvent in the material bulk. This work focuses extensively on the fabrication and properties of vapor based perovskite devices that is devoid of solvents. The initial part of my work focuses on the detailed fabrication of high efficiency consistent sequential vapor NIP devices made using P3HT as P-type Type II heterojunction. The sequential vapor devices experiences device anomalies like voltage evolution and IV hysteresis owing to charge trapping in TiO2. Hence, sequential PIN devices were fabricated using doped Type-II heterojunctions that had no device anomalies. The sequential PIN devices has processing restriction, as organic Type-II heterojunction materials cannot withstand high processing temperature, hence limiting device efficiency. Thereby bringing the need of co-evaporation for fabricating high efficiency consistent PIN devices, the approach has no-restriction on substrates and offers stoichiometric control. A comprehensive description of the fabrication, Co-evaporator setup and how to build it is described. The results of Co-evaporated devices clearly show that grain size, stoichiometry and doped transport layers are all critical for eliminating device anomalies and in fabricating high efficiency devices. Finally, Formamidinium based perovskite were fabricated using sequential approach. A thermal degradation study was conducted on Methyl Ammonium Vs. Formamidinium based perovskite films, Formamidinium based perovskites were found to be more stable. Lastly, inorganic films such as CdS and Nickel oxide were developed in this work.

Perchlorate Reduction by Yeast for Mars Exploration

NASA Technical Reports Server (NTRS)

Sharma, Alaisha

2015-01-01

Martian soil contains high levels (0.6 percentage by mass) of calcium perchlorate (Ca(ClO4)2), which readily dissociates into calcium and the perchlorate ion (ClO4-) in water. Even in trace amounts, perchlorates are toxic to humans and have been implicated in thyroid dysfunction. Devising methods to lessen perchlorate contamination is crucial to minimizing the health risks associated with human exploration and colonization of Mars. We designed a perchlorate reduction pathway, which sequentially reduces perchlorate to chloride (Cl-) and oxygen (O2), for implementation in the yeast Saccharomyces cerevisiae. Using genes obtained from perchlorate reducing bacteria Azospira oryzae and Dechloromonas aromatica, we plan to assemble this pathway directly within S. cerevisiae through recombinational cloning. A perchlorate reduction pathway would enable S. cerevisiae to lower perchlorate levels and produce oxygen, which may be harvested or used directly by S. cerevisiae for aerobic growth and compound synthesis. Moreover, using perchlorate as an external electron acceptor could improve the efficiency of redox-imbalanced production pathways in yeast. Although several perchlorate reducing bacteria have been identified and utilized in water treatment systems on Earth, the widespread use of S. cerevisiae as a synthetic biology platform justifies the development of a perchlorate reducing strain for implementation on Mars.

Computational multiscale modeling in protein--ligand docking.

PubMed

Taufer, Michela; Armen, Roger; Chen, Jianhan; Teller, Patricia; Brooks, Charles

2009-01-01

In biological systems, the binding of small molecule ligands to proteins is a crucial process for almost every aspect of biochemistry and molecular biology. Enzymes are proteins that function by catalyzing specific biochemical reactions that convert reactants into products. Complex organisms are typically composed of cells in which thousands of enzymes participate in complex and interconnected biochemical pathways. Some enzymes serve as sequential steps in specific pathways (such as energy metabolism), while others function to regulate entire pathways and cellular functions [1]. Small molecule ligands can be designed to bind to a specific enzyme and inhibit the biochemical reaction. Inhibiting the activity of key enzymes may result in the entire biochemical pathways being turned on or off [2], [3]. Many small molecule drugs marketed today function in this generic way as enzyme inhibitors. If research identifies a specific enzyme as being crucial to the progress of disease, then this enzyme may be targeted with an inhibitor, which may slow down or reverse the progress of disease. In this way, enzymes are targeted from specific pathogens (e.g., virus, bacteria, fungi) for infectious diseases [4], [5], and human enzymes are targeted for noninfectious diseases such as cardiovascular disease, cancer, diabetes, and neurodegenerative diseases [6].

Giant virus Megavirus chilensis encodes the biosynthetic pathway for uncommon acetamido sugars.

PubMed

Piacente, Francesco; De Castro, Cristina; Jeudy, Sandra; Molinaro, Antonio; Salis, Annalisa; Damonte, Gianluca; Bernardi, Cinzia; Abergel, Chantal; Tonetti, Michela G

2014-08-29

Giant viruses mimicking microbes, by the sizes of their particles and the heavily glycosylated fibrils surrounding their capsids, infect Acanthamoeba sp., which are ubiquitous unicellular eukaryotes. The glycans on fibrils are produced by virally encoded enzymes, organized in gene clusters. Like Mimivirus, Megavirus glycans are mainly composed of virally synthesized N-acetylglucosamine (GlcNAc). They also contain N-acetylrhamnosamine (RhaNAc), a rare sugar; the enzymes involved in its synthesis are encoded by a gene cluster specific to Megavirus close relatives. We combined activity assays on two enzymes of the pathway with mass spectrometry and NMR studies to characterize their specificities. Mg534 is a 4,6-dehydratase 5-epimerase; its three-dimensional structure suggests that it belongs to a third subfamily of inverting dehydratases. Mg535, next in the pathway, is a bifunctional 3-epimerase 4-reductase. The sequential activity of the two enzymes leads to the formation of UDP-l-RhaNAc. This study is another example of giant viruses performing their glycan synthesis using enzymes different from their cellular counterparts, raising again the question of the origin of these pathways. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

The BHEF National Higher Education and Workforce Initiative: A Model for Pathways to Baccalaureate Attainment and High-Skill Careers in Emerging Fields, Part 3

ERIC Educational Resources Information Center

Fitzgerald, Brian K.; Barkanic, Steve; Cárdenas-Navia, Isabel; Chen, Janet; Elzey, Karen; Hughes, Debbie; Troyan, Danielle

2016-01-01

BHEF has achieved particular success in operationalizing its National Higher Education and Workforce Initiative (HEWI) through regional initiatives in data science and analytics (DSA). Leveraging its membership of corporate CEOs, university presidents and government agency leaders, BHEF seeded new undergraduate pathways in DSA at Case Western…

Unsupervised classification of remote multispectral sensing data

NASA Technical Reports Server (NTRS)

Su, M. Y.

1972-01-01

The new unsupervised classification technique for classifying multispectral remote sensing data which can be either from the multispectral scanner or digitized color-separation aerial photographs consists of two parts: (a) a sequential statistical clustering which is a one-pass sequential variance analysis and (b) a generalized K-means clustering. In this composite clustering technique, the output of (a) is a set of initial clusters which are input to (b) for further improvement by an iterative scheme. Applications of the technique using an IBM-7094 computer on multispectral data sets over Purdue's Flight Line C-1 and the Yellowstone National Park test site have been accomplished. Comparisons between the classification maps by the unsupervised technique and the supervised maximum liklihood technique indicate that the classification accuracies are in agreement.

The Role of Self-Injury in the Organisation of Behaviour

ERIC Educational Resources Information Center

Sandman, C. A.; Kemp, A. S.; Mabini, C.; Pincus, D.; Magnusson, M.

2012-01-01

Background: Self-injuring acts are among the most dramatic behaviours exhibited by human beings. There is no known single cause and there is no universally agreed upon treatment. Sophisticated sequential and temporal analysis of behaviour has provided alternative descriptions of self-injury that provide new insights into its initiation and…

Developing and Implementing a Framework of Participatory Simulation for Mobile Learning Using Scaffolding

ERIC Educational Resources Information Center

Yin, Chengjiu; Song, Yanjie; Tabata, Yoshiyuki; Ogata, Hiroaki; Hwang, Gwo-Jen

2013-01-01

This paper proposes a conceptual framework, scaffolding participatory simulation for mobile learning (SPSML), used on mobile devices for helping students learn conceptual knowledge in the classroom. As the pedagogical design, the framework adopts an experiential learning model, which consists of five sequential but cyclic steps: the initial stage,…

Conceptual Distance and Word Learning: Patterns of Acquisition in Samoan-English Bilingual Children

ERIC Educational Resources Information Center

Hemsley, Gayle; Holm, Alison; Dodd, Barbara

2013-01-01

This study investigated cross-linguistic influence in acquisition of a second lexicon, evaluating Samoan-English sequentially bilingual children (initial mean age 4 ; 9) during their first 18 months of school. Receptive and Expressive Vocabulary tasks evaluated acquisition of four word types: cognates, matched nouns, phrasal nouns and holonyms.…

State Skill Standards: Digital Video & Broadcast Production

ERIC Educational Resources Information Center

Bullard, Susan; Tanner, Robin; Reedy, Brian; Grabavoi, Daphne; Ertman, James; Olson, Mark; Vaughan, Karen; Espinola, Ron

2007-01-01

The standards in this document are for digital video and broadcast production programs and are designed to clearly state what the student should know and be able to do upon completion of an advanced high-school program. Digital Video and Broadcast Production is a program that consists of the initial fundamentals and sequential courses that prepare…

Dynamic Processes at Semiconductor Interfaces: Atomic Intermixing, Diffusion Barriers, and Stability

DTIC Science & Technology

1991-08-15

that the movement of the Fermi level position at the Si surface and the variation of heterojunction band lineup correlated to the density of...that the topmost layer of As atoms was initially involved in a sequential two-step reaction to produce As l - and As 3+- like oxides. These reactions

Parallel Consolidation of Simple Features into Visual Short-Term Memory

ERIC Educational Resources Information Center

Mance, Irida; Becker, Mark W.; Liu, Taosheng

2012-01-01

Although considerable research has examined the storage limits of visual short-term memory (VSTM), little is known about the initial formation (i.e., the consolidation) of VSTM representations. A few previous studies have estimated the capacity of consolidation to be one item at a time. Here we used a sequential-simultaneous manipulation to…

Interactions between the Isolated-Interactive Elements Effect and Levels of Learner Expertise: Experimental Evidence from an Accountancy Class

ERIC Educational Resources Information Center

Blayney, Paul; Kalyuga, Slava; Sweller, John

2010-01-01

This study investigated interactions between the isolated-interactive elements effect and levels of learner expertise with first year undergraduate university accounting students. The isolated-interactive elements effect occurs when learning is facilitated by initially presenting elements of information sequentially in an isolated form rather than…

Post-Stop-Signal Slowing: Strategies Dominate Reflexes and Implicit Learning

ERIC Educational Resources Information Center

Bissett, Patrick G.; Logan, Gordon D.

2012-01-01

Control adjustments are necessary to balance competing cognitive demands. One task that is well-suited to explore control adjustments is the stop-signal paradigm, in which subjects must balance initiation and inhibition. One common adjustment in the stop-signal paradigm is post-stop-signal slowing. Existing models of sequential adjustments in the…

Speech Sequence Skill Learning in Adults Who Stutter

ERIC Educational Resources Information Center

Bauerly, Kim R.; De Nil, Luc F.

2011-01-01

The present study compared the ability of 12 people who stutter (PWS) and 12 people who do not stutter (PNS) to consolidate a novel sequential speech task. Participants practiced 100 repetitions of a single, monosyllabic, nonsense word sequence during an initial practice session and returned 24-h later to perform an additional 50 repetitions.…

Spatiotemporal transcriptome provides insights into early fruit development of tomato (Solanum lycopersicum).

PubMed

Zhang, Shuaibin; Xu, Meng; Qiu, Zhengkun; Wang, Ketao; Du, Yongchen; Gu, Lianfeng; Cui, Xia

2016-03-18

Early fruit development is crucial for crop production in tomato. After fertilization, the ovary undergoes cell division and cell expansion before maturation. Although the roles of regulatory signals such as hormone and carbohydrate during early fruit development have been studied, the spatial distribution and the sequential initiation of these regulatory signals still need to be explored. Using the tomato cultivar 'Moneymaker', we analyzed the transcriptome of the ovule and the ovary wall/pericarp dissected from four different stages of the early developing fruits by stereoscope. These datasets give us the whole picture about the spatial and temporal signal distribution in early development of ovule and pericarp. Our results indicate that the hormone signal was initiated in both ovule and pericarp after fertilization. After that, different signals were activated in ovule and pericarp due to their distinct developmental processes. Our study provides spatiotemporal regulatory landscape of gene expression with sequential information which was not studied by previous work and further strengthens the comprehension of the regulatory and metabolic events controlling early fruit development.

Preparation and evaluation of diblock copolymer-grafted silica by sequential surface initiated-atom transfer radical polymerization for reverse-phase/ion-exchange mixed-mode chromatography.

PubMed

Bo, Chun Miao; Wang, Chaozhan; Wei, Yin Mao

2017-12-01

A novel approach that involved the grafting of diblock copolymer with two types of monomer onto substrate by sequential surface initiated-atom transfer radical polymerization was proposed to prepare a mixed-mode chromatographic stationary phase. The distinguishing feature of this method is that it can be applied in the preparation of various mixed-mode stationary phases. In this study, a new reverse-phase/ion-exchange stationary phase was prepared by grafting hydrophobic styrene and cationic sodium 4-styrenesulfonate by the proposed approach onto silica surface. The chromatographic properties of the prepared stationary phase were evaluated by the separation of benzene derivatives, anilines, and β-agonists, and by the effect of pH values and acetonitrile content on the retention. Compared with typical RP columns, the prepared stationary phase achieved the better resolution and higher selectivity at a shorter separation time and lower organic content. Moreover, the application of the prepared column was proved by separating widely distributed polar and charged compounds simultaneously. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rapid Removal of Tetrabromobisphenol A by Ozonation in Water: Oxidation Products, Reaction Pathways and Toxicity Assessment

PubMed Central

Wang, Xinghao; Huang, Qingguo; Lu, Junhe; Wang, Liansheng; Wang, Zunyao

2015-01-01

Tetrabromobisphenol A (TBBPA) is one of the most widely used brominated flame retardants and has attracted more and more attention. In this work, the parent TBBPA with an initial concentration of 100 mg/L was completely removed after 6 min of ozonation at pH 8.0, and alkaline conditions favored a more rapid removal than acidic and neutral conditions. The presence of typical anions and humic acid did not significantly affect the degradation of TBBPA. The quenching test using isopropanol indicated that direct ozone oxidation played a dominant role during this process. Seventeen reaction intermediates and products were identified using an electrospray time-of-flight mass spectrometer. Notably, the generation of 2,4,6-tribromophenol was first observed in the degradation process of TBBPA. The evolution of reaction products showed that ozonation is an efficient treatment for removal of both TBBPA and intermediates. Sequential transformation of organic bromine to bromide and bromate was confirmed by ion chromatography analysis. Two primary reaction pathways that involve cleavage of central carbon atom and benzene ring cleavage concomitant with debromination were thus proposed and further justified by calculations of frontier electron densities. Furthermore, the total organic carbon data suggested a low mineralization rate, even after the complete removal of TBBPA. Meanwhile, the acute aqueous toxicity of reaction solutions to Photobacterium Phosphoreum and Daphnia magna was rapidly decreased during ozonation. In addition, no obvious difference in the attenuation of TBBPA was found by ozone oxidation using different water matrices, and the effectiveness in natural waters further demonstrates that ozonation can be adopted as a promising technique to treat TBBPA-contaminated waters. PMID:26430733

Dynamic Vibration Cooperates with Connective Tissue Growth Factor to Modulate Stem Cell Behaviors

PubMed Central

Tong, Zhixiang; Zerdoum, Aidan B.; Duncan, Randall L.

2014-01-01

Vocal fold disorders affect 3–9% of the U.S. population. Tissue engineering offers an alternative strategy for vocal fold repair. Successful engineering of vocal fold tissues requires a strategic combination of therapeutic cells, biomimetic scaffolds, and physiologically relevant mechanical and biochemical factors. Specifically, we aim to create a vocal fold-like microenvironment to coax stem cells to adopt the phenotype of vocal fold fibroblasts (VFFs). Herein, high frequency vibratory stimulations and soluble connective tissue growth factor (CTGF) were sequentially introduced to mesenchymal stem cells (MSCs) cultured on a poly(ɛ-caprolactone) (PCL)-derived microfibrous scaffold for a total of 6 days. The initial 3-day vibratory culture resulted in an increased production of hyaluronic acids (HA), tenascin-C (TNC), decorin (DCN), and matrix metalloproteinase-1 (MMP1). The subsequent 3-day CTGF treatment further enhanced the cellular production of TNC and DCN, whereas CTGF treatment alone without the vibratory preconditioning significantly promoted the synthesis of collagen I (Col 1) and sulfated glycosaminoglycans (sGAGs). The highest level of MMP1, TNC, Col III, and DCN production was found for cells being exposed to the combined vibration and CTGF treatment. Noteworthy, the vibration and CTGF elicited a differential stimulatory effect on elastin (ELN), HA synthase 1 (HAS1), and fibroblast-specific protein-1 (FSP-1). The mitogenic activity of CTGF was only elicited in naïve cells without the vibratory preconditioning. The combined treatment had profound, but opposite effects on mitogen-activated protein kinase (MAPK) pathways, Erk1/2 and p38, and the Erk1/2 pathway was critical for the observed mechano-biochemical responses. Collectively, vibratory stresses and CTGF signals cooperatively coaxed MSCs toward a VFF-like phenotype and accelerated the synthesis and remodeling of vocal fold matrices. PMID:24456068

NADP(+)-dependent D-xylose dehydrogenase from pig liver. Purification and properties.

PubMed

Zepeda, S; Monasterio, O; Ureta, T

1990-03-15

An NADP(+)-dependent D-xylose dehydrogenase from pig liver cytosol was purified about 2000-fold to apparent homogeneity with a yield of 15% and specific activity of 6 units/mg of protein. An Mr value of 62,000 was obtained by gel filtration. PAGE in the presence of SDS gave an Mr value of 32,000, suggesting that the native enzyme is a dimer of similar or identical subunits. D-Xylose, D-ribose, L-arabinose, 2-deoxy-D-glucose, D-glucose and D-mannose were substrates in the presence of NADP+ but the specificity constant (ratio kcat./Km(app.)) is, by far, much higher for D-xylose than for the other sugars. The enzyme is specific for NADP+; NAD+ is not reduced in the presence of D-xylose or other sugars. Initial-velocity studies for the forward direction with xylose or NADP+ concentrations varied at fixed concentrations of the nucleotide or the sugar respectively revealed a pattern of parallel lines in double-reciprocal plots. Km values for D-xylose and NADP+ were 8.8 mM and 0.99 mM respectively. Dead-end inhibition studies to confirm a ping-pong mechanism showed that NAD+ acted as an uncompetitive inhibitor versus NADP+ (Ki 5.8 mM) and as a competitive inhibitor versus xylose. D-Lyxose was a competitive inhibitor versus xylose and uncompetitive versus NADP+. These results fit better to a sequential compulsory ordered mechanism with NADP+ as the first substrate, but a ping-pong mechanism with xylose as the first substrate has not been ruled out. The presence of D-xylose dehydrogenase suggests that in mammalian liver D-xylose is utilized by a pathway other than the pentose phosphate pathway.

Transforming Growth Factor-β/SMAD Target Gene SKIL Is Negatively Regulated by the Transcriptional Cofactor Complex SNON-SMAD4*

PubMed Central

Tecalco-Cruz, Angeles C.; Sosa-Garrocho, Marcela; Vázquez-Victorio, Genaro; Ortiz-García, Layla; Domínguez-Hüttinger, Elisa; Macías-Silva, Marina

2012-01-01

The human SKI-like (SKIL) gene encodes the SMAD transcriptional corepressor SNON that antagonizes TGF-β signaling. SNON protein levels are tightly regulated by the TGF-β pathway: whereas a short stimulation with TGF-β decreases SNON levels by its degradation via the proteasome, longer TGF-β treatment increases SNON levels by inducing SKIL gene expression. Here, we investigated the molecular mechanisms involved in the self-regulation of SKIL gene expression by SNON. Bioinformatics analysis showed that the human SKIL gene proximal promoter contains a TGF-β response element (TRE) bearing four groups of SMAD-binding elements that are also conserved in mouse. Two regions of 408 and 648 bp of the human SKIL gene (∼2.4 kb upstream of the ATG initiation codon) containing the core promoter, transcription start site, and the TRE were cloned for functional analysis. Binding of SMAD and SNON proteins to the TRE region of the SKIL gene promoter after TGF-β treatment was demonstrated by ChIP and sequential ChIP assays. Interestingly, the SNON-SMAD4 complex negatively regulated basal SKIL gene expression through binding the promoter and recruiting histone deacetylases. In response to TGF-β signal, SNON is removed from the SKIL gene promoter, and then the activated SMAD complexes bind the promoter to induce SKIL gene expression. Subsequently, the up-regulated SNON protein in complex with SMAD4 represses its own expression as part of the negative feedback loop regulating the TGF-β pathway. Accordingly, when the SNON-SMAD4 complex is absent as in some cancer cells lacking SMAD4 the regulation of some TGF-β target genes is modified. PMID:22674574

A Two-Component para-Nitrophenol Monooxygenase Initiates a Novel 2-Chloro-4-Nitrophenol Catabolism Pathway in Rhodococcus imtechensis RKJ300

PubMed Central

Min, Jun; Zhang, Jun-Jie

2015-01-01

Rhodococcus imtechensis RKJ300 (DSM 45091) grows on 2-chloro-4-nitrophenol (2C4NP) and para-nitrophenol (PNP) as the sole carbon and nitrogen sources. In this study, by genetic and biochemical analyses, a novel 2C4NP catabolic pathway different from those of all other 2C4NP utilizers was identified with hydroxyquinol (hydroxy-1,4-hydroquinone or 1,2,4-benzenetriol [BT]) as the ring cleavage substrate. Real-time quantitative PCR analysis indicated that the pnp cluster located in three operons is likely involved in the catabolism of both 2C4NP and PNP. The oxygenase component (PnpA1) and reductase component (PnpA2) of the two-component PNP monooxygenase were expressed and purified to homogeneity, respectively. The identification of chlorohydroquinone (CHQ) and BT during 2C4NP degradation catalyzed by PnpA1A2 indicated that PnpA1A2 catalyzes the sequential denitration and dechlorination of 2C4NP to BT and catalyzes the conversion of PNP to BT. Genetic analyses revealed that pnpA1 plays an essential role in both 2C4NP and PNP degradations by gene knockout and complementation. In addition to catalyzing the oxidation of CHQ to BT, PnpA1A2 was also found to be able to catalyze the hydroxylation of hydroquinone (HQ) to BT, revealing the probable fate of HQ that remains unclear in PNP catabolism by Gram-positive bacteria. This study fills a gap in our knowledge of the 2C4NP degradation mechanism in Gram-positive bacteria and also enhances our understanding of the genetic and biochemical diversity of 2C4NP catabolism. PMID:26567304

Generalized trajectory surface-hopping method for internal conversion and intersystem crossing

NASA Astrophysics Data System (ADS)

Cui, Ganglong; Thiel, Walter

2014-09-01

Trajectory-based fewest-switches surface-hopping (FSSH) dynamics simulations have become a popular and reliable theoretical tool to simulate nonadiabatic photophysical and photochemical processes. Most available FSSH methods model internal conversion. We present a generalized trajectory surface-hopping (GTSH) method for simulating both internal conversion and intersystem crossing processes on an equal footing. We consider hops between adiabatic eigenstates of the non-relativistic electronic Hamiltonian (pure spin states), which is appropriate for sufficiently small spin-orbit coupling. This choice allows us to make maximum use of existing electronic structure programs and to minimize the changes to available implementations of the traditional FSSH method. The GTSH method is formulated within the quantum mechanics (QM)/molecular mechanics framework, but can of course also be applied at the pure QM level. The algorithm implemented in the GTSH code is specified step by step. As an initial GTSH application, we report simulations of the nonadiabatic processes in the lowest four electronic states (S0, S1, T1, and T2) of acrolein both in vacuo and in acetonitrile solution, in which the acrolein molecule is treated at the ab initio complete-active-space self-consistent-field level. These dynamics simulations provide detailed mechanistic insight by identifying and characterizing two nonadiabatic routes to the lowest triplet state, namely, direct S1 → T1 hopping as major pathway and sequential S1 → T2 → T1 hopping as minor pathway, with the T2 state acting as a relay state. They illustrate the potential of the GTSH approach to explore photoinduced processes in complex systems, in which intersystem crossing plays an important role.

Transient state kinetics of transcription elongation by T7 RNA polymerase.

PubMed

Anand, Vasanti Subramanian; Patel, Smita S

2006-11-24

The single subunit DNA-dependent RNA polymerase (RNAP) from bacteriophage T7 catalyzes both promoter-dependent transcription initiation and promoter-independent elongation. Using a promoter-free substrate, we have dissected the kinetic pathway of single nucleotide incorporation during elongation. We show that T7 RNAP undergoes a slow conformational change (0.01-0.03 s(-1)) to form an elongation competent complex with the promoter-free substrate (dissociation constant (Kd) of 96 nM). The complex binds to a correct NTP (Kd of 80 microM) and incorporates the nucleoside monophosphate (NMP) into RNA primer very efficiently (220 s(-1) at 25 degrees C). An overall free energy change (-5.5 kcal/mol) and internal free energy change (-3.7 kcal/mol) of single NMP incorporation was calculated from the measured equilibrium constants. In the presence of inorganic pyrophosphate (PPi), the elongation complex catalyzes the reverse pyrophosphorolysis reaction at a maximum rate of 0.8 s(-1) with PPi Kd of 1.2 mM. Several experiments were designed to investigate the rate-limiting step in the pathway of single nucleotide addition. Acid-quench and pulse-chase kinetics indicated that an isomerization step before chemistry is rate-limiting. The very similar rate constants of sequential incorporation of two nucleotides indicated that the steps after chemistry are fast. Based on available data, we propose that the preinsertion to insertion isomerization of NTP observed in the crystallographic studies of T7 RNAP is a likely candidate for the rate-limiting step. The studies here provide a kinetic framework to investigate structure-function and fidelity of RNA synthesis and to further explore the role of the conformational change in nucleotide selection during RNA synthesis.

Transforming growth factor-β/SMAD Target gene SKIL is negatively regulated by the transcriptional cofactor complex SNON-SMAD4.

PubMed

Tecalco-Cruz, Angeles C; Sosa-Garrocho, Marcela; Vázquez-Victorio, Genaro; Ortiz-García, Layla; Domínguez-Hüttinger, Elisa; Macías-Silva, Marina

2012-08-03

The human SKI-like (SKIL) gene encodes the SMAD transcriptional corepressor SNON that antagonizes TGF-β signaling. SNON protein levels are tightly regulated by the TGF-β pathway: whereas a short stimulation with TGF-β decreases SNON levels by its degradation via the proteasome, longer TGF-β treatment increases SNON levels by inducing SKIL gene expression. Here, we investigated the molecular mechanisms involved in the self-regulation of SKIL gene expression by SNON. Bioinformatics analysis showed that the human SKIL gene proximal promoter contains a TGF-β response element (TRE) bearing four groups of SMAD-binding elements that are also conserved in mouse. Two regions of 408 and 648 bp of the human SKIL gene (∼2.4 kb upstream of the ATG initiation codon) containing the core promoter, transcription start site, and the TRE were cloned for functional analysis. Binding of SMAD and SNON proteins to the TRE region of the SKIL gene promoter after TGF-β treatment was demonstrated by ChIP and sequential ChIP assays. Interestingly, the SNON-SMAD4 complex negatively regulated basal SKIL gene expression through binding the promoter and recruiting histone deacetylases. In response to TGF-β signal, SNON is removed from the SKIL gene promoter, and then the activated SMAD complexes bind the promoter to induce SKIL gene expression. Subsequently, the up-regulated SNON protein in complex with SMAD4 represses its own expression as part of the negative feedback loop regulating the TGF-β pathway. Accordingly, when the SNON-SMAD4 complex is absent as in some cancer cells lacking SMAD4 the regulation of some TGF-β target genes is modified.

Nitrergic Pathway Is the Major Mechanism for the Effect of DA-9701 on the Rat Gastric Fundus Relaxation.

PubMed

Min, Yang Won; Ko, Eun-Ju; Lee, Ji Yeon; Min, Byung-Hoon; Lee, Jun Haeng; Kim, Jae J; Rhee, Poong-Lyul

2014-07-31

DA-9701 significantly improved gastric accommodation by increasing the postprandial gastric volume. In this study, we investigated how DA-9701 affects the rat gastric fundus relaxation. Gastric fundus muscle strips (9 longitudinal and 7 circular muscles) were obtained from rats. Electrical field stimulation (EFS) was performed at various frequencies (1, 5, 10 and 20 Hz) and train durations (1, 5, 10 and 20 seconds) to select optimal condition for experiments. Isometric force measurements were performed in response to EFS. Peak and nadir were observed during the first 1 minute after initiation of EFS in control state and after sequential addition of atropine (1 μM), DA-9701 (0.5, 5, 25 and 50 μg), N-nitro-L-arginine (L-NNA, 100 μM), MRS2500 (1 μM) and tetrodotoxin (TTX, 1 μM) to the organ bath. The optimal frequency and duration of EFS to evoke nerve-mediated relaxation was determined as 5 Hz for 10 seconds. Addition of L-NNA in the presence of atropine and DA-9701 (50 μg) decreased nadir by inhibiting relaxation from -0.054 ± 0.021 g to -0.022 ± 0.015 g (P = 0.026) in longitudinal muscles. However, subsequent application of MRS2500 in the presence of atropine, DA-9701 (50 μg) and L-NNA did not affect nadir. In circular muscles, subsequent addition of L-NNA and MRS2500 in the presence of atropine and DA-9701 (50 μg) did not show significant change of nadir. Our data suggest that the effect of DA-9701 on the rat gastric fundus relaxation is mainly mediated by nitrergic rather than purinergic pathway.

Properties of the Nucleo-Olivary Pathway: An In Vivo Whole-Cell Patch Clamp Study

PubMed Central

Bazzigaluppi, Paolo; Ruigrok, Tom; Saisan, Payam; De Zeeuw, Chris I.; de Jeu, Marcel

2012-01-01

The inferior olivary nucleus (IO) forms the gateway to the cerebellar cortex and receives feedback information from the cerebellar nuclei (CN), thereby occupying a central position in the olivo-cerebellar loop. Here, we investigated the feedback input from the CN to the IO in vivo in mice using the whole-cell patch-clamp technique. This approach allows us to study how the CN-feedback input is integrated with the activity of olivary neurons, while the olivo-cerebellar system and its connections are intact. Our results show how IO neurons respond to CN stimulation sequentially with: i) a short depolarization (EPSP), ii) a hyperpolarization (IPSP) and iii) a rebound depolarization. The latter two phenomena can also be evoked without the EPSPs. The IPSP is sensitive to a GABAA receptor blocker. The IPSP suppresses suprathreshold and subthreshold activity and is generated mainly by activation of the GABAA receptors. The rebound depolarization re-initiates and temporarily phase locks the subthreshold oscillations. Lack of electrotonical coupling does not affect the IPSP of individual olivary neurons, nor the sensitivity of its GABAA receptors to blockers. The GABAergic feedback input from the CN does not only temporarily block the transmission of signals through the IO, it also isolates neurons from the network by shunting the junction current and re-initiates the temporal pattern after a fixed time point. These data suggest that the IO not only functions as a cerebellar controlled gating device, but also operates as a pattern generator for controlling motor timing and/or learning. PMID:23029495

Entry of Botulinum Neurotoxin Subtypes A1 and A2 into Neurons.

PubMed

Kroken, Abby R; Blum, Faith C; Zuverink, Madison; Barbieri, Joseph T

2017-01-01

Botulinum neurotoxins (BoNTs) are the most toxic proteins for humans but also are common therapies for neurological diseases. BoNTs are dichain toxins, comprising an N-terminal catalytic domain (LC) disulfide bond linked to a C-terminal heavy chain (HC) which includes a translocation domain (H N ) and a receptor binding domain (H C ). Recently, the BoNT serotype A (BoNT/A) subtypes A1 and A2 were reported to possess similar potencies but different rates of cellular intoxication and pathology in a mouse model of botulism. The current study measured H C A1 and H C A2 entry into rat primary neurons and cultured Neuro2A cells. We found that there were two sequential steps during the association of BoNT/A with neurons. The initial step was ganglioside dependent, while the subsequent step involved association with synaptic vesicles. H C A1 and H C A2 entered the same population of synaptic vesicles and entered cells at similar rates. The primary difference was that H C A2 had a higher degree of receptor occupancy for cells and neurons than HcA1. Thus, H C A2 and H C A1 share receptors and entry pathway but differ in their affinity for receptor. The initial interaction of H C A1 and H C A2 with neurons may contribute to the unique pathologies of BoNT/A1 and BoNT/A2 in mouse models. Copyright © 2016 American Society for Microbiology.

Double-bond-containing polyallene-based triblock copolymers via phenoxyallene and (meth)acrylate

NASA Astrophysics Data System (ADS)

Ding, Aishun; Lu, Guolin; Guo, Hao; Huang, Xiaoyu

2017-03-01

A series of ABA triblock copolymers, consisting of double-bond-containing poly(phenoxyallene) (PPOA), poly(methyl methacrylate) (PMMA), or poly(butyl acrylate) (PBA) segments, were synthesized by sequential free radical polymerization and atom transfer radical polymerization (ATRP). A new bifunctional initiator bearing azo and halogen-containing ATRP initiating groups was first prepared followed by initiating conventional free radical homopolymerization of phenoxyallene with cumulated double bond to give a PPOA-based macroinitiator with ATRP initiating groups at both ends. Next, PMMA-b-PPOA-b-PMMA and PBA-b-PPOA-b-PBA triblock copolymers were synthesized by ATRP of methyl methacrylate and n-butyl acrylate initiated by the PPOA-based macroinitiator through the site transformation strategy. These double-bond-containing triblock copolymers are stable under UV irradiation and free radical circumstances.

A Sequential Ensemble Prediction System at Convection Permitting Scales

NASA Astrophysics Data System (ADS)

Milan, M.; Simmer, C.

2012-04-01

A Sequential Assimilation Method (SAM) following some aspects of particle filtering with resampling, also called SIR (Sequential Importance Resampling), is introduced and applied in the framework of an Ensemble Prediction System (EPS) for weather forecasting on convection permitting scales, with focus to precipitation forecast. At this scale and beyond, the atmosphere increasingly exhibits chaotic behaviour and non linear state space evolution due to convectively driven processes. One way to take full account of non linear state developments are particle filter methods, their basic idea is the representation of the model probability density function by a number of ensemble members weighted by their likelihood with the observations. In particular particle filter with resampling abandons ensemble members (particles) with low weights restoring the original number of particles adding multiple copies of the members with high weights. In our SIR-like implementation we substitute the likelihood way to define weights and introduce a metric which quantifies the "distance" between the observed atmospheric state and the states simulated by the ensemble members. We also introduce a methodology to counteract filter degeneracy, i.e. the collapse of the simulated state space. To this goal we propose a combination of resampling taking account of simulated state space clustering and nudging. By keeping cluster representatives during resampling and filtering, the method maintains the potential for non linear system state development. We assume that a particle cluster with initially low likelihood may evolve in a state space with higher likelihood in a subsequent filter time thus mimicking non linear system state developments (e.g. sudden convection initiation) and remedies timing errors for convection due to model errors and/or imperfect initial condition. We apply a simplified version of the resampling, the particles with highest weights in each cluster are duplicated; for the model evolution for each particle pair one particle evolves using the forward model; the second particle, however, is nudged to the radar and satellite observation during its evolution based on the forward model.

Sequential cohort design applying propensity score matching to analyze the comparative effectiveness of atorvastatin and simvastatin in preventing cardiovascular events.

PubMed

Helin-Salmivaara, Arja; Lavikainen, Piia; Aarnio, Emma; Huupponen, Risto; Korhonen, Maarit Jaana

2014-01-01

Sequential cohort design (SCD) applying matching for propensity scores (PS) in accrual periods has been proposed to mitigate bias caused by channeling when calendar time is a proxy for strong confounders. We studied the channeling of patients according to atorvastatin and simvastatin initiation in Finland, starting from the market introduction of atorvastatin in 1998, and explored the SCD PS approach to analyzing the comparative effectiveness of atorvastatin versus simvastatin in the prevention of cardiovascular events (CVE). Initiators of atorvastatin or simvastatin use in the 45-75-year age range in 1998-2006 were characterized by their propensity of receiving atorvastatin over simvastatin, as estimated for 17 six-month periods. Atorvastatin (10 mg) and simvastatin (20 mg) initiators were matched 1∶1 on the PS, as estimated for the whole cohort and within each period. Cox regression models were fitted conventionally, and also for the PS matched cohort and the periodically PS matched cohort, to estimate the hazard ratios (HR) for CVEs. Atorvastatin (10 mg) was associated with a 11%-12% lower incidence of CVE in comparison with simvastatin (20 mg). The HR estimates were the same for a conventional Cox model (0.88, 95% confidence interval 0.85-0.91), for the analysis in which the PS was used to match across all periods and the Cox model was adjusted for strong confounders (0.89, 0.85-0.92), and for the analysis in which PS matching was applied within sequential periods (0.88, 0.84-0.92). The HR from a traditional PS matched analysis was 0.80 (0.77-0.83). The SCD PS approach produced effect estimates similar to those obtained in matching for PS within the whole cohort and adjusting the outcome model for strong confounders, but at the cost of efficiency. A traditional PS matched analysis without further adjustment in the outcome model produced estimates further away from unity.

The early identification of risk factors on the pathway to school dropout in the SIODO study: a sequential mixed-methods study.

PubMed

Theunissen, Marie-José; Griensven van, Ilse; Verdonk, Petra; Feron, Frans; Bosma, Hans

2012-11-27

School dropout is a persisting problem with major socioeconomic consequences. Although poor health probably contributes to pathways leading to school dropout and health is likely negatively affected by dropout, these issues are relatively absent on the public health agenda. This emphasises the importance of integrative research aimed at identifying children at risk for school dropout at an early stage, discovering how socioeconomic status and gender affect health-related pathways that lead to dropout and developing a prevention tool that can be used in public health services for youth. The SIODO study is a sequential mixed-methods study. A case-control study will be conducted among 18 to 24 year olds in the south of the Netherlands (n = 580). Data are currently being collected from compulsory education departments at municipalities (dropout data), regional public health services (developmental data from birth onwards) and an additional questionnaire has been sent to participants (e.g. personality data). Advanced analyses, including cluster and factor analyses, will be used to identify children at risk at an early stage. Using the quantitative data, we have planned individual interviews with participants and focus groups with important stakeholders such as parents, teachers and public health professionals. A thematic content analysis will be used to analyse the qualitative data. The SIODO study will use a life-course perspective, the ICF-CY model to group the determinants and a mixed-methods design. In this respect, the SIODO study is innovative because it both broadens and deepens the study of health-related determinants of school dropout. It examines how these determinants contribute to socioeconomic and gender differences in health and contributes to the development of a tool that can be used in public health practice to tackle the problem of school dropout at its roots.

Implementation of logic functions and computations by chemical kinetics

NASA Astrophysics Data System (ADS)

Hjelmfelt, A.; Ross, J.

We review our work on the computational functions of the kinetics of chemical networks. We examine spatially homogeneous networks which are based on prototypical reactions occurring in living cells and show the construction of logic gates and sequential and parallel networks. This work motivates the study of an important biochemical pathway, glycolysis, and we demonstrate that the switch that controls the flux in the direction of glycolysis or gluconeogenesis may be described as a fuzzy AND operator. We also study a spatially inhomogeneous network which shares features of theoretical and biological neural networks.

Use of an Adverse Outcome Pathway for Hepatic Steatosis to Build Chemical Groups

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework systematically documents the mechanisms underlying effects of chemicals starting with the initial interaction of chemicals with the biological system, i.e. the molecular initiating event (MIE). Chemical activity in assays designed to mo...

Concurrent activation of striatal direct and indirect pathways during action initiation.

PubMed

Cui, Guohong; Jun, Sang Beom; Jin, Xin; Pham, Michael D; Vogel, Steven S; Lovinger, David M; Costa, Rui M

2013-02-14

The basal ganglia are subcortical nuclei that control voluntary actions, and they are affected by a number of debilitating neurological disorders. The prevailing model of basal ganglia function proposes that two orthogonal projection circuits originating from distinct populations of spiny projection neurons (SPNs) in the striatum--the so-called direct and indirect pathways--have opposing effects on movement: activity of direct-pathway SPNs is thought to facilitate movement, whereas activity of indirect-pathway SPNs is presumed to inhibit movement. This model has been difficult to test owing to the lack of methods to selectively measure the activity of direct- and indirect-pathway SPNs in freely moving animals. Here we develop a novel in vivo method to specifically measure direct- and indirect-pathway SPN activity, using Cre-dependent viral expression of the genetically encoded calcium indicator (GECI) GCaMP3 in the dorsal striatum of D1-Cre (direct-pathway-specific) and A2A-Cre (indirect-pathway-specific) mice. Using fibre optics and time-correlated single-photon counting (TCSPC) in mice performing an operant task, we observed transient increases in neural activity in both direct- and indirect-pathway SPNs when animals initiated actions, but not when they were inactive. Concurrent activation of SPNs from both pathways in one hemisphere preceded the initiation of contraversive movements and predicted the occurrence of specific movements within 500 ms. These observations challenge the classical view of basal ganglia function and may have implications for understanding the origin of motor symptoms in basal ganglia disorders.

Aclacinomycin A Sensitizes K562 Chronic Myeloid Leukemia Cells to Imatinib through p38MAPK-Mediated Erythroid Differentiation

PubMed Central

Liu, Fu-Hwa; Huang, Yu-Wen; Huang, Huei-Mei

2013-01-01

Expression of oncogenic Bcr-Abl inhibits cell differentiation of hematopoietic stem/progenitor cells in chronic myeloid leukemia (CML). Differentiation therapy is considered to be a new strategy for treating this type of leukemia. Aclacinomycin A (ACM) is an antitumor antibiotic. Previous studies have shown that ACM induced erythroid differentiation of CML cells. In this study, we investigate the effect of ACM on the sensitivity of human CML cell line K562 to Bcr-Abl specific inhibitor imatinib (STI571, Gleevec). We first determined the optimal concentration of ACM for erythroid differentiation but not growth inhibition and apoptosis in K562 cells. Then, pretreatment with this optimal concentration of ACM followed by a minimally toxic concentration of imatinib strongly induced growth inhibition and apoptosis compared to that with simultaneous co-treatment, indicating that ACM-induced erythroid differentiation sensitizes K562 cells to imatinib. Sequential treatment with ACM and imatinib induced Bcr-Abl down-regulation, cytochrome c release into the cytosol, and caspase-3 activation, as well as decreased Mcl-1 and Bcl-xL expressions, but did not affect Fas ligand/Fas death receptor and procaspase-8 expressions. ACM/imatinib sequential treatment-induced apoptosis was suppressed by a caspase-9 inhibitor and a caspase-3 inhibitor, indicating that the caspase cascade is involved in this apoptosis. Furthermore, we demonstrated that ACM induced erythroid differentiation through the p38 mitogen-activated protein kinase (MAPK) pathway. The inhibition of erythroid differentiation by p38MAPK inhibitor SB202190, p38MAPK dominant negative mutant or p38MAPK shRNA knockdown, reduced the ACM/imatinib sequential treatment-mediated growth inhibition and apoptosis. These results suggest that differentiated K562 cells induced by ACM-mediated p38MAPK pathway become more sensitive to imatinib and result in down-regulations of Bcr-Abl and anti-apoptotic proteins, growth inhibition and apoptosis. These results provided a potential management by which ACM might have a crucial impact on increasing sensitivity of CML cells to imatinib in the differentiation therapeutic approaches. PMID:23613979

Aclacinomycin A sensitizes K562 chronic myeloid leukemia cells to imatinib through p38MAPK-mediated erythroid differentiation.

PubMed

Lee, Yueh-Lun; Chen, Chih-Wei; Liu, Fu-Hwa; Huang, Yu-Wen; Huang, Huei-Mei

2013-01-01

Expression of oncogenic Bcr-Abl inhibits cell differentiation of hematopoietic stem/progenitor cells in chronic myeloid leukemia (CML). Differentiation therapy is considered to be a new strategy for treating this type of leukemia. Aclacinomycin A (ACM) is an antitumor antibiotic. Previous studies have shown that ACM induced erythroid differentiation of CML cells. In this study, we investigate the effect of ACM on the sensitivity of human CML cell line K562 to Bcr-Abl specific inhibitor imatinib (STI571, Gleevec). We first determined the optimal concentration of ACM for erythroid differentiation but not growth inhibition and apoptosis in K562 cells. Then, pretreatment with this optimal concentration of ACM followed by a minimally toxic concentration of imatinib strongly induced growth inhibition and apoptosis compared to that with simultaneous co-treatment, indicating that ACM-induced erythroid differentiation sensitizes K562 cells to imatinib. Sequential treatment with ACM and imatinib induced Bcr-Abl down-regulation, cytochrome c release into the cytosol, and caspase-3 activation, as well as decreased Mcl-1 and Bcl-xL expressions, but did not affect Fas ligand/Fas death receptor and procaspase-8 expressions. ACM/imatinib sequential treatment-induced apoptosis was suppressed by a caspase-9 inhibitor and a caspase-3 inhibitor, indicating that the caspase cascade is involved in this apoptosis. Furthermore, we demonstrated that ACM induced erythroid differentiation through the p38 mitogen-activated protein kinase (MAPK) pathway. The inhibition of erythroid differentiation by p38MAPK inhibitor SB202190, p38MAPK dominant negative mutant or p38MAPK shRNA knockdown, reduced the ACM/imatinib sequential treatment-mediated growth inhibition and apoptosis. These results suggest that differentiated K562 cells induced by ACM-mediated p38MAPK pathway become more sensitive to imatinib and result in down-regulations of Bcr-Abl and anti-apoptotic proteins, growth inhibition and apoptosis. These results provided a potential management by which ACM might have a crucial impact on increasing sensitivity of CML cells to imatinib in the differentiation therapeutic approaches.

A left lateral accessory pathway unmasked by rivastigmine.

PubMed

Guenancia, Charles; Fichot, Marie; Garnier, Fabien; Montoy, Mathieu; Laurent, Gabriel

A 75-year-old woman was referred for advice regarding surface electrocardiographic modifications after the initiation of rivastigmine. In our patient, the baseline ECGs appeared perfectly normal. However, the initiation of a cholinesterase inhibitor unmasked a left lateral accessory pathway that had never been diagnosed before. Although cholinesterase inhibitors are known to increase vagal tone, the PR interval was shortened after rivastigmine administration, thus excluding this hypothesis to explain the appearance of the accessory pathway. Therefore, we hypothesized that cholinesterase inhibitors may have increased conduction velocity in the accessory pathway or in the atria. Copyright © 2017 Elsevier Inc. All rights reserved.

Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation

PubMed Central

Bohne, Felix; Martínez-Llordella, Marc; Lozano, Juan-José; Miquel, Rosa; Benítez, Carlos; Londoño, María-Carlota; Manzia, Tommaso-María; Angelico, Roberta; Swinkels, Dorine W.; Tjalsma, Harold; López, Marta; Abraldes, Juan G.; Bonaccorsi-Riani, Eliano; Jaeckel, Elmar; Taubert, Richard; Pirenne, Jacques; Rimola, Antoni; Tisone, Giuseppe; Sánchez-Fueyo, Alberto

2011-01-01

Following organ transplantation, lifelong immunosuppressive therapy is required to prevent the host immune system from destroying the allograft. This can cause severe side effects and increased recipient morbidity and mortality. Complete cessation of immunosuppressive drugs has been successfully accomplished in selected transplant recipients, providing proof of principle that operational allograft tolerance is attainable in clinical transplantation. The intra-graft molecular pathways associated with successful drug withdrawal, however, are not well defined. In this study, we analyzed sequential blood and liver tissue samples collected from liver transplant recipients enrolled in a prospective multicenter immunosuppressive drug withdrawal clinical trial. Before initiation of drug withdrawal, operationally tolerant and non-tolerant recipients differed in the intra-graft expression of genes involved in the regulation of iron homeostasis. Furthermore, as compared with non-tolerant recipients, operationally tolerant patients exhibited higher serum levels of hepcidin and ferritin and increased hepatocyte iron deposition. Finally, liver tissue gene expression measurements accurately predicted the outcome of immunosuppressive withdrawal in an independent set of patients. These results point to a critical role for iron metabolism in the regulation of intra-graft alloimmune responses in humans and provide a set of biomarkers to conduct drug-weaning trials in liver transplantation. PMID:22156196

Simulation of nucleation and growth of atomic layer deposition phosphorus for doping of advanced FinFETs

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

Seidel, Thomas E., E-mail: zoomtotom@gmail.com; Goldberg, Alexander; Halls, Mat D.

2016-01-15

Simulations for the nucleation and growth of phosphorus films were carried out using density functional theory. The surface was represented by a Si{sub 9}H{sub 12} truncated cluster surface model with 2 × 1-reconstructured (100) Si-OH terminations for the initial reaction sites. Chemistries included phosphorous halides (PF{sub 3}, PCl{sub 3}, and PBr{sub 3}) and disilane (Si{sub 2}H{sub 6}). Atomic layer deposition (ALD) reaction sequences were illustrated with three-dimensional molecular models using sequential PF{sub 3} and Si{sub 2}H{sub 6} reactions and featuring SiFH{sub 3} as a byproduct. Exothermic reaction pathways were developed for both nucleation and growth for a Si-OH surface. Energetically favorable reactionsmore » for the deposition of four phosphorus atoms including lateral P–P bonding were simulated. This paper suggests energetically favorable thermodynamic reactions for the growth of elemental phosphorus on (100) silicon. Phosphorus layers made by ALD are an option for doping advanced fin field-effect transistors (FinFETs). Phosphorus may be thermally diffused into the silicon or recoil knocked in; simulations of the recoil profile of phosphorus into a FinFET surface are illustrated.« less

ROS Initiated Oxidation of Dopamine under Oxidative Stress Conditions in Aqueous and Lipidic Environments

PubMed Central

2011-01-01

Dopamine is known to be an efficient antioxidant and to protect neurocytes from oxidative stress by scavenging free radicals. In this work, we have carried out a systematic quantum chemistry and computational kinetics study on the reactivity of dopamine toward hydroxyl (•OH) and hydroperoxyl (•OOH) free radicals in aqueous and lipidic simulated biological environments, within the density functional theory framework. Rate constants and branching ratios for the different paths contributing to the overall reaction, at 298 K, are reported. For the reactivity of dopamine toward hydroxyl radicals, in water at physiological pH, the main mechanism of the reaction is proposed to be the sequential electron proton transfer (SEPT), whereas in the lipidic environment, hydrogen atom transfer (HAT) and radical adduct formation (RAF) pathways contribute almost equally to the total reaction rate. In both environments, dopamine reacts with hydroxyl radicals at a rate that is diffusion-controlled. Reaction with the hydroperoxyl radical is much slower and occurs only by abstraction of any of the phenolic hydrogens. The overall rate coefficients are predicted to be 2.23 × 105 and 8.16 × 105 M–1 s–1, in aqueous and lipidic environment, respectively, which makes dopamine a very good •OOH, and presumably •OOR, radical scavenger. PMID:21919526

Impact of sequential proton density fat fraction for quantification of hepatic steatosis in nonalcoholic fatty liver disease.

PubMed

Idilman, Ilkay S; Keskin, Onur; Elhan, Atilla Halil; Idilman, Ramazan; Karcaaltincaba, Musturay

2014-05-01

To determine the utility of sequential MRI-estimated proton density fat fraction (MRI-PDFF) for quantification of the longitudinal changes in liver fat content in individuals with nonalcoholic fatty liver disease (NAFLD). A total of 18 consecutive individuals (M/F: 10/8, mean age: 47.7±9.8 years) diagnosed with NAFLD, who underwent sequential PDFF calculations for the quantification of hepatic steatosis at two different time points, were included in the study. All patients underwent T1-independent volumetric multi-echo gradient-echo imaging with T2* correction and spectral fat modeling. A close correlation for quantification of hepatic steatosis between the initial MRI-PDFF and liver biopsy was observed (rs=0.758, p<0.001). The median interval between two sequential MRI-PDFF measurements was 184 days. From baseline to the end of the follow-up period, serum GGT level and homeostasis model assessment score were significantly improved (p=0.015, p=0.006, respectively), whereas BMI, serum AST, and ALT levels were slightly decreased. MRI-PDFFs were significantly improved (p=0.004). A good correlation between two sequential MRI-PDFF calculations was observed (rs=0.714, p=0.001). With linear regression analyses, only delta serum ALT levels had a significant effect on delta MRI-PDFF calculations (r2=38.6%, p=0.006). At least 5.9% improvement in MRI-PDFF is needed to achieve a normalized abnormal ALT level. The improvement of MRI-PDFF score was associated with the improvement of biochemical parameters in patients who had improvement in delta MRI-PDFF (p<0.05). MRI-PDFF can be used for the quantification of the longitudinal changes of hepatic steatosis. The changes in serum ALT levels significantly reflected changes in MRI-PDFF in patients with NAFLD.

Depth treatment of coal-chemical engineering wastewater by a cost-effective sequential heterogeneous Fenton and biodegradation process.

PubMed

Fang, Yili; Yin, Weizhao; Jiang, Yanbin; Ge, Hengjun; Li, Ping; Wu, Jinhua

2018-05-01

In this study, a sequential Fe 0 /H 2 O 2 reaction and biological process was employed as a low-cost depth treatment method to remove recalcitrant compounds from coal-chemical engineering wastewater after regular biological treatment. First of all, a chemical oxygen demand (COD) and color removal efficiency of 66 and 63% was achieved at initial pH of 6.8, 25 mmol L -1 of H 2 O 2 , and 2 g L -1 of Fe 0 in the Fe 0 /H 2 O 2 reaction. According to the gas chromatography-mass spectrometer (GC-MS) and gas chromatography-flame ionization detector (GC-FID) analysis, the recalcitrant compounds were effectively decomposed into short-chain organic acids such as acetic, propionic, and butyric acids. Although these acids were resistant to the Fe 0 /H 2 O 2 reaction, they were effectively eliminated in the sequential air lift reactor (ALR) at a hydraulic retention time (HRT) of 2 h, resulting in a further decrease of COD and color from 120 to 51 mg L -1 and from 70 to 38 times, respectively. A low operational cost of 0.35 $ m -3 was achieved because pH adjustment and iron-containing sludge disposal could be avoided since a total COD and color removal efficiency of 85 and 79% could be achieved at an original pH of 6.8 by the above sequential process with a ferric ion concentration below 0.8 mg L -1 after the Fe 0 /H 2 O 2 reaction. It indicated that the above sequential process is a promising and cost-effective method for the depth treatment of coal-chemical engineering wastewaters to satisfy discharge requirements.

Temporal Characteristics of Radiologists' and Novices' Lesion Detection in Viewing Medical Images Presented Rapidly and Sequentially.

PubMed

Nakashima, Ryoichi; Komori, Yuya; Maeda, Eriko; Yoshikawa, Takeharu; Yokosawa, Kazuhiko

2016-01-01

Although viewing multiple stacks of medical images presented on a display is a relatively new but useful medical task, little is known about this task. Particularly, it is unclear how radiologists search for lesions in this type of image reading. When viewing cluttered and dynamic displays, continuous motion itself does not capture attention. Thus, it is effective for the target detection that observers' attention is captured by the onset signal of a suddenly appearing target among the continuously moving distractors (i.e., a passive viewing strategy). This can be applied to stack viewing tasks, because lesions often show up as transient signals in medical images which are sequentially presented simulating a dynamic and smoothly transforming image progression of organs. However, it is unclear whether observers can detect a target when the target appears at the beginning of a sequential presentation where the global apparent motion onset signal (i.e., signal of the initiation of the apparent motion by sequential presentation) occurs. We investigated the ability of radiologists to detect lesions during such tasks by comparing the performances of radiologists and novices. Results show that overall performance of radiologists is better than novices. Furthermore, the temporal locations of lesions in CT image sequences, i.e., when a lesion appears in an image sequence, does not affect the performance of radiologists, whereas it does affect the performance of novices. Results indicate that novices have greater difficulty in detecting a lesion appearing early than late in the image sequence. We suggest that radiologists have other mechanisms to detect lesions in medical images with little attention which novices do not have. This ability is critically important when viewing rapid sequential presentations of multiple CT images, such as stack viewing tasks.

Temporal Characteristics of Radiologists' and Novices' Lesion Detection in Viewing Medical Images Presented Rapidly and Sequentially

PubMed Central

Nakashima, Ryoichi; Komori, Yuya; Maeda, Eriko; Yoshikawa, Takeharu; Yokosawa, Kazuhiko

2016-01-01

Although viewing multiple stacks of medical images presented on a display is a relatively new but useful medical task, little is known about this task. Particularly, it is unclear how radiologists search for lesions in this type of image reading. When viewing cluttered and dynamic displays, continuous motion itself does not capture attention. Thus, it is effective for the target detection that observers' attention is captured by the onset signal of a suddenly appearing target among the continuously moving distractors (i.e., a passive viewing strategy). This can be applied to stack viewing tasks, because lesions often show up as transient signals in medical images which are sequentially presented simulating a dynamic and smoothly transforming image progression of organs. However, it is unclear whether observers can detect a target when the target appears at the beginning of a sequential presentation where the global apparent motion onset signal (i.e., signal of the initiation of the apparent motion by sequential presentation) occurs. We investigated the ability of radiologists to detect lesions during such tasks by comparing the performances of radiologists and novices. Results show that overall performance of radiologists is better than novices. Furthermore, the temporal locations of lesions in CT image sequences, i.e., when a lesion appears in an image sequence, does not affect the performance of radiologists, whereas it does affect the performance of novices. Results indicate that novices have greater difficulty in detecting a lesion appearing early than late in the image sequence. We suggest that radiologists have other mechanisms to detect lesions in medical images with little attention which novices do not have. This ability is critically important when viewing rapid sequential presentations of multiple CT images, such as stack viewing tasks. PMID:27774080

PINK1 is degraded through the N-end rule pathway

PubMed Central

Yamano, Koji; Youle, Richard J

2013-01-01

PINK1, a mitochondrial serine/threonine kinase, is the product of a gene mutated in an autosomal recessive form of Parkinson disease. PINK1 is constitutively degraded by an unknown mechanism and stabilized selectively on damaged mitochondria where it can recruit the E3 ligase PARK2/PARKIN to induce mitophagy. Here, we show that, under steady-state conditions, endogenous PINK1 is constitutively and rapidly degraded by E3 ubiquitin ligases UBR1, UBR2 and UBR4 through the N-end rule pathway. Following precursor import into mitochondria, PINK1 is cleaved in the transmembrane segment by a mitochondrial intramembrane protease PARL generating an N-terminal destabilizing amino acid and then retrotranslocates from mitochondria to the cytosol for N-end recognition and proteasomal degradation. Thus, sequential actions of mitochondrial import, PARL-processing, retrotranslocation and recognition by N-end rule E3 enzymes for the ubiquitin proteosomal degradation defines the rapid PINK1 turnover. PINK1 steady-state elimination by the N-end rule identifies a novel organelle to cytoplasm turnover pathway that yields a mechanism to flag damaged mitochondria for autophagic elimination. PMID:24121706

Visual agnosia and focal brain injury.

PubMed

Martinaud, O

Visual agnosia encompasses all disorders of visual recognition within a selective visual modality not due to an impairment of elementary visual processing or other cognitive deficit. Based on a sequential dichotomy between the perceptual and memory systems, two different categories of visual object agnosia are usually considered: 'apperceptive agnosia' and 'associative agnosia'. Impaired visual recognition within a single category of stimuli is also reported in: (i) visual object agnosia of the ventral pathway, such as prosopagnosia (for faces), pure alexia (for words), or topographagnosia (for landmarks); (ii) visual spatial agnosia of the dorsal pathway, such as cerebral akinetopsia (for movement), or orientation agnosia (for the placement of objects in space). Focal brain injuries provide a unique opportunity to better understand regional brain function, particularly with the use of effective statistical approaches such as voxel-based lesion-symptom mapping (VLSM). The aim of the present work was twofold: (i) to review the various agnosia categories according to the traditional visual dual-pathway model; and (ii) to better assess the anatomical network underlying visual recognition through lesion-mapping studies correlating neuroanatomical and clinical outcomes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Simplified Protein Models: Predicting Folding Pathways and Structure Using Amino Acid Sequences

NASA Astrophysics Data System (ADS)

Adhikari, Aashish N.; Freed, Karl F.; Sosnick, Tobin R.

2013-07-01

We demonstrate the ability of simultaneously determining a protein’s folding pathway and structure using a properly formulated model without prior knowledge of the native structure. Our model employs a natural coordinate system for describing proteins and a search strategy inspired by the observation that real proteins fold in a sequential fashion by incrementally stabilizing nativelike substructures or “foldons.” Comparable folding pathways and structures are obtained for the twelve proteins recently studied using atomistic molecular dynamics simulations [K. Lindorff-Larsen, S. Piana, R. O. Dror, D. E. Shaw, Science 334, 517 (2011)], with our calculations running several orders of magnitude faster. We find that nativelike propensities in the unfolded state do not necessarily determine the order of structure formation, a departure from a major conclusion of the molecular dynamics study. Instead, our results support a more expansive view wherein intrinsic local structural propensities may be enhanced or overridden in the folding process by environmental context. The success of our search strategy validates it as an expedient mechanism for folding both in silico and in vivo.

Regulation of the nuclear factor (NF)-kappaB pathway by ISGylation.

PubMed

Minakawa, Miki; Sone, Takayuki; Takeuchi, Tomoharu; Yokosawa, Hideyoshi

2008-12-01

Post-translational modification with ISG15 (interferon-stimulated gene 15 kDa) (ISGylation) is mediated by a sequential reaction similar to ubiquitination, and various target proteins for ISGylation have been identified. We previously reported that ISGylation of the E2 ubiquitin-conjugating enzyme Ubc13 suppresses its E2 activity. Ubc13 forms a heterodimer with Uev1A, a ubiquitin-conjugating enzyme variant, and the Ubc13-Uev1A complex catalyzes the assembly of a Lys63-linked polyubiquitin chain, which plays a non-proteolytic role in the nuclear factor (NF)-kappaB pathway. In this study, we examined the effect of ISGylation on tumor necrosis factor receptor-associated factor (TRAF)-6/transforming growth factor beta-activated kinase (TAK)-1-dependent NF-kappaB activation. We found that expression of the ISGylation system suppresses NF-kappaB activation via TRAF6 and TAK1 and that the level of polyubiquitinated TRAF6 is reduced by expression of the ISGylation system. Taken together, the results suggest that the NF-kappaB pathway is negatively regulated by ISGylation.

Specificity and rate of human and mouse liver and plasma phosphatidylcholine synthesis analyzed in vivo[S

PubMed Central

Pynn, Christopher J.; Henderson, Neil G.; Clark, Howard; Koster, Grielof; Bernhard, Wolfgang; Postle, Anthony D.

2011-01-01

Phosphatidylcholine (PC) synthesis by the direct cytidine diphosphate choline (CDP-choline) pathway in rat liver generates predominantly mono- and di-unsaturated molecular species, while polyunsaturated PC species are synthesized largely by the phosphatidylethanolamine-N-methyltransferase (PEMT) pathway. Although altered PC synthesis has been suggested to contribute to development of hepatocarcinoma and nonalcoholic steatohepatitis, analysis of the specificity of hepatic PC metabolism in human patients has been limited by the lack of sensitive and safe methodologies. Here we incorporated a deuterated methyl-d9-labled choline chloride, to quantify biosynthesis fluxes through both of the PC synthetic pathways in vivo in human volunteers and compared these fluxes with those in mice. Rates and molecular specificities of label incorporated into mouse liver and plasma PC were very similar and strongly suggest that label incorporation into human plasma PC can provide a direct measure of hepatic PC synthesis in human subjects. Importantly, we demonstrate for the first time that the PEMT pathway in human liver is selective for polyunsaturated PC species, especially those containing docosahexaenoic acid. Finally, we present a multiple isotopomer distribution analysis approach, based on transfer of deuterated methyl groups to S-adenosylmethionine and subsequent sequential methylations of PE, to quantify absolute flux rates through the PEMT pathway that are applicable to studies of liver dysfunction in clinical studies. PMID:21068006

Assembly and multiple gene expression of thermophilic enzymes in Escherichia coli for in vitro metabolic engineering.

PubMed

Ninh, Pham Huynh; Honda, Kohsuke; Sakai, Takaaki; Okano, Kenji; Ohtake, Hisao

2015-01-01

In vitro reconstitution of an artificial metabolic pathway is an emerging approach for the biocatalytic production of industrial chemicals. However, several enzymes have to be separately prepared (and purified) for the construction of an in vitro metabolic pathway, thereby limiting the practical applicability of this approach. In this study, genes encoding the nine thermophilic enzymes involved in a non-ATP-forming chimeric glycolytic pathway were assembled in an artificial operon and co-expressed in a single recombinant Escherichia coli strain. Gene expression levels of the thermophilic enzymes were controlled by their sequential order in the artificial operon. The specific activities of the recombinant enzymes in the cell-free extract of the multiple-gene-expression E. coli were 5.0-1,370 times higher than those in an enzyme cocktail prepared from a mixture of single-gene-expression strains, in each of which a single one of the nine thermophilic enzymes was overproduced. Heat treatment of a crude extract of the multiple-gene-expression cells led to the denaturation of indigenous proteins and one-step preparation of an in vitro synthetic pathway comprising only a limited number of thermotolerant enzymes. Coupling this in vitro pathway with other thermophilic enzymes including the H2 O-forming NADH oxidase or the malate/lactate dehydrogenase facilitated one-pot conversion of glucose to pyruvate or lactate, respectively. © 2014 Wiley Periodicals, Inc.

Research on Automatic Programming

DTIC Science & Technology

1975-12-31

Sequential processes, deadlocks, and semaphore primitives , Ph.D. Thesis, Harvard University, November 1974; Center for Research in Computing...verified. 13 Code generated to effect the synchronization makes use of the ECL control extension facility (Prenner’s CI, see [Prenner]). The... semaphore operations [Dijkstra] is being developed. Initial results for this code generator are very encouraging; in many cases generated code is

Trajectories of Social Anxiety during Adolescence and Relations with Cognition, Social Competence, and Temperament

ERIC Educational Resources Information Center

Miers, A. C.; Blote, A. W.; de Rooij, M.; Bokhorst, C. L.; Westenberg, P. M.

2013-01-01

This cohort-sequential study examined developmental trajectories of social anxiety in a nonclinical sample (N = 331, 161 girls) aged 9 to 17 years at initial and 12 to 21 years at final assessment. We tested whether variables assessing cognition, social competence, and temperament discriminated between the trajectories. Variables were collected…

Temporal processes that contribute to nonlinearity in vegetation responses to ozone exposure and dose

Treesearch

Robert L. Heath; Allen S. Lefohn; Robert C. Musselman

2009-01-01

Ozone interacts with plant tissue through distinct temporal processes. Sequentially, plants are exposed to ambient O3 hat (1) moves through the leaf boundary layer, (2) is taken up into plant tissue primarily through stomata, and (3) undergoes chemical interaction within plant tissue, first by initiating alterations and then as part of plant...

75 FR 32773 - Auction of 218-219 MHz Service and Phase II 220 MHz Service Licenses Scheduled for December 7...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-09

... licenses included in Auction 89 using the Commission's standard simultaneous multiple-round auction format... sequential bidding rounds. The initial bidding schedule will be announced in a public notice to be released.... For Auction 89, the Bureau proposes to employ a simultaneous stopping rule approach. A simultaneous...

Overview of the ToxCast Research Program: Applications to Predictive Toxicology and Chemical Prioritization

EPA Science Inventory

EPA’s ToxCast program, the NTP’s HTS initiative, and the NCGC’s Molecular Libraries Initiative into a collaborative research program focused on identifying toxicity pathways and developing in vitro assays to characterize the ability of chemicals to perturb those pathways. The go...

Production and sequential decay of charmed hyperons

NASA Astrophysics Data System (ADS)

Fäldt, Göran

2018-03-01

We investigate production and decay of the Λc+ hyperon. The production considered is through the e+e- annihilation channel, e+e-→Λc+Λ¯c - , with summation over the Λ¯c- antihyperon spin directions. It is in this situation that the Λc+ decay chain is identified. Two kinds of sequential decays are studied. The first one is the doubly weak decay B1→B2M2 , followed by B2→B3M3. The other one is the mixed weak-electromagnetic decay B1→B2M2, followed by B2→B3γ . In both schemes B denotes baryons and M mesons. We should also mention that the initial state of the Λc+ hyperon is polarized.

The Production of Porous Hydroxyapatite Scaffolds with Graded Porosity by Sequential Freeze-Casting.

PubMed

Lee, Hyun; Jang, Tae-Sik; Song, Juha; Kim, Hyoun-Ee; Jung, Hyun-Do

2017-03-31

Porous hydroxyapatite (HA) scaffolds with porosity-graded structures were fabricated by sequential freeze-casting. The pore structures, compressive strengths, and biocompatibilities of the fabricated porous HA scaffolds were evaluated. The porosities of the inner and outer layers of the graded HA scaffolds were controlled by adjusting the initial HA contents of the casting slurries. The interface between the dense and porous parts was compact and tightly adherent. The porosity and compressive strengths of the scaffold were controlled by the relative thicknesses of the dense/porous parts. In addition, the porous HA scaffolds showed good biocompatibility in terms of preosteoblast cell attachment and proliferation. The results suggest that porous HA scaffolds with load-bearing parts have potential as bone grafts in hard-tissue engineering.

The Production of Porous Hydroxyapatite Scaffolds with Graded Porosity by Sequential Freeze-Casting

PubMed Central

Lee, Hyun; Jang, Tae-Sik; Song, Juha; Kim, Hyoun-Ee; Jung, Hyun-Do

2017-01-01

Porous hydroxyapatite (HA) scaffolds with porosity-graded structures were fabricated by sequential freeze-casting. The pore structures, compressive strengths, and biocompatibilities of the fabricated porous HA scaffolds were evaluated. The porosities of the inner and outer layers of the graded HA scaffolds were controlled by adjusting the initial HA contents of the casting slurries. The interface between the dense and porous parts was compact and tightly adherent. The porosity and compressive strengths of the scaffold were controlled by the relative thicknesses of the dense/porous parts. In addition, the porous HA scaffolds showed good biocompatibility in terms of preosteoblast cell attachment and proliferation. The results suggest that porous HA scaffolds with load-bearing parts have potential as bone grafts in hard-tissue engineering. PMID:28772735

Plasticity in Cell Division Patterns and Auxin Transport Dependency during in Vitro Embryogenesis in Brassica napus[C][W

PubMed Central

Soriano, Mercedes; Li, Hui; Jacquard, Cédric; Angenent, Gerco C.; Krochko, Joan; Offringa, Remko; Boutilier, Kim

2014-01-01

In Arabidopsis thaliana, zygotic embryo divisions are highly regular, but it is not clear how embryo patterning is established in species or culture systems with irregular cell divisions. We investigated this using the Brassica napus microspore embryogenesis system, where the male gametophyte is reprogrammed in vitro to form haploid embryos in the absence of exogenous growth regulators. Microspore embryos are formed via two pathways: a zygotic-like pathway, characterized by initial suspensor formation followed by embryo proper formation from the distal cell of the suspensor, and a pathway characterized by initially unorganized embryos lacking a suspensor. Using embryo fate and auxin markers, we show that the zygotic-like pathway requires polar auxin transport for embryo proper specification from the suspensor, while the suspensorless pathway is polar auxin transport independent and marked by an initial auxin maximum, suggesting early embryo proper establishment in the absence of a basal suspensor. Polarity establishment in this suspensorless pathway was triggered and guided by rupture of the pollen exine. Irregular division patterns did not affect cell fate establishment in either pathway. These results confirm the importance of the suspensor and suspensor-driven auxin transport in patterning, but also uncover a mechanism where cell patterning is less regular and independent of auxin transport. PMID:24951481

Simulation of dual carbon-bromine stable isotope fractionation during 1,2-dibromoethane degradation.

PubMed

Jin, Biao; Nijenhuis, Ivonne; Rolle, Massimo

2018-06-01

We performed a model-based investigation to simultaneously predict the evolution of concentration, as well as stable carbon and bromine isotope fractionation during 1,2-dibromoethane (EDB, ethylene dibromide) transformation in a closed system. The modelling approach considers bond-cleavage mechanisms during different reactions and allows evaluating dual carbon-bromine isotopic signals for chemical and biotic reactions, including aerobic and anaerobic biological transformation, dibromoelimination by Zn(0) and alkaline hydrolysis. The proposed model allowed us to accurately simulate the evolution of concentrations and isotope data observed in a previous laboratory study and to successfully identify different reaction pathways. Furthermore, we illustrated the model capabilities in degradation scenarios involving complex reaction systems. Specifically, we examined (i) the case of sequential multistep transformation of EDB and the isotopic evolution of the parent compound, the intermediate and the reaction product and (ii) the case of parallel competing abiotic pathways of EDB transformation in alkaline solution.

Structural basis for precursor protein-directed ribosomal peptide macrocyclization

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

Li, Kunhua; Condurso, Heather L.; Li, Gengnan

Macrocyclization is a common feature of natural product biosynthetic pathways including the diverse family of ribosomal peptides. Microviridins are architecturally complex cyanobacterial ribosomal peptides that target proteases with potent reversible inhibition. The product structure is constructed via three macrocyclizations catalyzed sequentially by two members of the ATP-grasp family, a unique strategy for ribosomal peptide macrocyclization. Here we describe in detail the structural basis for the enzyme-catalyzed macrocyclizations in the microviridin J pathway of Microcystis aeruginosa. The macrocyclases MdnC and MdnB interact with a conserved α-helix of the precursor peptide using a novel precursor-peptide recognition mechanism. The results provide insight intomore » the unique protein–protein interactions that are key to the chemistry, suggest an origin for the natural combinatorial synthesis of microviridin peptides, and provide a framework for future engineering efforts to generate designed compounds.« less

Reaction Mechanisms on Multiwell Potential Energy Surfaces in Combustion (and Atmospheric) Chemistry

DOE PAGES

Osborn, David L.

2017-03-15

Chemical reactions occurring on a potential energy surface with multiple wells are ubiquitous in low temperature combustion and the oxidation of volatile organic compounds in earth’s atmosphere. The rich variety of structural isomerizations that compete with collisional stabilization make characterizing such complex-forming reactions challenging. This review describes recent experimental and theoretical advances that deliver increasingly complete views of their reaction mechanisms. New methods for creating reactive intermediates coupled with multiplexed measurements provide many experimental observables simultaneously. Automated methods to explore potential energy surfaces can uncover hidden reactive pathways, while master equation methods enable a holistic treatment of both sequential andmore » well-skipping pathways. Our ability to probe and understand nonequilibrium effects and reaction sequences is increasing. These advances provide the fundamental science base for predictive models of combustion and the atmosphere that are crucial to address global challenges.« less

Frontal-thalamic circuits associated with language

PubMed Central

Barbas, Helen; García-Cabezas, Miguel Ángel; Zikopoulos, Basilis

2012-01-01

Thalamic nuclei associated with language including the ventral lateral, ventral anterior, intralaminar and mediodorsal form a hub that uniquely receives the output of the basal ganglia and cerebellum, and is connected with frontal (premotor and prefrontal) cortices through two parallel circuits: a thalamic pathway targets the middle frontal cortical layers focally, and the other innervates widely cortical layer 1, poised to recruit other cortices and thalamic nuclei for complex cognitive operations. Return frontal pathways to the thalamus originate from cortical layers 6 and 5. Information through this integrated thalamo-cortical system is gated by the inhibitory thalamic reticular nucleus and modulated by dopamine, representing a specialization in primates. The intricate dialogue of distinct thalamic nuclei with the basal ganglia, cerebellum, and specific dorsolateral prefrontal and premotor cortices associated with language, suggests synergistic roles in the complex but seemingly effortless sequential transformation of cognitive operations for speech production in humans. PMID:23211411

Cortical Actomyosin Breakage Triggers Shape Oscillations in Cells and Cell Fragments

PubMed Central

Paluch, Ewa; Piel, Matthieu; Prost, Jacques; Bornens, Michel; Sykes, Cécile

2005-01-01

Cell shape and movements rely on complex biochemical pathways that regulate actin, microtubules, and substrate adhesions. Some of these pathways act through altering the cortex contractility. Here we examined cellular systems where contractility is enhanced by disassembly of the microtubules. We found that adherent cells, when detached from their substrate, developed a membrane bulge devoid of detectable actin and myosin. A constriction ring at the base of the bulge oscillated from one side of the cell to the other. The movement was accompanied by sequential redistribution of actin and myosin to the membrane. We observed this oscillatory behavior also in cell fragments of various sizes, providing a simplified, nucleus-free system for biophysical studies. Our observations suggest a mechanism based on active gel dynamics and inspired by symmetry breaking of actin gels growing around beads. The proposed mechanism for breakage of the actomyosin cortex may be used for cell polarization. PMID:15879479

Reaction Mechanisms on Multiwell Potential Energy Surfaces in Combustion (and Atmospheric) Chemistry

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

Osborn, David L.

Chemical reactions occurring on a potential energy surface with multiple wells are ubiquitous in low temperature combustion and the oxidation of volatile organic compounds in earth’s atmosphere. The rich variety of structural isomerizations that compete with collisional stabilization make characterizing such complex-forming reactions challenging. This review describes recent experimental and theoretical advances that deliver increasingly complete views of their reaction mechanisms. New methods for creating reactive intermediates coupled with multiplexed measurements provide many experimental observables simultaneously. Automated methods to explore potential energy surfaces can uncover hidden reactive pathways, while master equation methods enable a holistic treatment of both sequential andmore » well-skipping pathways. Our ability to probe and understand nonequilibrium effects and reaction sequences is increasing. These advances provide the fundamental science base for predictive models of combustion and the atmosphere that are crucial to address global challenges.« less

Identification and Herc5-mediated ISGylation of novel target proteins.

PubMed

Takeuchi, Tomoharu; Inoue, Satoshi; Yokosawa, Hideyoshi

2006-09-22

ISG15, a protein containing two ubiquitin-like domains, is an interferon-stimulated gene product that functions in antiviral response and is conjugated to various cellular proteins (ISGylation) upon interferon stimulation. ISGylation occurs via a pathway similar to the pathway for ubiquitination that requires the sequential action of E1/E2/E3: the E1 (UBE1L), E2 (UbcH8), and E3 (Efp/Herc5) enzymes for ISGylation have been hitherto identified. In this study, we identified six novel candidate target proteins for ISGylation by a proteomic approach. Four candidate target proteins were demonstrated to be ISGylated in UBE1L- and UbcH8-dependent manners, and ISGylation of the respective target proteins was stimulated by Herc5. In addition, Herc5 was capable of binding with the respective target proteins. Thus, these results suggest that Herc5 functions as a general E3 ligase for protein ISGylation.

Positron emission tomography suggests that the rate of progression of idiopathic parkinsonism is slow

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

Bhatt, M.H.; Snow, B.J.; Martin, W.R.

1991-06-01

The authors performed sequential positron emission tomography scans with 6-(18F)fluoro-L-dopa in 9 patients with idiopathic parkinsonism and 7 age-matched normal control subjects to compare changes in the nigrostriatal dopaminergic pathway over time. The mean interval between the scans was 3.3 years for the group with idiopathic parkinsonism and 3.9 years for the control subjects. The scans were analyzed by calculating the ratio of striatal to background radioactivity. Both groups showed statistically significant reductions of striatal uptake over the interval. The rate of decrease was almost identical in each group (p = 0.6). They infer that the usual rate of lossmore » of integrity of the dopaminergic nigrostriatal pathway in patients with idiopathic parkinsonism is slow and the rate of change between the two groups was comparable.« less

From planes to bowls: Photodissociation of the bisanthenequinone cation

NASA Astrophysics Data System (ADS)

Chen, Tao; Zhen, Junfeng; Wang, Ying; Linnartz, Harold; Tielens, Alexander G. G. M.

2018-01-01

We present a combined experimental and theoretical study of the photodissociation of the bisanthenequinone (C28H12O2) cation, Bq+. The experiments show that, upon photolysis, the Bq+ cation does not dehydrogenate, but instead fragments through the sequential loss of the two neutral carbonyl groups, causing the formation of five-membered carbon cycles. Quantum chemical calculations confirm this Bq+ → [Bq - CO]+ → [Bq - 2CO]+ sequence as the energetically most favorable reaction pathway. For the first CO loss, a transition state with a barrier of ∼3.2 eV is found, substantially lower than the lowest calculated H loss dissociation pathway (∼4.9 eV). A similar situation applies for the second CO loss channel (∼3.8 eV vs. ∼4.7 eV), but where the first dissociation step does not strongly alter the planar PAH geometry, the second step transforms the molecule into a bowl-shaped one.

Divergent pathways to influence: Cognition and behavior differentially mediate the effects of optimism on physical and mental quality of life in Chinese university students.

PubMed

Ramsay, Jonathan E; Yang, Fang; Pang, Joyce S; Lai, Ching-Man; Ho, Roger Cm; Mak, Kwok-Kei

2015-07-01

Previous research has indicated that both cognitive and behavioral variables mediate the positive effect of optimism on quality of life; yet few attempts have been made to accommodate these constructs into a single explanatory framework. Adopting Fredrickson's broaden-and-build perspective, we examined the relationships between optimism, self-rated health, resilience, exercise, and quality of life in 365 Chinese university students using path analysis. For physical quality of life, a two-stage model, in which the effects of optimism were sequentially mediated by cognitive and behavioral variables, provided the best fit. A one-stage model, with full mediation by cognitive variables, provided the best fit for mental quality of life. This suggests that optimism influences physical and mental quality of life via different pathways. © The Author(s) 2013.

Concurrent Activation of Striatal Direct and Indirect Pathways During Action Initiation

PubMed Central

Cui, Guohong; Jun, Sang Beom; Jin, Xin; Pham, Michael D.

2014-01-01

Summary The basal ganglia are subcortical nuclei that control voluntary actions, and are affected by a number of debilitating neurological disorders1–4. The prevailing model of basal ganglia function proposes that two orthogonal projection circuits originating from distinct populations of spiny projection neurons (SPNs) in the striatum5,6 - the so-called direct and indirect pathways - have opposing effects on movement: while activity of direct-pathway SPNs purportedly facilitates movement, activity of indirect-pathway SPNs inhibits movement1,2. This model has been difficult to test due to the lack of methods to selectively measure the activity of direct- and indirect-pathway SPNs in freely moving animals. We developed a novel in-vivo method that allowed us to specifically measure direct- and indirect-pathway SPN activity using Cre-dependent viral expression of the genetically encoded calcium indicator (GECI) GCAMP3 in the dorsal striatum of D1-Cre (direct-pathway specific6,7) and A2A-Cre (indirect-pathway specific8,9) mice10. Using fiber optics and time-correlated single photon counting (TCSPC) in mice performing an operant task, we observed transient increases in neural activity in both direct- and indirect-pathway SPNs when animals initiated actions, but not when they were inactive. Concurrent activation of SPNs from both pathways in one hemisphere preceded the initiation of contraversive movements, and predicted the occurrence of specific movements within 500 ms. These observations challenge the classical view of basal ganglia function, and may have implications for understanding the origin of motor symptoms in basal ganglia disorders. PMID:23354054

p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans

PubMed Central

Wild, Peter J; Ikenberg, Kristian; Fuchs, Thomas J; Rechsteiner, Markus; Georgiev, Strahil; Fankhauser, Niklaus; Noske, Aurelia; Roessle, Matthias; Caduff, Rosmarie; Dellas, Athanassios; Fink, Daniel; Moch, Holger; Krek, Wilhelm; Frew, Ian J

2012-01-01

Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours. PMID:22678923

Community College Pathways: 2013-2014 Descriptive Report

ERIC Educational Resources Information Center

Sowers, Nicole; Yamada, Hiroyuki

2015-01-01

The Community College Pathways initiative consists of two pathways, Statway® and Quantway®, that accelerate post-secondary students' progress through their developmental mathematics sequence and a college-level course for credit. Launched in 2011, the Pathways have been remarkably successful, helping thousands of students achieve success in…

Calcium signaling in brain mitochondria: interplay of malate aspartate NADH shuttle and calcium uniporter/mitochondrial dehydrogenase pathways.

PubMed

Contreras, Laura; Satrústegui, Jorgina

2009-03-13

Ca2+ signaling in mitochondria has been mainly attributed to Ca2+ entry to the matrix through the Ca2+ uniporter and activation of mitochondrial matrix dehydrogenases. However, mitochondria can also sense increases in cytosolic Ca2+ through a mechanism that involves the aspartate-glutamate carriers, extramitochondrial Ca2+ activation of the NADH malate-aspartate shuttle (MAS). Both pathways are linked through the shared substrate alpha-ketoglutarate (alphaKG). Here we have studied the interplay between the two pathways under conditions of Ca2+ activation. We show that alphaKG becomes limiting when Ca2+ enters in brain or heart mitochondria, but not liver mitochondria, resulting in a drop in alphaKG efflux through the oxoglutarate carrier and in a drop in MAS activity. Inhibition of alphaKG efflux and MAS activity by matrix Ca2+ in brain mitochondria was fully reversible upon Ca2+ efflux. Because of their differences in cytosolic calcium concentration requirements, the MAS and Ca2+ uniporter-mitochondrial dehydrogenase pathways are probably sequentially activated during a Ca2+ transient, and the inhibition of MAS at the center of the transient may provide an explanation for part of the increase in lactate observed in the stimulated brain in vivo.

Purinergic signaling pathways in endocrine system.

PubMed

Bjelobaba, Ivana; Janjic, Marija M; Stojilkovic, Stanko S

2015-09-01

Adenosine-5'-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5'-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5'-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5'-triphosphate hydrolysis to adenosine-5'-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling. Published by Elsevier B.V.

Purinergic Signaling Pathways in Endocrine System

PubMed Central

Bjelobaba, Ivana; Janjic, Marija M.; Stojilkovic, Stanko S.

2015-01-01

Adenosine-5′-triphosphate is released by neuroendocrine, endocrine, and other cell types and acts as an extracellular agonist for ligand-gated P2X cationic channels and G protein-coupled P2Y receptors in numerous organs and tissues, including the endocrine system. The breakdown of ATP by ectonucleotidases not only terminates its extracellular messenger functions, but also provides a pathway for the generation of two additional agonists: adenosine 5′-diphosphate, acting via some P2Y receptors, and adenosine, a native agonist for G protein-coupled adenosine receptors, also expressed in the endocrine system. This article provides a review of purinergic signaling pathways in the hypothalamic magnocellular neurosecretory cells and neurohypophysis, hypothalamic parvocellular neuroendocrine system, adenohypophysis, and effector glands organized in five axes: hypothalamic-pituitary-gonadal, hypothalamic-pituitary-thyroid, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-growth hormone, and hypothalamic-pituitary-prolactin. We attempted to summarize current knowledge of purinergic receptor subtypes expressed in the endocrine system, including their roles in intracellular signaling, hormone secretion, and other cell functions. We also briefly review the release mechanism for adenosine-5′-triphosphate by neuroendocrine, endocrine and surrounding cells, the enzymes involved in adenosine-5′-triphosphate hydrolysis to adenosine-5′-diphosphate and adenosine, and the relevance of this pathway for sequential activation of receptors and termination of signaling. PMID:25960051

A sequential decision framework for increasing college students' support for organ donation and organ donor registration.

PubMed

Peltier, James W; D'Alessandro, Anthony M; Dahl, Andrew J; Feeley, Thomas Hugh

2012-09-01

Despite the fact that college students support social causes, this age group has underparticipated in organ donor registration. Little research attention has been given to understanding deeper, higher-order relationships between the antecedent attitudes toward and perceptions of organ donation and registration behavior. To test a process model useful for understanding the sequential ordering of information necessary for moving college students along a hierarchical decision-making continuum from awareness to support to organ donor registration. The University of Wisconsin organ procurement organization collaborated with the Collegiate American Marketing Association on a 2-year grant funded by the US Health Resources and Services Administration. A total of 981 association members responded to an online questionnaire. The 5 antecedent measures were awareness of organ donation, need acknowledgment, benefits of organ donation, social support, and concerns about organ donation. The 2 consequence variables were support for organ donation and organ donation registration. Structural equation modeling indicated that 5 of 10 direct antecedent pathways led significantly into organ donation support and registration. The impact of the nonsignificant variables was captured via indirect effects through other decision variables. Model fit statistics were good: the goodness of fit index was .998, the adjusted goodness of fit index was .992, and the root mean square error of approximation was .001. This sequential decision-making model provides insight into the need to enhance the acceptance of organ donation and organ donor registration through a series of communications to move people from awareness to behavior.

"Shotgun" versus sequential testing. Cost-effectiveness of diagnostic strategies for vaginitis.

PubMed

Carr, Phyllis L; Rothberg, Michael B; Friedman, Robert H; Felsenstein, Donna; Pliskin, Joseph S

2005-09-01

Although vaginitis is a common outpatient problem, only 60% of patients can be diagnosed at the initial office visit of a primary care provider using the office procedures of pH testing, whiff tests, normal saline, and potassium hydroxide preps. To determine the most cost-effective diagnostic and treatment approach for the medical management of vaginitis. Decision and cost-effectiveness analyses. Healthy women with symptoms of vaginitis undiagnosed after an initial pelvic exam, wet mount preparations, pH, and the four criteria to diagnose bacterial vaginosis. General office practice. We evaluated 28 diagnostic strategies comprised of combinations of pH testing, vaginal cultures for yeast and Trichomonas vaginalis, Gram's stain for bacterial vaginosis, and DNA probes for Neisseria gonorrhoeae and Chlamydia. Data sources for the study were confined to English language literature. The outcome measures were symptom-days and costs. The least expensive strategy was to perform yeast culture, gonorrhoeae and Chlamydia probes at the initial visit, and Gram's stain and Trichomonas culture only when the vaginal pH exceeded 4.9 (330 dollars, 7.30 symptom days). Other strategies cost 8 dollars to 76 dollars more and increased duration of symptoms by up to 1.3 days. In probabilistic sensitivity analysis, this strategy was always the most effective strategy and was also least expensive 58% of the time. For patients with vaginitis symptoms undiagnosed by pelvic examination, wet mount preparations and related office tests, a comprehensive, pH-guided testing strategy at the initial office visit is less expensive and more effective than ordering tests sequentially.

Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT.

PubMed

Regan, M M; Walley, B A; Francis, P A; Fleming, G F; Láng, I; Gómez, H L; Colleoni, M; Tondini, C; Pinotti, G; Salim, M; Spazzapan, S; Parmar, V; Ruhstaller, T; Abdi, E A; Gelber, R D; Coates, A S; Goldhirsch, A; Pagani, O

2017-09-01

Recent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation. We analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling. Distributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72-1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69-1.84) who are less likely to develop chemotherapy-induced amenorrhea. Based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected. NCT00066690 and NCT00066703. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Thermal decomposition pathways of hydroxylamine: theoretical investigation on the initial steps.

PubMed

Wang, Qingsheng; Wei, Chunyang; Pérez, Lisa M; Rogers, William J; Hall, Michael B; Mannan, M Sam

2010-09-02

Hydroxylamine (NH(2)OH) is an unstable compound at room temperature, and it has been involved in two tragic industrial incidents. Although experimental studies have been carried out to study the thermal stability of hydroxylamine, the detailed decomposition mechanism is still in debate. In this work, several density functional and ab initio methods were used in conjunction with several basis sets to investigate the initial thermal decomposition steps of hydroxylamine, including both unimolecular and bimolecular reaction pathways. The theoretical investigation shows that simple bond dissociations and unimolecular reactions are unlikely to occur. The energetically favorable initial step of decomposition pathways was determined as a bimolecular isomerization of hydroxylamine into ammonia oxide with an activation barrier of approximately 25 kcal/mol at the MPW1K level of theory. Because hydroxylamine is available only in aqueous solutions, solvent effects on the initial decomposition pathways were also studied using water cluster methods and the polarizable continuum model (PCM). In water, the activation barrier of the bimolecular isomerization reaction decreases to approximately 16 kcal/mol. The results indicate that the bimolecular isomerization pathway of hydroxylamine is more favorable in aqueous solutions. However, the bimolecular nature of this reaction means that more dilute aqueous solution will be more stable.

A three-tiered approach for linking pharmacokinetic ...

EPA Pesticide Factsheets

The power of the adverse outcome pathway (AOP) framework arises from its utilization of pathway-based data to describe the initial interaction of a chemical with a molecular target (molecular initiating event; (MIE), followed by a progression through a series of key events that lead to an adverse outcome relevant for regulatory purposes. The AOP itself is not chemical specific, thus providing the biological context necessary for interpreting high throughput (HT) toxicity screening results. Application of the AOP framework and HT predictions in ecological and human health risk assessment, however, requires the consideration of chemical-specific properties that influence external exposure doses and target tissue doses. To address this requirement, a three-tiered approach was developed to provide a workflow for connecting biology-based AOPs to biochemical-based pharmacokinetic properties (absorption, distribution, metabolism, excretion; ADME), and then to chemical/human activity-based exposure pathways. This approach included: (1) The power of the adverse outcome pathway (AOP) framework arisesfrom its utilization of pathway-based data to describe the initial interaction of a chemical with a molecular target (molecular initiating event; (MIE), followed by a progression through a series of key events that lead to an adverse outcome relevant for regulatory purposes. The AOP itself is not chemical specific, thus providing the biological context necessary for interpreti

Building Integrated Pathways to Sustainable Careers: An Introduction to the Accelerated Opportunity Initiative

ERIC Educational Resources Information Center

Pleasants, Rachel

2011-01-01

"Accelerating Opportunity" responds to the nation's growing need for improved pathways from Adult Basic Education (ABE) to credentials of value in the labor market. It builds on promising practices developed in "Breaking Through," an initiative of Jobs for the Future and the National Council for Workforce Education, and…

A cascading activity-based probe sequentially targets E1–E2–E3 ubiquitin enzymes

PubMed Central

Mulder, Monique P.C.; Witting, Katharina; Berlin, Ilana; Pruneda, Jonathan N.; Wu, Kuen-Phon; Chang, Jer-Gung; Merkx, Remco; Bialas, Johanna; Groettrup, Marcus; Vertegaal, Alfred C.O.; Schulman, Brenda A.; Komander, David; Neefjes, Jacques; Oualid, Farid El; Ovaa, Huib

2016-01-01

Post-translational modifications of proteins with ubiquitin (Ub) and ubiquitin-like (Ubl) modifiers, orchestrated by a cascade of specialized E1, E2 and E3 enzymes, control a staggering breadth of cellular processes. To monitor catalysis along these complex reaction pathways, we developed a cascading activity-based probe, UbDha. Akin to the native Ub, upon ATP-dependent activation by the E1, UbDha can travel downstream to the E2 (and subsequently E3) enzymes through sequential trans-thioesterifications. Unlike the native Ub, at each step along the cascade UbDha has the option to react irreversibly with active site cysteine residues of target enzymes, thus enabling their detection. We show that our cascading probe ‘hops’ and ‘traps’ catalytically active ubiquitin-modifying enzymes (but not their substrates) by a mechanism diversifiable to Ubls. Our founder methodology, amenable to structural studies, proteome-wide profiling and monitoring of enzymatic activities in living cells, presents novel and versatile tools to interrogate the Ub/Ubl cascades. PMID:27182664

Cotranslational structure acquisition of nascent polypeptides monitored by NMR spectroscopy.

PubMed

Eichmann, Cédric; Preissler, Steffen; Riek, Roland; Deuerling, Elke

2010-05-18

The folding of proteins in living cells may start during their synthesis when the polypeptides emerge gradually at the ribosomal exit tunnel. However, our current understanding of cotranslational folding processes at the atomic level is limited. We employed NMR spectroscopy to monitor the conformation of the SH3 domain from alpha-spectrin at sequential stages of elongation via in vivo ribosome-arrested (15)N,(13)C-labeled nascent polypeptides. These nascent chains exposed either the entire SH3 domain or C-terminally truncated segments thereof, thus providing snapshots of the translation process. We show that nascent SH3 polypeptides remain unstructured during elongation but fold into a compact, native-like beta-sheet assembly when the entire sequence information is available. Moreover, the ribosome neither imposes major conformational constraints nor significantly interacts with exposed unfolded nascent SH3 domain moieties. Our data provide evidence for a domainwise folding of the SH3 domain on ribosomes without significant population of folding intermediates. The domain follows a thermodynamically favorable pathway in which sequential folding units are stabilized, thus avoiding kinetic traps during the process of cotranslational folding.

A Cascade of Sequentially Expressed Sucrose Transporters in the Seed Coat and Endosperm Provides Nutrition for the Arabidopsis Embryo[OPEN

PubMed Central

Chen, Li-Qing; Lin, I Winnie; Qu, Xiao-Qing; Sosso, Davide; McFarlane, Heather E.; Londoño, Alejandra; Samuels, A. Lacey; Frommer, Wolf B.

2015-01-01

Developing plant embryos depend on nutrition from maternal tissues via the seed coat and endosperm, but the mechanisms that supply nutrients to plant embryos have remained elusive. Sucrose, the major transport form of carbohydrate in plants, is delivered via the phloem to the maternal seed coat and then secreted from the seed coat to feed the embryo. Here, we show that seed filling in Arabidopsis thaliana requires the three sucrose transporters SWEET11, 12, and 15. SWEET11, 12, and 15 exhibit specific spatiotemporal expression patterns in developing seeds, but only a sweet11;12;15 triple mutant showed severe seed defects, which include retarded embryo development, reduced seed weight, and reduced starch and lipid content, causing a “wrinkled” seed phenotype. In sweet11;12;15 triple mutants, starch accumulated in the seed coat but not the embryo, implicating SWEET-mediated sucrose efflux in the transfer of sugars from seed coat to embryo. This cascade of sequentially expressed SWEETs provides the feeding pathway for the plant embryo, an important feature for yield potential. PMID:25794936

Enhanced biodegradation of antibiotic combinations via the sequential treatment of the sludge resulting from pharmaceutical wastewater treatment using white-rot fungi Trametes versicolor and Bjerkandera adusta.

PubMed

Aydin, Sevcan

2016-07-01

While anaerobic treatment is capable of treating pharmaceutical wastewater and removing antibiotics in liquid phases, solid phases may still contain significant amounts of antibiotics following this treatment. The main goal of this study was to evaluate the use of white-rot fungi to remove erythromycin, sulfamethoxazole, and tetracycline combinations from biosolids. The degradation potential of Trametes versicolor and Bjerkandera adusta was evaluated via the sequential treatment of anaerobic sludge. Polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) analyses were used to identify competition between the autochthonous microbial communities and white-rot fungi. Solid-phase treatment using white-rot fungi substantially reduced antibiotic concentrations and toxicity in sludge. According to PCR-DGGE results, there is an association between species of fungus and antibiotic type as a result of the different transformation pathways of fungal strains. Fungal post-treatment of sludge represents a promising method of removing antibiotic combinations, therefore holding a significant promise as an environmentally friendly means of degrading the antibiotics present in sludge.

In vitro pharmacodynamics of human simulated exposures of ceftaroline and daptomycin against MRSA, hVISA, and VISA with and without prior vancomycin exposure.

PubMed

Bhalodi, Amira A; Hagihara, Mao; Nicolau, David P; Kuti, Joseph L

2014-01-01

The effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistant Staphylococcus aureus (MRSA) have not been widely studied. Humanized free-drug exposures of vancomycin at 1 g every 12 h (q12h), ceftaroline at 600 mg q12h, and daptomycin at 10 mg/kg of body weight q24h were simulated in a 96-h in vitro pharmacodynamic model against three MRSA isolates, including one heteroresistant vancomycin-intermediate S. aureus (hVISA) isolate and one VISA isolate. A total of five regimens were tested: vancomycin, ceftaroline, and daptomycin alone for the entire 96 h, and then sequential therapy with vancomycin for 48 h followed by ceftaroline or daptomycin for 48 h. Microbiological responses were measured by the changes in log10 CFU during 96 h from baseline. Control isolates grew to 9.16 ± 0.32, 9.13 ± 0.14, and 8.69 ± 0.28 log10 CFU for MRSA, hVISA, and VISA, respectively. Vancomycin initially achieved ≥3 log10 CFU reductions against the MRSA and hVISA isolates, followed by regrowth beginning at 48 h; minimal activity was observed against VISA. The change in 96-h log10 CFU was largest for sequential therapy with vancomycin followed by ceftaroline (-5.22 ± 1.2, P = 0.010 versus ceftaroline) and for sequential therapy with vancomycin followed by ceftaroline (-3.60 ± 0.6, P = 0.037 versus daptomycin), compared with daptomycin (-2.24 ± 1.0), vancomycin (-1.40 ± 1.8), and sequential therapy with vancomycin followed by daptomycin (-1.32 ± 1.0, P > 0.5 for the last three regimens). Prior exposure of vancomycin at 1 g q12h reduced the initial microbiological response of daptomycin, particularly for hVISA and VISA isolates, but did not affect the response of ceftaroline. In the scenario of poor vancomycin response for high-inoculum MRSA infection, a ceftaroline-containing regimen may be preferred.

Mixing modes in a population-based interview survey: comparison of a sequential and a concurrent mixed-mode design for public health research.

PubMed

Mauz, Elvira; von der Lippe, Elena; Allen, Jennifer; Schilling, Ralph; Müters, Stephan; Hoebel, Jens; Schmich, Patrick; Wetzstein, Matthias; Kamtsiuris, Panagiotis; Lange, Cornelia

2018-01-01

Population-based surveys currently face the problem of decreasing response rates. Mixed-mode designs are now being implemented more often to account for this, to improve sample composition and to reduce overall costs. This study examines whether a concurrent or sequential mixed-mode design achieves better results on a number of indicators of survey quality. Data were obtained from a population-based health interview survey of adults in Germany that was conducted as a methodological pilot study as part of the German Health Update (GEDA). Participants were randomly allocated to one of two surveys; each of the surveys had a different design. In the concurrent mixed-mode design ( n  = 617) two types of self-administered questionnaires (SAQ-Web and SAQ-Paper) and computer-assisted telephone interviewing were offered simultaneously to the respondents along with the invitation to participate. In the sequential mixed-mode design ( n  = 561), SAQ-Web was initially provided, followed by SAQ-Paper, with an option for a telephone interview being sent out together with the reminders at a later date. Finally, this study compared the response rates, sample composition, health indicators, item non-response, the scope of fieldwork and the costs of both designs. No systematic differences were identified between the two mixed-mode designs in terms of response rates, the socio-demographic characteristics of the achieved samples, or the prevalence rates of the health indicators under study. The sequential design gained a higher rate of online respondents. Very few telephone interviews were conducted for either design. With regard to data quality, the sequential design (which had more online respondents) showed less item non-response. There were minor differences between the designs in terms of their costs. Postage and printing costs were lower in the concurrent design, but labour costs were lower in the sequential design. No differences in health indicators were found between the two designs. Modelling these results for higher response rates and larger net sample sizes indicated that the sequential design was more cost and time-effective. This study contributes to the research available on implementing mixed-mode designs as part of public health surveys. Our findings show that SAQ-Paper and SAQ-Web questionnaires can be combined effectively. Sequential mixed-mode designs with higher rates of online respondents may be of greater benefit to studies with larger net sample sizes than concurrent mixed-mode designs.

[Molecules involved in sperm-zona pellucida interaction in mammals. Role in human fertility].

PubMed

Serres, Catherine; Auer, Jana; Petit, François; Patrat, Catherine; Jouannet, Pierre

2008-01-01

Fertilization in mammals requires an initial interaction of sperm with the oocyte envelope, the zona pellucida (ZP), before it reaches the oocyte. ZP is a highly glycosylated structure, composed of three (mouse) or four (rabbit, boar, bovine, humans...) glycoproteins. The presence of ZP around the oocyte does not allow heterospecific fertilization. This barrier is principally due to the presence of species-specific glycosylations on ZP proteins. Sperm bind ZP by means of membrane receptors which recognize carbohydrate moieties on ZP glycoproteins according to a well-precised sequential process. Upon initial attachment, spermatozoa bind ZP3/ZP4 which induces the sperm acrosome exocytosis followed by a secondary binding of acrosome reacted spermatozoa to ZP2 and by ZP penetration. The sperm receptors are adhesive proteins or integral plasma membrane proteins linked to intraspermatic signalling pathways activating the acrosome reaction. Over the last twenty years, numerous studies have been carried out to identify sperm receptors to ZP in several species, but the data in humans are still incomplete. Work initiated in our research group has identified several proteins interacting with recombinant human ZP2, ZP3 and ZP4, among which are glycolytic enzymes. These enzymes are involved in the gamete interaction by means of their affinity to sugars and not by their catalytic properties. From a clinical point of view, an observed lack or weak expression of some sperm receptors to ZP3 in cases of idiopathic infertility associated with in vitro fertilization failure suggests that knowing the molecular mechanism driving the gamete recognition can be important at the diagnostic level. Furthermore, it has been shown that proteins that mediate gamete recognition diverge rapidly, as a result of positive darwinian selection. A sexual conflict can drive co-evolution of reproductive molecules in both sexes resulting in reproductive isolation and species emergence.

Development of New Lipid-Based Paclitaxel Nanoparticles Using Sequential Simplex Optimization

PubMed Central

Dong, Xiaowei; Mattingly, Cynthia A.; Tseng, Michael; Cho, Moo; Adams, Val R.; Mumper, Russell J.

2008-01-01

The objective of these studies was to develop Cremophor-free lipid-based paclitaxel (PX) nanoparticle formulations prepared from warm microemulsion precursors. To identify and optimize new nanoparticles, experimental design was performed combining Taguchi array and sequential simplex optimization. The combination of Taguchi array and sequential simplex optimization efficiently directed the design of paclitaxel nanoparticles. Two optimized paclitaxel nanoparticles (NPs) were obtained: G78 NPs composed of glyceryl tridodecanoate (GT) and polyoxyethylene 20-stearyl ether (Brij 78), and BTM NPs composed of Miglyol 812, Brij 78 and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Both nanoparticles successfully entrapped paclitaxel at a final concentration of 150 μg/ml (over 6% drug loading) with particle sizes less than 200 nm and over 85% of entrapment efficiency. These novel paclitaxel nanoparticles were stable at 4°C over three months and in PBS at 37°C over 102 hours as measured by physical stability. Release of paclitaxel was slow and sustained without initial burst release. Cytotoxicity studies in MDA-MB-231 cancer cells showed that both nanoparticles have similar anticancer activities compared to Taxol®. Interestingly, PX BTM nanocapsules could be lyophilized without cryoprotectants. The lyophilized powder comprised only of PX BTM NPs in water could be rapidly rehydrated with complete retention of original physicochemical properties, in-vitro release properties, and cytotoxicity profile. Sequential Simplex Optimization has been utilized to identify promising new lipid-based paclitaxel nanoparticles having useful attributes. PMID:19111929

Sequential Change of Wound Calculated by Image Analysis Using a Color Patch Method during a Secondary Intention Healing.

PubMed

Yang, Sejung; Park, Junhee; Lee, Hanuel; Kim, Soohyun; Lee, Byung-Uk; Chung, Kee-Yang; Oh, Byungho

2016-01-01

Photographs of skin wounds have the most important information during the secondary intention healing (SIH). However, there is no standard method for handling those images and analyzing them efficiently and conveniently. To investigate the sequential changes of SIH depending on the body sites using a color patch method. We performed retrospective reviews of 30 patients (11 facial and 19 non-facial areas) who underwent SIH for the restoration of skin defects and captured sequential photographs with a color patch which is specially designed for automatically calculating defect and scar sizes. Using a novel image analysis method with a color patch, skin defects were calculated more accurately (range of error rate: -3.39% ~ + 3.05%). All patients had smaller scar size than the original defect size after SIH treatment (rates of decrease: 18.8% ~ 86.1%), and facial area showed significantly higher decrease rate compared with the non-facial area such as scalp and extremities (67.05 ± 12.48 vs. 53.29 ± 18.11, P < 0.05). From the result of estimating the date corresponding to the half of the final decrement, all of the facial area showed improvements within two weeks (8.45 ± 3.91), and non-facial area needed 14.33 ± 9.78 days. From the results of sequential changes of skin defects, SIH can be recommended as an alternative treatment method for restoration with more careful dressing for initial two weeks.

Acetobacter pasteurianus metabolic change induced by initial acetic acid to adapt to acetic acid fermentation conditions.

PubMed

Zheng, Yu; Zhang, Renkuan; Yin, Haisong; Bai, Xiaolei; Chang, Yangang; Xia, Menglei; Wang, Min

2017-09-01

Initial acetic acid can improve the ethanol oxidation rate of acetic acid bacteria for acetic acid fermentation. In this work, Acetobacter pasteurianus was cultured in ethanol-free medium, and energy production was found to increase by 150% through glucose consumption induced by initial acetic acid. However, oxidation of ethanol, instead of glucose, became the main energy production pathway when upon culturing ethanol containing medium. Proteome assay was used to analyze the metabolism change induced by initial acetic acid, which provided insight into carbon metabolic and energy regulation of A. pasteurianus to adapt to acetic acid fermentation conditions. Results were further confirmed by quantitative real-time PCR. In summary, decreased intracellular ATP as a result of initial acetic acid inhibition improved the energy metabolism to produce more energy and thus adapt to the acetic acid fermentation conditions. A. pasteurianus upregulated the expression of enzymes related to TCA and ethanol oxidation to improve the energy metabolism pathway upon the addition of initial acetic acid. However, enzymes involved in the pentose phosphate pathway, the main pathway of glucose metabolism, were downregulated to induce a change in carbon metabolism. Additionally, the enhancement of alcohol dehydrogenase expression promoted ethanol oxidation and strengthened the acetification rate, thereby producing a strong proton motive force that was necessary for energy production and cell tolerance to acetic acid.

Research Needs and Learning Format Preferences of Graduate Students at a Large Public University: An Exploratory Study

ERIC Educational Resources Information Center

Bussell, Hilary; Hagman, Jessica; Guder, Christopher S.

2017-01-01

This article reports on a study of research needs and learning preferences of graduate students at a public research university. A sequential exploratory mixed-method design was used, with a survey instrument developed from an initial qualitative stage. Significant differences were found between master's and doctoral students' and on-campus and…

Multiple laser pulse ignition method and apparatus

DOEpatents

Early, James W.

1998-01-01

Two or more laser light pulses with certain differing temporal lengths and peak pulse powers can be employed sequentially to regulate the rate and duration of laser energy delivery to fuel mixtures, thereby improving fuel ignition performance over a wide range of fuel parameters such as fuel/oxidizer ratios, fuel droplet size, number density and velocity within a fuel aerosol, and initial fuel temperatures.

Universal and Language-Specific Constraints on Phonemic Awareness: Evidence from Russian-Hebrew Bilingual Children

ERIC Educational Resources Information Center

Saiegh-Haddad, Elinor; Kogan, Nadya; Walters, Joel

2010-01-01

The study tested phonemic awareness in the two languages of Russian (L1)-Hebrew (L2) sequential bilingual children (N = 20) using phoneme deletion tasks where the phoneme to be deleted occurred word initial, word final, as a singleton, or part of a cluster, in long and short words and stressed and unstressed syllables. The experiments were…

Continuous-flow extraction system for elemental association study: a case of synthetic metal-doped iron hydroxide.

PubMed

Hinsin, Duangduean; Pdungsap, Laddawan; Shiowatana, Juwadee

2002-12-06

A continuous-flow extraction system originally developed for sequential extraction was applied to study elemental association of a synthetic metal-doped amorphous iron hydroxide phase. The homogeneity and metal association of the precipitates were evaluated by gradual leaching using the system. Leachate was collected in fractions for determination of elemental concentrations. The result obtained as extractograms indicated that the doped metals were adsorbed more on the outermost surface rather than homogeneously distributed in the precipitates. The continuous-flow extraction method was also used for effective removal of surface adsorbed metals to obtain a homogeneous metal-doped synthetic iron hydroxide by a sequential extraction using acetic acid and small volume of hydroxylamine hydrochloride solution. The system not only ensures complete washing, but the extent of metal immobilization in the synthetic iron hydroxide could be determined with high accuracy from the extractograms. The initial metal/iron mole ratio (M/Fe) in solution affected the M/Fe mole ratio in homogeneous doped iron hydroxide phase. The M/Fe mole ratio of metal incorporation was approximately 0.01-0.02 and 0.03-0.06, for initial solution M/Fe mole ratio of 0.025 and 0.100, respectively.

Inhibition during response preparation is sensitive to response complexity

PubMed Central

Saks, Dylan; Hoang, Timothy; Ivry, Richard B.

2015-01-01

Motor system excitability is transiently suppressed during the preparation of movement. This preparatory inhibition is hypothesized to facilitate response selection and initiation. Given that demands on selection and initiation processes increase with movement complexity, we hypothesized that complexity would influence preparatory inhibition. To test this hypothesis, we probed corticospinal excitability during a delayed-response task in which participants were cued to prepare right- or left-hand movements of varying complexity. Single-pulse transcranial magnetic stimulation was applied over right primary motor cortex to elicit motor evoked potentials (MEPs) from the first dorsal interosseous (FDI) of the left hand. MEP suppression was greater during the preparation of responses involving coordination of the FDI and adductor digiti minimi relative to easier responses involving only the FDI, independent of which hand was cued to respond. In contrast, this increased inhibition was absent when the complex responses required sequential movements of the two muscles. Moreover, complexity did not influence the level of inhibition when the response hand was fixed for the trial block, regardless of whether the complex responses were performed simultaneously or sequentially. These results suggest that preparatory inhibition contributes to response selection, possibly by suppressing extraneous movements when responses involve the simultaneous coordination of multiple effectors. PMID:25717168

In Vitro Development from Leaf Explants of Sugar Beet (Beta vulgaris L). Rhizogenesis and the Effect of Sequential Exposure to Auxin and Cytokinin

PubMed Central

Gürel, Ekrem; Wren, M. Jill

1995-01-01

Adventitious root development in lamina and midrib-petiole junction expiants of sugar beet cv. Primo was investigated using scanning electron microscopy and light microscopy. Primordia developed close to the vascular strands and areas of newly dividing cells (meristematic centres) were seen adjacent to the intrafascicular cambium after 2 d incubation on medium containing 30 mg 1−11-naphthalene acetic acid. Clearly defined primordia were visible at 4 d and the first roots had emerged by 6 d. A minimum of 24 h exposure to NAA was necessary for root induction. Four days on NAA caused twice as many roots to be initiated but more prolonged exposure (5 and 10 d) inhibited root development. Root initiation continued after transfer to medium containing no plant growth regulators, new primordia appearing as the older ones extended as roots. Attempts were made to modify the development of primordia by sequential culture on cytokinin after induction by auxin. Incubation on N6-benzylaminopurine within 48 h of exposure to NAA disrupted the development of primordia and roots but did not induce shoot formation. PMID:21247910

Precise chronology of differentiation of developing human primary dentition.

PubMed

Hu, Xuefeng; Xu, Shan; Lin, Chensheng; Zhang, Lishan; Chen, YiPing; Zhang, Yanding

2014-02-01

While correlation of developmental stage with embryonic age of the human primary dentition has been well documented, the available information regarding the differentiation timing of the primary teeth was largely based on the observation of initial mineralization and varies significantly. In this study, we aimed to document precise differentiation timing of the developing human primary dentition. We systematically examined the expression of odontogenic differentiation markers along with the formation of mineralized tissue in each developing maxillary and mandibular teeth from human embryos with well-defined embryonic age. We show that, despite that all primary teeth initiate development at the same time, odontogenic differentiation begins in the maxillary incisors at the 15th week and in the mandibular incisors at the 16th week of gestation, followed by the canine, the first primary premolar, and the second primary premolar at a week interval sequentially. Despite that the mandibular primary incisors erupt earlier than the maxillary incisors, this distal to proximal sequential differentiation of the human primary dentition coincides in general with the sequence of tooth eruption. Our results provide an accurate chronology of odontogenic differentiation of the developing human primary dentition, which could be used as reference for future studies of human tooth development.

Blunt pancreatic trauma: A persistent diagnostic conundrum?

PubMed Central

Kumar, Atin; Panda, Ananya; Gamanagatti, Shivanand

2016-01-01

Blunt pancreatic trauma is an uncommon injury but has high morbidity and mortality. In modern era of trauma care, pancreatic trauma remains a persistent challenge to radiologists and surgeons alike. Early detection of pancreatic trauma is essential to prevent subsequent complications. However early pancreatic injury is often subtle on computed tomography (CT) and can be missed unless specifically looked for. Signs of pancreatic injury on CT include laceration, transection, bulky pancreas, heterogeneous enhancement, peripancreatic fluid and signs of pancreatitis. Pan-creatic ductal injury is a vital decision-making parameter as ductal injury is an indication for laparotomy. While lacerations involving more than half of pancreatic parenchyma are suggestive of ductal injury on CT, ductal injuries can be directly assessed on magnetic resonance imaging (MRI) or encoscopic retrograde cholangio-pancreatography. Pancreatic trauma also shows temporal evolution with increase in extent of injury with time. Hence early CT scans may underestimate the extent of injures and sequential imaging with CT or MRI is important in pancreatic trauma. Sequential imaging is also needed for successful non-operative management of pancreatic injury. Accurate early detection on initial CT and adopting a multimodality and sequential imaging strategy can improve outcome in pancreatic trauma. PMID:26981225

The Doctrine of Original Antigenic Sin: Separating Good From Evil.

PubMed

Monto, Arnold S; Malosh, Ryan E; Petrie, Joshua G; Martin, Emily T

2017-06-15

The term "original antigenic sin" was coined approximately 60 years ago to describe the imprinting by the initial first influenza A virus infection on the antibody response to subsequent vaccination. These studies did not suggest a reduction in the response to current antigens but instead suggested anamnestic recall of antibody to earlier influenza virus strains. Then, approximately 40 years ago, it was observed that sequential influenza vaccination might lead to reduced vaccine effectiveness (VE). This conclusion was largely dismissed after an experimental study involving sequential administration of then-standard influenza vaccines. Recent observations have provided convincing evidence that reduced VE after sequential influenza vaccination is a real phenomenon. We propose that such reduction in VE be termed "negative antigenic interaction," given that there is no age cohort effect. In contrast, the potentially positive protective effect of early influenza virus infection later in life continues to be observed. It is essential that we understand better the immunologic factors underlying both original antigenic sin and negative antigenic interaction, to support development of improved influenza vaccines and vaccination strategies. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Brief Assessment of Parental Perception (BAPP): Development and validation of a new measure for assessing paediatric outcomes after bilateral cochlear implantation.

PubMed

Samuel, V; Gamble, C; Cullington, H; Bathgate, F; Bennett, E; Coop, N; Cropper, J; Emond, A; Kentish, R; Edwards, L

2016-11-01

In contrast to previous clinical practice, current guidelines recommend bilateral cochlear implantation in children, resulting in a cohort of children who initially received one implant, but have subsequently had a second, contralateral implant. This study aimed to explore satisfaction and quality of life in children implanted simultaneously or sequentially. A novel measure of satisfaction and quality of life following paediatric bilateral cochlear implantation (the Brief Assessment of Parental Perception; BAPP) was developed and preliminary validation undertaken as part of a large, national project of bilateral implantation. Children's parents completed the measure yearly for up to three years following implantation. Children from 14 UK implant centres were recruited into the study; data were available for 410 children one year post-implantation. The BAPP was found to have good face and convergent validity, and internal consistency. Results indicated very high levels of satisfaction with the devices, and improvements in quality of life. However there was evidence that children implanted sequentially were less willing to wear their second implant in the first two years than those children receiving simultaneous implants. Simultaneous and sequential cochlear implants have a positive impact on the quality of life of deaf children.

Sequential Stenting for Extensive Malignant Airway Stenosis

PubMed Central

Takahama, Makoto; Nakajima, Ryu; Kimura, Michitaka; Tei, Keiko; Yamamoto, Ryoji

2014-01-01

Purpose: Malignant airway stenosis extending from the bronchial bifurcation to the lower lobar orifice was treated with airway stenting. We herein examine the effectiveness of airway stenting for extensive malignant airway stenosis. Methods: Twelve patients with extensive malignant airway stenosis underwent placement of a silicone Dumon Y stent (Novatech, La Ciotat, France) at the tracheal bifurcation and a metallic Spiral Z-stent (Medico’s Hirata, Osaka, Japan) at either distal side of the Y stent. We retrospectively analyzed the therapeutic efficacy of the sequential placement of these silicone and metallic stents in these 12 patients. Results: The primary disease was lung cancer in eight patients, breast cancer in two patients, tracheal cancer in one patient, and thyroid cancer in one patient. The median survival period after airway stent placement was 46 days. The Hugh–Jones classification and performance status improved in nine patients after airway stenting. One patient had prolonged hemoptysis and died of respiratory tract hemorrhage 15 days after the treatment. Conclusion: Because the initial disease was advanced and aggressive, the prognosis after sequential airway stent placement was significantly poor. However, because respiratory distress decreased after the treatment in most patients, this treatment may be acceptable for selected patients with extensive malignant airway stenosis. PMID:25273272

Sequential chemotherapy with dose-dense docetaxel, cisplatin, folinic acid and 5-fluorouracil (TCF-dd) followed by combination of oxaliplatin, folinic acid, 5-fluorouracil and irinotecan (COFFI) in metastatic gastric cancer: results of a phase II trial.

PubMed

Dalla Chiesa, Matteo; Tomasello, Gianluca; Buti, Sebastiano; Rovere, Rodrigo Kraft; Brighenti, Matteo; Lazzarelli, Silvia; Donati, Gianvito; Passalacqua, Rodolfo

2011-01-01

To evaluate a new strategy of two sequential, intensified chemotherapy regimens in metastatic gastric cancer. Chemo-naïve patients with metastatic gastric cancer were enrolled to receive 4 cycles of TCF-dd (docetaxel initially 85 mg/m(2) and cisplatin initially 75 mg/m(2) on day 1 [later modified due to toxicity: 70 and 60 mg/m(2) respectively], l-folinic acid 100 mg/m(2) on days 1 and 2, 5-fluorouracil 400 mg/m(2) bolus and then 600 mg/m(2) as a 22 h continuous infusion on day 1 and 2, every 14 days). Subsequently, patients with CR, PR or SD received 4 cycles of COFFI (oxaliplatin 85 mg/m(2), irinotecan 140 mg/m(2), l-folinic acid 200 mg/m(2), 5-fluorouracil bolus 400 mg/m(2) on day 1 followed by 2,400 mg/m(2) as a 48 h continuous infusion, every 14 days). In both regimens pegfilgrastim 6 mg subcutaneously on day 3 was included. Forty consecutive patients were enrolled. TCF-dd regimen achieved an ORR of 55% (95% CI, 40-70). Twenty-three patients proceeded to COFFI. After this regimen the ORR was then increased to 60% (95% CI, 45-75). Among the 21 patients treated with TCF-dd after the protocol amendments, main grade 3-4 toxicities were: neutropenia (29%), thrombocytopenia (19%), asthenia (24%) and diarrhea (14%). COFFI caused grade 3-4 neutropenia (all not febrile) and diarrhea in 35% and 17% of patients respectively. A sequential strategy with TCF-dd followed by COFFI is very active and may be of special interest in selected patients.

Relevant factors for the optimal duration of extended endocrine therapy in early breast cancer.

PubMed

Blok, Erik J; Kroep, Judith R; Meershoek-Klein Kranenbarg, Elma; Duijm-de Carpentier, Marjolijn; Putter, Hein; Liefers, Gerrit-Jan; Nortier, Johan W R; Rutgers, Emiel J Th; Seynaeve, Caroline M; van de Velde, Cornelis J H

2018-04-01

For postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy. In the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses. In node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47-0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38-0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13-1.06), although this additional analysis was underpowered for definite conclusions. This study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.

Trafficking regulation of proteins in Alzheimer’s disease

PubMed Central

2014-01-01

The β-amyloid (Aβ) peptide has been postulated to be a key determinant in the pathogenesis of Alzheimer’s disease (AD). Aβ is produced through sequential cleavage of the β-amyloid precursor protein (APP) by β- and γ-secretases. APP and relevant secretases are transmembrane proteins and traffic through the secretory pathway in a highly regulated fashion. Perturbation of their intracellular trafficking may affect dynamic interactions among these proteins, thus altering Aβ generation and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD. PMID:24410826

Polycondensation of Asparagine-comprising Dipeptides in Aqueous Media-A Simulation of Polypeptide Formation in Primordial Earth Hydrosphere

NASA Astrophysics Data System (ADS)

Munegumi, Toratane; Tanikawa, Naoya

2017-09-01

Asparagine and aspartic acid might have mutually transformed in the primordial hydrosphere of the earth, if ammonia and aspartic acid had existed in equilibrium. These amino acids seem to contribute to polypeptides, while the simple amino acids glycine and alanine easily form cyclic dipeptides and do not achieve long peptide chains. Asparagine-comprising dipeptides contribute some kinds of activation forms of dipeptides because these can polymerize faster than asparagine only. The new finding of polypeptide formation suggests a pathway of sequential polypeptides to evolve a diversity of polypeptides.

Anxiety and Alcohol Use Disorders

PubMed Central

Smith, Joshua P.; Randall, Carrie L.

2012-01-01

The co-occurrence of anxiety disorders and alcohol use disorders (AUDs) is relatively common and is associated with a complex clinical presentation. Sound diagnosis and treatment planning requires that clinicians have an integrated understanding of the developmental pathways and course of this comorbidity. Moreover, standard interventions for anxiety disorders or AUDs may need to be modified and combined in targeted ways to accommodate the unique needs of people who have both disorders. Optimal combination of evidence-based treatments should be based on a comparative balance that considers the advantages and disadvantages of sequential, parallel, and integrated approaches. PMID:23584108

Reaction pathways involved in CH4 conversion on Pd/Al2O3 catalysts : TAP as a powerful tool for the elucidation of the effective role of the metal/support interface

NASA Astrophysics Data System (ADS)

Granger, Pascal

2016-02-01

Temporal Analysis of Products (TAP) reactor offers an alternative to draw direct structure/activity relationships checked on Natural Gas-fuelled Vehicle (NGV) catalysts Determination of accurate kinetic constants for methane adsorption from single pulse experiments and subsequent investigation of sequential surface reactions from alternative CH4/O2 pulse experiments provides a straightforward visualization of the involvement of the metal/support interface on freshly-prepared catalysts and the loss of this effect on aged single palladium based catalysts.

Polycondensation of Asparagine-comprising Dipeptides in Aqueous Media-A Simulation of Polypeptide Formation in Primordial Earth Hydrosphere.

PubMed

Munegumi, Toratane; Tanikawa, Naoya

2017-09-01

Asparagine and aspartic acid might have mutually transformed in the primordial hydrosphere of the earth, if ammonia and aspartic acid had existed in equilibrium. These amino acids seem to contribute to polypeptides, while the simple amino acids glycine and alanine easily form cyclic dipeptides and do not achieve long peptide chains. Asparagine-comprising dipeptides contribute some kinds of activation forms of dipeptides because these can polymerize faster than asparagine only. The new finding of polypeptide formation suggests a pathway of sequential polypeptides to evolve a diversity of polypeptides.

Trait- and density-mediated indirect interactions initiated by an exotic invasive plant autogenic ecosystem engineer

Treesearch

Dean E. Pearson

2010-01-01

Indirect interactions are important for structuring ecological systems. However, research on indirect effects has been heavily biased toward top-down trophic interactions, and less is known about other indirect-interaction pathways. As autogenic ecosystem engineers, plants can serve as initiators of nontrophic indirect interactions that, like top-down pathways, can...

[Impact of care pathway on the delay for initiation of antituberculosis treatment in Conakry, Guinea].

PubMed

Camara, A; Bah-Sow, O Y; Baldé, N M; Camara, L M; Barry, I S; Bah, B; Diallo, M; Chaperon, J; Riou, F

2009-06-01

Complex care pathways can result in detrimental treatment delay particularly in tuberculosis patients. The purpose of this retrospective study was to assess the care pathways followed by tuberculosis patients prior to diagnosis and to assess impact on the delay for initiation of treatment in Conakry, Guinea. A total of 112 patients were interviewed at the time of first admission for pulmonary tuberculosis with positive bacilloscopy. Based on interview data, pathways were classified as conventional (use of health care facilities only) and mixed (use of health care facilities, self-medication, and traditional medicine). The correlation between patient characteristics and type of pathway was assessed by univariate and multivariate analysis and the two groups, i.e., conventional vs. mixed, were compared with regard to delay for initiation of treatment. The care pathway was classified as mixed in two out of three patients. Multivariate analysis showed that this type of pathway was only correlated with schooling (p=0.02). The mean delay for treatment was similar, i.e., 13.4 and 12.8 weeks for conventional and mixed pathways respectively (p<0.68). The percentage of pathways including three consultations at health care facilities was significantly higher in the conventional than mixed group (72% vs. 30%, p<0.001). The main reasons given for delayed use of health care facilities were poor knowledge of tuberculosis symptoms (26%) and high cost of care (12%). The findings of this study indicate that tuberculosis patients follow a variety of care pathways that can lead to delayed treatment. An information campaign is needed to increase awareness among the population and care providers.

Alternative initial proton acceptors for the D pathway of Rhodobacter sphaeroides cytochrome c oxidase

PubMed Central

Varanasi, Lakshman; Hosler, Jonathan

2011-01-01

In order to characterize protein structures that control proton uptake, forms of cytochrome c oxidase (CcO) containing a carboxyl or a thiol group in line with the initial, internal waters of the D pathway for proton transfer have been assayed in the presence and absence of subunit III. Subunit III provides approximately half of the protein surrounding the entry region of the D pathway. The mutant N139D-D132N contains a carboxyl group 6Å within the D pathway and lacks the normal, surface-exposed proton acceptor, Asp-132. With subunit III, the steady-state activity of this mutant is slow but once subunit III is removed its activity is the same as wild-type CcO lacking subunit III (∼1800 H+ s-1). Thus, a carboxyl group ∼25% within the pathway enhances proton uptake even though the carboxyl has no direct contact with bulk solvent. Protons from solvent apparently move to internal Asp-139 through a short file of waters, normally blocked by subunit III. Cysteine-139 also supports rapid steady-state proton uptake, demonstrating that an anion other than a carboxyl can attract and transfer protons into the D pathway. When both Asp-132 and Asp/Cys-139 are present, the removal of subunit III increases CcO activity to rates greater than that of normal CcO due to simultaneous proton uptake by two initial acceptors. The results show how the environment of the initial proton acceptor for the D pathway in these CcO forms dictates the pH range of CcO activity, with implications for the function of Asp-132, the normal proton acceptor. PMID:21344856

Interleukin-6 signalling: more than Jaks and STATs.

PubMed

Eulenfeld, René; Dittrich, Anna; Khouri, Christina; Müller, Pia J; Mütze, Barbara; Wolf, Alexandra; Schaper, Fred

2012-01-01

The hallmark of signalling by many cytokines is the activation of the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) pathway. However, cytokines additionally activate other pathways. In past years we realised that these pathways significantly contribute to the physiological functions of IL-6 and pathophysiological functions in the context of many inflammatory and proliferative diseases. Whereas other articles in this issue of the European Journal of Cell Biology focus on STAT activation and its regulation we here aim to summarise our knowledge and some remaining questions on interleukin-6 (IL-6)-induced STAT-independent pathways as well as the cross-talk with the Jak/STAT pathway. In the early stages of studying cytokine signalling we were used to analysing individual signalling pathways. These days we know about the importance of both, the crosstalk between pathways initiated by combinations of cytokines as well as the crosstalk between individual pathways initiated by a single cytokine. Whereas the inter-cytokine crosstalk can be studied relatively easily, more sophisticated experimental approaches are required to elucidate the intra-cytokine crosstalk. Copyright © 2011 Elsevier GmbH. All rights reserved.

Mind-to-mind heteroclinic coordination: Model of sequential episodic memory initiation.

PubMed

Afraimovich, V S; Zaks, M A; Rabinovich, M I

2018-05-01

Retrieval of episodic memory is a dynamical process in the large scale brain networks. In social groups, the neural patterns, associated with specific events directly experienced by single members, are encoded, recalled, and shared by all participants. Here, we construct and study the dynamical model for the formation and maintaining of episodic memory in small ensembles of interacting minds. We prove that the unconventional dynamical attractor of this process-the nonsmooth heteroclinic torus-is structurally stable within the Lotka-Volterra-like sets of equations. Dynamics on this torus combines the absence of chaos with asymptotic instability of every separate trajectory; its adequate quantitative characteristics are length-related Lyapunov exponents. Variation of the coupling strength between the participants results in different types of sequential switching between metastable states; we interpret them as stages in formation and modification of the episodic memory.

Mind-to-mind heteroclinic coordination: Model of sequential episodic memory initiation

NASA Astrophysics Data System (ADS)

Afraimovich, V. S.; Zaks, M. A.; Rabinovich, M. I.

2018-05-01

Retrieval of episodic memory is a dynamical process in the large scale brain networks. In social groups, the neural patterns, associated with specific events directly experienced by single members, are encoded, recalled, and shared by all participants. Here, we construct and study the dynamical model for the formation and maintaining of episodic memory in small ensembles of interacting minds. We prove that the unconventional dynamical attractor of this process—the nonsmooth heteroclinic torus—is structurally stable within the Lotka-Volterra-like sets of equations. Dynamics on this torus combines the absence of chaos with asymptotic instability of every separate trajectory; its adequate quantitative characteristics are length-related Lyapunov exponents. Variation of the coupling strength between the participants results in different types of sequential switching between metastable states; we interpret them as stages in formation and modification of the episodic memory.

Transaction costs and sequential bargaining in transferable discharge permit markets.

PubMed

Netusil, N R; Braden, J B

2001-03-01

Market-type mechanisms have been introduced and are being explored for various environmental programs. Several existing programs, however, have not attained the cost savings that were initially projected. Modeling that acknowledges the role of transactions costs and the discrete, bilateral, and sequential manner in which trades are executed should provide a more realistic basis for calculating potential cost savings. This paper presents empirical evidence on potential cost savings by examining a market for the abatement of sediment from farmland. Empirical results based on a market simulation model find no statistically significant change in mean abatement costs under several transaction cost levels when contracts are randomly executed. An alternative method of contract execution, gain-ranked, yields similar results. At the highest transaction cost level studied, trading reduces the total cost of compliance relative to a uniform standard that reflects current regulations.

Radionuclide studies of chronic schistosomal uropathy

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

Lamki, L.M.; Lamki, N.

1981-08-01

Fifty patients with chronic urinary tract schistosomiasis were studied with /sup 99m/Tc-DTPA. All had a flow study, sequential analog imaging, and digital imaging for 25-35 minutes (20-sec. frames). Time-activity curves (DTPA renograms) were extracted; 12 patients had /sup 131/I-Hippuran probe renograms as well. Renal changes included diminished perfusion and structural abnormalities ranging from minor calyceal dilatation to overt hydronephrosis. Ureteral changes included dilatation, tortuosity, and kinking. Marked distortion of the ureterovesical tunction was seen in some patients due to periureteral and perivesicular fibrosis, which is a major factor in upper urinary tract damage. Renograms showed varying obstruction and parenchymal damage.more » Nuclear medicine complements excretory urography and is sometimes preferable for visualization of the ureters. After the initial urogram, sequential DTPA scanning and renography are sufficient for follow-up.« less

By Changing Dimensionality, Sequential Culturing of Midbrain Cells, rather than Two-Dimensional Culture, Generates a Neuron-Glia Ratio Closer to in vivo Adult Midbrain.

PubMed

Ganapathy, Kavina; Sowmithra, Sowmithra; Bhonde, Ramesh; Datta, Indrani

2016-07-16

The neuron-glia ratio is of prime importance for maintaining the physiological homeostasis of neuronal and glial cells, and especially crucial for dopaminergic neurons because a reduction in glial density has been reported in postmortem reports of brains affected by Parkinson's disease. We thus aimed at developing an in vitro midbrain culture which would replicate a similar neuron-glia ratio to that in in vivo adult midbrain while containing a similar number of dopaminergic neurons. A sequential culture technique was adopted to achieve this. Neural progenitors (NPs) were generated by the hanging-drop method and propagated as 3D neurospheres followed by the derivation of outgrowth from these neurospheres on a chosen extracellular matrix. The highest proliferation was observed in neurospheres from day in vitro (DIV) 5 through MTT and FACS analysis of Ki67 expression. FACS analysis using annexin/propidium iodide showed an increase in the apoptotic population from DIV 8. DIV 5 neurospheres were therefore selected for deriving the differentiated outgrowth of midbrain on a poly-L-lysine-coated surface. Quantitative RT-PCR showed comparable gene expressions of the mature neuronal marker β-tubulin III, glial marker GFAP and dopaminergic marker tyrosine hydroxylase (TH) as compared to in vivo adult rat midbrain. The FACS analysis showed a similar neuron-glia ratio obtained by the sequential culture in comparison to adult rat midbrain. The yield of β-tubulin III and TH was distinctly higher in the sequential culture in comparison to 2D culture, which showed a higher yield of GFAP immunopositive cells. Functional characterization indicated that both the constitutive and inducible (KCl and ATP) release of dopamine was distinctly higher in the sequential culture than the 2D culture. Thus, the sequential culture technique succeeded in the initial enrichment of NPs in 3D neurospheres, which in turn resulted in an optimal attainment of the neuron-glia ratio on outgrowth culture from these neurospheres. © 2016 S. Karger AG, Basel.

[Sequential prescriptions: Arguments for a change of therapeutic patterns in treatment resistant depressions].

PubMed

Allouche, G

2016-02-01

Among the therapeutic strategies in treatment of resistant depression, the use of sequential prescriptions is discussed here. A number of observations, initially quite isolated and few controlled studies, some large-scale, have been reported, which showed a definite therapeutic effect of certain requirements in sequential treatment of depression. The Sequenced Treatment Alternatives to Relieve Depression Study (STAR*D) is up to now the largest clinical trial exploring treatment strategies in non psychotic resistant depression in real-life conditions with an algorithm of sequential decision. The main conclusions of this study are the following: after two unsuccessful attempts, the chance of remission decreases considerably. A 12-months follow-up showed that the higher the use of the processing steps were high, the more common the relapses were during this period. The pharmacological differences between psychotropic did not cause clinically significant difference. The positive effect of lithium in combination with antidepressants has been known since the work of De Montigny. Antidepressants allow readjustment of physiological sequence involving different monoaminergic systems together. Studies with tricyclic antidepressant-thyroid hormone T3: in depression, decreased norepinephrine at the synaptic receptors believed to cause hypersensitivity of these receptors. Thyroid hormones modulate the activity of adrenergic receptors. There would be a balance of activity between alpha and beta-adrenergic receptors, depending on the bioavailability of thyroid hormones. ECT may in some cases promote pharmacological response in case of previous resistance, or be effective in preventing relapse. Cognitive therapy and antidepressant medications likely have an effect on different types of depression. We can consider the interest of cognitive therapy in a sequential pattern after effective treatment with an antidepressant effect for treatment of residual symptoms, preventing relapses and recurrences, in antidepressant maintenance. These data support the interest of therapeutic strategies based on evolutionary criteria. Sequential models inspired by statistical methods may incorporate the effects of a future treatment by measuring the current one. Copyright © 2015 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Phase transformation dependence on initial plastic deformation mode in Si via nanoindentation

DOE PAGES

Wong, Sherman; Haberl, Bianca; Williams, James S.; ...

2016-09-30

Silicon in its diamond-cubic phase is known to phase transform to a technologically interesting mixture of the body-centred cubic and rhombohedral phases under nanoindentation pressure. In this study, we demonstrate that during plastic deformation the sample can traverse two distinct pathways, one that initially nucleates a phase transformation while the other initially nucleates crystalline defects. These two pathways remain distinct even after sufficient pressure is applied such that both deformation mechanisms are present within the sample. Here, it is further shown that the indents that initially nucleate a phase transformation generate larger, more uniform volumes of the phase transformed materialmore » than indents that initially nucleate crystalline defects.« less

Recent advances in understanding of meiosis initiation and the apomictic pathway in plants.

PubMed

Wang, Chung-Ju R; Tseng, Ching-Chih

2014-01-01

Meiosis, a specialized cell division to produce haploid cells, marks the transition from a sporophytic to a gametophytic generation in the life cycle of plants. In angiosperms, meiosis takes place in sporogenous cells that develop de novo from somatic cells in anthers or ovules. A successful transition from the mitotic cycle to the meiotic program in sporogenous cells is crucial for sexual reproduction. By contrast, when meiosis is bypassed or a mitosis-like division occurs to produce unreduced cells, followed by the development of an embryo sac, clonal seeds can be produced by apomixis, an asexual reproduction pathway found in 400 species of flowering plants. An understanding of the regulation of entry into meiosis and molecular mechanisms of apomictic pathway will provide vital insight into reproduction for plant breeding. Recent findings suggest that AM1/SWI1 may be the key gene for entry into meiosis, and increasing evidence has shown that the apomictic pathway is epigenetically controlled. However, the mechanism for the initiation of meiosis during sexual reproduction or for its omission in the apomictic pathway still remains largely unknown. Here we review the current understanding of meiosis initiation and the apomictic pathway and raised several questions that are awaiting further investigation.

SURF Model Calibration Strategy

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

Menikoff, Ralph

2017-03-10

SURF and SURFplus are high explosive reactive burn models for shock initiation and propagation of detonation waves. They are engineering models motivated by the ignition & growth concept of high spots and for SURFplus a second slow reaction for the energy release from carbon clustering. A key feature of the SURF model is that there is a partial decoupling between model parameters and detonation properties. This enables reduced sets of independent parameters to be calibrated sequentially for the initiation and propagation regimes. Here we focus on a methodology for tting the initiation parameters to Pop plot data based on 1-Dmore » simulations to compute a numerical Pop plot. In addition, the strategy for tting the remaining parameters for the propagation regime and failure diameter is discussed.« less

Pathways to STEM Initiative (PSI): Evaluation Report for an Investing in Innovation (I3) Development Grant

ERIC Educational Resources Information Center

Nakamoto, Jonathan; Bojorquez, Juan Carlos

2017-01-01

The purpose of this study was to assess the impact of the Pathways to STEM Initiative (PSI) on students and science teachers and to describe the level of PSI implementation. One group of middle schools participated in PSI, which included project-based science, technology, engineering, and math (STEM) coursework; extra-curricular STEM opportunities…

Explaining the Impact of Disabled Children's Engagement with Physical Activity on Their Parents' Smartphone Addiction Levels: A Sequential Explanatory Mixed Methods Research

ERIC Educational Resources Information Center

Gündogdu, Cemal; Aygün, Yalin; Ilkim, Mehmet; Tüfekçi, Sakir

2018-01-01

In this research, quantitative findings and qualitative follow-up themes were used to quantify, conceptualize and finally try to explain the impact of disabled children's engagement with physical activity on their parents' smartphone addiction levels. An initial phase of quantitative investigation was conducted with 116 parents. Analyses of…

Portable-Beacon Landing System for Helicopters

NASA Technical Reports Server (NTRS)

Davis, Thomas J.; Clary, George R.; Chisholm, John P.; Macdonald, Stanley L.

1987-01-01

Prototype beacon landing system (BLS) allows helicopters to make precise landings in all weather. BLS easily added to existing helicopter avionic equipment and readily deployed at remote sites. Small and light, system employs X-band radar and digital processing. Variety of beams pulsed sequentially by ground station after initial interrogation by weather radar of approaching helicopter. Airborne microprocessor processes pulses to determine glide slope, course deviation, and range.

Factors That Influence a Wisconsin School Board's Decision to Hire an Internal Candidate to the Superintendency

ERIC Educational Resources Information Center

Thompson, Annette VanHook

2012-01-01

This sequential mixed-methods study determined to what extent the factors identified in the literature were present in the decision to hire an internal candidate to the superintendency in Wisconsin in the last ten years. An initial survey was sent to all 424 Wisconsin public school districts and follow-up surveys sent to school board members in…

Deposition and growth of domains in one dimension

NASA Astrophysics Data System (ADS)

Rodgers, G. J.; Tavassoli, Z.

1998-09-01

A model of deposition and growth in one dimension is studied in which finite sized domains are deposited by the random sequential adsorption process. The domains then grow with a time dependent growth rate. When the initial deposited domains are monomers and dimers the coverage is found exactly for a number of different growth rates. A continuum version of this model is also considered.

Multiple laser pulse ignition method and apparatus

DOEpatents

Early, J.W.

1998-05-26

Two or more laser light pulses with certain differing temporal lengths and peak pulse powers can be employed sequentially to regulate the rate and duration of laser energy delivery to fuel mixtures, thereby improving fuel ignition performance over a wide range of fuel parameters such as fuel/oxidizer ratios, fuel droplet size, number density and velocity within a fuel aerosol, and initial fuel temperatures. 18 figs.

Clinical pathways for acute coronary syndromes in China: protocol for a hospital quality improvement initiative.

PubMed

Rong, Ye; Turnbull, Fiona; Patel, Anushka; Du, Xin; Wu, Yangfeng; Gao, Runlin

2010-09-01

Clinical pathways have been shown to be effective in improving quality of care for patients admitted to hospital for acute coronary syndromes (ACS) in high-income countries. However, their utility has not formally been evaluated in low- or middle-income countries. The Clinical Pathways for Acute Coronary Syndromes in China program is a 7-year study with the overall goal of reducing evidence-practice gaps in the management of patients admitted to hospitals in China with suspected ACS. The program comprises 2 phases: a prospective survey of current management of ACS patients to identify the areas that evidence-based patient care can be potentially improved, and a quality care initiative to maximize the use of evidence-based investigations and treatments for ACS patients in China. In this article, we outline the details of the study protocol, including key aspects of the development, implementation, and evaluation of the quality improvement initiative (clinical pathway) for management of patients with suspected ACS.

Random Initialisation of the Spectral Variables: an Alternate Approach for Initiating Multivariate Curve Resolution Alternating Least Square (MCR-ALS) Analysis.

PubMed

Kumar, Keshav

2017-11-01

Multivariate curve resolution alternating least square (MCR-ALS) analysis is the most commonly used curve resolution technique. The MCR-ALS model is fitted using the alternate least square (ALS) algorithm that needs initialisation of either contribution profiles or spectral profiles of each of the factor. The contribution profiles can be initialised using the evolve factor analysis; however, in principle, this approach requires that data must belong to the sequential process. The initialisation of the spectral profiles are usually carried out using the pure variable approach such as SIMPLISMA algorithm, this approach demands that each factor must have the pure variables in the data sets. Despite these limitations, the existing approaches have been quite a successful for initiating the MCR-ALS analysis. However, the present work proposes an alternate approach for the initialisation of the spectral variables by generating the random variables in the limits spanned by the maxima and minima of each spectral variable of the data set. The proposed approach does not require that there must be pure variables for each component of the multicomponent system or the concentration direction must follow the sequential process. The proposed approach is successfully validated using the excitation-emission matrix fluorescence data sets acquired for certain fluorophores with significant spectral overlap. The calculated contribution and spectral profiles of these fluorophores are found to correlate well with the experimental results. In summary, the present work proposes an alternate way to initiate the MCR-ALS analysis.

Recovering metabolic pathways via optimization.

PubMed

Beasley, John E; Planes, Francisco J

2007-01-01

A metabolic pathway is a coherent set of enzyme catalysed biochemical reactions by which a living organism transforms an initial (source) compound into a final (target) compound. Some of the different metabolic pathways adopted within organisms have been experimentally determined. In this paper, we show that a number of experimentally determined metabolic pathways can be recovered by a mathematical optimization model.

Informatics approaches in the Biological Characterization of Adverse Outcome Pathways

EPA Science Inventory

Adverse Outcome Pathways (AOPs) are a conceptual framework to characterize toxicity pathways by a series of mechanistic steps from a molecular initiating event to population outcomes. This framework helps to direct risk assessment research, for example by aiding in computational ...

Fanconi Anemia Proteins and Their Interacting Partners: A Molecular Puzzle

PubMed Central

Kaddar, Tagrid; Carreau, Madeleine

2012-01-01

In recent years, Fanconi anemia (FA) has been the subject of intense investigations, primarily in the DNA repair research field. Many discoveries have led to the notion of a canonical pathway, termed the FA pathway, where all FA proteins function sequentially in different protein complexes to repair DNA cross-link damages. Although a detailed architecture of this DNA cross-link repair pathway is emerging, the question of how a defective DNA cross-link repair process translates into the disease phenotype is unresolved. Other areas of research including oxidative metabolism, cell cycle progression, apoptosis, and transcriptional regulation have been studied in the context of FA, and some of these areas were investigated before the fervent enthusiasm in the DNA repair field. These other molecular mechanisms may also play an important role in the pathogenesis of this disease. In addition, several FA-interacting proteins have been identified with roles in these “other” nonrepair molecular functions. Thus, the goal of this paper is to revisit old ideas and to discuss protein-protein interactions related to other FA-related molecular functions to try to give the reader a wider perspective of the FA molecular puzzle. PMID:22737580

Probing de novo sphingolipid metabolism in mammalian cells utilizing mass spectrometry.

PubMed

Snider, Justin M; Snider, Ashley J; Obeid, Lina M; Luberto, Chiara; Hannun, Yusuf A

2018-06-01

Sphingolipids constitute a dynamic metabolic network that interconnects several bioactive molecules, including ceramide (Cer), sphingosine (Sph), Sph 1-phosphate, and Cer 1-phosphate. The interconversion of these metabolites is controlled by a cohort of at least 40 enzymes, many of which respond to endogenous or exogenous stimuli. Typical probing of the sphingolipid pathway relies on sphingolipid mass levels or determination of the activity of individual enzymes. Either approach is unable to provide a complete analysis of flux through sphingolipid metabolism, which, given the interconnectivity of the sphingolipid pathway, is critical information to identify nodes of regulation. Here, we present a one-step in situ assay that comprehensively probes the flux through de novo sphingolipid synthesis, post serine palmitoyltransferase, by monitoring the incorporation and metabolism of the 17 carbon dihydrosphingosine precursor with LC/MS. Pulse labeling and analysis of precursor metabolism identified sequential well-defined phases of sphingolipid synthesis, corresponding to the activity of different enzymes in the pathway, further confirmed by the use of specific inhibitors and modulators of sphingolipid metabolism. This work establishes precursor pulse labeling as a practical tool for comprehensively studying metabolic flux through de novo sphingolipid synthesis and complex sphingolipid generation.

Scene Segmentation For Autonomous Robotic Navigation Using Sequential Laser Projected Structured Light

NASA Astrophysics Data System (ADS)

Brown, C. David; Ih, Charles S.; Arce, Gonzalo R.; Fertell, David A.

1987-01-01

Vision systems for mobile robots or autonomous vehicles navigating in an unknown terrain environment must provide a rapid and accurate method of segmenting the scene ahead into regions of pathway and background. A major distinguishing feature between the pathway and background is the three dimensional texture of these two regions. Typical methods of textural image segmentation are very computationally intensive, often lack the required robustness, and are incapable of sensing the three dimensional texture of various regions of the scene. A method is presented where scanned laser projected lines of structured light, viewed by a stereoscopically located single video camera, resulted in an image in which the three dimensional characteristics of the scene were represented by the discontinuity of the projected lines. This image was conducive to processing with simple regional operators to classify regions as pathway or background. Design of some operators and application methods, and demonstration on sample images are presented. This method provides rapid and robust scene segmentation capability that has been implemented on a microcomputer in near real time, and should result in higher speed and more reliable robotic or autonomous navigation in unstructured environments.

Natural Attenuation of Fuel Hydrocarbon Contaminants: Correlation of Biodegradation with Hydraulic Conductivity in a Field Case Study

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

Lu, Guoping; Zheng, Chunmiao

Two biodegradation models are developed to represent natural attenuation of fuel-hydrocarbon contaminants as observed in a comprehensive natural-gradient tracer test in a heterogeneous aquifer on the Columbus Air Force Base in Mississippi, USA. The first, a first-order mass loss model, describes the irreversible losses of BTEX and its individual components, i.e., benzene (B), toluene (T), ethyl benzene (E), and xylene (X). The second, a reactive pathway model, describes sequential degradation pathways for BTEX utilizing multiple electron acceptors, including oxygen, nitrate, iron and sulfate, and via methanogenesis. The heterogeneous aquifer is represented by multiple hydraulic conductivity (K) zones delineated on themore » basis of numerous flowmeter K measurements. A direct propagation artificial neural network (DPN) is used as an inverse modeling tool to estimate the biodegradation rate constants associated with each of the K zones. In both the mass loss model and the reactive pathway model, the biodegradation rate constants show an increasing trend with the hydraulic conductivity. The finding of correlation between biodegradation kinetics and hydraulic conductivity distributions is of general interest and relevance to characterization and modeling of natural attenuation of hydrocarbons in other petroleum-product contaminated sites.« less

Natural attenuation of fuel hydrocarbon contaminants: Hydraulic conductivity dependency of biodegradation rates in a field case study

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

Lu, Guoping; Zheng, Chunmiao

Two biodegradation models are developed to represent natural attenuation of fuel-hydrocarbon contaminants as observed in a comprehensive natural-gradient tracer test in a heterogeneous aquifer on the Columbus Air Force Base in Mississippi. The first, a first-order mass loss model, describes the irreversible losses of BTEX and its individual components, i.e., benzene (B), toluene (T), ethyl benzene (E), and xylene (X). The second, a reactive pathway model, describes sequential degradation pathways for BTEX utilizing multiple electron acceptors, including oxygen, nitrate, iron and sulfate, and via methanogenesis. The heterogeneous aquifer is represented by multiple hydraulic conductivity (K) zones delineated on the basismore » of numerous flowmeter K measurements. A direct propagation artificial neural network (DPN) is used as an inverse modeling tool to estimate the biodegradation rate constants associated with each of the K zones. In both the mass loss model and the reactive pathway model, the biodegradation rate constants show an increasing trend with the hydraulic conductivity. The finding of correlation between biodegradation kinetics and hydraulic conductivity distributions is of general interest and relevance to characterization and modeling of natural attenuation of hydrocarbons in other petroleum-product contaminated sites.« less

Reprogramming cellular events by poly(ADP-ribose)-binding proteins

PubMed Central

Pic, Émilie; Ethier, Chantal; Dawson, Ted M.; Dawson, Valina L.; Masson, Jean-Yves; Poirier, Guy G.; Gagné, Jean-Philippe

2013-01-01

Poly(ADP-ribosyl)ation is a posttranslational modification catalyzed by the poly(ADP-ribose) polymerases (PARPs). These enzymes covalently modify glutamic, aspartic and lysine amino acid side chains of acceptor proteins by the sequential addition of ADP-ribose (ADPr) units. The poly(ADP-ribose) (pADPr) polymers formed alter the physico-chemical characteristics of the substrate with functional consequences on its biological activities. Recently, non-covalent binding to pADPr has emerged as a key mechanism to modulate and coordinate several intracellular pathways including the DNA damage response, protein stability and cell death. In this review, we describe the basis of non-covalent binding to pADPr that has led to the emerging concept of pADPr-responsive signaling pathways. This review emphasizes the structural elements and the modular strategies developed by pADPr-binding proteins to exert a fine-tuned control of a variety of pathways. Poly(ADP-ribosyl)ation reactions are highly regulated processes, both spatially and temporally, for which at least four specialized pADPr-binding modules accommodate different pADPr structures and reprogram protein functions. In this review, we highlight the role of well-characterized and newly discovered pADPr-binding modules in a diverse set of physiological functions. PMID:23268355

Systemic Lupus Erythematosus and Deficiencies of Early Components of the Complement Classical Pathway

PubMed Central

Macedo, Ana Catarina Lunz; Isaac, Lourdes

2016-01-01

The complement system plays an important role in the innate and acquired immune response against pathogens. It consists of more than 30 proteins found in soluble form or attached to cell membranes. Most complement proteins circulate in inactive forms and can be sequentially activated by the classical, alternative, or lectin pathways. Biological functions, such as opsonization, removal of apoptotic cells, adjuvant function, activation of B lymphocytes, degranulation of mast cells and basophils, and solubilization and clearance of immune complex and cell lysis, are dependent on complement activation. Although the activation of the complement system is important to avoid infections, it also can contribute to the inflammatory response triggered by immune complex deposition in tissues in autoimmune diseases. Paradoxically, the deficiency of early complement proteins from the classical pathway (CP) is strongly associated with development of systemic lupus erythematous (SLE) – mainly C1q deficiency (93%) and C4 deficiency (75%). The aim of this review is to focus on the deficiencies of early components of the CP (C1q, C1r, C1s, C4, and C2) proteins in SLE patients. PMID:26941740

Histamine H4-Receptors Inhibit Mast Cell Renin Release in Ischemia/Reperfusion via Protein Kinase Cε-Dependent Aldehyde Dehydrogenase Type-2 Activation

PubMed Central

Aldi, Silvia; Takano, Ken-ichi; Tomita, Kengo; Koda, Kenichiro; Chan, Noel Y.-K.; Marino, Alice; Salazar-Rodriguez, Mariselis; Thurmond, Robin L.

2014-01-01

Renin released by ischemia/reperfusion (I/R) from cardiac mast cells (MCs) activates a local renin-angiotensin system (RAS) causing arrhythmic dysfunction. Ischemic preconditioning (IPC) inhibits MC renin release and consequent activation of this local RAS. We postulated that MC histamine H4-receptors (H4Rs), being Gαi/o-coupled, might activate a protein kinase C isotype–ε (PKCε)–aldehyde dehydrogenase type-2 (ALDH2) cascade, ultimately eliminating MC-degranulating and renin-releasing effects of aldehydes formed in I/R and associated arrhythmias. We tested this hypothesis in ex vivo hearts, human mastocytoma cells, and bone marrow–derived MCs from wild-type and H4R knockout mice. We found that activation of MC H4Rs mimics the cardioprotective anti-RAS effects of IPC and that protection depends on the sequential activation of PKCε and ALDH2 in MCs, reducing aldehyde-induced MC degranulation and renin release and alleviating reperfusion arrhythmias. These cardioprotective effects are mimicked by selective H4R agonists and disappear when H4Rs are pharmacologically blocked or genetically deleted. Our results uncover a novel cardioprotective pathway in I/R, whereby activation of H4Rs on the MC membrane, possibly by MC-derived histamine, leads sequentially to PKCε and ALDH2 activation, reduction of toxic aldehyde-induced MC renin release, prevention of RAS activation, reduction of norepinephrine release, and ultimately to alleviation of reperfusion arrhythmias. This newly discovered protective pathway suggests that MC H4Rs may represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure. PMID:24696042

A practical grinding-assisted dry synthesis of nanocrystalline NiMoO{sub 4} polymorphs for oxidative dehydrogenation of propane

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

Chen Miao, E-mail: chenmiao@sinochem.com; Zhejiang Chemical Industry Research Institute, Hangzhou 310023; Wu Jialing

2011-12-15

A practical two-stage reactive grinding-assisted pathway waste-free and cost-effective for the synthesis of NiMoO{sub 4} has been successfully developed. It was demonstrated that proper design in synthetic strategy for grinding plays a crucial role in determining the ultimate polymorph of NiMoO{sub 4}. Specifically, direct grinding (DG) of MoO{sub 3} and NiO rendered {alpha}-NiMoO{sub 4} after annealing, whereas sequential grinding (SG) of the two independently pre-ground oxides followed by annealing generated {beta}-NiMoO{sub 4} solid solution. Characterizations in terms of Raman and X-ray diffraction suggest the creation of {beta}-NiMoO{sub 4} precursor in the latter alternative is the key aspect for the formationmore » of {beta}-NiMoO{sub 4}. The DG-derived {alpha}-NiMoO{sub 4} tested by oxidative dehydrogenation of propane exhibited superior activity in contrast to its analog synthesized via conventional coprecipitation. It is suggested that the favorable chemical composition facilely obtained via grinding in contrast to that by coprecipitation was essential for achieving a more selective production of propylene. - Graphical Abstract: Grinding-assisted synthesis of NiMoO{sub 4} offers higher and more reproducible activities in contrast to coprecipitation for oxidative dehydrogenation of propane, and both {alpha}- and {beta}-NiMoO{sub 4} can be synthesized. Highlights: Black-Right-Pointing-Pointer NiMoO{sub 4} was prepared through grinding-assisted pathway. Black-Right-Pointing-Pointer Direct/sequential grinding rendered {alpha}-, {beta}-NiMoO{sub 4}, respectively. Black-Right-Pointing-Pointer Grinding-derived {alpha}-NiMoO{sub 4} showed high and reproducible activity for oxidative dehydrogenation of propane.« less

Stimulation of the Nonneuronal Cholinergic System by Highly Diluted Acetylcholine in Keratinocytes.

PubMed

Uberti, Francesca; Bardelli, Claudio; Morsanuto, Vera; Ghirlanda, Sabrina; Cochis, Andrea; Molinari, Claudio

2017-01-01

The physiological effects of acetylcholine on keratinocytes depend on the presence of nicotinic and muscarinic receptors. The role of nonneuronal acetylcholine in keratinocytes could have important clinical implications for patients with various skin disorders such as nonhealing wounds. In order to evaluate the efficacy of highly diluted acetylcholine solutions obtained by sequential kinetic activation, we aimed to investigate the effects of these solutions on normal human keratinocytes. Two different concentrations (10 fg/mL and 1 pg/mL) and formulations (kinetically activated and nonkinetically activated) of acetylcholine were used to verify keratinocyte viability, proliferation, and migration and the intracellular pathways involved using MTT, crystal violet, wound healing, and Western blot compared to 147 ng/mL acetylcholine. The activated formulations (1 pg/mL and 10 fg/mL) revealed a significant capacity to increase migration, cell viability, and cell proliferation compared to 147 ng/mL acetylcholine, and these effects were more evident after a single administration. Sequential kinetic activation resulted in a statistically significant decrease in reactive oxygen species production accompanied by an increase in mitochondrial membrane potential and a decrease in oxygen consumption compared to 147 ng/mL acetylcholine. The M1 muscarinic receptor was involved in these effects. Finally, the involvement of ERK/mitogen-activated protein kinases (MAPK) and KI67 confirmed the effectiveness of the single treatment on cell proliferation. The intracellular pathways of calcium were investigated as well. Our results indicate for the first time that highly diluted and kinetically activated acetylcholine seems to play an active role in an in vitro model of wound healing. Moreover, the administration of acetylcholine within the physiological range may not only be effective but is also likely to be safe. © 2016 S. Karger AG, Basel.

Uncovering key patterns in self-harm in adolescents: Sequence analysis using the Card Sort Task for Self-harm (CaTS).

PubMed

Townsend, E; Wadman, R; Sayal, K; Armstrong, M; Harroe, C; Majumder, P; Vostanis, P; Clarke, D

2016-12-01

Self-harm is a significant clinical issue in adolescence. There is little research on the interplay of key factors in the months, weeks, days and hours leading to self-harm. We developed the Card Sort Task for Self-harm (CaTS) to investigate the pattern of thoughts, feelings, events and behaviours leading to self-harm. Forty-five young people (aged 13-21 years) with recent repeated self-harm completed the CaTS to describe their first ever/most recent self-harm episode. Lag sequential analysis determined significant transitions in factors leading to self-harm (presented in state transition diagrams). A significant sequential structure to the card sequences produced was observed demonstrating similarities and important differences in antecedents to first and most recent self-harm. Life-events were distal in the self-harm pathway and more heterogeneous. Of significant clinical concern was that the wish to die and hopelessness emerged as important antecedents in the most recent episode. First ever self-harm was associated with feeling better afterward, but this disappeared for the most recent episode. Larger sample sizes are necessary to examine longer chains of sequences and differences in genders, age and type of self-harm. The sample was self-selected with 53% having experience of living in care. The CaTs offers a systematic approach to understanding the dynamic interplay of factors that lead to self-harm in young people. It offers a method to target key points for intervention in the self-harm pathway. Crucially the factors most proximal to self-harm (negative emotions, impulsivity and access to means) are modifiable with existing clinical interventions. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Dispersion Analysis Using Particle Tracking Simulations Through Heterogeneity Based on Outcrop Lidar Imagery

NASA Astrophysics Data System (ADS)

Klise, K. A.; Weissmann, G. S.; McKenna, S. A.; Tidwell, V. C.; Frechette, J. D.; Wawrzyniec, T. F.

2007-12-01

Solute plumes are believed to disperse in a non-Fickian manner due to small-scale heterogeneity and variable velocities that create preferential pathways. In order to accurately predict dispersion in naturally complex geologic media, the connection between heterogeneity and dispersion must be better understood. Since aquifer properties can not be measured at every location, it is common to simulate small-scale heterogeneity with random field generators based on a two-point covariance (e.g., through use of sequential simulation algorithms). While these random fields can produce preferential flow pathways, it is unknown how well the results simulate solute dispersion through natural heterogeneous media. To evaluate the influence that complex heterogeneity has on dispersion, we utilize high-resolution terrestrial lidar to identify and model lithofacies from outcrop for application in particle tracking solute transport simulations using RWHet. The lidar scan data are used to produce a lab (meter) scale two-dimensional model that captures 2-8 mm scale natural heterogeneity. Numerical simulations utilize various methods to populate the outcrop structure captured by the lidar-based image with reasonable hydraulic conductivity values. The particle tracking simulations result in residence time distributions used to evaluate the nature of dispersion through complex media. Particle tracking simulations through conductivity fields produced from the lidar images are then compared to particle tracking simulations through hydraulic conductivity fields produced from sequential simulation algorithms. Based on this comparison, the study aims to quantify the difference in dispersion when using realistic and simplified representations of aquifer heterogeneity. Sandia is a multiprogram laboratory operated by Sandia Corporation, a Lockheed Martin Company, for the United States Department of Energy's National Nuclear Security Administration under contract DE-AC04-94AL85000.

Regulation of root hair initiation and expansin gene expression in Arabidopsis

NASA Technical Reports Server (NTRS)

Cho, Hyung-Taeg; Cosgrove, Daniel J.

2002-01-01

The expression of two Arabidopsis expansin genes (AtEXP7 and AtEXP18) is tightly linked to root hair initiation; thus, the regulation of these genes was studied to elucidate how developmental, hormonal, and environmental factors orchestrate root hair formation. Exogenous ethylene and auxin, as well as separation of the root from the medium, stimulated root hair formation and the expression of these expansin genes. The effects of exogenous auxin and root separation on root hair formation required the ethylene signaling pathway. By contrast, blocking the endogenous ethylene pathway, either by genetic mutations or by a chemical inhibitor, did not affect normal root hair formation and expansin gene expression. These results indicate that the normal developmental pathway for root hair formation (i.e., not induced by external stimuli) is independent of the ethylene pathway. Promoter analyses of the expansin genes show that the same promoter elements that determine cell specificity also determine inducibility by ethylene, auxin, and root separation. Our study suggests that two distinctive signaling pathways, one developmental and the other environmental/hormonal, converge to modulate the initiation of the root hair and the expression of its specific expansin gene set.

Colon Cancer Tumorigenesis Initiated by the H1047R Mutant PI3K.

PubMed

Yueh, Alexander E; Payne, Susan N; Leystra, Alyssa A; Van De Hey, Dana R; Foley, Tyler M; Pasch, Cheri A; Clipson, Linda; Matkowskyj, Kristina A; Deming, Dustin A

2016-01-01

The phosphoinositide 3-kinase (PI3K) signaling pathway is critical for multiple important cellular functions, and is one of the most commonly altered pathways in human cancers. We previously developed a mouse model in which colon cancers were initiated by a dominant active PI3K p110-p85 fusion protein. In that model, well-differentiated mucinous adenocarcinomas developed within the colon and initiated through a non-canonical mechanism that is not dependent on WNT signaling. To assess the potential relevance of PI3K mutations in human cancers, we sought to determine if one of the common mutations in the human disease could also initiate similar colon cancers. Mice were generated expressing the Pik3caH1047R mutation, the analog of one of three human hotspot mutations in this gene. Mice expressing a constitutively active PI3K, as a result of this mutation, develop invasive adenocarcinomas strikingly similar to invasive adenocarcinomas found in human colon cancers. These tumors form without a polypoid intermediary and also lack nuclear CTNNB1 (β-catenin), indicating a non-canonical mechanism of tumor initiation mediated by the PI3K pathway. These cancers are sensitive to dual PI3K/mTOR inhibition indicating dependence on the PI3K pathway. The tumor tissue remaining after treatment demonstrated reduction in cellular proliferation and inhibition of PI3K signaling.

Colon Cancer Tumorigenesis Initiated by the H1047R Mutant PI3K

PubMed Central

Yueh, Alexander E.; Payne, Susan N.; Leystra, Alyssa A.; Van De Hey, Dana R.; Foley, Tyler M.; Pasch, Cheri A.; Clipson, Linda; Matkowskyj, Kristina A.; Deming, Dustin A.

2016-01-01

The phosphoinositide 3-kinase (PI3K) signaling pathway is critical for multiple important cellular functions, and is one of the most commonly altered pathways in human cancers. We previously developed a mouse model in which colon cancers were initiated by a dominant active PI3K p110-p85 fusion protein. In that model, well-differentiated mucinous adenocarcinomas developed within the colon and initiated through a non-canonical mechanism that is not dependent on WNT signaling. To assess the potential relevance of PI3K mutations in human cancers, we sought to determine if one of the common mutations in the human disease could also initiate similar colon cancers. Mice were generated expressing the Pik3caH1047R mutation, the analog of one of three human hotspot mutations in this gene. Mice expressing a constitutively active PI3K, as a result of this mutation, develop invasive adenocarcinomas strikingly similar to invasive adenocarcinomas found in human colon cancers. These tumors form without a polypoid intermediary and also lack nuclear CTNNB1 (β-catenin), indicating a non-canonical mechanism of tumor initiation mediated by the PI3K pathway. These cancers are sensitive to dual PI3K/mTOR inhibition indicating dependence on the PI3K pathway. The tumor tissue remaining after treatment demonstrated reduction in cellular proliferation and inhibition of PI3K signaling. PMID:26863299

Veterans' experiences initiating VA-based mental health care.

PubMed

Bovin, Michelle J; Miller, Christopher J; Koenig, Christopher J; Lipschitz, Jessica M; Zamora, Kara A; Wright, Patricia B; Pyne, Jeffrey M; Burgess, James F

2018-05-21

Military veterans who could benefit from mental health services often do not access them. Research has revealed a range of barriers associated with initiating United States Department of Veterans Affairs (VA) care, including those specific to accessing mental health care (e.g., fear of stigmatization). More work is needed to streamline access to VA mental health-care services for veterans. In the current study, we interviewed 80 veterans from 9 clinics across the United States about initiation of VA mental health care to identify barriers to access. Results suggested that five predominant factors influenced veterans' decisions to initiate care: (a) awareness of VA mental health services; (b) fear of negative consequences of seeking care; (c) personal beliefs about mental health treatment; (d) input from family and friends; and (e) motivation for treatment. Veterans also spoke about the pathways they used to access this care. The four most commonly reported pathways included (a) physical health-care appointments; (b) the service connection disability system; (c) non-VA care; and (d) being mandated to care. Taken together, these data lend themselves to a model that describes both modifiers of, and pathways to, VA mental health care. The model suggests that interventions aimed at the identified pathways, in concert with efforts designed to reduce barriers, may increase initiation of VA mental health-care services by veterans. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

A Quantative Adverse Outcome Pathway Linking Aromatase Inhibition in Fathead Minnows with Population Dynamics

EPA Science Inventory

A Quantitative Adverse Outcome Pathway Linking Aromatase Inhibition in Fathead Minnows with Population DynamicsAn adverse outcome pathway (AOP) is a qualitative description linking a molecular initiating event (MIE) with measureable key events leading to an adverse outcome (AO). ...

Development of an adverse outcome pathway for acetylcholinesterase inhibition leading to acute mortality

EPA Science Inventory

Adverse outcome pathways (AOPs) are designed to describe linkages of key events (KEs) within a biological pathway that result in an adverse outcome associated with chemical perturbation of a well-defined molecular initiating event (MIE). Risk assessors have traditionally relied ...

Application of Signaling Pathway-Based Adverse Outcome Pathways and High Throughput Toxicokinetic-PBPK for Developmental Cardiac Malformations

EPA Science Inventory

Associating putative molecular initiating events (MIE) with downstream cell signaling pathways and modeling fetal exposure kinetics is an important challenge for integration in developmental systems toxicology. Here, we describe an integrative systems toxicology model for develop...

Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in BXPC-3 and PANC-1 human pancreatic cancer cells.

PubMed

Wang, Lin; Zhu, Zhi-Xia; Zhang, Wen-Ying; Zhang, Wei-Min

2011-09-01

Previous studies have shown that both pemetrexed, a cytotoxic drug, and erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), inhibit the cell growth of pancreatic cancer cells. However, whether they exert a synergistic antitumor effect on pancreatic cancer cells remains unknown. The present study aimed to assess the synergistic effect of erlotinib in combination with pemetrexed using different sequential administration schedules on the proliferation of human pancreatic cancer BXPC-3 and PANC-1 cells and to probe its cellular mechanism. The EGFR and K-ras gene mutation status was examined by quantitative PCR high-resolution melting (qPCR-HRM) analysis. BXPC-3 and PANC-1 cells were incubated with pemetrexed and erlotinib using different administration schedules. MTT assay was used to determine cytotoxicity, and cell cycle distribution was determined by flow cytometry. The expression and phosphorylation of EGFR, HER3, AKT and MET were determined using Western blotting. Both pemetrexed and erlotinib inhibited the proliferation of BXPC-3 and PANC-1 cells in a dose- and time-dependent manner in vitro. Synergistic effects on cell proliferation were observed when pemetrexed was used in combination with erlotinib. The degree of the synergistic effects depended on the administration sequence, which was most obvious when erlotinib was sequentially administered at 24-h interval following pemetrexed. Cell cycle studies revealed that pemetrexed induced S arrest and erlotinib induced G(0)/G(1) arrest. The sequential administration of erlotinib following pemetrexed induced S arrest. Western blot analyses showed that pemetrexed increased and erlotinib decreased the phosphorylation of EGFR, HER3 and AKT, respectively. However, both pemetrexed and erlotinib exerted no significant effects on the phosphorylation of c-MET. The phosphorylation of EGFR, HER3 and AKT was significantly suppressed by scheduled incubation with pemetrexed followed by erlotinib, but not by concomitant or sequential incubation with erlotinib followed by pemetrexed. In summary, our results demonstrated that the combined use of erlotinib and pemetrexed exhibited a strong synergism in BXPC-3 and PANC-1 cells. The inhibitory effects were strongest after sequential administration of pemetrexed followed by erlotinib. The synergistic effects may be related to activation of the EGFR/HER3/AKT pathway induced by pemetrexed.

Diagnostic causal reasoning with verbal information.

PubMed

Meder, Björn; Mayrhofer, Ralf

2017-08-01

In diagnostic causal reasoning, the goal is to infer the probability of causes from one or multiple observed effects. Typically, studies investigating such tasks provide subjects with precise quantitative information regarding the strength of the relations between causes and effects or sample data from which the relevant quantities can be learned. By contrast, we sought to examine people's inferences when causal information is communicated through qualitative, rather vague verbal expressions (e.g., "X occasionally causes A"). We conducted three experiments using a sequential diagnostic inference task, where multiple pieces of evidence were obtained one after the other. Quantitative predictions of different probabilistic models were derived using the numerical equivalents of the verbal terms, taken from an unrelated study with different subjects. We present a novel Bayesian model that allows for incorporating the temporal weighting of information in sequential diagnostic reasoning, which can be used to model both primacy and recency effects. On the basis of 19,848 judgments from 292 subjects, we found a remarkably close correspondence between the diagnostic inferences made by subjects who received only verbal information and those of a matched control group to whom information was presented numerically. Whether information was conveyed through verbal terms or numerical estimates, diagnostic judgments closely resembled the posterior probabilities entailed by the causes' prior probabilities and the effects' likelihoods. We observed interindividual differences regarding the temporal weighting of evidence in sequential diagnostic reasoning. Our work provides pathways for investigating judgment and decision making with verbal information within a computational modeling framework. Copyright © 2017 Elsevier Inc. All rights reserved.

Sleep to the beat: A nap favours consolidation of timing.

PubMed

Verweij, Ilse M; Onuki, Yoshiyuki; Van Someren, Eus J W; Van der Werf, Ysbrand D

2016-06-01

Growing evidence suggests that sleep is important for procedural learning, but few studies have investigated the effect of sleep on the temporal aspects of motor skill learning. We assessed the effect of a 90-min day-time nap on learning a motor timing task, using 2 adaptations of a serial interception sequence learning (SISL) task. Forty-two right-handed participants performed the task before and after a 90-min period of sleep or wake. Electroencephalography (EEG) was recorded throughout. The motor task consisted of a sequential spatial pattern and was performed according to 2 different timing conditions, that is, either following a sequential or a random temporal pattern. The increase in accuracy was compared between groups using a mixed linear regression model. Within the sleep group, performance improvement was modeled based on sleep characteristics, including spindle- and slow-wave density. The sleep group, but not the wake group, showed improvement in the random temporal, but especially and significantly more strongly in the sequential temporal condition. None of the sleep characteristics predicted improvement on either general of the timing conditions. In conclusion, a daytime nap improves performance on a timing task. We show that performance on the task with a sequential timing sequence benefits more from sleep than motor timing. More important, the temporal sequence did not benefit initial learning, because differences arose only after an offline period and specifically when this period contained sleep. Sleep appears to aid in the extraction of regularities for optimal subsequent performance. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Effects of a combined parent-student alcohol prevention program on intermediate factors and adolescents' drinking behavior: A sequential mediation model.

PubMed

Koning, Ina M; Maric, Marija; MacKinnon, David; Vollebergh, Wilma A M

2015-08-01

Previous work revealed that the combined parent-student alcohol prevention program (PAS) effectively postponed alcohol initiation through its hypothesized intermediate factors: increase in strict parental rule setting and adolescents' self-control (Koning, van den Eijnden, Verdurmen, Engels, & Vollebergh, 2011). This study examines whether the parental strictness precedes an increase in adolescents' self-control by testing a sequential mediation model. A cluster randomized trial including 3,245 Dutch early adolescents (M age = 12.68, SD = 0.50) and their parents randomized over 4 conditions: (1) parent intervention, (2) student intervention, (3) combined intervention, and (4) control group. Outcome measure was amount of weekly drinking measured at age 12 to 15; baseline assessment (T0) and 3 follow-up assessments (T1-T3). Main effects of the combined and parent intervention on weekly drinking at T3 were found. The effect of the combined intervention on weekly drinking (T3) was mediated via an increase in strict rule setting (T1) and adolescents' subsequent self-control (T2). In addition, the indirect effect of the combined intervention via rule setting (T1) was significant. No reciprocal sequential mediation (self-control at T1 prior to rules at T2) was found. The current study is 1 of the few studies reporting sequential mediation effects of youth intervention outcomes. It underscores the need of involving parents in youth alcohol prevention programs, and the need to target both parents and adolescents, so that change in parents' behavior enables change in their offspring. (c) 2015 APA, all rights reserved).

Efficacy of sequential three-step empirical therapy for chronic cough.

PubMed

Yu, Li; Xu, Xianghuai; Hang, Jingqing; Cheng, Kewen; Jin, Xiaoyan; Chen, Qiang; Lv, Hanjing; Qiu, Zhongmin

2017-06-01

Empirical three-step therapy has been proved in just one hospital. This study aimed to demonstrate applicability of the sequential empirical three-step therapy for chronic cough in different clinical settings. Sequential empirical three-step therapy was given to patients with chronic cough in one tertiary and three secondary care respiratory clinics. Recruiters were initially treated with methoxyphenamine compound as the first-step therapy, followed by corticosteroids as the second-step therapy and the combination of a proton-pump inhibitor and a prokinetic agent as the third-step therapy. The efficacy of the therapy was verified according to the changes in cough symptom score between pre- and post-treatment, and compared among the different clinics. In total 155 patients in one tertiary clinic and 193 patients in secondary care clinics were recruited. The total dropout ratio is significantly higher in the secondary care clinics than that in the tertiary clinic (9.3% versus 3.2%, p = 0.023). The therapeutic success rate for cough was 38.7% at first-step therapy, 32.3% at second-step therapy and 20.0% at third-step therapy in the tertiary clinic, and comparable to corresponding 49.7%, 31.1% and 4.1% in secondary care clinics. Furthermore, the overall cough resolution rate was not significantly different (91.0% versus 85.0%, p = 0.091). However, the efficacy of the third-step therapy is much higher (20.0% versus 4.1%, p = 0.001) in the tertiary clinic than in the secondary care clinics. Sequential empirical three-step therapy is universally efficacious and useful for management of chronic cough in different clinical settings.

Deformation behavior and mechanical analysis of vertically aligned carbon nanotube (VACNT) bundles

NASA Astrophysics Data System (ADS)

Hutchens, Shelby B.

Vertically aligned carbon nanotubes (VACNTs) serve as integral components in a variety of applications including MEMS devices, energy absorbing materials, dry adhesives, light absorbing coatings, and electron emitters, all of which require structural robustness. It is only through an understanding of VACNT's structural mechanical response and local constitutive stress-strain relationship that future advancements through rational design may take place. Even for applications in which the structural response is not central to device performance, VACNTs must be sufficiently robust and therefore knowledge of their microstructure-property relationship is essential. This thesis first describes the results of in situ uniaxial compression experiments of 50 micron diameter cylindrical bundles of these complex, hierarchical materials as they undergo unusual deformation behavior. Most notably they deform via a series of localized folding events, originating near the bundle base, which propagate laterally and collapse sequentially from bottom to top. This deformation mechanism accompanies an overall foam-like stress-strain response having elastic, plateau, and densification regimes with the addition of undulations in the stress throughout the plateau regime that correspond to the sequential folding events. Microstructural observations indicate the presence of a strength gradient, due to a gradient in both tube density and alignment along the bundle height, which is found to play a key role in both the sequential deformation process and the overall stress-strain response. Using the complicated structural response as both motivation and confirmation, a finite element model based on a viscoplastic solid is proposed. This model is characterized by a flow stress relation that contains an initial peak followed by strong softening and successive hardening. Analysis of this constitutive relation results in capture of the sequential buckling phenomenon and a strength gradient effect. This combination of experimental and modeling approaches motivates discussion of the particular microstructural mechanisms and local material behavior that govern the non-trivial energy absorption via sequential, localized buckle formation in the VACNT bundles.

Randomized open-label non-comparative multicenter phase II trial of sequential erlotinib and docetaxel versus docetaxel alone in patients with non-small-cell lung cancer after failure of first-line chemotherapy: GFPC 10.02 study.

PubMed

Auliac, J B; Chouaid, C; Greillier, L; Greiller, L; Monnet, I; Le Caer, H; Falchero, L; Corre, R; Descourt, R; Bota, S; Berard, H; Schott, R; Bizieux, A; Fournel, P; Labrunie, A; Marin, B; Vergnenegre, A

2014-09-01

Concomitant administration of erlotinib with standard chemotherapy does not appear to improve survival among patients with non-small-cell lung cancer (NSCLC), but preliminary studies suggest that sequential administration might be effective. To assess the efficacy and tolerability of second-line sequential administration of erlotinib and docetaxel in advanced NSCLC. In an open-label phase II trial, patients with advanced NSCLC, EGFR wild-type or unknown, PS 0-2, in whom initial cisplatin-based chemotherapy had failed were randomized to sequential erlotinib 150 mg/d (day 2-16)+docetaxel (75 mg/m(2) d1) (arm ED) or docetaxel (75 mg/m(2) d1) alone (arm D) (21-day cycle). The primary endpoint was the progression-free survival rate at 15 weeks (PFS 15). Secondary endpoints included PFS, overall survival (OS), the overall response rate (ORR) and tolerability. Based on a Simon optimal two-stage design, the ED strategy was rejected if the primary endpoint was below 33/66 patients at the end of the two Simon stages. 147 patients were randomized (median age: 60±8 years, PS 0/1/2: 44/83/20 patients; males: 78%). The ED strategy was rejected, with only 18 of 73 patients achieving PFS15 in arm ED at the end of stage 2 and 17 of 74 patients in arm D. In arms ED and D, respectively, median PFS was 2.2 and 2.5 months and median OS was 6.5 and 8.3 months. Sequential erlotinib and docetaxel was not more effective than docetaxel alone as second-line treatment for advanced NSCLC with wild-type or unknown EGFR status. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Mechanisms and regulation of DNA replication initiation in eukaryotes

PubMed Central

Parker, Matthew W.; Botchan, Michael R.; Berger, James M.

2017-01-01

Cellular DNA replication is initiated through the action of multiprotein complexes that recognize replication start sites in the chromosome (termed origins) and facilitate duplex DNA melting within these regions. In a given cell cycle, initiation occurs only once per origin and each round of replication is tightly coupled to cell division. To avoid aberrant origin firing and re-replication, eukaryotes tightly regulate two events in the initiation process: loading of the replicative helicase, MCM2-7, onto chromatin by the Origin Recognition Complex (ORC), and subsequent activation of the helicase by incorporation into a complex known as the CMG. Recent work has begun to reveal the details of an orchestrated and sequential exchange of initiation factors on DNA that give rise to a replication-competent complex, the replisome. Here we review the molecular mechanisms that underpin eukaryotic DNA replication initiation – from selecting replication start sites to replicative helicase loading and activation – and describe how these events are often distinctly regulated across different eukaryotic model organisms. PMID:28094588

Mechanisms and regulation of DNA replication initiation in eukaryotes.

PubMed

Parker, Matthew W; Botchan, Michael R; Berger, James M

2017-04-01

Cellular DNA replication is initiated through the action of multiprotein complexes that recognize replication start sites in the chromosome (termed origins) and facilitate duplex DNA melting within these regions. In a typical cell cycle, initiation occurs only once per origin and each round of replication is tightly coupled to cell division. To avoid aberrant origin firing and re-replication, eukaryotes tightly regulate two events in the initiation process: loading of the replicative helicase, MCM2-7, onto chromatin by the origin recognition complex (ORC), and subsequent activation of the helicase by its incorporation into a complex known as the CMG. Recent work has begun to reveal the details of an orchestrated and sequential exchange of initiation factors on DNA that give rise to a replication-competent complex, the replisome. Here, we review the molecular mechanisms that underpin eukaryotic DNA replication initiation - from selecting replication start sites to replicative helicase loading and activation - and describe how these events are often distinctly regulated across different eukaryotic model organisms.

Reactions Involved in the Lower Pathway for Degradation of 4-Nitrotoluene by Mycobacterium Strain HL 4-NT-1

PubMed Central

He, Zhongqi; Spain, Jim C.

2000-01-01

In spite of the variety of initial reactions, the aerobic biodegradation of aromatic compounds generally yields dihydroxy intermediates for ring cleavage. Recent investigation of the degradation of nitroaromatic compounds revealed that some nitroaromatic compounds are initially converted to 2-aminophenol rather than dihydroxy intermediates by a number of microorganisms. The complete pathway for the metabolism of 2-aminophenol during the degradation of nitrobenzene by Pseudomonas pseudoalcaligenes JS45 has been elucidated previously. The pathway is parallel to the catechol extradiol ring cleavage pathway, except that 2-aminophenol is the ring cleavage substrate. Here we report the elucidation of the pathway of 2-amino-4-methylphenol (6-amino-m-cresol) metabolism during the degradation of 4-nitrotoluene by Mycobacterium strain HL 4-NT-1 and the comparison of the substrate specificities of the relevant enzymes in strains JS45 and HL 4-NT-1. The results indicate that the 2-aminophenol ring cleavage pathway in strain JS45 is not unique but is representative of the pathways of metabolism of other o-aminophenolic compounds. PMID:10877799

The pertussis hypothesis: Bordetella pertussis colonization in the pathogenesis of Alzheimer's disease.

PubMed

Rubin, Keith; Glazer, Steven

2017-02-01

While a number of endogenous risk factors including age and genetics are established for Alzheimer's disease (AD), identification of acquired, potentially preventable or treatable causes, remains limited. In this paper, we review three epidemiologic case studies and present extensive biologic, immunologic and anatomic evidence to support a novel hypothesis that Bordetella pertussis (BP), the bacterium better known to cause whooping cough, is an important potential cause of AD. Cross-cultural documentation of nasopharyngeal subclinical BP colonization reflecting BP-specific mucosal immunodeficiency, proximate anatomy of intranasal mucosal surfaces to central nervous system (CNS) olfactory pathways, and mechanisms by which BP and BP toxin account for all hallmark pathology of AD are reviewed, substantiating biologic plausibility. Notably, respiratory BP infection and BP toxin secreted from subclinical BP colonization can account for the initiation and accumulation of amyloid β plaques and tau tangles. Additional mechanisms consistent with the immunobiologic effects of subclinical BP colonization include microglial activation and inflammation, atrophy and neurodegeneration, excitotoxicity, distinctive anatomic distribution and sequential spread of disease, impaired glucose utilization, and other characteristic CNS pathology of AD. We conclude by assessing the evidence for causation against the Bradford Hill criteria, and advocate for further investigation into the potential role of BP in the etiology of AD. Copyright © 2016 The Author(s). Published by Elsevier GmbH.. All rights reserved.

Design Principles as a Guide for Constraint Based and Dynamic Modeling: Towards an Integrative Workflow.

PubMed

Sehr, Christiana; Kremling, Andreas; Marin-Sanguino, Alberto

2015-10-16

During the last 10 years, systems biology has matured from a fuzzy concept combining omics, mathematical modeling and computers into a scientific field on its own right. In spite of its incredible potential, the multilevel complexity of its objects of study makes it very difficult to establish a reliable connection between data and models. The great number of degrees of freedom often results in situations, where many different models can explain/fit all available datasets. This has resulted in a shift of paradigm from the initially dominant, maybe naive, idea of inferring the system out of a number of datasets to the application of different techniques that reduce the degrees of freedom before any data set is analyzed. There is a wide variety of techniques available, each of them can contribute a piece of the puzzle and include different kinds of experimental information. But the challenge that remains is their meaningful integration. Here we show some theoretical results that enable some of the main modeling approaches to be applied sequentially in a complementary manner, and how this workflow can benefit from evolutionary reasoning to keep the complexity of the problem in check. As a proof of concept, we show how the synergies between these modeling techniques can provide insight into some well studied problems: Ammonia assimilation in bacteria and an unbranched linear pathway with end-product inhibition.

Inhibition and biochemical characterization of methicillin-resistant Staphylococcus aureus shikimate dehydrogenase: an in silico and kinetic study.

PubMed

Avitia-Domínguez, Claudia; Sierra-Campos, Erick; Salas-Pacheco, José Manuel; Nájera, Hugo; Rojo-Domínguez, Arturo; Cisneros-Martínez, Jorge; Téllez-Valencia, Alfredo

2014-04-10

Methicillin-resistant Staphylococcus auerus (MRSA) strains are having a major impact worldwide, and due to their resistance to all β-lactams, an urgent need for new drugs is emerging. In this regard, the shikimate pathway is considered to be one of the metabolic features of bacteria and is absent in humans. Therefore enzymes involved in this route, such as shikimate dehydrogenase (SDH), are considered excellent targets for discovery of novel antibacterial drugs. In this study, the SDH from MRSA (SaSDH) was characterized. The results showed that the enzyme is a monomer with a molecular weight of 29 kDa, an optimum temperature of 65 °C, and a maximal pH range of 9-11 for its activity. Kinetic studies revealed that SDH showed Michaelis-Menten kinetics toward both substrates (shikimate and NADP+). Initial velocity analysis suggested that SaSDH catalysis followed a sequential random mechanism. Additionally, a tridimensional model of SaSDH was obtained by homology modeling and validated. Through virtual screening three inhibitors of SaSDH were found (compounds 238, 766 and 894) and their inhibition constants and mechanism were obtained. Flexible docking studies revealed that these molecules make interactions with catalytic residues. The data of this study could serve as starting point in the search of new chemotherapeutic agents against MRSA.

Deciphering spreading mechanisms in amyotrophic lateral sclerosis: clinical evidence and potential molecular processes.

PubMed

Pradat, Pierre-François; Kabashi, Edor; Desnuelle, Claude

2015-10-01

The aim of this review is to refer to recent arguments supporting the existence of specific propagation mechanisms associated with spreading of neuron injury in amyotrophic lateral sclerosis (ALS). Misfolded ALS-linked protein accumulation can induce aggregation of their native equivalent isoforms through a mechanism analogous to the infectious prion proteins initiation and its propagation. Although ALS is clinically heterogeneous, a shared characteristic is the focal onset and the progressive extension to all body regions. Being viewed until now as just summation of the increased number of affected neurons, dispersion is now rather considered as the result of a seeded self-propagating process. A sequential regional spreading pattern is supported by the distribution of TDP-43 aggregates in ALS autopsy cases. Electrophysiology and advanced neuroimaging methods also recently provided some evidence for propagation of lesions both in the brain and spinal cord, more longitudinal studies being still needed. Lesions are supposed to spread cell-to-cell regionally or through connected neuronal pathway. At the molecular level, the prion-like spreading is an emerging mechanism hypothesis, but other machineries such as those that are in charge of dealing with misfolded proteins and secretion of deleterious peptides may be involved in the propagation of neuron loss. Deciphering the mechanisms underlying spreading of ALS symptoms is of crucial importance to better understand this neurodegenerative disease, build new and appropriate animal models and to define novel therapeutic targets.

Lipoxin A4 activates ALX/FPR2 Receptor to Regulate Conjunctival Goblet Cell Secretion

PubMed Central

Hodges, Robin R.; Li, Dayu; Shatos, Marie A.; Bair, Jeffrey A.; Lippestad, Marit; Serhan, Charles N.; Dartt, Darlene A.

2016-01-01

Conjunctival goblet cells play a major role in maintaining the mucous layer of the tear film under physiological conditions as well as in inflammatory diseases like dry eye and allergic conjunctivitis.. Resolution of inflammation is mediated by pro-resolution agonists such as lipoxin A4 (LXA4) that can also function under physiological conditions. The purpose of this study was to determine the actions of LXA4 on cultured rat conjunctival goblet cell mucin secretion, intracellular [Ca2+] ([Ca2+]i) and identify signaling pathways activated by LXA4. ALX/FPR was localized to goblet cells in rat conjunctiva and in cultured goblet cells. LXA4 significantly increased mucin secretion, [Ca2+]i, and ERK 1/2 activation. These functions were inhibited by ALX/FPR2 inhibitors. Stable analogs of LXA4 increased [Ca2+]i to the same extent as LXA4. Sequential addition of either LXA4 or resolvin D1 followed by the second compound decreased [Ca2+]i of the second compound compared to its initial response. LXA4 activated phospholipase C, -D, and A2 and downstream molecules protein kinase C, ERK 1/2, and Ca2+/calmodulin dependent kinase to increase mucin secretion and [Ca2+]i. We conclude that conjunctival goblet cells respond to LXA4 to maintain the homeostasis of the ocular surface and could be a novel treatment for dry eye diseases. PMID:27072607

Coagulation under flow: the influence of flow-mediated transport on the initiation and inhibition of coagulation.

PubMed

Fogelson, Aaron L; Tania, Nessy

2005-01-01

A mathematical model of intravascular coagulation is presented; it encompasses the biochemistry of the tissue factor pathway, platelet activation and deposition on the subendothelium, and flow- and diffusion-mediated transport of coagulation proteins and platelets. Simulation experiments carried out with the model indicate the predominant role played by the physical processes of platelet deposition and flow-mediated removal of enzymes in inhibiting coagulation in the vicinity of vascular injury. Sufficiently rapid production of factors IXa and Xa by the TF:VIIa complex can overcome this inhibition and lead to formation of significant amounts of the tenase complex on the surface of activated platelets and, as a consequence, to substantial thrombin production. Chemical inhibitors are seen to play almost no (TFPI) or little (AT-III and APC) role in determining whether substantial thrombin production will occur. The role of APC is limited by the necessity for diffusion of thrombin from the site of injury to nearby endothelial cells to form the thrombomodulin-thrombin complex and for diffusion in the reverse direction of the APC made by this complex. TFPI plays an insignificant part in inhibiting the TF:VIIa complex under the conditions studied whether its action involves sequential binding of TFPI to Xa and then TFPI:Xa to TF:VIIa, or direct binding of TFPI to Xa already bound to the TF:VIIa complex. Copyright 2005 S. Karger AG, Basel.

Reaction Intermediates of Quinol Oxidation in a Photoactivatable System that Mimics Electron Transfer in the Cytochrome bc1 Complex

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

Cape, Jonathan L.; Bowman, Michael K.; Kramer, David M.

2005-03-30

Current competing models for the two-electron oxidation of quinol (QH{sub 2}) at the cytochrome bc{sub 1} complex and related complexes have different requirements for the reaction intermediate. At present, the intermediate species of the enzymatic oxidation process have not been observed or characterized, probably due to their transient nature. Here, we use a biomimetic oxidant, Ru(bpy){sub 2}(pbim)(PF6)2 (bpy = 2,2'-dipyridyl, pbim = 2-(2-benzimidazolate)pyridine) in an aprotic medium to probe the oxidation of the ubiquinol analogue, 2,3-dimethoxy-5-methyl-1,4-benzoquinol (UQH{sub 2}-0), an the plastoquinol analogue, trimethyl-1,4-benzoquinol (TMQH{sub 2}-0), using time-resolved and steady state spectroscopic techniques. This system qualitatively reproduces key features observed duringmore » ubiquinol oxidation by the mitochondrial cytochrome bc1 complex. Comparison of isotope dependent activation properties in the native and synthetic systems, as well as, analysis of the time-resolved direct-detection electron para magnetic resonance signals in the synthetic system allows us to conclude that: (1) the initial and rate-limiting step in quinol oxidation, both in the biological and biomimetic systems, involves electron and proton transfer, probably via a proton coupled electron transfer mechanism; (2) a neutral semiquinone intermediate is formed in the biomimetic system; and (3) oxidation of the QH*/QH{sub 2} couple for UQH{sub 2}-0, but not TMQH{sub 2}-0, exhibits a non-classical primary deuterium kinetic isotope effect on its Arrhenius activation energy ({Delta}G{sup TS}), where {Delta}G{sup TS} for the protiated form is larger than for the deuterated form. The same behavior is observed during steady state turnover of the cyt bc{sub 1} complex using ubiquinol, but not plastoquinol, as a substrate, leading to the conclusion that similar chemical pathways are involved in both systems. The synthetic system is an unambiguous n=1 electron acceptor and it is thus inferred that sequential oxidation of ubiquinol (by two sequential n=1 processes) is more rapid than a truly concerted (n=2) oxidation in the cyt bc{sub 1} complex.« less

Reversible thermo-pneumatic valves on centrifugal microfluidic platforms.

PubMed

Aeinehvand, Mohammad Mahdi; Ibrahim, Fatimah; Harun, Sulaiman Wadi; Kazemzadeh, Amin; Rothan, Hussin A; Yusof, Rohana; Madou, Marc

2015-08-21

Centrifugal microfluidic systems utilize a conventional spindle motor to automate parallel biochemical assays on a single microfluidic disk. The integration of complex, sequential microfluidic procedures on these platforms relies on robust valving techniques that allow for the precise control and manipulation of fluid flow. The ability of valves to consistently return to their former conditions after each actuation plays a significant role in the real-time manipulation of fluidic operations. In this paper, we introduce an active valving technique that operates based on the deflection of a latex film with the potential for real-time flow manipulation in a wide range of operational spinning speeds. The reversible thermo-pneumatic valve (RTPV) seals or reopens an inlet when a trapped air volume is heated or cooled, respectively. The RTPV is a gas-impermeable valve composed of an air chamber enclosed by a latex membrane and a specially designed liquid transition chamber that enables the efficient usage of the applied thermal energy. Inputting thermo-pneumatic (TP) energy into the air chamber deflects the membrane into the liquid transition chamber against an inlet, sealing it and thus preventing fluid flow. From this point, a centrifugal pressure higher than the induced TP pressure in the air chamber reopens the fluid pathway. The behaviour of this newly introduced reversible valving system on a microfluidic disk is studied experimentally and theoretically over a range of rotational frequencies from 700 RPM to 2500 RPM. Furthermore, adding a physical component (e.g., a hemispherical rubber element) to induce initial flow resistance shifts the operational range of rotational frequencies of the RTPV to more than 6000 RPM. An analytical solution for the cooling of a heated RTPV on a spinning disk is also presented, which highlights the need for the future development of time-programmable RTPVs. Moreover, the reversibility and gas impermeability of the RTPV in the microfluidic networks are validated on a microfluidic disk designed for performing liquid circulation. Finally, an array of RTPVs is integrated into a microfluidic cartridge to enable sequential aliquoting for the conversion of dengue virus RNA to cDNA and the preparation of PCR reaction mixtures.

The sequence of cortical activity inferred by response latency variability in the human ventral pathway of face processing.

PubMed

Lin, Jo-Fu Lotus; Silva-Pereyra, Juan; Chou, Chih-Che; Lin, Fa-Hsuan

2018-04-11

Variability in neuronal response latency has been typically considered caused by random noise. Previous studies of single cells and large neuronal populations have shown that the temporal variability tends to increase along the visual pathway. Inspired by these previous studies, we hypothesized that functional areas at later stages in the visual pathway of face processing would have larger variability in the response latency. To test this hypothesis, we used magnetoencephalographic data collected when subjects were presented with images of human faces. Faces are known to elicit a sequence of activity from the primary visual cortex to the fusiform gyrus. Our results revealed that the fusiform gyrus showed larger variability in the response latency compared to the calcarine fissure. Dynamic and spectral analyses of the latency variability indicated that the response latency in the fusiform gyrus was more variable than in the calcarine fissure between 70 ms and 200 ms after the stimulus onset and between 4 Hz and 40 Hz, respectively. The sequential processing of face information from the calcarine sulcus to the fusiform sulcus was more reliably detected based on sizes of the response variability than instants of the maximal response peaks. With two areas in the ventral visual pathway, we show that the variability in response latency across brain areas can be used to infer the sequence of cortical activity.

Anterograde and retrograde tracing with high molecular weight biotinylated dextran amine through thalamocortical and corticothalamic pathways.

PubMed

Zhang, Wenjie; Xu, Dongsheng; Cui, Jingjing; Jing, Xianghong; Xu, Nenggui; Liu, Jianhua; Bai, Wanzhu

2017-02-01

Biotinylated dextran amine (BDA) has been used for neural pathway tracing in the central nervous system for many decades, in which high molecular weight BDA appeared to be transported predominantly in the anterograde direction and less in the retrograde direction. In the current study, we reexamined the properties of neural labeling with high molecular weight BDA through a reciprocal neural pathway between thalamus and somatosensory cortex. After injection of BDA into the ventral posteromedial nucleus of thalamus (VPM) in the rat, the BDA labeling was sequentially examined on somatosensory cortex at 3, 5, 7, 10, and 14 survival days. Both of anterogradely labeled axonal terminals and retrogradely labeled neuronal cell bodies were observed simultaneously on the somatosensory cortex. With the increasing of survival times after injection, morphological changes occurred on the labeled axonal arbors and neuronal dendrites, in which the high quality of BDA labeling appeared on the tenth survival day. These results indicate that high molecular weight BDA is not only a sensitive anterograde tracer but also an excellent retrograde marker to be used for tracing through thalamocortical and corticothalamic pathways. And the detailed structure of neural labeling with BDA similar to Golgi-like resolution can be obtained at optimal survival times of animals after the injection of high molecular weight BDA. © 2016 Wiley Periodicals, Inc.

Natural products inhibiting the ubiquitin-proteasome proteolytic pathway, a target for drug development.

PubMed

Tsukamoto, Sachiko; Yokosawa, Hideyoshi

2006-01-01

The ubiquitin-proteasome proteolytic pathway plays a major role in selective protein degradation and regulates various cellular events including cell cycle progression, transcription, DNA repair, signal transduction, and immune response. Ubiquitin, a highly conserved small protein in eukaryotes, attaches to a target protein prior to degradation. The polyubiquitin chain tagged to the target protein is recognized by the 26S proteasome, a high-molecular-mass protease subunit complex, and the protein portion is degraded by the 26S proteasome. The potential of specific proteasome inhibitors, which act as anti-cancer agents, is now under intensive investigation, and bortezomib (PS-341), a proteasome inhibitor, has been recently approved by FDA for multiple myeloma treatment. Since ubiquitination of proteins requires the sequential action of three enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), and polyubiquitination is a prerequisite for proteasome-mediated protein degradation, inhibitors of E1, E2, and E3 are reasonably thought to be drug candidates for treatment of diseases related to ubiquitination. Recently, various compounds inhibiting the ubiquitin-proteasome pathway have been isolated from natural resources. We also succeeded in isolating inhibitors against the proteasome and E1 enzyme from marine natural resources. In this review, we summarize the structures and biological activities of natural products that inhibit the ubiquitin-proteasome proteolytic pathway.

The Breast International Group 1-98 trial: big results for women with hormone-sensitive early breast cancer.

PubMed

Monnier, Alain M

2007-05-01

As there is a risk for relapse in early breast cancer, especially at 1-3 years post surgery, the need for adjuvant therapy is clear. In terms of disease-free survival, aromatase inhibitors have emerged as superior to tamoxifen for the adjuvant treatment of hormone-sensitive breast cancer in several Phase III clinical trials. Of these trials, the Breast International Group (BIG) 1-98 trial stands out as unique in design, as it is the only trial to address whether an aromatase inhibitor is more effective as initial adjuvant therapy or as sequential therapy with an aromatase inhibitor and tamoxifen in either order and in rigor of end points and safety evaluations. When compared with tamoxifen, letrozole has been shown to significantly reduce recurrence risk in the overall population by 19% and also significantly reduced recurrence risk in the patient subgroups at increased risk: node-positive and previously chemotherapy-treated patients. Letrozole is the only aromatase inhibitor to demonstrate a significant 27% reduction in the risk of distant metastases (p = 0.001) in the clinically relevant, hormone receptor-positive population in the initial adjuvant setting. Recent results also suggest that letrozole in particular reduces the risk of distant metastases early on after initial surgery for breast cancer. This is important, as early distant metastatic events compose the majority of early recurrences and are a well-recognized predictor of breast cancer death. Letrozole has been found to be well tolerated in the initial adjuvant treatment setting, and these data have been confirmed by long-term safety data from the monotherapy analysis in the BIG 1-98 study. Thus far, the results from the BIG 1-98 trial provide clear support for the use of letrozole in the initial adjuvant treatment of breast cancer. Future studies will provide the definitive answer to questions of which initial adjuvant therapy is superior (i.e., anastrozole or letrozole) and information as to the optimal treatment strategy (i.e., initial adjuvant aromatase inhibitor therapy or sequential adjuvant aromatase inhibitor therapy).

Programs of Study as a State Policy Mandate: A Longitudinal Study of the South Carolina Personal Pathways to Success Initiative. Technical Appendix B

ERIC Educational Resources Information Center

Hammond, Cathy; Drew, Sam F.; Withington, Cairen; Griffith, Cathy; Swiger, Caroline M.; Mobley, Catherine; Sharp, Julia L.; Stringfield, Samuel C.; Stipanovic, Natalie; Daugherty, Lindsay

2013-01-01

This Technical Appendix discusses how researchers from the National Research Center for Career and Technical Education (NRCCTE) conducted the five-year longitudinal study of South Carolina's Personal Pathway to Success initiative, which was authorized by the state's Education and Economic Development Act (EEDA) in 2005, and how they defined and…

Speciation and transformation of heavy metals during vermicomposting of animal manure.

PubMed

Lv, Baoyi; Xing, Meiyan; Yang, Jian

2016-06-01

This work was conducted to evaluate the effects of vermicomposting on the speciation and mobility of heavy metals (Zn, Pb, Cr, and Cu) in cattle dung (CD) and pig manure (PM) using tessier sequential extraction method. Results showed that the pH, total organic carbon and C/N ratio were reduced, while the electric conductivity and humic acid increased after 90days vermicomposting. Moreover, the addition of earthworm could accelerate organic stabilization in vermicomposting. The total heavy metals in final vermicompost from CD and PM were higher than the initial values and the control without worms. Sequential extraction indicated that vermicomposting decreased the migration and availability of heavy metals, and the earthworm could reduce the mobile fraction, while increase the stable fraction of heavy metals. Furthermore, these results indicated that vermicomposting played a positive role in stabilizing heavy metals in the treatment of animal manure. Copyright © 2016 Elsevier Ltd. All rights reserved.

Regio- and Enantioselective Sequential Dehalogenation of rac-1,3-Dibromobutane by Haloalkane Dehalogenase LinB.

PubMed

Gross, Johannes; Prokop, Zbyněk; Janssen, Dick; Faber, Kurt; Hall, Mélanie

2016-08-03

The hydrolytic dehalogenation of rac-1,3-dibromobutane catalyzed by the haloalkane dehalogenase LinB from Sphingobium japonicum UT26 proceeds in a sequential fashion: initial formation of intermediate haloalcohols followed by a second hydrolytic step to produce the final diol. Detailed investigation of the course of the reaction revealed favored nucleophilic displacement of the sec-halogen in the first hydrolytic event with pronounced R enantioselectivity. The second hydrolysis step proceeded with a regioselectivity switch at the primary position, with preference for the S enantiomer. Because of complex competition between all eight possible reactions, intermediate haloalcohols formed with moderate to good ee ((S)-4-bromobutan-2-ol: up to 87 %). Similarly, (S)-butane-1,3-diol was formed at a maximum ee of 35 % before full hydrolysis furnished the racemic diol product. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effect of Sequential Exposition to Short- and Long-Wavelength Radiation on the Optical Absorption in the Bismuth Titanium Oxide Crystal Doped by Aluminum

NASA Astrophysics Data System (ADS)

Dyu, V. G.; Kisteneva, M. G.; Shandarov, S. M.; Khudyakova, E. S.; Smirnov, S. V.; Kargin, Yu. F.

Changes in the spectral dependences of the optical absorption induced in the bismuth titanium oxide crystal doped by aluminum as a result of sequential exposition to cw laser radiation first with the wavelength λi = 532 nm and then with the longer wavelength λn = 633, 655, 663, 780, 871, or 1064 nm are investigated. Our experiments show that after the short-wavelength exposition to radiation with λi = 532 nm, the optical absorption in the crystal increases, and in the range 470-1000 nm, yields the spectrum whose form is independent of the initial crystal state. The subsequent exposition to longer-wavelength radiation leads to enhanced transmittance of the crystal in the examined spectral range. A maximum decrease of the optical absorption in the crystal is observed upon exposure to radiation with the wavelength λn = 663 nm.

Comprehension of Navigation Directions

NASA Technical Reports Server (NTRS)

Healy, Alice F.; Schneider, Vivian I.

2002-01-01

Subjects were shown navigation instructions varying in length directing them to move in a space represented by grids on a computer screen. They followed the instructions by clicking on the grids in the locations specified. Some subjects repeated back the instructions before following them, some did not, and others repeated back the instructions in reduced form, including only the critical words. The commands in each message were presented simultaneously for half of the subjects and sequentially for the others. For the longest messages, performance was better on the initial commands and worse on the final commands with simultaneous than with sequential presentation. Instruction repetition depressed performance, but reduced repetition removed this disadvantage. Effects of presentation format were attributed to visual scanning strategies. The advantage for reduced repetition was attributable either to enhanced visual scanning or to reduced output interference. A follow-up study with auditory presentation supported the visual scanning explanation.

A sequential linear optimization approach for controller design

NASA Technical Reports Server (NTRS)

Horta, L. G.; Juang, J.-N.; Junkins, J. L.

1985-01-01

A linear optimization approach with a simple real arithmetic algorithm is presented for reliable controller design and vibration suppression of flexible structures. Using first order sensitivity of the system eigenvalues with respect to the design parameters in conjunction with a continuation procedure, the method converts a nonlinear optimization problem into a maximization problem with linear inequality constraints. The method of linear programming is then applied to solve the converted linear optimization problem. The general efficiency of the linear programming approach allows the method to handle structural optimization problems with a large number of inequality constraints on the design vector. The method is demonstrated using a truss beam finite element model for the optimal sizing and placement of active/passive-structural members for damping augmentation. Results using both the sequential linear optimization approach and nonlinear optimization are presented and compared. The insensitivity to initial conditions of the linear optimization approach is also demonstrated.

Radionuclide studies of chronic schistosomal uropathy. [/sup 99m/Tc-DTPA; /sup 131/I-hippuran

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

Lamki, L.M.; Lamki, N.

1981-08-01

Fifty patients with chronic urinary tract schistosomiasis were studied with /sup 99m/Tc-DTPA. All had a flow study, sequential analog imaging, and digital imaging for 25 to 35 min (20-sec frames). Time-activity curves (DTPA renograms) were extracted; 12 patients had /sup 131/I-Hippuran probe renograms as well. Renal changes included diminished perfusion and structural abnormalities ranging from minor calyceal dilatation to overt hydronephrosis. Ureteral changes included dilatation, tortuosity, and kinking. Marked distortion of the ureterovesical junction was seen in some patients due to periureteral and perivesicular fibrosis, which is a major factor in upper urinary tract damage. Renograms showed varying obstruction andmore » parenchymal damage. Nuclear medicine complements excretory urography and is sometimes preferable for visualization of the ureters. After the initial urogram, sequential DTPA scanning and renography are sufficient for follow-up.« less

Cooperative working of bacterial chromosome replication proteins generated by a reconstituted protein expression system

PubMed Central

Fujiwara, Kei; Katayama, Tsutomu; Nomura, Shin-ichiro M.

2013-01-01

Replication of all living cells relies on the multirounds flow of the central dogma. Especially, expression of DNA replication proteins is a key step to circulate the processes of the central dogma. Here we achieved the entire sequential transcription–translation–replication process by autonomous expression of chromosomal DNA replication machineries from a reconstituted transcription–translation system (PURE system). We found that low temperature is essential to express a complex protein, DNA polymerase III, in a single tube using the PURE system. Addition of the 13 genes, encoding initiator, DNA helicase, helicase loader, RNA primase and DNA polymerase III to the PURE system gave rise to a DNA replication system by a coupling manner. An artificial genetic circuit demonstrated that the DNA produced as a result of the replication is able to provide genetic information for proteins, indicating the in vitro central dogma can sequentially undergo two rounds. PMID:23737447

Use of the adverse outcome pathway framework to represent cross-species consequences of specific pathway perturbations

EPA Science Inventory

The adverse outcome pathway (AOP) framework has been developed as a means for assembling scientifically defensible descriptions of how particular molecular perturbations, termed molecular initiating events (MIEs), can evoke a set of predictable responses at different levels of bi...

Pathways from Poverty Educational Network.

ERIC Educational Resources Information Center

Northeast Regional Center for Rural Development, University Park, PA.

Pathways from Poverty is a public policy education and research initiative organized by the Rural Sociological Society's Task Force on Persistent Rural Poverty and the four regional rural development centers. This publication focuses on project efforts in the Northeast and includes three sections. The first section describes the Pathways from…

Identification of Putative Cardiovascular System Developmental Toxicants using a Classification Model based on Signaling Pathway-Adverse Outcome Pathways

EPA Science Inventory

An important challenge for an integrative approach to developmental systems toxicology is associating putative molecular initiating events (MIEs), cell signaling pathways, cell function and modeled fetal exposure kinetics. We have developed a chemical classification model based o...

Mechanism-based classification of PAH mixtures to predict carcinogenic potential

DOE PAGES

Tilton, Susan C.; Siddens, Lisbeth K.; Krueger, Sharon K.; ...

2015-04-22

We have previously shown that relative potency factors and DNA adduct measurements are inadequate for predicting carcinogenicity of certain polycyclic aromatic hydrocarbons (PAHs) and PAH mixtures, particularly those that function through alternate pathways or exhibit greater promotional activity compared to benzo[ a]pyrene (BaP). Therefore, we developed a pathway based approach for classification of tumor outcome after dermal exposure to PAH/mixtures. FVB/N mice were exposed to dibenzo[ def,p]chrysene (DBC), BaP or environmental PAH mixtures (Mix 1-3) following a two-stage initiation/promotion skin tumor protocol. Resulting tumor incidence could be categorized by carcinogenic potency as DBC>>BaP=Mix2=Mix3>Mix1=Control, based on statistical significance. Gene expression profilesmore » measured in skin of mice collected 12 h post-initiation were compared to tumor outcome for identification of short-term bioactivity profiles. A Bayesian integration model was utilized to identify biological pathways predictive of PAH carcinogenic potential during initiation. Integration of probability matrices from four enriched pathways (p<0.05) for DNA damage, apoptosis, response to chemical stimulus and interferon gamma signaling resulted in the highest classification accuracy with leave-one-out cross validation. This pathway-driven approach was successfully utilized to distinguish early regulatory events during initiation prognostic for tumor outcome and provides proof-of-concept for using short-term initiation studies to classify carcinogenic potential of environmental PAH mixtures. As a result, these data further provide a ‘source-to outcome’ model that could be used to predict PAH interactions during tumorigenesis and provide an example of how mode-of-action based risk assessment could be employed for environmental PAH mixtures.« less

Utility of Risk Stratification for Paclitaxel Hypersensitivity Reactions.

PubMed

Otani, Iris M; Lax, Timothy; Long, Aidan A; Slawski, Benjamin R; Camargo, Carlos A; Banerji, Aleena

2017-10-03

Hypersensitivity reactions (HSRs) are a common impediment to paclitaxel therapy. Management strategies to guide care after a paclitaxel-induced HSR are needed. The objective was to evaluate the utility and safety of risk stratification on the basis of severity of the initial HSR. A risk stratification pathway was developed on the basis of a retrospective review of the management and outcome of 130 patients with paclitaxel-induced HSRs at Massachusetts General Hospital. This pathway was then studied prospectively in patients referred to Allergy/Immunology with paclitaxel-induced HSRs. The study population (n = 35) had a mean age of 56.1 ± 12 years and most were women (n = 33 [94%]). All 5 patients (15%) with grade 1 initial HSRs were successfully reexposed to paclitaxel, 1 patient at the standard infusion rate and 4 patients at 50% of the standard infusion rate. Thirty patients (85%) with grade 2 to 4 initial HSRs underwent initial paclitaxel desensitization based on the risk stratification pathway. No patients developed severe HSRs using the pathway. Eleven (31%) patients had HSRs that were mild to moderate in nature (grade 1, n = 4 [11%]; grade 2, n = 6 [17%]; grade 3, n = 1 [3%]) during their first desensitization. Sixteen (46%) of the 35 patients safely returned to the outpatient infusion setting for paclitaxel treatment at 50% of the standard infusion rate. Seven (20%) discontinued paclitaxel before the completion of the risk stratification pathway because of disease progression, completion of therapy, or death. A management strategy using the initial HSR severity for risk stratification allowed patients to receive paclitaxel safely. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Patients or volunteers? The impact of motivation for trial participation on the efficacy of patient decision Aids: a secondary analysis of a Cochrane systematic review.

PubMed

Brown, James G; Joyce, Kerry E; Stacey, Dawn; Thomson, Richard G

2015-05-01

Efficacy of patient decision aids (PtDAs) may be influenced by trial participants' identity either as patients seeking to benefit personally from involvement or as volunteers supporting the research effort. To determine if study characteristics indicative of participants' trial identity might influence PtDA efficacy. We undertook exploratory subgroup meta-analysis of the 2011 Cochrane review of PtDAs, including trials that compared PtDA with usual care for treatment decisions. We extracted data on whether participants initiated the care pathway, setting, practitioner interactions, and 6 outcome variables (knowledge, risk perception, decisional conflict, feeling informed, feeling clear about values, and participation). The main subgroup analysis categorized trials as "volunteerism" or "patienthood" on the basis of whether participants initiated the care pathway. A supplementary subgroup analysis categorized trials on the basis of whether any volunteerism factors were present (participants had not initiated the care pathway, had attended a research setting, or had a face-to-face interaction with a researcher). Twenty-nine trials were included. Compared with volunteerism trials, pooled effect sizes were higher in patienthood trials (where participants initiated the care pathway) for knowledge, decisional conflict, feeling informed, feeling clear, and participation. The subgroup difference was statistically significant for knowledge only (P = 0.03). When trials were compared on the basis of whether volunteerism factors were present, knowledge was significantly greater in patienthood trials (P < 0.001), but there was otherwise no consistent pattern of differences in effects across outcomes. There is a tendency toward greater PtDA efficacy in trials in which participants initiate the pathway of care. Knowledge acquisition appears to be greater in trials where participants are predominantly patients rather than volunteers. © The Author(s) 2015.

Mechanism-Based Classification of PAH Mixtures to Predict Carcinogenic Potential.

PubMed

Tilton, Susan C; Siddens, Lisbeth K; Krueger, Sharon K; Larkin, Andrew J; Löhr, Christiane V; Williams, David E; Baird, William M; Waters, Katrina M

2015-07-01

We have previously shown that relative potency factors and DNA adduct measurements are inadequate for predicting carcinogenicity of certain polycyclic aromatic hydrocarbons (PAHs) and PAH mixtures, particularly those that function through alternate pathways or exhibit greater promotional activity compared to benzo[a]pyrene (BaP). Therefore, we developed a pathway-based approach for classification of tumor outcome after dermal exposure to PAH/mixtures. FVB/N mice were exposed to dibenzo[def,p]chrysene (DBC), BaP, or environmental PAH mixtures (Mix 1-3) following a 2-stage initiation/promotion skin tumor protocol. Resulting tumor incidence could be categorized by carcinogenic potency as DBC > BaP = Mix2 = Mix3 > Mix1 = Control, based on statistical significance. Gene expression profiles measured in skin of mice collected 12 h post-initiation were compared with tumor outcome for identification of short-term bioactivity profiles. A Bayesian integration model was utilized to identify biological pathways predictive of PAH carcinogenic potential during initiation. Integration of probability matrices from four enriched pathways (P < .05) for DNA damage, apoptosis, response to chemical stimulus, and interferon gamma signaling resulted in the highest classification accuracy with leave-one-out cross validation. This pathway-driven approach was successfully utilized to distinguish early regulatory events during initiation prognostic for tumor outcome and provides proof-of-concept for using short-term initiation studies to classify carcinogenic potential of environmental PAH mixtures. These data further provide a 'source-to-outcome' model that could be used to predict PAH interactions during tumorigenesis and provide an example of how mode-of-action-based risk assessment could be employed for environmental PAH mixtures. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Integrating nitric oxide into salicylic acid and jasmonic acid/ ethylene plant defense pathways.

PubMed

Mur, Luis A J; Prats, Elena; Pierre, Sandra; Hall, Michael A; Hebelstrup, Kim H

2013-01-01

Plant defense against pests and pathogens is known to be conferred by either salicylic acid (SA) or jasmonic acid (JA)/ethylene (ET) pathways, depending on infection or herbivore-grazing strategy. It is well attested that SA and JA/ET pathways are mutually antagonistic allowing defense responses to be tailored to particular biotic stresses. Nitric oxide (NO) has emerged as a major signal influencing resistance mediated by both signaling pathways but no attempt has been made to integrate NO into established SA/JA/ET interactions. NO has been shown to act as an inducer or suppressor of signaling along each pathway. NO will initiate SA biosynthesis and nitrosylate key cysteines on TGA-class transcription factors to aid in the initiation of SA-dependent gene expression. Against this, S-nitrosylation of NONEXPRESSOR OF PATHOGENESIS-RELATED PROTEINS1 (NPR1) will promote the NPR1 oligomerization within the cytoplasm to reduce TGA activation. In JA biosynthesis, NO will initiate the expression of JA biosynthetic enzymes, presumably to over-come any antagonistic effects of SA on JA-mediated transcription. NO will also initiate the expression of ET biosynthetic genes but a suppressive role is also observed in the S-nitrosylation and inhibition of S-adenosylmethionine transferases which provides methyl groups for ET production. Based on these data a model for NO action is proposed but we have also highlighted the need to understand when and how inductive and suppressive steps are used.

Integrating nitric oxide into salicylic acid and jasmonic acid/ ethylene plant defense pathways

PubMed Central

Mur, Luis A. J.; Prats, Elena; Pierre, Sandra; Hall, Michael A.; Hebelstrup, Kim H.

2013-01-01

Plant defense against pests and pathogens is known to be conferred by either salicylic acid (SA) or jasmonic acid (JA)/ethylene (ET) pathways, depending on infection or herbivore-grazing strategy. It is well attested that SA and JA/ET pathways are mutually antagonistic allowing defense responses to be tailored to particular biotic stresses. Nitric oxide (NO) has emerged as a major signal influencing resistance mediated by both signaling pathways but no attempt has been made to integrate NO into established SA/JA/ET interactions. NO has been shown to act as an inducer or suppressor of signaling along each pathway. NO will initiate SA biosynthesis and nitrosylate key cysteines on TGA-class transcription factors to aid in the initiation of SA-dependent gene expression. Against this, S-nitrosylation of NONEXPRESSOR OF PATHOGENESIS-RELATED PROTEINS1 (NPR1) will promote the NPR1 oligomerization within the cytoplasm to reduce TGA activation. In JA biosynthesis, NO will initiate the expression of JA biosynthetic enzymes, presumably to over-come any antagonistic effects of SA on JA-mediated transcription. NO will also initiate the expression of ET biosynthetic genes but a suppressive role is also observed in the S-nitrosylation and inhibition of S-adenosylmethionine transferases which provides methyl groups for ET production. Based on these data a model for NO action is proposed but we have also highlighted the need to understand when and how inductive and suppressive steps are used. PMID:23818890

System 2020 - Strategic Initiative

DTIC Science & Technology

2010-08-26

needs  fast,  flexible  and  adaptable  capabilities  (and  tools  that   enable  the   development   of  these...S2020  (and   enabling  acquisition   improvements)   System  Design   and   Development   Speed   Sequential  single-­‐step... development   time   as   a   function   of   SLOC   up   to   1250   KSLOC.

Experimenters' reference based upon Skylab experiment management

NASA Technical Reports Server (NTRS)

1974-01-01

The methods and techniques for experiment development and integration that evolved during the Skylab Program are described to facilitate transferring this experience to experimenters in future manned space programs. Management responsibilities and the sequential process of experiment evolution from initial concept through definition, development, integration, operation and postflight analysis are outlined and amplified, as appropriate. Emphasis is placed on specific lessons learned on Skylab that are worthy of consideration by future programs.

Initial Principal Readiness to Interconnect Positive Behavioral Interventions and Supports and School Mental Health: A Sequential Multivariate Exploratory Analysis

ERIC Educational Resources Information Center

Ecker, Andrew Joseph

2017-01-01

Approximately 20% of youth in the U.S. are experiencing a mental health challenge; a rate that is said to increase by more than 50% by 2020. Schools are the largest provider of mental health services to youth, yet two of schools' most efficacious evidence-based systems, Positive Behavioral Interventions and Supports (PBIS) and school mental health…

Sequential Insertion Heuristic with Adaptive Bee Colony Optimisation Algorithm for Vehicle Routing Problem with Time Windows

PubMed Central

Jawarneh, Sana; Abdullah, Salwani

2015-01-01

This paper presents a bee colony optimisation (BCO) algorithm to tackle the vehicle routing problem with time window (VRPTW). The VRPTW involves recovering an ideal set of routes for a fleet of vehicles serving a defined number of customers. The BCO algorithm is a population-based algorithm that mimics the social communication patterns of honeybees in solving problems. The performance of the BCO algorithm is dependent on its parameters, so the online (self-adaptive) parameter tuning strategy is used to improve its effectiveness and robustness. Compared with the basic BCO, the adaptive BCO performs better. Diversification is crucial to the performance of the population-based algorithm, but the initial population in the BCO algorithm is generated using a greedy heuristic, which has insufficient diversification. Therefore the ways in which the sequential insertion heuristic (SIH) for the initial population drives the population toward improved solutions are examined. Experimental comparisons indicate that the proposed adaptive BCO-SIH algorithm works well across all instances and is able to obtain 11 best results in comparison with the best-known results in the literature when tested on Solomon’s 56 VRPTW 100 customer instances. Also, a statistical test shows that there is a significant difference between the results. PMID:26132158

Initial experience of using high field strength intraoperative MRI for neurosurgical procedures.

PubMed

Raheja, Amol; Tandon, Vivek; Suri, Ashish; Sarat Chandra, P; Kale, Shashank S; Garg, Ajay; Pandey, Ravindra M; Kalaivani, Mani; Mahapatra, Ashok K; Sharma, Bhawani S

2015-08-01

We report our initial experience to optimize neurosurgical procedures using high field strength intraoperative magnetic resonance imaging (IOMRI) in 300 consecutive patients as high field strength IOMRI rapidly becomes the standard of care for neurosurgical procedures. Three sequential groups (groups A, B, C; n=100 each) were compared with respect to time management, complications and technical difficulties to assess improvement in these parameters with experience. We observed a reduction in the number of technical difficulties (p<0.001), time to induction (p<0.001) and total anesthesia time (p=0.007) in sequential groups. IOMRI was performed for neuronavigation guidance (n=252) and intraoperative validation of extent of resection (EOR; n=67). Performing IOMRI increased the EOR over and beyond the primary surgical attempt in 20.5% (29/141) and 18% (11/61) of patients undergoing glioma and pituitary surgery, respectively. Overall, EOR improved in 59.7% of patients undergoing IOMRI (40/67). Intraoperative tractography and real time navigation using re-uploaded IOMRI images (accounting for brain shift) helps in intraoperative planning to reduce complications. IOMRI is an asset to neurosurgeons, helping to augment the EOR, especially in glioma and pituitary surgery, with no significant increase in morbidity to the patient. Copyright © 2015 Elsevier Ltd. All rights reserved.

Knee Kinematics is Altered Post-Fatigue While Performing a Crossover Task

PubMed Central

Cortes, Nelson; Greska, Eric; Ambegaonkar, Jatin P.; Kollock, Roger O.; Caswell, Shane V.; Onate, James A.

2013-01-01

Purpose To examine the effect of a sequential fatigue protocol on lower extremity biomechanics during a crossover cutting task in female soccer players. Methods Eighteen female collegiate soccer players alternated between a fatigue protocol and two consecutive unanticipated crossover trials until fatigue was reached. Lower extremity biomechanics were evaluated during the crossover using a 3D motion capture system and two force plates. Repeated measures ANOVAs analyzed differences between three sequential stages of fatigue (pre, 50%, 100%) for each dependent variable (α=0.05). Results Knee flexion angles at initial contact (IC) for pre- (−32±9°) and 50% (−29±11°) were significantly higher than at 100% fatigue (−22±9°) (p<0.001 and p=0.015, respectively). Knee adduction angles at IC for pre- (9±5°) and 50% (8±4°) were significantly higher (p=0.006 and p=0.049, respectively) than at 100% fatigue (6±4°). Conclusions Fatigue altered sagittal and frontal knee kinematics after 50% fatigue whereupon participants had diminished knee control at initial contact. Interventions should attempt to reduce the negative effects of fatigue on lower extremity biomechanics by promotion appropriate frontal plane alignment, and increased knee flexion during fatigue status. PMID:24045915

Extremely accurate sequential verification of RELAP5-3D

DOE PAGES

Mesina, George L.; Aumiller, David L.; Buschman, Francis X.

2015-11-19

Large computer programs like RELAP5-3D solve complex systems of governing, closure and special process equations to model the underlying physics of nuclear power plants. Further, these programs incorporate many other features for physics, input, output, data management, user-interaction, and post-processing. For software quality assurance, the code must be verified and validated before being released to users. For RELAP5-3D, verification and validation are restricted to nuclear power plant applications. Verification means ensuring that the program is built right by checking that it meets its design specifications, comparing coding to algorithms and equations and comparing calculations against analytical solutions and method ofmore » manufactured solutions. Sequential verification performs these comparisons initially, but thereafter only compares code calculations between consecutive code versions to demonstrate that no unintended changes have been introduced. Recently, an automated, highly accurate sequential verification method has been developed for RELAP5-3D. The method also provides to test that no unintended consequences result from code development in the following code capabilities: repeating a timestep advancement, continuing a run from a restart file, multiple cases in a single code execution, and modes of coupled/uncoupled operation. In conclusion, mathematical analyses of the adequacy of the checks used in the comparisons are provided.« less

Multi-objective design optimization of antenna structures using sequential domain patching with automated patch size determination

NASA Astrophysics Data System (ADS)

Koziel, Slawomir; Bekasiewicz, Adrian

2018-02-01

In this article, a simple yet efficient and reliable technique for fully automated multi-objective design optimization of antenna structures using sequential domain patching (SDP) is discussed. The optimization procedure according to SDP is a two-step process: (i) obtaining the initial set of Pareto-optimal designs representing the best possible trade-offs between considered conflicting objectives, and (ii) Pareto set refinement for yielding the optimal designs at the high-fidelity electromagnetic (EM) simulation model level. For the sake of computational efficiency, the first step is realized at the level of a low-fidelity (coarse-discretization) EM model by sequential construction and relocation of small design space segments (patches) in order to create a path connecting the extreme Pareto front designs obtained beforehand. The second stage involves response correction techniques and local response surface approximation models constructed by reusing EM simulation data acquired in the first step. A major contribution of this work is an automated procedure for determining the patch dimensions. It allows for appropriate selection of the number of patches for each geometry variable so as to ensure reliability of the optimization process while maintaining its low cost. The importance of this procedure is demonstrated by comparing it with uniform patch dimensions.

Features of computerized clinical decision support systems supportive of nursing practice: a literature review.

PubMed

Lee, Seonah

2013-10-01

This study aimed to organize the system features of decision support technologies targeted at nursing practice into assessment, problem identification, care plans, implementation, and outcome evaluation. It also aimed to identify the range of the five stage-related sequential decision supports that computerized clinical decision support systems provided. MEDLINE, CINAHL, and EMBASE were searched. A total of 27 studies were reviewed. The system features collected represented the characteristics of each category from patient assessment to outcome evaluation. Several features were common across the reviewed systems. For the sequential decision support, all of the reviewed systems provided decision support in sequence for patient assessment and care plans. Fewer than half of the systems included problem identification. There were only three systems operating in an implementation stage and four systems in outcome evaluation. Consequently, the key steps for sequential decision support functions were initial patient assessment, problem identification, care plan, and outcome evaluation. Providing decision support in such a full scope will effectively help nurses' clinical decision making. By organizing the system features, a comprehensive picture of nursing practice-oriented computerized decision support systems was obtained; however, the development of a guideline for better systems should go beyond the scope of a literature review.

Prebiotic selection and assembly of proteinogenic amino acids and natural nucleotides from complex mixtures

NASA Astrophysics Data System (ADS)

Islam, Saidul; Bučar, Dejan-Krešimir; Powner, Matthew W.

2017-06-01

A central problem for the prebiotic synthesis of biological amino acids and nucleotides is to avoid the concomitant synthesis of undesired or irrelevant by-products. Additionally, multistep pathways require mechanisms that enable the sequential addition of reactants and purification of intermediates that are consistent with reasonable geochemical scenarios. Here, we show that 2-aminothiazole reacts selectively with two- and three-carbon sugars (glycolaldehyde and glyceraldehyde, respectively), which results in their accumulation and purification as stable crystalline aminals. This permits ribonucleotide synthesis, even from complex sugar mixtures. Remarkably, aminal formation also overcomes the thermodynamically favoured isomerization of glyceraldehyde into dihydroxyacetone because only the aminal of glyceraldehyde separates from the equilibrating mixture. Finally, we show that aminal formation provides a novel pathway to amino acids that avoids the synthesis of the non-proteinogenic α,α-disubstituted analogues. The common physicochemical mechanism that controls the proteinogenic amino acid and ribonucleotide assembly from prebiotic mixtures suggests that these essential classes of metabolite had a unified chemical origin.

Antioxidative mechanisms in chlorogenic acid.

PubMed

Tošović, Jelena; Marković, Svetlana; Dimitrić Marković, Jasmina M; Mojović, Miloš; Milenković, Dejan

2017-12-15

Although chlorogenic acid (5CQA) is an important ingredient of various foods and beverages, mechanisms of its antioxidative action have not been fully clarified. Besides electron spin resonance experiment, this study includes thermodynamic and mechanistic investigations of the hydrogen atom transfer (HAT), radical adduct formation (RAF), sequential proton loss electron transfer (SPLET), and single electron transfer - proton transfer (SET-PT) mechanisms of 5CQA in benzene, ethanol, and water solutions. The calculations were performed using the M06-2X/6-311++G(d,p) level of theory and CPCM solvation model. It was found that SET-PT is not a plausible antioxidative mechanism of 5CQA. RAF pathways are faster, but HAT yields thermodynamically more stable radical products, indicating that in acidic and neutral media 5CQA can take either HAT or RAF pathways. In basic environment (e.g. at physiological pH) SPLET is the likely antioxidative mechanism of 5CQA with extremely high rate. Copyright © 2017 Elsevier Ltd. All rights reserved.

Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal.

PubMed

Fuentealba, Luis C; Eivers, Edward; Ikeda, Atsushi; Hurtado, Cecilia; Kuroda, Hiroki; Pera, Edgar M; De Robertis, Edward M

2007-11-30

BMP receptors determine the intensity of BMP signals via Smad1 C-terminal phosphorylations. Here we show that a finely controlled cell biological pathway terminates this activity. The duration of the activated pSmad1(Cter) signal was regulated by sequential Smad1 linker region phosphorylations at conserved MAPK and GSK3 sites required for its polyubiquitinylation and transport to the centrosome. Proteasomal degradation of activated Smad1 and total polyubiquitinated proteins took place in the centrosome. Inhibitors of the Erk, p38, and JNK MAPKs, as well as GSK3 inhibitors, prolonged the duration of a pulse of BMP7. Wnt signaling decreased pSmad1(GSK3) antigen levels and redistributed it from the centrosome to cytoplasmic LRP6 signalosomes. In Xenopus embryos, it was found that Wnts induce epidermis and that this required an active BMP-Smad pathway. Epistatic experiments suggested that the dorsoventral (BMP) and anteroposterior (Wnt/GSK3) patterning gradients are integrated at the level of Smad1 phosphorylations during embryonic pattern formation.

High-quality draft genome sequence of the Thermus amyloliquefaciens type strain YIM 77409 T with an incomplete denitrification pathway

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

Zhou, En -Min; Murugapiran, Senthil K.; Mefferd, Chrisabelle C.

Thermus amyloliquefaciens type strain YIM 77409 T is a thermophilic, Gram-negative, non-motile and rod-shaped bacterium isolated from Niujie Hot Spring in Eryuan County, Yunnan Province, southwest China. In the present study we describe the features of strain YIM 77409 T together with its genome sequence and annotation. The genome is 2,160,855 bp long and consists of 6 scaffolds with 67.4 % average GC content. A total of 2,313 genes were predicted, comprising 2,257 protein-coding and 56 RNA genes. The genome is predicted to encode a complete glycolysis, pentose phosphate pathway, and tricarboxylic acid cycle. Additionally, a large number of transportersmore » and enzymes for heterotrophy highlight the broad heterotrophic lifestyle of this organism. Furthermore, a denitrification gene cluster included genes predicted to encode enzymes for the sequential reduction of nitrate to nitrous oxide, consistent with the incomplete denitrification phenotype of this strain.« less

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

PubMed Central

Lever, Melissa; Lim, Hong-Sheng; Kruger, Philipp; Nguyen, John; Trendel, Nicola; Abu-Shah, Enas; Maini, Philip Kumar; van der Merwe, Philip Anton

2016-01-01

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose–response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways. PMID:27702900

High-quality draft genome sequence of the Thermus amyloliquefaciens type strain YIM 77409 T with an incomplete denitrification pathway

DOE PAGES

Zhou, En -Min; Murugapiran, Senthil K.; Mefferd, Chrisabelle C.; ...

2016-02-27

Thermus amyloliquefaciens type strain YIM 77409 T is a thermophilic, Gram-negative, non-motile and rod-shaped bacterium isolated from Niujie Hot Spring in Eryuan County, Yunnan Province, southwest China. In the present study we describe the features of strain YIM 77409 T together with its genome sequence and annotation. The genome is 2,160,855 bp long and consists of 6 scaffolds with 67.4 % average GC content. A total of 2,313 genes were predicted, comprising 2,257 protein-coding and 56 RNA genes. The genome is predicted to encode a complete glycolysis, pentose phosphate pathway, and tricarboxylic acid cycle. Additionally, a large number of transportersmore » and enzymes for heterotrophy highlight the broad heterotrophic lifestyle of this organism. Furthermore, a denitrification gene cluster included genes predicted to encode enzymes for the sequential reduction of nitrate to nitrous oxide, consistent with the incomplete denitrification phenotype of this strain.« less

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose.

PubMed

Lever, Melissa; Lim, Hong-Sheng; Kruger, Philipp; Nguyen, John; Trendel, Nicola; Abu-Shah, Enas; Maini, Philip Kumar; van der Merwe, Philip Anton; Dushek, Omer

2016-10-25

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose-response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways.

Evaluation of non-animal methods for assessing skin sensitisation hazard: A Bayesian Value-of-Information analysis.

PubMed

Leontaridou, Maria; Gabbert, Silke; Van Ierland, Ekko C; Worth, Andrew P; Landsiedel, Robert

2016-07-01

This paper offers a Bayesian Value-of-Information (VOI) analysis for guiding the development of non-animal testing strategies, balancing information gains from testing with the expected social gains and costs from the adoption of regulatory decisions. Testing is assumed to have value, if, and only if, the information revealed from testing triggers a welfare-improving decision on the use (or non-use) of a substance. As an illustration, our VOI model is applied to a set of five individual non-animal prediction methods used for skin sensitisation hazard assessment, seven battery combinations of these methods, and 236 sequential 2-test and 3-test strategies. Their expected values are quantified and compared to the expected value of the local lymph node assay (LLNA) as the animal method. We find that battery and sequential combinations of non-animal prediction methods reveal a significantly higher expected value than the LLNA. This holds for the entire range of prior beliefs. Furthermore, our results illustrate that the testing strategy with the highest expected value does not necessarily have to follow the order of key events in the sensitisation adverse outcome pathway (AOP). 2016 FRAME.

Sequential protein association with nascent 60S ribosomal particles.

PubMed

Saveanu, Cosmin; Namane, Abdelkader; Gleizes, Pierre-Emmanuel; Lebreton, Alice; Rousselle, Jean-Claude; Noaillac-Depeyre, Jacqueline; Gas, Nicole; Jacquier, Alain; Fromont-Racine, Micheline

2003-07-01

Ribosome biogenesis in eukaryotes depends on the coordinated action of ribosomal and nonribosomal proteins that guide the assembly of preribosomal particles. These intermediate particles follow a maturation pathway in which important changes in their protein composition occur. The mechanisms involved in the coordinated assembly of the ribosomal particles are poorly understood. We show here that the association of preribosomal factors with pre-60S complexes depends on the presence of earlier factors, a phenomenon essential for ribosome biogenesis. The analysis of the composition of purified preribosomal complexes blocked in maturation at specific steps allowed us to propose a model of sequential protein association with, and dissociation from, early pre-60S complexes for several preribosomal factors such as Mak11, Ssf1, Rlp24, Nog1, and Nog2. The presence of either Ssf1 or Nog2 in complexes that contain the 27SB pre-rRNA defines novel, distinct pre-60S particles that contain the same pre-rRNA intermediates and that differ only by the presence or absence of specific proteins. Physical and functional interactions between Rlp24 and Nog1 revealed that the assembly steps are, at least in part, mediated by direct protein-protein interactions.